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# basic NLP
import nltk, codecs, string, random, math, cPickle as pickle, re, datetime
from collections import Counter
from string import punctuation

# scikit-learn
from sklearn.feature_extraction.text import TfidfVectorizer
from sklearn.linear_model import LogisticRegression
import numpy as np
from sklearn.metrics.pairwise import linear_kernel

# plotting
%matplotlib inline
from matplotlib import pyplot as plt

from __future__ import division

sent_tokenizer=nltk.data.load('tokenizers/punkt/english.pickle')
stopset = set(nltk.corpus.stopwords.words('english'))


    

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# trial descriptions
trial_desc = pickle.load(open('../data/trial_desc.pkl','rb'))


    

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tfidf = TfidfVectorizer(stop_words=stopset)
train_mat = tfidf.fit_transform([' '.join(t) for t in trial_desc.values()])


    

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train_mat = pickle.load(open('../data/tfidf_matrix_alldesc.pkl','rb'))


    

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f = codecs.open('../data/ratings_description.txt','w','utf-8')
for t, s in zip(trial_desc.keys(),[m.item(0) for m in train_mat.sum(axis=1)]):
    f.write('%s\t%g\n' % (t, s))

f.close()


    

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from sqlalchemy import create_engine, Table, Column, Float, Integer, String, MetaData
from sqlalchemy.sql import func, select, and_, or_, not_, desc
from connect import mysqlusername, mysqlpassword, mysqlserver, mysqldbname


    

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metadata = MetaData()

RatingsDescription = Table('ratings_description_stars', metadata,
                        Column('nct_id', String(50), primary_key=True),
                        Column('tfidf_sum', Float),
                        Column('score', Float)
                        )


    

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conn.close()


    

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#mysqlserver = 'localhost'
engine = create_engine('mysql://%s:%s@%s/%s' % (mysqlusername, mysqlpassword, mysqlserver, mysqldbname))
conn = engine.connect()
metadata.create_all(engine)


    

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uniqness = dict(zip(trial_desc.keys(),train_mat.sum(axis=1)))


    

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for k in range(0,len(uniqness.keys()),10000):
    print k
    conn.execute(RatingsDescription.insert(), [{'nct_id': n,
                                                 'tfidf_sum': uniqness[n].item(0),
                                                 'score': 1 + (round(min([uniqness[n].item(0)*2,20]) * .4) / 2)
                                                 }
                                                for n in uniqness.keys()[k:k+10000]])


    

In [38]:

    

cnt, bins, patch = plt.hist(train_mat.sum(axis=1), bins=range(25))


    

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uniqness = dict(zip(trial_desc.keys(),train_mat.sum(axis=1)))


    

In [39]:

    

cur = 0
uniqness_s = sorted(uniqness.items(), key=lambda x: x[1])
for i in range(len(cnt)-1):
    cur += cnt[i]
    print 'This is what %g looks like:' % uniqness_s[int(cur)][1][0]
    print '*' * 40
    print ' '.join(trial_desc[uniqness_s[int(cur)][0]])
    print
    print


    

    




This is what 1 looks like:
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Hypersensitivity 


This is what 2.00084 looks like:
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To demonstrate the clinical effectiveness of MK0812 in the treatment of Arthritis. 


This is what 3.00003 looks like:
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The purpose of this study is to evaluate the safety and efficacy of patisiran (ALN-TTR02) in patients with transthyretin (TTR) mediated amyloidosis 


This is what 4.00001 looks like:
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The aim of this study is to investigate peripheral effects of Somatostatin on glucose metabolism and growth hormone (GH) signalling in healthy men. Eight subjects will be enrolled. The hypothesis is that Somatostatin infusion reverses insulin resistance caused by GH. 


This is what 5.00001 looks like:
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Investigate whether ranolazine, a novel anti-anginal agent with antiarrhythmic properties, has a role in the management of symptomatic ventricular premature beats. The main objective is to compare the effect of ranolazine versus placebo on premature ventricular beats (using 24-hour ambulatory electrocardiographic monitoring) for subjects with symptomatic palpitations. Subject population will consist of seventy-two adult subjects of both sexes who have greater than 1,000 premature ventricular beats during initial monitoring.


This is what 6.00002 looks like:
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Treatment: five intro-articular Hyaluronic Acid injection  Assessment has two parts, that are as follow:  1. Postural stability and risk of fall assessment using Biodex stability index and "Timed up and Go" test  2. Gait and stair climbing assessment using Vicon motion capture system synchronized with four force plates.  For knee OA subjects, assessment was done in week one or before injection; and for healthy controls one assessment was performed. This study aimed to assess the effect of hyaluronic acid injection on Postural stability, biomechanics of gait and stair climbing in individuals with bilateral knee osteoarthritis (OA).  Participants were individuals with knee OA (control and treatment) and healthy people.


This is what 7 looks like:
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Objectives: We conducted a randomized controlled trial (RCT) of Students for Nutrition and eXercise (SNaX), a middle-school-based obesity-prevention intervention combining school-wide environmental changes, multimedia, encouragement to eat healthy school cafeteria foods, and peer-led education and marketing.  Methods: We randomly selected schools from the Los Angeles Unified School District (LAUSD) and assigned five to the intervention group and five to a wait-list control group. School records were obtained for number of fruits and vegetables served, students served lunch, and snacks sold per attending student. Pre- and post-intervention surveys assessed psychosocial variables among 2,997 seventh-graders (75% of all seventh-graders across schools).  Hypotheses: For the RCT of SNaX, we hypothesized that SNaX would lead to increases in the proportion of students served in the cafeteria (because SNaX markets cafeterias' healthy foods); increased fruit and vegetable servings (because SNaX increases access to sliced/bite-sized fruits and vegetables); decreased school store snack sales; and greater water consumption. We also hypothesized that SNaX would lead to more positive attitudes about the cafeteria and water, improve obesity-prevention knowledge, and increase intentions to drink water. 


This is what 8.00008 looks like:
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The study aims to evaluate the effectiveness of a cognitive behaviour therapy program (FRIENDS) for anxiety disorders in children aged 8-15 years who have been referred to child and adolescent mental health clinics in Western Norway. Cognitive behaviour therapy (CBT) has been shown to be an efficacious treatment for anxiety disorders in youths when delivered in university settings. However, there is a lack of studies evaluating the effectiveness of CBT in regular clinical settings.  The current study will compare a CBT program developed for anxiety in youths (the FRIENDS program by Paula Barrett, Australia), with a wait-list control condition. Group and individual treatment will also be compared in the study. Groups will be divided by age, with younger including 8-12-year-olds, and older 12-15-year-olds. Parents are also involved at the end of all therapy sessions, as well as in separate parent sessions. Assessment and treatment is delivered by clinicians working in seven outpatient clinics in Western Norway.  There will be 10 therapy sessions, with booster sessions 4 and 12 weeks later. Effectiveness will be evaluated post-treatment, and at 1 and 5 years follow-up. The study will have a randomized design. Children randomized to the wait-list condition will be offered treatment if they still meet inclusion criteria after the waiting period.


This is what 9.00005 looks like:
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The primary aim of this study is to examine the efficacy of a 12-week nurse-delivered relapse management intervention designed with conceptual underpinnings from Self-efficacy Theory to enhance smoking abstinence of hospitalized smokers following their hospital discharge. Specifically this study asks, does a 12-week Self-efficacy Theory driven relapse management intervention enhance smoking abstinence following hospitalization by increasing smoking abstinence point prevalence as measured by carbon monoxide validated self-reports of smoking, when compared to subjects receiving only enhanced usual care? A randomized controlled two-group design with an intent-to-treat approach for handling protocol deviations will be used to examine the primary aim of this project. The sample will consist of 80 consenting smokers prospectively recruited during hospitalization. Subjects will be randomly assigned by equal allocation to an intervention group or an enhanced usual only group. A baseline adaptive randomization procedure will adjust the random equal ratio of treatment assignment to maintain sampling balance of the groups for race (White/Black/Other), gender (male/female), and three comorbid categories (only tobacco related illnesses/ tobacco related and unrelated to tobacco illnesses/ unrelated to tobacco illnesses). All subjects will receive enhanced usual care, which will consist of receiving a supportive message to quit smoking and smoking cessation materials. Subjects assigned to the intervention group will receive 9 intervention sessions with a nurse aimed to enhance their self-efficacy in self-management of tobacco abstinence. These sessions will occur over 12 weeks following hospital discharge. All but the initial session will occur by telephone. Subjects will be asked to participate with follow-up activities 12 weeks and 24 weeks following their hospital discharge, which requires the measurement of exhaled carbon monoxide and the completion of questionnaires by self-administration and interview with study personnel. Subjects will exit from study following the 24-week follow-up.


This is what 10 looks like:
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The purpose of this study is to compare the sound pressure levels (SPLs) from three of the most frequently implanted mechanical heart valve prostheses, in order to determine whether there was any significant difference between the intensities of the valve sounds Patient's perception of mechanical heart valve sounds: psychoacoustics and quality of life  Background: Approximately 90.000 mechanical prosthetic heart valves are implanted every year all over the world. They generate a clicking sound at closure, which can be a major problem for some patients. About 12% of them all experience annoyance, concentration disturbance, sleeping disorders and social embarrassment. All those factors could affect patients' quality of life.  Aim: to compare the sound pressure levels (SPLs) from three of the most frequently implanted mechanical heart valve prostheses, in order to determine whether there was any significant difference between the intensities of the valve sounds.  Material and Methods: We intended to include 150 patients with an implanted mechanical heart valve (ATS Medical, Medtronic-Hall or St. Jude Medical) in the aortic position between 3 months and 4 years before the analysis. For logistical reasons, the actual number of the patients included was 84. The total conducted valve sound was measured (by a method designed by the authors) for each patient. The measures took place in a bioacoustical laboratory built with a sound-insulated chamber with a very low background noise, designed for the purposes of the study. The measures were performed in German patients followed by "The Heart Centre" in Bad Oeynhausen (Herz- und Diabeteszentrum Nordrhein Westfalen, University of Bochum), where the mentioned laboratory is constructed. The sound analysis of the present study was conducted in a specially designed soundproof bioacoustic laboratory, which isolates the outside sound and vibration from the environment indoors. Inside the laboratory, heavy soundinsulated curtains were placed between the patient and the investigator chambers. The total background noise inside the patient chamber was 19 dB(A), and this was reduced further to 9 dB(A) by using a 250 Hz high-pass filter. The sounds were recorded with the patient in the supine position, and without clothes covering the chest. The valve closing sounds were recorded using a microphone (Brüel and Kjær 4179) placed 5 cm above the patient's chest. This sound was then preamplified (Brüel and Kjær 2660), amplified (Brüel and Kjær 2610) and 250 Hz high-pass filtered (Krohn-Hite 3944) (see Fig. 1). All valve sounds were recorded by the same experienced investigator and stored on an instrumentation recorder (TEAC 510) for later off-line analysis. The data acquisition time for each patient was approximately 10 min.  The patients were asked to fuldill a quality of life questionnaire (SF-36), which will be assessed in a future study regarding psychoacoustics for mechanical heart valve sounds.  Perspectives: The results obtained from this analysis will contribute to expand knowledge concerning the sound produced by these three different types of mechanical heart valve prosthesis. The study can add one important parameter in the choice of the implanted valve: patient's pleasantness. It will assess some of the most sold mechanical heart valve worldwide and the final results can contribute to elucidate which type, among those valves, that should be chosen to a specific patient.


This is what 11.0001 looks like:
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Background:  - Stem cell transplants from related donors (allogenic stem cell transplants) can be used to treat individuals with certain kinds of severe blood diseases or cancers, such as severe anemia. Allogenic stem cell transplants encourage the growth of new bone marrow to replace that of the recipient. Because stem cell transplants can have serious complications, researchers are interested in developing new approaches to stem cell transplants that will reduce the likelihood of these complications.  - By reducing the number of white blood cells included in the blood taken during the stem cell collection process, and replacing them with a smaller amount of white blood cells collected prior to stem cell donation, the stem cell transplant may be less likely to cause severe complications for the recipient. Researchers are investigating whether altering the stem cell transplant donation procedure in this manner will improve the likelihood of a successful stem cell transplant with fewer complications.  Objectives:  - To evaluate a new method of stem cell transplantation that may reduce the possibly of severe side effects or transplant rejection in the recipient.  Eligibility:  - Recipient: Individuals between 8 and 80 years of age who have been diagnosed with a blood disease that can be treated with allogenic stem cell transplants, and who have a related donor to provide the stem cells.  - Donor: Individuals between 2 and 80 years of age who are related to the recipient and are eligible to donate blood.  Design:  - All participants will be screened with a physical examination and medical history.  - DONORS:  - Donors will undergo an initial apheresis procedure to donate white blood cells.  - After the initial donation, donors will receive injections of filgrastim to release bone marrow cells into the blood.  - After 5 days of filgrastim injections, donors will have apheresis again to donate stem cells that are present in the blood.  - RECIPIENTS:  - Recipients will provide an initial donation of white blood cells to be used for research purposes only.  - From 7 days before the stem cell transplant, participants will be admitted to the inpatient unit of the National Institutes of Health Clinical Center and will receive regular doses of cyclophosphamide, fludarabine, and anti-thymocyte globulin to suppress their immune system and prepare for the transplant.  - After the initial chemotherapy, participants will receive the donated white blood cells and stem cells as a single infusion.  - After the stem cell and white blood cell transplant, participants will have regular doses of cyclosporine and methotrexate to prevent rejection of the donor cells. Participants will have three doses of methotrexate within the week after the transplant, but will continue to take cyclosporine for up to 4 months after the transplant.  - Participants will remain in inpatient care for up to 1 month after the transplant, and will be followed with regular visits for up to 3 years with periodic visits thereafter to evaluate the success of the transplant and any side effects. Allogeneic hematopoietic stem cell transplantation (aHSCT) can cure patients with a variety of bone marrow failure syndromes (BMFS) including severe aplastic anemia (SAA), paroxysmal nocturnal hemoglobinuria (PNH) or myelodysplastic syndrome (MDS) associated with cytopenias. Patients with BMFS have traditionally been transplanted with bone marrow (BM) as a stem cell source. Although chronic graft versus host disease (cGVHD) occurs less commonly with BM compared to filgrastim (G-CSF) mobilized peripheral blood stem cell (PBSC) transplants, BM allografts have lower CD34+ progenitor cell numbers, which increases the risk of graft rejection in heavily transfused BMFS patients to 15-20 percent. To overcome this risk, our group developed a novel transplant approach for patients at high risk for graft rejection that utilized cyclophosphamide, fludarabine and anti-thymocyte globulin (ATG) conditioning followed by infusion of a CD34+ cell rich, T-cell replete G-CSF mobilized PBSC allograft. Remarkably, in 56 consecutive BMFS patients who had multiple risk factors for graft rejection who underwent this transplant approach graft rejection did not occur, with all patients achieving complete donor lymphohematopoietic chimerism. Unfortunately, recipients of G-CSF mobilized PBSC had a higher incidence of chronic GVHD than has historically been observed with BM transplantation (72 percent vs. 50 percent cumulative incidence of cGVHD at 1 year respectively). G-CSF mobilized PBSC transplants contained approximately a 20 fold higher dose of T-cells that had undergone a TH- 2 type cytokine polarization, a factor which likely contributed to this high incidence of cGVHD. In this protocol, we attempt to prevent graft failure and to reduce the incidence of cGVHD by transplanting high numbers of CD34+ selected PBSC co-infused with a reduced dose of non-mobilized donor T-cells that have not undergone a TH-2 cytokine polarization.  Subjects with BMFS at high risk for graft rejection will undergo allogeneic stem cell transplantation from an HLA identical sibling using the identical conditioning regimen utilized in protocol 99-H-0050. Using the Miltenyi CliniMACs system, recipients will receive an allograft on day 0 containing donor CD34+ cells that have been positively selected and T-cell depleted following G-CSF mobilization (goal CD34+ cell dose of 5 times 10(6) CD34+ cells /kg recipient) combined with 2 times 10(7) cells/kg of non-mobilized CD3+ T-cells previously collected and cryopreserved from the same donor by apheresis prior to G-CSF mobilization.  Primary objective: To evaluate whether administering a CD34+ selected, T-cell depleted peripheral blood stem cell graft with a concomitant infusion of non-mobilized donor T-cells at a dose that matches the T-cell dose that is infused in historical bone marrow transplant cohorts will reduce the incidence of cGVHD at 1 year to that observed with a conventional bone marrow transplant (50 percent) without increasing the risk of graft failure. This trial design will allow the trial to stop early if it is unlikely that we have reduced the proportion of one year cGVHD to 50 percent or if the combined event rate for failed donor engraftment or treatment related mortality (TRM) at day 100 exceeds 20 percent.  The primary endpoint of this study will be cGVHD at day 365.  Secondary end points include transplant related mortality, engraftment, degree of donor-host chimerism, incidence of acute and chronic graft versus host disease (GVHD), transplant related morbidity and overall survival. Health related quality of life will also be assessed as a secondary outcome measure pre-transplant, 30 and 100 days post transplant and every 6 months until 5 years post transplant.


This is what 12.0003 looks like:
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The investigators want to compare the use of MRI with PET/CT preformed after 1 hour and 3 hours in preoperative assessment of resectability.  The investigators' hypothesis is that dual time PET/CT performed at 60 and 180 minutes will increase the diagnostic accuracy of conventional PET (performed at 60 minutes) in preoperative assessment of resectability.  Further more the investigators suggest that the GLUT/G6Pase index correlates to the SUVmax. And retention index (RI, see Methods - PET protocol) is a prognostic marker in ovarian cancer. The use of PET/CT in ovarian cancer has not been well-established.  The diagnosis usually includes physical examination (incl. pelvic examination), blood test incl. CA-125 and transvaginal ultrasound. Furthermore imaging includes CT of thorax/abdomen and/or MR of pelvic. Ninety per cent of the ovarian cancers are epithelial carcinoma (EOC), which can be divided into serous (45%), mucinous (4%), endometrioid (5%), clear cell, undifferentiated and mixed types. All EOC are treated equally.  Treatment of ovarian cancer involves surgery and chemotherapy. The decision of operability is made at the multidisciplinary conference. Prognosis depends not only in the stage and histological type of the tumor but also at the end result of surgery. Residual disease after initial surgery is a strong prognostic factor for survival, with improvement on both overall and progression free survival being greatest in women with no or minimal (tumor < 1 cm) visible disease at the end surgery. Supra radical surgery is a radical procedure plus e.g. extensive peritonectomy, resection of liver metastases, splenectomy, resection of the tail of pancreas and bowel resection. Only 60% of patients in advanced stage ovarian cancer are deemed optimal debulked peroperative. Patients with optimal debulking have a 5 year survival of 42% versus patients not possible of achieve radical operation with 5 year survival of 15%, resulting in a hazard rate of 2,12 for optimal vs. not optimal debulking. A correct preoperative assessment is important in planning of operation and to avoid futile operation in patients not resectable.  Preoperative CT has shown to have a predictive value in assessment of the completeness of cytoreduction. But also PET/CT is has shown to be a independent predictor of resectability. Currently MR is standard in evaluating patient operability.  Studies has shown PET/CT to be particularly useful in distinguishing patients with stages I-IIIB and IIIC-IV, with an accuracy of 98% compared to 88% with CT alone. The latter group is important to identify because optimal debulking often is not possible and they will benefit from preoperative chemotherapy. Currently the use of PET/CT in staging ovarian cancer is controversial, mainly because of the relatively low specificity, due to FDG-uptake in inflammatory cells and benign lesions. The concordance of PET/CT and surgical staging of ovarian cancer have been reported to range from 69% to 78%.8,9, And a recent study found good correlation between PET/CT findings and laparoscopy but a high rate of false negative results in lesions < 5 mm. But dual time point imaging is maybe the solution to this problem. Today it is standard to perform PET/CT scan 60-90 minutes after injection of tracer. Theoretically, you should get increased tumor/background ratio by performing a late scan, thus better being able to distinguish between malignant and benign. Dual time imaging studies in head and neck cancers, breast cancer and lung cancer suggests improvement in diagnostic accuracy of PET. But the use of delayed imaging in ovarian cancer has not been studied.  The tracer used in PET is 18F-fluoro-2-deoxy-d-glucose. Generally cancer cells are thought to have low or absent G6Pase expression compared to normal cells and cancer cells have increased expression of GLUT (especially GLUT1) and hexokinase (especially HK2), which further leads to intracellular trapping of FDG-6-phosphate in malignant cells and there by yielding high maximum standardized uptake value (SUVmax). But ovarian cancers have found to have a relatively low ratio of hexokinase/phosphatase maybe explaining the low/absent rise in FDG-uptake. The amounts of GLUT, hexokinase and G6Pase are responsible for the FDG trapping intracellular and the retention on the late scans.


This is what 13.0014 looks like:
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Valproic acid is a leading mood stabilizer for the treatment of bipolar disorder. Its well-known teratogenicity limits its use in young women of childbearing age. According to toxicologic studies the teratogenicity of valproate stems from its free carboxylic group. Valnoctamide is an isomer and an analog of valpromide. Unlike valpromide, valnoctamide does not undergo a biotransformation to the corresponding free acid. It is also likely or at least possible that valnoctamide is anti-bipolar. In mice valnoctamide has been shown to be distinctly less teratogenic than valproate. An injection at day 8 of gestation produced only 1% exencephaly (as compared to 0-1% in control mice and 53% in valproate treated mice).  The investigators are performing a double-blind controlled trial of valnoctamide as an anti-bipolar drug. If shown to be anti-bipolar, valnoctamide could be an important valproate substitute for young women with bipolar disorder who are at risk of pregnancy. Patients newly admitted to the Beersheva Mental Health Center may participate if they meet Diagnostic and Statistical Manual of Mental Disorders - 4th edition (DSM-IV) criteria for mania or schizoaffective disorder, manic type. Patients admitted to the study are treated with risperidone at doses of the physicians' discretion beginning with 2 mg daily on days 1 and 2. Valnoctamide or placebo is begun at doses of 600 mg per day (200 mg three times daily) and increased to 1200 mg (400 mg three times daily) after four days.  Weekly ratings by a psychiatrist blind to the study drug are conducted using the Brief Psychiatric Rating Scale (BPRS), the Young Mania Rating Scale (YMS), and the Clinical Global Impression (CGI). Weekly blood is drawn for drug levels of valnoctamide to be measured by gas chromatography. Each patient receives valnoctamide or placebo for 5 weeks.  Low teratogenic mood stabilizers are a high priority for current research. Valproic acid is a leading mood stabilizer for the treatment of bipolar disorder. Its well-known teratogenicity limits its use in young women of childbearing age (1-3). The alternative mood stabilizers such as lithium and carbamazepine also have teratogenic potential so the treatment of bipolar disorder in young women is problematic. The difficulties are particularly acute in those young women patients who respond well to anti-bipolar therapy and maintain or begin normal interpersonal and marital relations and desire to have children.  One approach to this problem has been the search for valproic acid derivatives with less teratogenic potential (4). According to toxicologic studies the teratogenicity of valproate stems from its free carboxylic group (2, 3). Valpromide is an amide derivative of valproate without the suspect free carboxylic group. It was synthesized and marketed and has anticonvulsant efficacy, at least as good as valproic acid (1). There are some reports of its efficacy in bipolar disorder as well (5). In some animal species, only a small amount of valpromide is metabolized to valproic acid. However, in humans valpromide is metabolized to a large degree to valproic acid and so it does not solve the problem of teratogenicity (1, 6).  Valnoctamide is an isomer and an analog of valpromide. Unlike valpromide, valnoctamide does not undergo biotransformation to the corresponding free acid (6-9). In animal studies it is at least as anticonvulsant as valproate and valpromide (1, 6, 10). It has been marketed as an anxiolytic and sedative in several European countries (as Nirvanil) including Italy, Holland and Switzerland but has not actively been promoted as an anticonvulsant. It was marketed in the USA as Axiquel by McNeil in the 1970's. Unfortunately, despite considerable efforts we have not been able to obtain pharmacovigilance data from this period. Given its equivalence to valproate and valpromide as an anticonvulsant in animal models of epilepsy (1, 6, 10), it is reasonable to assume that valnoctamide is also anticonvulsant in humans. It is also likely or at least possible that valnoctamide is anti-bipolar. In mice valnoctamide has been shown to be distinctly less teratogenic than valproate (11). Injection at day 8 of gestation produced only 1percent exencephaly (as compared to 0-1percent in control mice and 53 percent in valproate treated mice). Embryolethality rates showed similar results: 52 percent with valproate vs. 5percent in the controls and 2 percent with valnoctamide.  Valnoctamide's patent is expired (12) and it is not the property of any major pharmaceutical company. Pharmaceutical company support cannot be obtained for our trial; therefore it is investigator initiated.  Valnoctamide will be synthesized for our study by Banyan Chemical in India (which has been inspected by the FDA) by GLP (good laboratory practice) in a manner acceptable for human use by the Israel Ministry of Health (and in principle for an IND by the FDA). Banyan manufactures at the same site generic compounds, atenolol for instance, sold in the USA and distributed by international companies, Novartis for instance.  Study Design:  The study has been submitted to our Helsinki Committee and only patients who give informed written consent will be accepted. Patients newly admitted to the Beersheva Mental Health Center may participate if they meet DSM-IV criteria for mania or schizoaffective disorder, manic type. Minimal Young Mania Scale = 20. Only patients admitted to the hospital within the previous 72 hours will be eligible for the study. Exclusion criteria will be as in previous studies of mania with this design by our group (15-17) and will include drug abuse, active physical illness, and of course pregnancy.  Patients admitted to the study will be treated with risperidone at doses of physicians' discretion beginning with 2 mg daily on days 1 and 2. On days 3 and 4 the risperidone dose could be increased to a maximum of 4 mg daily or decreased to 1mg daily. On days 5 to study end the dose could be increased to a maximum of 6 mg daily or decreased to a minimum of 1mg (see ref #18). Dose of risperidone will be a secondary outcome measure (see reference #15 & #16). No washout from previous medication is required but patients who received depot neuroleptics within the past 2 weeks or more than 300 mg of chlorpromazine equivalents in the past three days will be excluded. Trihexyphenidyl (up to 4 mg daily) will be available as necessary for extrapyramidal symptoms and benzodiazepines for sleep. Valnoctamide or placebo will be begun at doses of 600 mg per day (200 mg three times daily) and increased to 1200 mg (400 mg three times daily) after four days. This dose is based on relative anticonvulsant effects of valproate and valnoctamide in animal studies (1, 6, 10).  Patients will receive valnoctamide or identical capsules of placebo as assigned by the control psychiatrist according to random order; manic and schizoaffective manic patients will be randomized separately. Weekly ratings by a psychiatrist blind to the study drug will be conducted using the Brief Psychiatric Rating Scale (BPRS), the Young Mania Rating Scale (YMS), and the Clinical Global Impression (CGI). Primary outcome measure will be BPRS. Weekly blood will be drawn for drug levels of valnoctamide to be measured by gas chromatography (19). Each patient will receive valnoctamide or placebo for 5 weeks.  Power Analysis:  We have demonstrated significant effects as add-on in mania in this design with lithium (15), carbamazepine (16), and phenytoin (17). Each study had an N of about 40 patients, recruited over 18 months in each study. In each study as in the present proposal, a mood stabilizer or potential mood stabilizer was added to haloperidol at doses of physician's discretion for five weeks.  Lithium adds clinically and statistically significant benefit to haloperidol treatment of mania (15) as does carbamazepine (16) and phenytoin (17). Such an "add-on" design is consistent with clinical practice and makes sense since dopamine blockers and mood stabilizers probably work by different mechanisms in mania. Valproate is typically used clinically in acute mania as an add-on to neuroleptics as well. Three positive studies published in excellent journals (15-17) from our group using this design are probably better than formal power analysis, which depends on a range of assumptions that are collapsible into the experience of our three studies. Because the prior probability of an effect of valnoctamide is lower than that of the above well-known compounds, we suggest recruitment of 80 patients over 36 months to adequately power this study rather than the 40 patients in each of our previous studies. Since valnoctamide is no longer patented, orphan drug procedures or a use patent of the type granted to Abbott for divalproex sodium will be necessary to make this drug available for bipolar patients at risk for pregnancy in the future. An adequately powered study is therefore important at this stage.  References  1. Bialer M, Haj-Yehia A, Badir K, Hadad S: Can we develop improved derivatives of valproic acid? Pharm World Sci 1994; 16(1):2-6.  2. Nau H, Headrick X: Valproic acid teratogenesis. ISI Atlas Sci Pharmacol 1987; 1:52-56  3. Nau H, Hauck RS, Ehlers K: Valproic acid-induced neural tube defects in mouse and human: aspects of chirality, alternative drug development, pharmacokinetics and possible mechanisms. Pharmacol Toxicol 1991; 69(5):310-21.  4. Bialer M: Pharmacokinetic considerations in the design of better and safer new antiepileptic drugs. J Control Release 1999; 62(1-2):187-92.  5. Lemoine P, Fondarai J, Faivre T: Valpromide increases amplitude of heart rate circadian rhythm in remitted bipolar and unipolar disorders. A placebo-controlled study. Eur Psychiatry 2000; 15(7):424-32.  6. Bialer M: Clinical pharmacology of valpromide. Clin Pharmacokinet 1991; 20(2):114-22.  7. Bialer M, Haj-Yehia A, Barzaghi N, Pisani F, Perucca E: Pharmacokinetics of a valpromide isomer, valnoctamide, in healthy subjects. Eur J Clin Pharmacol 1990; 38(3):289-91.  8. Haj-Yehia A, Bialer M: Pharmacokinetics of valpromide isomer valnoctamide in dogs. J Pharm Sci 1988; 77:831-834.  9. Pisani F, Haj-Yehia A, Fazio A, Artesi C, Oteri G, Perucca E, Kroetz DL, Levy RH, Bialer M: Carbamazepine-valnoctamide interaction in epileptic patients: in vitro/in vivo correlation. Epilepsia 1993; 34(5):954-9.  10. Loscher W, Nau H: Pharmacological evaluation of various metabolites and analogues of valproic acid. Anticonvulsant and toxic potencies in mice. Neuropharmacology 1985; 24(5):427-35.  11. Radatz M, Ehlers K, Yagen B, Bialer M, Nau H: Valnoctamide, valpromide and valnoctic acid are much less teratogenic in mice than valproic acid. Epilepsy Res 1998; 30(1):41-8.  12. US Patent 3,056,726 (1962): alpha-ethyl-beta-methylvaleramide for mental hyperirritability. McNeil Laboratories Inc.  13. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS: Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 2001; 276(39):36734-41.  14. Shaltiel G, Shamir A, Belmaker RH, Greenberg ML, Agam G: Valproate inhibits inositol-P synthase: mood stabilization by inositol depletion elaborated. submitted  15. Biederman J, Lerner Y, Belmaker RH: Combination of lithium carbonate and haloperidol in schizo-affective disorder: a controlled study. Arch Gen Psychiatry 1979; 36(3):327-33.  16. Klein E, Bental E, Lerer B, Belmaker RH: Carbamazepine and haloperidol v placebo and haloperidol in excited psychoses. A controlled study. Arch Gen Psychiatry 1984; 41(2):165-70.  17. Mishory A, Yaroslavsky Y, Bersudsky Y, Belmaker RH: Phenytoin as an antimanic anticonvulsant: a controlled study. Am J Psychiatry 2000; 157(3):463-5.  18. Yatham LN, Grossman F, Augustyns I, Vieta E, Ravindran A: Mood stabilisers plus risperidone or placebo in the treatment of acute mania. International, double-blind, randomised controlled trial. Br J Psychiatry 2003; 182:141-7.  19. Bialer M, Hoch B: Rapid gas chromatographic assay for monitoring valnoctamide in plasma. J Chromatogr 1985; 337:408-411.


This is what 14.0016 looks like:
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This project focuses on social and character development of elementary and middle school-aged children and responds to an urgent national need that schools improve their capacity to address a range of student outcomes, including social skills, character, behavior, academic achievement and health outcomes. This study is a school-based randomized trial to evaluate the Positive Action program. The Positive Action program was designed to promote social and character development and improve behavior and school performance. This project is one of seven in a multi-site trial of different programs that has been nationally implemented. Oregon State University (OSU) and University of Illinois at Chicago (UIC) are conducting a school-based randomized trial to evaluate the efficacy of the Positive Action program (PA) to find out how the program works, to determine the effectiveness of the Positive Action program on reducing negative behaviors (including health-related behaviors), increasing positive behaviors and improving academic achievement of elementary school students. The Positive Action program was designed to promote social and character development (respect, responsibility, altruism, civic virtue, prosocial behavior) in ways that reduce anti-social behavior (violence, substance use, delinquency) and improve school performance (attendance, test scores). Fourteen eligible schools selected during winter 2004 are comprised of 7 matched pairs (treatment and control); the schools were matched on a 'risk score' composed of multiple school characteristics. Students in grade 3 in the 2004-05 school year, their parents, and their teachers and principals were surveyed at baseline (Fall 2004), spring and fall of 2005, spring 2006 and spring 2007. Evaluation is based on multiple kinds of process, mediator variable and outcome data from school records (attendance, transience, grades, test performance, disciplinary actions and suspensions, and changes in school and student population characteristics), student records, student surveys, parent surveys, teacher ratings and surveys, and administrator surveys, collected from schools in both conditions (except information about delivery of the Positive Action program). The work being done at OSU is confined to Dr. Flay's overall supervision of all aspects of the project, and data analysis using de-identified data received from Dr. DuBois at UIC and research paper writing. The work being done at UIC, directed by Dr. David DuBois, includes all of the intervention work, data collection, data entering, and some data analysis and report writing. The U.S. Department of Education/IES hired a national contractor, Mathematica Policy Research, Inc. (MPR) to conduct core surveys at all sites of the multi-site trial through spring 2007. In addition, OSU/UIC is administering a site-specific student survey that is complementary to the multi-site surveys during all waves of data collection. As the project funding followed Dr. Flay's move from UIC to OSU in September 2005, OSU IRB provides a review for the overall project. As of April 2008, new funding allows continuation of the study through March 2012 and follows the target cohort of students through the end of 8th grade as they and their teachers and principals are surveyed fall 2008, spring 2009 and again along with their parents in spring 2010. Data collection for the continuation study also includes collection of height and weight of children and process evaluation data from students and teachers. There will be no involvement of MPR. Data collection was completed June 2010.  Consent Rates and Mobility:  Parental consent was obtained before students, parents or teachers completed surveys when students were in grade 3. Seventy-nine percent of parents provided consent at baseline. Students joining the study at later waves were consented at that time; consent rates for them ranged from 65% to 78% for Waves 2-5. All students were re-consented for the second phase of funding at Wave 6 (beginning of grade 7); consent rates were lower at Waves 6 through 8 ( ≈ 58 to 64%). This is consistent with previous studies that have found that consent rates drop as grade levels increase. The percentages of consenting parents who provided reports on their children were 72.3%, 58.9%, 52.2%, 50.5%, and 72.9% at Waves 1, 2, 4, 5 and 8, respectively. Two factors that likely increased parent response rate at Wave 8 were (1) an increase in the financial incentive for completing the parent report and (2) an intensive period of phone outreach to families to note the incentive increase and to encourage survey completion. Percentages of consented students for whom teachers completed ratings were 74.6%, 74.8%, 72.4%, 78.3%, 74.4%, and 92.7% for Waves 1, 2, 4, 5, 7, and 8, respectively. At Wave 8, we introduced an additional school-level incentive for 100% rates of teacher survey completion, which likely resulted in the increase in completed teacher ratings. Mobility patterns were identified using results from a latent class analysis in which a 5-class solution was found to be the most appropriate fit for the data: 1) stayers (average study duration of 5.72 years, N = 158), 2) temporary participants (1.30 years, only in grades 4 or 5; N=196), 3) late joiners (1.38 years; N=308); 4) early leavers (0.94 years; N=263), and 5) late leavers (3.23 years; N=287).  Planned Statistical Analyses:  Because the trial was cluster-focused, we assessed students who entered schools after the beginning of the trial (joiners), but did not follow individual students who stopped attending the study schools (leavers). From the standpoint of students, across time they could be considered a "dynamic" (i.e. changing) grade cohort. Multilevel models will be used to take into account variation at the school and student levels. Missing data will be addressed using the missing-at-random (MAR) assumption, as it is unlikely that a single unmeasured variable or set of variables would predict missingness for all students who left or joined the trial schools after randomization We propose a three-level (occasions of measurement nested within students nested within schools) growth-curve model for analyzing treatment effects on various student-level outcomes. These models will account for all observations and model school differences. This approach allows for a complete analysis of the multiple waves of available data and takes into account the patterns of change over time. Random-intercept growth-curve models will first be estimated. Following the random-intercept model, a random-coefficient model will be run to test whether there is significant variation in student change across time, rather than all students in each condition having the same change pattern. A Likelihood Ratio Chi-square (LR) test will be used to compare model fit with and without the random coefficient. If a model with a random time coefficient provides a significantly better fit for a given outcome, it will be reported as the final model. Intervention effects on scales collected only at later waves (Waves 5 or 6 onwards) will be tested with the intercept set at the endpoint (Wave 8) with the condition term indicating a possible difference in effects at the last (Wave 8).  Because only 14 schools are in this trial, and the PA effect is tested at the school level in a cluster-randomized trial, we will conduct several sensitivity analyses. First, we will assess the statistical significance of the PA coefficient estimate and its standard error using the t-distribution with 12 degrees of freedom: 14 schools - 1 (the condition effect) - 1 = 12 df providing for a more conservative approach. A second approach will be a pair-level analysis, estimated as a four-level model: occasions of measurement nested within students, nested within schools, nested within matched pairs.  In addition to the student-level survey data, several school-level archival measures will be analyzed. Because these data are at the school level, the growth-curve models will be two-level (observations within schools) rather than three-level. Because of the small amount of data (the number of schools times the number of waves) and the resulting power limitations, these analyses will use the random-intercept model only.  We will test for moderation by gender and by student mobility. The moderation tests will reveal for whom the program has its effects; that is, these tests will allow us to assess whether program effects differ by gender or a child's mobility. We will not test for moderation by ethnicity because it is highly confounded with school, with 3 pairs of schools having a mostly African-American enrollment and 2 pairs of schools having a mostly Hispanic enrollment.  While all 14 schools were retained throughout the CRCT, the student population in this trial was highly mobile. Thus, it is important to test for potential moderating effects of student mobility patterns. A recent approach to analyzing mobility patterns is latent class analysis (LCA). The mobility patterns described above can then be tested as a moderator of program effects; that is, examining whether students with different mobility patterns have different program effects.  Mediation analyses will allow us to examine the PA program's mechanisms of action. We will first estimate the bivariate effect of X on Y without the mediator included in the model. Then, we will simultaneously estimate the direct effect of X on Y with the mediator included in the model, as well as the mediated effect, which consists of the effect of X on M × M on Y.


This is what 15.0008 looks like:
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We hypothesize that specifically selected probiotics can alleviate symptoms of allergy in lactose tolerant individuals. Two strains of probiotics, Lactobacillus rhamnosus GR-1, and Bifidobacterium adolescentis 7007-05 will be used to create a yogurt product. Additionally a non-probiotic yogurt product will also be made as a placebo. Allergy sufferers will be asked to consume one of the two types of yogurts (blinded) for two months. During the two months there will be 3 sampling days, for blood samples and nasal lavage samples. Additionally Mini Rhinoconjunctivitis Quality of Life Questionnaires will be filled out weekly over the two months. After the two months of perceived responses as well sample analysis we should have a better idea of how these specific probiotic effect the immune system and allergies. Probiotics are "live microorganisms which when administered in adequate amounts confer a health benefit on the host". Many studies have been performed which indicate that probiotics can temporarily modify the composition of gut microbiota, and potentially these can reduce susceptibility to allergy (Noverr & Huffnagle, 2005) (Tannock et al. 2000), leading to health benefits for the host. Numerous studies show that these benefits include ones primed through the immune response of the host.  Animals maintained free of microorganisms have drastic abnormalities in their immune response. These germ-free animals have altered Peyer's Patches, reduced levels of IgA associated with increased risk for gastrointestinal infections, and they are unable to develop oral tolerance to ingested antigens (Moreau et al. 1988). When these animals are later colonized by normal intestinal bacteria, they overcome their past deficiencies, and have a restored ability for oral tolerance. This allows for the blockade of IgE production which is a key factor in allergic disease (Moreau et. al 1988).  Studies on inflammatory bowel disease patients have shown that certain probiotics can actually reduce inflammation and diminish disease (Bruzzese et al. 2004) (Baroja et al. submitted). The former study investigated 75 children, while our study (Baroja) showed down regulation of inflammation in 8/20 inflammatory bowel diseased patients. Allergic disease is almost non-existent in underdeveloped countries where, interestingly, fermented foods are consumed regularly. This differs considerably from the numerous allergies and lack of fermented food intake in the Western World. Investigators hypothesize that the human gut ecosystem has evolved to require daily intake of lactic acid bacteria (Molin 2001), and these bacteria maintain immunological regulation which protects against allergic sensitization and development of allergic disease.  Recent studies have shown that probiotics do have a significant influence on allergic reactions. The consumption of Lactobacillus rhamnosus GG by pregnant women lowered the occurrence of babies born with atopic dermatitis compared to those births from women who had not consumed the probiotic (Kalliomaki et al. 2001). Another study on 27 infants suffering from atopic eczema, showed that probiotic-supplemented formula decreased the severity of the condition (Isolauri et al 2000). The efficacy of probiotics in treating allergy has been further shown with Bifidobacterium longum BB536 in which it relieved Japanese cedar tree pollinosis, probably through the modulation of Th2-skewed immune response (Xiao et al. 2006). Another Japanese study showed that a synbiotic L. casei subsp. casei with dextran was an effective supplement for the prevention and treatment of allergic reactions cedar pollen (Ogawa et al. 2006). Not all studies have shown benefits, and one performed in teenagers and young adults allergic to birch pollen and apple food, showed no effect on intermittent symptoms of atopic allergy and/or mild asthma. We have now isolated strains of bifidobacteria from the stool of subjects with no history of any allergy, and these along with two lactobacilli probiotics have shown strong anti-allergy potential in vitro. In short, there is evidence to indicate that studies are worthwhile using food based probiotics, if not to completely prevent allergies, but to contribute towards their alleviation.  Objective 1. We will examine the cell types in nasal cavity with the expectation that this will shift as the probiotics are consumed, with a decrease in number of eosinophils, characteristic of late-phase allergic inflammatory symptoms, as the study progresses, and a corresponding decrease in neutrophils.  Objective 2. We will characterize the subject's sensitivities to inhalant seasonal and potentially year-round allergens. Routine RAST tests will be performed at the beginning of the study to test sensitivity towards mixed grasses, mixed trees, mixed weeds, mixed molds, ragweed, house dust, cat dander and dog dander. From this we will be able to differentiate subjects who are highly susceptible to allergy and those moderately susceptible. At the end of the trial we will perform further RAST tests using ragweed and mixed grass allergens, with the anticipation that the probiotic treatment with anti-allergic strains will decrease the subject's sensitivity to those particular allergens, while those receiving regular yogurt will have no effect.  Objective 3. We will identify changes in serum cytokine levels that would indicate a shift from an inflammatory state to one of reduced inflammation. We anticipate that the presence of inflammatory cytokines, IL-5, IL-4 and IL-13 will be decreased as the subject's intestinal flora is boosted by the anti-allergic probiotics; likewise, the presence of anti-inflammatory cytokines, IL-10, TGFβ2, IFN-γ will be increased by the treatment. This shift in cytokine production should be reflected in reduced allergic symptoms. In addition, Affymetrix Human Genome U133 Plus 2.0 Arrays will be performed on selected blood samples to characterize immunological signal transduction pathways activated by the probiotic bacteria.  Objective 4. We will characterize the perceived effects of anti-allergic strains of probiotics using a questionnaire. Subjects will self-administer validated Mini Rhinoconjunctivitis Quality of Life Questionnaire (MiniRQLQ)© (Juniper et al., 2000) on day 0 and weekly during the study period. The questionnaire includes 14 questions in five domains: activity limitations, practical problems and nose symptoms, eye symptoms and other symptoms. The questions are answered on scale 0-6 (from not troubled to extremely troubled) depending how troubled the subjects have been due to their nose/eye symptoms during the past week. Possible lung symptoms (cough, dyspnoea and wheezing) will be recorded separately using the same scale. This perceived effect may actually be the single most important outcome to our study. If the samples actually do show a decrease in inflammatory cytokines etc. but the subject does not perceive any changes to their allergy symptoms, then the probiotics cannot be stated to have affected the allergic response. We hope that all shifts in cytokine and cellular levels towards the anti-inflammatory state are reflected in the subject's awareness of decreased allergy symptoms.  At the end of this study we hope to know whether or not regular and probiotic yogurts have the potential to alleviate symptoms of allergic rhinitis, as well as down regulate the inflammatory processes in humans. It is anticipated that at least one of the yogurts will show promise in this regard. However, even a negative result would be informative, as the experiments will show us how consumers respond physiologically to different fermented food.


This is what 16.0015 looks like:
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This study is a ten-week, placebo-controlled, double-blind, cross-over, randomized trial of the novel antipsychotic agent, aripiprazole, added to 20 obese stable olanzapine-treated patients with schizophrenia or schizoaffective disorder. The advantage of the crossover design is that each subject will act as their own control and fewer subjects will be required than a between-group design. Specific Aims:  This study is a ten-week, placebo-controlled, double-blind, cross-over, randomized trial of the novel antipsychotic agent, aripiprazole, added to 20 obese stable olanzapine-treated patients with schizophrenia or schizoaffective disorder. The advantage of the crossover design is that each subject will act as their own control and fewer subjects will be required.  Study Procedures:  We have designed this trial to examine effects upon weight, lipids, glucose metabolism, positive symptoms, negative symptoms, and depressive symptoms. This project, examining the usefulness of combination therapy, may offer a possible intervention for patients who are obese and treated with olanzapine, but otherwise experiencing a good clinical response. Many patients, despite the medical problems that may occur, are reluctant to switch their antipsychotic agent.  Location:  This study will be performed at the Freedom Trail Clinic of the Erich Lindemann Mental Health Center by faculty of the Schizophrenia Program of the Massachusetts General Hospital and staff of the Freedom Trail Clinic.  Subjects:  Subjects will include 20 stable outpatients with schizophrenia or schizoaffective disorder treated with olanzapine for at least one year. Prior to enrollment, we will determine that the clinician has optimized the dose of the antipsychotic and maintained the medication at a stable dose for at least 1 month. Patients will be excluded for significant medical illness, substance abuse, or inability to provide informed consent.  Safety Assessments:  Medication Trial:  Patients will have a baseline assessment performed and then randomized to placebo or aripiprazole 15 mg/day for 4 weeks. After the initial 4 weeks of medication patients will be reassessed, have a 2-week washout period and then crossover to the other treatment for another 4 weeks. The olanzapine dose will be unchanged during the trial. Patients will be given a two-week supply of medication at baseline and week 2 and then again at weeks 6 and 8.  Screening Visit The diagnosis of schizophrenia or schizoaffective disorder will be confirmed by a research psychiatrist using DSM IV criteria. A physical examination will be performed and medical history, vital signs, weight, height, waist/hip circumference, skin-fold measurements, 12-lead EKG and demographic information will be obtained. Laboratory measures will include olanzapine blood levels, fasting glucose, insulin, basic chemistry profiles, liver enzymes, CBC, lipid profile, leptin, LDL- particle size, PAI-1, C-reactive protein, sICAM, vWF and a DNA sample will be drawn at screening for future analysis of the 5-HT-2C and H1 receptor genes.  Baseline Assessment:  The following scales will be completed at baseline and will comprise the treatment efficacy battery: Positive and Negative Syndrome Scale (PANSS), Scale for Assessment of Negative Symptoms (SANS), Clinical Global Impressions scale (CGI), Hamilton Depression Rating Scale (HAM-D), Global Assessment Scale (GAS), Fatigue Scale Inventory (FSI) Trauma History Questionnaire (THQ) and the Quality of Life Scale (QOL). A single rater will perform all assessments. If it is necessary to use a second rater, inter-rater reliability will be established before the addition of the second rater and will be repeated every three months by use of videotaped interviews. The treatment efficacy battery will be repeated at week 4, 6 and 10 except for the THQ, which will only be administered at the beginning of the study.  Safety and Monitoring Assessments:  Blood pressure, heart rate, temperature, weight, waist/hip circumference will be performed at each visit (baseline, weeks 2, 4, 6, 8 and 10). Side effects will be monitored at baseline and weeks 2, 4, 6, 8, and 10 using the Systematic Assessment for Treatment Emergent Events (SAFTEE). Body fat composition will be measured by skin-fold calipers at baseline, week 4, 6 and 10. EPS will be evaluated at baseline and weeks 2, 4, 6, 8 and 10 using the Simpson-Angus Scale, Barnes Akathisia Scale, and the Abnormal Involuntary Movement Scale (AIMS).  Measure of Energy Expenditure and Dietary Assessment:  Patients will be asked to wear an accelerometer for four consecutive days to obtain an objective measure of physical activity. During the same four days the patients will maintain a four-day food record of all food and beverages consumed. This will provide a means of assessing energy intake verses energy output. Patients will also complete the Modifiable Activity Questionnaire (MAQ). Energy expenditure and dietary intake will be assessed at baseline, weeks 4, 6 and 10.  Randomization:  The double-blind, placebo-controlled, crossover study will consist of two random order 4-week treatment arms (aripiprazole 15 mg or placebo) separated by a 2-week adjuvant treatment washout. Following baseline, subjects will be randomized, double-blind, to either aripiprazole or placebo for 4 weeks. After the initial 4 weeks of medication patients will be reassessed, have a 2-week washout period and then crossover to the other treatment for another 4 weeks.  Subject Recruitment:  Potential subjects will be identified by their clinicians at the Freedom Trail Clinic. Patients will give their physician verbal permission to be contacted for research purposes. A member of the research team will meet with the subject and explain the study protocol, including a review of risks and potential benefits. A copy of the study consent form will be provided to the patient at this time. Patients who express interest after this first meeting will be evaluated for competency to provide informed consent by a physician who is not a member of the research team. Patients who are judged to be competent will then be asked to meet with the principal investigator who will review the study protocol and consent form with the patient and obtain informed consent. The human rights officer of the North Suffolk Mental Health Association will be asked to participate in this meeting unless the patient declines. Family and residential staff will also be invited to participate if the patient agrees.  Potential Risks:  Aripiprazole did not produce any serious adverse effects in animal and human safety studies. No consistent abnormality of vital signs, laboratory, EKG or EEG has emerged. In clinical trials, no side effects occurred at rates greater than 2x placebo. Nausea, vomiting, anxiety, headache, dyspepsia, somnolence, orthostatic hypotension, tachycardia, insomnia, akathisia, EPS, and weight gain may be potential side effects.  Benefits:  It is not known if aripiprazole added to olanzapine will help a subject's mood, motivation, hallucinations, and unusual experiences. Other patients may benefit if this study finds that aripiprazole added to olanzapine is useful for treating symptoms of schizophrenia.  Data Management and Statistical Analysis:  Data management and statistical analysis will be provided by Dr. David Schoenfeld from the Massachusetts General Hospital, Biostatistics Center.  Protection of Human Subjects:  Principal members of our research team have all completed certification for protection of human subjects in clinical trials. The clinical protocol will be submitted for approval by the institutional review boards of the Massachusetts Department of Mental Health. Potential subjects will be referred by their clinicians. Clinicians will be asked to sign a statement that verifies that the patient is interested in participating, understands that participation is voluntary, and understands that declining participation will not affect treatment at the facility. A member of the research team will meet with the patient and explain the study protocol, including a review of risks and potential benefits. A copy of the study consent form will be provided to the patient at that time to share with family members or residential staff. Patients who continue to express interest after this first meeting will be evaluated by a physician who is not a member of the research team for capacity to provide informed consent. Patients who are judged to be competent will then be asked to meet with the principal investigator or co-investigator who will review the study protocol and consent form with the patient and obtain informed consent.


This is what 17.0067 looks like:
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Obesity is a major health problem in the US and many Western countries, with more than half of the population being overweight or obese. Yet, despite intense research efforts into the mechanisms underlying obesity and into the development of novel pharmacologic interventions, bariatric surgery, including gastric bypass surgery is the only successful treatment for severe obesity. Mimicking one of the effects of bariatric surgery, e.g. the increased secretion of glucagon-like peptide 1 (GLP-1) could be an effective strategy against obesity.  Obese individuals may be more sensitive to the rewarding aspects of food and less responsive to signals from the gut about actual energy needs. Using functional MRI scanning the investigators plan to examine the effect of Exenatide (a GLP-1 analog known to reduce caloric intake and produce weight loss in both obese and lean individuals) on activity within brain regions/networks involved in reward/motivation and in regulation of energy requirements. The investigators expect the peptide to change the balance between desire to eat for pleasure and the need to eat to maintain homeostasis. PRIMARY STUDY OBJECTIVE The proposed study aims to address two important questions regarding the mechanisms underlying the weight loss associated with exenatide. The investigators primary study objective is to determine whether Exenatide changes the resting state activity of the brain, and alters the connectivity between brain regions involved in homeostatic and hedonic brain circuits.  SECONDARY STUDY OBJECTIVE The secondary study objective is to determine if/how these changes differ between lean and obese subjects  SIGNIFICANCE Obesity is a major health problem in the US and many Western countries, with more than half of the population being overweight or obese. Yet, despite intense research efforts into the mechanisms underlying obesity and into the development of novel pharmacologic interventions, bariatric surgery, including gastric bypass surgery is the only successful treatment for severe obesity (le Roux, 2006; le Roux, 2007). Mimicking one of the effects of bariatric surgery, e.g. the increased secretion of glucagon-like peptide 1 (GLP-1) could be an effective strategy against obesity (Torekov, 2011).  The impact of gut peptides on the brain in the regulation of ingestive behavior is an area of great interest, since the involved signaling mechanisms may be potential targets for the treatment of obesity. Both endocrine, paracrine and neurocrine (vagal) signaling pathways are involved in gut to brain signaling of nutrient related information (Holst, 2007). Human studies have demonstrated that long acting hormones like leptin and insulin act on brain regions such as the hypothalamus and brainstem, influencing both food intake and response (Ahima, 2010). More short -term gut signals relayed by hormones such as CCK and PYY have also been shown in humans to have an effect on subcortical regions (including the hypothalamus, nucleus tractus solitarius (NTS), pons, thalamus) as well as on cortical regions (middle temporal gyrus, insula and anterior cingulate cortex (ACC) (Ahima, 2010). Whereas CCK infusion in healthy human subjects was found to result in increased activity primarily in homeostatic brain regions (hypothalamus, brainstem), PYY infusions were associated with increased activity in regions of reward-circuits (orbitalfrontal cortex, insula, anterior cingulate cortex). To our knowledge, the central effects of GLP-1 in humans have not been studied. (Ahima, 2010)  HYPOTHESIS  1. Exenatide changes intrinsic activity in the NTS and hypothalamus, and connectivity between NTS and homeostatic and hedonic brain circuits  2. These changes are seen both in lean and in obese subjects  3. Changes in the engagement of brain circuits induced by Exenatide are correlated with increased ratings of satiety following a test meal  METHODS  The study design is a double-blind, placebo controlled, crossover study.  Twenty healthy female subjects between the ages of 18-40 years are needed The subjects will be divided into two age-matched groups of obese and lean women. The ten obese females will have a BMI between 30-35kg/ m2 and the 10 lean females will have a BMI between 19-25kg/m2. All subjects will be asked to participate in the entire protocol of 3 visits. There will be a screening visit to determine eligibility followed by two functional MRI visits where the subject is given a subcutaneous injection (sc) of 10ug of Exenatide (a GLP-1 analog) at one visit and a an injection of saline at the other MRI visit. The choice of female participants is based on the greater prevalence of obesity in women and the longstanding interest of the center's interest in women's health. In order to control for menstrual cycle hormonal fluctuation all participants will be scanned during the follicular phase of the menstrual cycle, for this study defined as the 4th-12th day after starting menstruation.  Screening (Visit 1):  All potential subjects will be asked to complete an initial screening visit approximately 1.5 hours of time. This visit will take place at the Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress at 10833 Le Conte Ave., Los Angeles, CA 90095 Room 47-126. At the beginning of this visit, the subject will be given ample time to read and sign the informed consent. The protocol will be discussed and reviewed with a study MD or RN.  The screening will include a medical history and physical examination. A urine test for pregnancy will also be done. If the pregnancy test is positive the subject will be immediately dropped from participation. Female subjects of child bearing potential will be asked to practice a medically approved birth control method during the study, including the oral contraceptive pill, abstinence, double barrier method (spermicide and condoms), or IUD. A menstrual cycle history will be obtained as part of the medical history and the first day of their last menses will be documented. fMRI visits will be planned during the follicular stage- specifically day 4-12 of their cycle. A 5 cc (1 tsp) blood draw for glucose will be collected. If the non- fasting blood glucose result is more than 200mg/dl the subject will be considered a screen fail. This value was chosen in order to exclude subjects with undiagnosed underlying diabetes.  Subjects will be asked to fill out several behavioral questionnaires: the UCLA bowel symptom questionnaire (BSQ 5.0), the Hospital Anxiety and Depression scale (HAD), the Spielberger State and Trait Anxiety Inventory (STAI-Y1 and Y2) and the MRI safety screening questionnaire; requiring about 20 minutes to complete.  The RN, NP or MD will review the inclusion and exclusion criteria with the subject to determine eligibility.  A brief structured psychological interview (MINI+) will be done to identify any major Axis I psychiatric disorders in DSM-IV and ICD-10, such as anxiety, depression, substance abuse or phobias.  If the subject is eligible and wishes to participate, they will be provided with instructions for the following study visit. As noted this visit will be scheduled during the follicular phase of the individual's menstrual cycle.  Visit 2 MRI scanning visit 1:  This visit will take approximately 2 hours of time. Subject will be asked to fast (except water) for eight hours prior to admission. Eligibility criteria for continuance in the study, including adverse events and any change in medication usage will be reviewed and recorded. The 1st day of last menstrual period will be noted and a urine pregnancy test will be performed. If positive the subject will be removed from study enrollment.  Subjects will be escorted to the CTSI (General clinical research area) and an IV will be placed for the four blood draws. A baseline fasting blood glucose will be done. It needs to be between 65mg/dl and 126mg/dl or the visit will be cancelled. The subject will then be escorted to the UCLA Ahmanson-Lovelace Brain Mapping Center, 660 Charles Young Dr. South, Los Angeles, CA 90095-7085 and prepared for scanning. Subjects will be asked to complete a PROMIS questionnaire prior to scanning to evaluate the previous nights sleep quality (for RSN analysis) and a Fullness Questionnaire (FQ); a visual analog scale used to measure hunger and satiety.  After wanding for metal safety they will be escorted into the MRI chamber. They will be given a synopsis of the study tests and prepared for placement in the scanner. They will be monitored for pulse oximetry and respiratory rate as a measure of autonomic nervous system and as a safety measure (after Exenatide injection) while scanning. These measures will be collected during all functional resting state network (RSN) scans.  Following placement structural scans will be done After the structural scans the subject will undergo a 10-minute resting state (RSN) scan during which then they will be asked to lie still with their eyes closed but not fall asleep.  After that RSN scan, subjects will be partially moved out of the scanner to receive either a subcutaneous injection of 10ug of Exenatide or a 0.5cc injection of saline (placebo) in the upper arm, thigh or abdomen. Randomization will be done by the UCLA research pharmacy where the drug is stored and dispensed. Subject and investigator will blinded to the randomization.  Immediately following the injection the subject will be moved back into the scanner and have a 8.5 minute structural scanner (MP Rage: a three-dimensional, T1-weighted, gradient-echo sequence used for study analysis). Immediately following the MP Rage, the subject will have the second 10-minute RSN scan (10-minutes post drug) with the same RSN instructions. After the second RSN scan is completed the subjects will complete the second Fullness Questionnaire (FQ). This will be presented on the screen via goggles and the answers will be given to the scanner operator via intercom. The subject will then be partially moved out of the scanner for a 1 teaspoon (5cc) blood draw. This serum sample will be for glucose, insulin and exenatide pharmacokinetic.  The subject will then be moved back into the scanner for the third and final 10-minute RSN with the same previous instructions. Immediately following this scan the subject will complete the third FQ and have 1 teaspoon (5cc) of blood drawn for glucose, insulin and Exenatide pharmacokinetic levels.  After scanning, subjects will be taken to the CTSI and provided a full balanced standard meal of 1200 calories. All subjects will have 2 lunch meal choices to choose from (chicken or ham) and will be instructed to "eat until you are full". After the meal, the subject will complete the fourth FQ and a final 5cc blood draw for glucose, insulin and Exenatide PK level. Approximate blood sampling for the whole day will be 1-2 ounces.  All scanning will be done in the morning, between ~9am-12pm, to account for hormonal fluctuation and for fasting comfort of the subject.  Visit 3 MRI scanning Visit 2:  Visit 3 is identical to Visit 2 except the subject will receive the opposite injection. If the subject was randomized to receive 10ug of Exenatide during Visit 2 then she will receive .5cc of saline (placebo) during Visit 3. Otherwise study procedures will be identical.


This is what 18.0026 looks like:
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The purpose of the study is to examine cognitive and brain function in stage I-III breast cancer patients who have undergone adjuvant systemic therapy (chemotherapy or chemotherapy plus anti-hormonal therapy) in comparison to a group of healthy controls.  Our hypothesis is that systemic adjuvant therapy in the form of chemotherapy or chemotherapy and anti-hormonal therapy given to primary breast cancer patients can cause cognitive impairment. We hypothesize that the use of simultaneous PET/MRI will allow us to determine key regions in the brain that show metabolic, structural, and functional deficits in a semi-quantitative manner and reveal subtle changes that are often missed during neuropsychological tests due to the low sensitivity of neuropsychological batteries. Breast cancer is the most common cancer amongst women worldwide, with a lifetime risk of 7-8% in women and incidence rates ranging from 19.3-89.7 per 100,000 women in developing and developed countries. More than 1,383,500 cases of invasive breast cancer are estimated to be diagnosed worldwide,and approximately 1490 women were diagnosed to have breast cancer in Singapore every year. However, the mortality rates are lesser at 6-19 per 100,000 women because of the more favourable survival of breast cancer in high-incidence developed regions. In Southeast Asian Chinese 5-year overall survival is about 75.8%, although lower for Indians and Malays at 68% and 58.5% respectively. These improving outcomes are largely due to earlier detection and the availability of more successful treatment options. With rising prevalence of this disease and improving survivorship, the long term effects of current treatment options are becoming increasingly survivorship issues.An early Early Breast Trialists' Collaborative Group (EBCTCG) meta-analyses, reported that adjuvant chemotherapy produces an absolute 10-year survival improvement of 7-11% for those < 50 years of age, and 2- 3% for those aged 50 -69 years. This benefit was most recently confirmed by an update which reported that adjuvant chemotherapy trials demonstrated recurrence and mortality reductions compared to no-chemotherapy trials.Hence, chemotherapy remains an important strategy in the adjuvant setting. However, several studies have reported reduced cognitive function in a proportion of breast cancer patients receiving chemotherapy, also known as the "chemobrain" effect. In these patients, cognitive impairments ranging from deficits in memory, attention, concentration, executive and psychomotor functioning to deficits in nearly all cognitive domains have been reported. Other studies however have disputed this association, and it thus remains unclear if cognitive impairment is indeed a potential risk of systemic treatment. There are a number of difference adjuvant chemotherapy regimens which comprise anthracyclines and/or taxanes in various regimens. An adjuvant regimen utilising weekly paclitaxel after standard doxorubicin/cyclophosphamide has been shown to improve disease-free and overall survival over 3-weekly taxanes given after the same standard anthracycline-based regimen In order to minimise heterogeneity, this study will only recruit patients utilising this adjuvant chemotherapy regimen.Anti-hormonal therapy has become a mainstay in the adjuvant treatment of hormone receptor-positive patients. Tamoxifen for 5 years reduces recurrence rates throughout the first 10 years (RR 0·53 during years 0-4 and RR 0·68 [0·06] during years 5-9 [both 2p<0·00001]; and breast cancer mortality by about a third throughout the first 15 years. In addition, the use of aromatase inhibitors (AIs) in post-menopausal breast cancers has been reported to confer a significant 2.9% decrease in recurrence compared with tamoxifen (9.6% for AI v 12.6% for tamoxifen; 2P < .00001) and a non-significant absolute 1.1% decrease in breast cancer mortality (4.8% for AI v 5.9% for tamoxifen; 2P = .1) in a recent meta-analyses by Dowsett et al.Compared to chemotherapy, there is a relative paucity of data pertaining to endocrine therapy-induced cognitive changes. Nonetheless, there have been several pertinent studies examining datasets within the larger context of pre-existing large multicenter adjuvant hormonal therapy trials which are outlined below.A growing body of literature suggests that adjuvant systemic therapy for breast cancer may be associated with cognitive impairment, which may persist for years and can impair decision-making abilities and disrupt the ability of women to fulfill family, career, and community responsibilities.The magnitude of these deficits may be moderated by depression, anxiety, fatigue, concomitant medications, genetics, education, intelligence, and menopause.Studies associating cognitive changes with chemotherapy had been reported since the mid 1970s;but systematic research did not come about until the mid 1990's to early 2000's.However, early studies were limited by lack of a pre-treatment assessment, the importance of which is illustrated by a study by Wefel et al.This was one of the first prospective longitudinal studies comparing pre- and post-treatment cognitive measures. Although there were no mean differences between patients who received 5- fluorouracil/doxorubicin/ cyclophosphamide (FAC) chemotherapy and normal controls, intra-individual analyses in patients demonstrated a 61% cognitive decline for learning, attention and processing speed. Without a baseline assessment, 46% of patients who had normal post-treatment scores would have their cognitive impairments missed, highlighting that cognitive dysfunctions can be subtle and small differences may be clinically significant. Furthermore, although acute cognitive changes during chemotherapy are common,long-term post-treatment cognitive changes seem to persist in only 17-34% of cancer survivors.Several additional longitudinal studies since then have assessed cancer or treatment-related cognitive difficulties using standard neuropsychological assessments.About 12-82% of patients had detected cognitive impairments in the domains of executive function, memory, psychomotor speed and attention, these being the most frequent measures affected. These studies used a variety of cognitive assessment tools and control groups, different treatment regimens and varying testing timepoints. A study comparing breast cancer patients, majority of which were exposed to adjuvant anthracycline and/or taxane-based chemotherapy, to those breast cancer patients who were chemonaive or healthy controls, reported the greatest deficits in processing speed and verbal ability domains for the chemotherapy-exposed group. Therefore, research is needed needed to look at the factors contributing to a decline and thereafter, a long-lasting impairment.Of interest, cognitive deficits have been detected in cancer patients pre-chemotherapy in several studies. For instance, Wefel et al described 33% of women in the current cohort exhibiting cognitive impairment even before systemic therapy.Another study reported a 23% impairment in cognition prior to adjuvant breast cancer chemotherapy.These could be related to psychological variables such as stress, anxiety or depression, or to other factors such as differing socioeconomic, educational or intrinsic cognitive levels. Research is needed to look at the factors contributing to a decline and thereafter, a long-lasting impairment. These data also suggest that systemic therapy-associated cognitive changes need to be examined within the broader context of risk factors and biological processes associated with cancer development.Inclusion of assessments of confounding factors which could play a role in influencing cognitive function is vital. Fan et al in their study reported that fatigue, menopausal symptoms and cognitive were important adverse effects of chemotherapy that improved in most patient over a period of 1-2 years.In comparison, hormonal therapy had minimal impact on them. Self-perceived cognitive deficits may not be reflective of objective test scores and hence is interesting to evaluate. In a population-based study in Denmark consisting of women <60 years old who received adjuvant anthracycline-based chemotherapy or tamoxifen compared with healthy controls, it was shown that the patients were up to 3 times more likely than healthy controls to rate themselves cognitively impaired at 6 months, although neuropsychological tests did not reveal any evident or consistent pattern of cognitive change in any of the patient groups.Most clinical data on cognitive function and anti-hormonal therapy have been on selective estrogen receptor modulators (SERMS) such as tamoxifen, although focus on aromatase inhibitors has been increasing in recent years. A substudy (designated the CoSTAR trial) pooled subjects from the pre-existing National Surgical Adjuvant Breast and Bowel Project (NSABP) Study of Tamoxifen and Raloxifene (STAR) randomizing women =35 years old with increased risk of breast cancer by Gail model evaluation to either tamoxifen or raloxifene.The substudy required women to perform an 83-minute standardized test battery covering multiple domains. Outcomes on cognitive testing were similar in both groups. In the landmark NSABP Breast Cancer Prevention Trial (P-1) which included 13,388 women at increased breast cancer risk, treatment with 5 years of tamoxifen resulted in a reduced risk of breast cancer by 49% relative to placebo.A separate report documented results of the P-1 Symptom Checklist assessment encompassing a few self-report domains spanning cognition, musculoskeletal pain, vasomotor symptoms, nausea, sexual problems, bladder problems, body image and vaginal symptoms.The cognitive assessment included questions related to concentration, forgetfulness, avoidance of social affairs, and tendency towards accidents. There was little difference in cognitive dysfunction between groups. Notably, for these 2 studies, evaluation was conducted during the period of active therapy. To address this issue, a study by Paganini-Hill et al in a population-based case-control study examined 1163 women between 55-75 years old diagnosed with primary breast cancer.Previous tamoxifen users were classified as short-term users (<4 years) or long-term users (=6 years) and were compared with never users. Women who had used tamoxifen for 4-5 years had more memory problems reported to their physician compared to never users (3.8% vs 1.5%, p=0.04), especially for women currently on tamoxifen. However, no differences were seen among never and past users suggesting limited long-term sequelae. Even among the premenopausal population on tamoxifen, significantly lower processing speeds which appeared to interfere with executive functioning have been reported in a cross-sectional study comparing women on adjuvant tamoxifen to healthy controls.Clinical data on the effects of aromatase inhibitors on cognitive function are emerging. The largest dataset comes from the International Breast Intervention Study II (IBIS II) studying postmenopausal women at increased risk of breast cancer receiving either anastrozole or placebo for 5 years, testing being done at 0, 6 and 24 months. No differences in cognitive function between the 2 groups were detected. However the neurocognitive testing was done during the period of treatment as in other previously described studies and in a postmenopausal hypoestrogenic population. As such, the effects of AIs could have been blunted.In a substudy of the Anastrazole, Tamoxifen and Combined (ATAC) trial which recruited patients with localized breast cancer to adjuvant tamoxifen, anastrozole or combination therapy, 94 patients from the ATAC trial were compared to 35 non-cancer controls. Their mean length of study time was 36 months. The patient group was significantly impaired compared to the control group on measures of verbal memory (p=0.026) and processing speed (p=0.032). Comparisons between anastrozole and tamoxifen have been done in a cross-sectional and longitudinal study, both of which demonstrated the anastrozole exposed group experiencing worse cognitive impairments.There were poorer verbal and visual learning and memory in the study by Bender et al,44 while the prospective longitudinal study showed a nine-fold and five-fold increase in risk of cognitive decline in the anastrozole and tamoxifen groups respectively relative to healthy controls; the most common domains affected being processing speed and verbal memory.A neuropsychological substudy was carried out from the pivotal Tamoxifen and Exemestane Multinational (TEAM) trial which randomized patients to adjuvant exemestane for 5 years or adjuvant tamoxifen for 2.5-3 years followed by exemestane for 2-2.5 years .The neuropsychological assessment was carried out pre-endocrine therapy and after a year of treatment, and included 80 tamoxifen and 99 exemestane users. Interestingly, exemestane users did not perform statistically worse than healthy controls on any cognitive domain, but tamoxifen users had significantly worse verbal memory and executive functioning compared to healthy controls, and significantly worse information processing speed compared to exemestane users. However, it has been postulated that exemestane's mildly androgenic properties may ultimately preserve cognition.A recent cognitive testing report of the Breast International Group (BIG)1-98 study randomizing women to adjuvant monotherapy of tamoxifen or letrozole for 5 years, or sequential therapy with letrozole followed by tamoxifen or vice versa revealed that women taking letrozole in the 5th year had better overall cognitive function than those taking tamoxifen (p=0.04).A significant improvement in composite cognitive function for both groups was observed in years 5-6 when treatment was ceased. In summary, with repect to AIs, a greater cognitive decline has been observed with anastrozole as compared to tamoxifen, while a lesser decline is seen with exemestane and letrozole.Larger studies are clearly need to validate these findings. Results from many of these studies need to be interpreted cautiously, as there have been various limitations in studies pertaining to this field. Many studies have been hampered by a variety of inherent methodological problems. These include lack of a baseline assessment, lack of a longitudinal design, and failure to control for physical and psychosocial confounding factors such as hormonal factors, depression, anxiety, fatigue and educational level.Furthermore, studies have also differed considerably with respect to regimens and doses of chemotherapy received, previous exposure to anti-hormonal therapy and length of time post-treatment. In addition, a limitation of several studies is the lack of pre-treatment evaluations of cognitive function.This is especially problematic because it makes it impossible to determine whether deficits were present before treatment or to detect changes from baseline. The timing of cognitive function assessment after the completion of therapy was also not uniform. Most studies lacked non-treated comparison groups and failed to measure potential moderators of cognitive function. Several studies failed to include a comprehensive assessment of the multiple domains of cognitive function, and occasionally relied on the use of a self-report questionnaire. Importantly, cognitive studies in the Asian population have been grossly limited. Certain biological pathways, genetic polymorphisms and epigenetic changes could lead to alterations in cognitive functioning in only a subgroup of people exposed to chemotherapy. For example, several genetic polymorphisms of multidrug resistance 1 (MDR1) have been identified that may influence P-glycoprotein (P-gp) function, one of the most studied polymorphisms being C3435T in exon26.P-gp which is present in the blood brain barrier affects the amount of drug uptake into the brain by actively transporting them out of the cells. Polymorphisms associated with lower expression or functionality of P-gp may cause increased vulnerability to chemotherapy-induced cognitive changes. Oxidative stress is the most frequent cause of DNA damage in neuronal cells, and has been associated with various neurodegenerative diseases including Alzheimer's and Parkinson's disease. DNA damage and repair systems have been linked to neurodegeneration such as in ataxia telengectasia and xeroderma pigmentosum. So far the relation of cognitive functions to the level of DNA damage post-chemotherapy has not been well studied. As mentioned, certain studies have detected higher than expected rates of cognitive impairment pre-chemotherapy. In addition higher levels of oxidative DNA damage have been found in women with breast cancer.These data are consistent with research linking certain DNA repair polymorphisms with a decreased DNA repair capacity and thus an increased cancer risk. Hence, changes in cognitive function following chemotherapy can be evaluated within the context of genetic factors that increase cancer risk but also increase risk of cognitive dysfunction pre-treatment. Certain polymorphisms in the base-excision pathway may also be worthwhile studying because of their importance in modulating oxidative stress and cancer risk.Cytokines play a role in central nervous system function, including modulation of neuronal and glial cell functioning, neural repair and metabolism of dopamine and serotonin, which are important neurotransmitters for cognition. Longitudinal studies of interferon-a and IL2 in cancer populations have shown decrements in cognitive performance, particularly in the domains of information processing speed, executive function, spatial ability and reaction time.Both chemotherapy and persistent fatigue have been linked to increased cytokine levels.Genetic polymorphisms have been identified that influence cytokine activity and are associated with Alzheimer's disease and depression. However, so far the relationships between these polymorphisms and chemotherapy-induced cognitive changes have not been well studied. The catechol-O-methyltransferase (COMT) valine genotype has been linked to chemotherapy-related cognitive impairment in breast cancer survivors and is worthwhile of further study. Chemotherapy in mouse models has also been demonstrated to decrease hippocampal cell proliferation, increase histone acetylation and decrease histone deacetylase activity. Hence, it would therefore be relevant to study the particular candidate mechanisms which are likely to influence cognitive changes in certain susceptible individuals. Inclusion of assessments of confounding factors which could play a role in influencing cognitive function is vital. Fan et al in their study reported that fatigue, menopausal symptoms and cognitive were important adverse effects of chemotherapy that improved in most patient over a period of 1-2 years. In comparison, hormonal therapy had minimal impact on them.But, even with the use of increasingly sophisticated performance-based assessments, subtle differences are often being missed along with the obscurity of the neural circuits and structures underlying the cognitive changes. For this reason, neuro-imaging tools have gained advantage because they provide the opportunity to examine the effects of chemotherapy on brain and cognition. However, such studies have been very limited in the field and therefore the need for further brain imaging studies. MRI has emerged as a noninvasive method with the potential to produce high resolution and contrast images of the brain. From the anatomical findings, adjuvant chemotherapy was associated with long-term injury to white matter and also damage to gray matter with associated functional deficits. An early study by Inagaki et al. comparing 51 adjuvant chemotherapy treated breast cancer patients with 55 patients who did not receive chemotherapy, showed that chemotherapy patients had smaller volumes in key areas involved in cognitive processing. The patients showed a strong positive correlation between volume loss and performance on the WMSR (Wechsler Memory Scale Revised) test of attention and memory. A serious weakness of this study was the failure to consider the effect of adjuvant endocrine therapy and the lack of prechemotherapy baseline assessment. Only three studies to date have investigated the integrity of white matter tracts and structural connectivity using diffusion tensor imaging (DTI). Results revealed structural neural changes over time as well as indicated region specific differences inherent to most of the cognitive deficits.The corpus callosum, an area important for communication between hemispheres, exhibited reduced white matter integrity which may explain the reduced processing speed reported in the chemotherapy-treated patients. The effect of endocrine treatment was not considered in the analysis which provides a drawback for proper interpretation. Another study showed decreased Fractional Anisotropy (FA) in frontal and temporal white matter tracts as well as increased Mean Diffusivity (MD) in frontal white matter. A significant correlation was also seen between the FA scores and the neuropsychological tests (attention and processing speed) in the chemotherapy-treated patients. White matter organization, particularly in the frontal, parietal and occipital white matter tracts, was negatively impacted by chemotherapy and this correlated strongly with cognitive functioning scores. This suggests that microstructural white matter changes or abnormalities may underlie reported cognitive dysfunctions found in chemotherapy treated cancer patients, especially that cerebral white matter is vulnerable to neurotoxins.In addition to the small number of structural imaging studies, a limited number of functional imaging studies have assessed neural changes in chemotherapy treated cancer patients. Combining the anatomical/structural assessment with functional imaging techniques provides a wider window of evaluation onto the functional changes associated with such cognitive deficits. To understand the underlying functional changes associated with poor executive function and processing in chemotherapy patients, a study by Saykin et al was one of the first to incorporate working memory assessments with functional MRI readouts. This was one of the first prospective longitudinal studies comparing pre- and post-treatment on a working memory N-back task. Although the authors reported no group differences in task performance with the expected main effect of working memory load on performance at baseline, patients assessed one month post-chemotherapy showed increased activation in posterior frontal and parietal regions compared to controls with less bilateral activity in more anterior frontal regions. This study illustrates that the cognitive changes associated with chemotherapy may be too subtle to reliably be detected with standard neuropsychologial assessments and underscore the importance of and potential for using functional MRI to elucidate underlying neurobiological changes.Interestingly, while investigating declarative memory in 14 breast cancer patients three years following chemotherapy, patients showed less activity in bilateral frontal gyri and postcentral gyrus with greater activation in parahippocampal, bilateral cerebellum, cingulate and precuneus while exhibiting normal cognitive assessment and cortisol levels (a measure of distress) compared to control. The increased activation in several brain areas compared to controls indicates that patients required greater and more global neural effort than controls when attempting to recall task information. More interestingly, this study showed that the type of chemotherapy regimen contributed to differential patient verbal memory impairments; CMF treated patients showed lower prefrontal cortex activity during encoding compared to patients on the adriamycine/cyclophosphamide/taxol regimen. This indeed highlights the importance of distinguishing between different types of chemotherapy treatment. Although functional MRI is the gold standard for evaluation of brain function, it is an indirect measure and functional readouts do not represent the underlying neuronal mechanisms involved. Other methods have been investigated to assess mere brain activity and more directly detect the underlying mechanism of cognitive dysfunction in chemotherapy patients. Only two PET (Positron Emission Tomography) imaging studies have been conducted to date. A recent study was conducted in 5 year post-chemotherapy patients. Patients exhibited lower resting metabolism in the frontal cortex and basal ganglia. A major drawback of this study was the lack of baseline assessment and the inhomogeneous study group where eight of the patients were on tamoxifen treatment.Another PET/CT study to assess brain metabolism after chemotherapy in 128 patients is still ongoing.Results from many of these studies need to be interpreted cautiously, as there have been various limitations in studies pertaining to this field. Many studies have been hampered by a variety of inherent methodological problems. These include lack of a baseline assessment, lack of a longitudinal design, and failure to control for physical and psychosocial confounding factors such as hormonal factors, depression, anxiety, fatigue and educational level. Furthermore, studies have also differed considerably with respect to regimens and doses of chemotherapy received, previous exposure to anti-hormonal therapy and length of time post-treatment. In addition, a limitation of several studies is the lack of pre-treatment evaluations of cognitive function. This is especially problematic because it makes it impossible to determine whether deficits were present before treatment or to detect changes from baseline. The timing of cognitive function assessment after the completion of therapy was also not uniform. Most studies lacked non-treated comparison groups and failed to measure potential moderators of cognitive function. Several studies failed to include a comprehensive assessment of the multiple domains of cognitive function, and occasionally relied on the use of a self-report questionnaire. Importantly, cognitive studies in the Asian population have been grossly limited. Taking these shortcomings into consideration, we designed a study intended to minimise biases mentioned as above. The chemotherapy regimen utilised will be limited to that of anthracyclines and taxanes; specifically we will use patients given doxorubicin/cyclophosphamide (AC) for 4 cycles followed by weekly paclitaxel for 12 cycles as per the adjuvant breast cancer study by Sparano et al as this is the chemotherapy regimen most commonly used in our division. Furthermore, we will have a baseline pre-treatment assessment for both CANTAB and imaging assessments, a longitudinal study design, and a more uniform evaluation taking 6 months and one year post-chemotherapy or after starting one year of anti-hormonal therapy as a cut-off point for CANTAB and imaging assessments. We will also attempt to minimize biases by analyzing confounders such as anxiety, depression and hormonal fluctuations using questionnaires and also recruit a control group of healthy subjects with similar age, gender and social background.


This is what 19.0236 looks like:
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Protocol Title: A Nationwide Epidemiological, Non-Interventional Study Evaluating an Educational Support Program for Improving Treatment Adherence in Patients with Hepatitis B Viral Infection  Objective(s): The primary objectives of the study are to assess:  - HBV treatment adherence rate in patients enrolled in the Support Program  - Adherence rates at 6m, 12m.  The secondary objectives are to assess:  - Adverse events rate and profile.  - Actual treatment duration and dose taken vs. prescribed.  - The impact of SMS reminders.  Study Design: Eligible patients will be randomized into one of four groups: Group 1 shall receive both a weekly phone call from a supporter and a daily SMS reminder. Group 2 will receive a weekly phone call only. Group 3 will receive a daily SMS reminder only and group 4 (Control) shall receive no support.  Study Population: Adult newly diagnosed with Hep B patients, eligible to begin treatment with first line therapy.  Data Collection Methods:  1. Supporter's documentations of patient's self assessment.  2. Drugs dispense data from pharmacies  3. Pills count. Page: 1  Protocol Number: AI463-972 Date: 23-Oct-2013 Ver: 2 Observational Study Protocol AI463-972 Help-B  A Nationwide Epidemiological, Non-Interventional Study Evaluating an Educational Support Program for Improving Treatment Adherence in Patients with Hepatitis B Viral Infection  Prof. Eli Zuckerman; Dr. Yoram Menachem; Prof. Rifat Safadi; Prof. Assy Nimer; Dr. Rawi Hazzan; Dr. Michal Carmiel  Treatment for Chronic HBV The objectives of HBV therapy are to improve upon the spontaneous rates of sustained disease remission (as defined by long-term HBeAg and HBsAg seroconversion rates off-treatment), thereby reducing the risk of disease progression, with resultant improvements in quality of life and reductions in healthcare costs. Seven drugs are presently approved in the USA and/or EU for the treatment of CHB in patients with HBeAg-positive and -negative disease. They fall into 2 classes: antiviral/immunomodulators (IFNα and pegIFNα-2a) and antiviral nucleos(t)ide analogs (NUCs). [7, 8] EASL and AASLD Treatment Guidelines (2009) [7, 8] recommend that HBV therapy may be initiated with any of the currently approved agents, but that IFNα (standard or pegylated), Tenofovir (TDF) or Entecavir (ETV) are preferred first-line options for treatment of CHB patients with HBeAg-positive and HBeAg-negative disease.  Poor adherence to therapy is a complex challenge for physicians treating patients with chronic diseases. In clini¬cal practice, adherence rates averages 50%, falling most dramatically after the first 6 mo of treatment. [9] Guidelines on CHB therapy emphasise the need for optimal adherence, with risk of resistant viral strains emerging if the virus has a drug free holiday. [10] For ex¬ample, antiviral resistance has been reported in up to 70% patients after 4 years on Lamivudine, 29% after 5 years of Adefovir dipivoxil and 1% after 4 years of Entecavir monohydrate[11-13]. The number of dose omissions that may lead to this is variable but any omission poses a po¬tential risk of viral replication breakthrough. Although, the data for CHB are lacking, it is evident from the HIV literature that near-perfect adherence (> 95% adherence rates) is needed to achieve a non detectable viral load and avoid emergence of resistant strains[14, 15]. Hence, in the clinical setting of CHB therapy, the goal of adherence remains 100%.  Unlike other chronic conditions, the rapid viral rep¬lication potential and mutation rates of hepatitis B virus require very high levels of adherence to achieve and maintain virological suppression. [16] Suboptimal adher¬ence risks exacerbating existing liver disease, which can be life-threatening particularly in patients with advanced cirrhosis. Furthermore, it can lead to the development of drug-resistant strains, limiting therapeutic options and additionally poses the public health risks of transmission of drug-resistant viral strains to non-immune individuals in the community, or to those whose previous vaccina¬tion are no longer protective. [17, 18] Given the global burden of the disease, widespread transmission of drug-resistant strains may have serious and wide-reaching consequences.  1.1 Study Rationale Non- adherence to treatment is a well known issue across many therapeutic areas. In Hep C, literature review shows that adherence in real life may reach 65%, with most drop-outs during first 3 months, mainly due to minor side effects. In Hep B, reported adherence studies show 50%-80% adherence, with an average of ~65%. Most drop-outs are during first 6 months of treatment. Non-adherence to treatment is believed to contribute not only to liver deterioration but also to emerging viral resistance.  Studies for adherence support show an average improvement of around 10%-15% at the best. Assessed methods are:  - Patient education  - Patients empowerment  - SMS reminders  - Pills' boxes with electronic reminders  The lack of symptoms along with chronicity of treatment, financial burden and lack of patient's education - are recognized as important factors for non-adherence.  The abundance of new drugs for viral hepatitis, high disease prevalence and the close relation between effective treatment and clinical outcomes - create a clear need for not only providing treatment but also an efficient support system aimed at supporting patients' adherence.  1.2 Research Question We expect that an ongoing patients' support system will contribute to adherence increase. The support should be provided by HCPs, be continuous and provide reminders, medical education and direct contact between patients and HCPs.  Therefore, study hypothesis is:  - An ongoing 6 months adherence support will increase adherence rates for Hep B patients  - Adherence rate increase will be at least 20%.  - Direct weekly telephone contacts will contribute major improvement. Smart phone application daily reminders will contribute as well and there is need to assess its relative contribution.  2 OBJECTIVES 2.1 Primary Objectives At least 20% improvement in adherence rates for newly treated Hep B patients. Adherence rate will be defined as the per cent of days the patients took their hepatitis B virus medications during study treatment and the number of missed doses.  2.2 Secondary Objectives  The difference in adherence improvement among 3 types of adherence support:  1. Weekly telephone call + daily text messages reminders.  2. Weekly telephone calls.  3. Daily text messages reminders.  4. Control - no adherence support  3 STUDY DESIGN 3.1 Overview of Study Design This is an epidemiological non-interventional study conducted in the community. Medical students (Hereinafter "Supporters"), attending senior years (4th or 5th year) will receive training about the Educational Support Program. In case not all vacancies can be filled with suitable medical students, senior years nursing students will be approached. Every supporter will be supporting a maximum of 10 recruited patients simultaneously. Every 5 supporters will report to a nurse. Every 2 nurses will report to a Hepatologist (Hereinafter "Investigator"). Overall, every Hepatologist shall be recruiting a maximum of 100 patients.  During the pre-study phase, eligible patients, who are prescribed with HBV treatment with Entecavir by their respective Investigator, will be informed of the Support Program. Interested patients will receive ICF for signature. Upon signature, the recruiting Investigator will randomize the newly recruited patient into one of the four study groups.  Randomization will be provided by CHS computerized system (Randomization engine).  Patients in the supported groups (Groups 1; 2 and 3) shall undergo the procedure described hereby:  Upon recruitment, the patient will be introduced to the nurse, who will appoint a supporter to the patient, install the smart-phone reminder application (to relevant groups - Group 1 and Group 3) and explain the support format according to patient's group:  Group 1:  Receive weekly phone calls from their Supporters who will monitor HBV treatment adherence and adverse events, respond to the patients' queries, suggest possible remedies to patients' basic complaints (per definition and qualification in training), refer more complex queries and/or complaints to respective nurse and refer patients to physicians for further treatment, if required. The Supporter will record the data on a Patient Follow-Up Form and report, on a monthly basis, to the respective nurse. In addition, patients in this group will install the reminder application on their smart-phones and will be reminded on a daily basis, by the application, to take their medication.  Group 2:  Receive weekly phone calls from their Supporters who will monitor HBV treatment adherence and adverse events, respond to the patients' queries, suggest possible remedies to patients' basic complaints (per definition and qualification in training), refer more complex queries and/or complaints to respective nurse and refer patients to physicians for further treatment, if required. The Supporter will record the data on a Patient Follow-Up Form and report, on a monthly basis, to the respective nurse.  Group 3:  Patients in this group will install the reminder application on their smart-phones and will be reminded on a daily basis, by the application, to take their medication.  Group 4:  Patients in the 4th group (control group) will continue the SOC without any further support.  Every month, patients will receive a letter from their respective Investigators, summarizing their study status in the previous month (Appendix A). Every quarter (3 months), each nurse will report study progress to responsible Investigator and schedule a follow-up appointment for the patient with the investigator. The patient will bring the pill boxes to the follow-up appointment for counting.  At the end of the supporting phase, the patients will continue HBV treatment according to standard care and their physician's instructions. During the follow-up phase, all groups will be handled as Group 4 patients.  3.2 Study Population  Approximately 250 Naïve Hep B patients are expected to participate in the study and will be divided into 4 study arms:  Group 1: 63 pts receiving weekly telephone contact & daily text messages for 6 months.  Group 2: 63 patients receiving weekly telephone contacts for 6 months. Group 3: 63 patients receiving daily text messages for 6 months. Group 4: 63 patients receiving no adherence support.  3.2.1 Inclusion Criteria  - Adult male and female patient (> 18 years).  - Prescribed treatment of Entecavir for HBV  - Must have access to a smart-phone.  - Written informed consent.  3.2.2 Exclusion Criteria  - Patients with hepatitis C, hepatitis D or HIV co-infection.  - Co-infected patients who require additional medication.  - Patients with prior liver transplantation  - Patients with impaired renal function requiring dialysis  - Immune-suppressed patients receiving HBV antiviral prophylaxis  - Pregnant patients.  - Inability or unwillingness to provide informed consent or abide by the requirements of the study.  - Parallel participation in another clinical trial.  - Patients who cannot take medication independently. 3.3 Data Source/Data Collection Process  Adherence to treatment will be assessed by 3 methods:  1. Supporters' weekly documentations.  2. Pill count - Patients will be instructed to bring the boxes to quarterly follow-up visits with the Hepatologist.  3. Drugs dispense data from pharmacies - every 3 months.  Safety assessment will be completed by:  1. Supporters' weekly documentations.  2. Documentation by treating hepatologists, during ongoing visits. 3.4 Definitions of Study Variables Adherence will be quantified into percentage and will be calculated as the percent of days in which the patient took the prescribed medication out of the number of days the patient was instructed to take the medication by prescription.  3.4.1 Outcomes/Endpoint Variables  Primary endpoint:  Adherence rate will be defined as the percentage of days the patients took their hepatitis B virus medications during study treatment and the number of missed doses. Adherence will be measured as a combination of:  1. Drug dispense at pharmacy (every month)  2. Self report by patient (every week)  3. Pills count (every 3 months)  A responder will be defined as a patient with at least 80% adherence to drug treatment.  Secondary endpoint:  The difference in adherence improvement among 3 types of adherence support  1. Weekly Phone Call + Daily Application Reminder  2. Weekly Phone Call  3. Daily Application Reminder  4 STATISTICAL ANALYSIS 4.1 Statistical Analysis Methods All measured variables and derived parameters will be listed individually and, if appropriate, tabulated by descriptive statistics.  For categorical variables summary tables will be provided giving sample size, absolute and relative frequency and 95% CI (Confidence Interval) for proportions by study arm.  For continuous variables summary tables will be provided giving sample size, arithmetic mean, standard deviation, coefficient of variation (if appropriate), median, minimum and maximum, percentiles and 95% CI (Confidence Interval) by study arm for means of variables.  4.1.1 Primary Objective Responders will be defined as patients with at least 80% adherence to drug treatment. 95% Confidence Interval (95% CI) will be calculated for the rate of responders per study arm (arms 1, 2 and 3).  4.1.2 Secondary Objectives Chi-square test or Fisher's Exact test (as is appropriate) will be applied for testing the statistical significance of the difference in responders rate between study arms 1 (Weekly Phone Call + Daily Application Reminder), 2 (Weekly Phone Call) and 3(Daily Application Reminder) vs. group 4 (no support).  The effect of telephone call will be tested comparing groups 1+2 vs. groups 3+4.  The effect of daily SMS will be tested comparing groups 1+3 vs. group 2+4. Logistic Regression model will be applied for testing the statistical significance of the difference in responders' rate between study arms 1, 2 and 3 vs. group 4 and between the active groups with adjustment to suspected confounders related to study outcome which will be found different between the arms.  Logistic regression will be applied for analyzing the effect of telephone call and daily SMS (as described above) with adjustment to suspected confounders.  All tests will be two-tailed, and a p value of 5% or less will be considered statistically significant.  The data will be analyzed using the SAS ® version 9.1 (SAS Institute, Cary North Carolina).  4.2 Power/Sample Size Rational for Sample size calculation Sample size calculation is based on demonstrating a difference of at least 21% in response rate in the comparison between study arms 1, 2 and 3 vs. group 4. This difference reflects an odds ratio of 0.23 with statistical significance of 5% with statistical power of 80% when the sample size is 252, 63 in each study arm.  Sample Size Justification A two group continuity corrected Chi square test with a 0.050 two-sided significance level will have 80% power to detect the difference between a Group 1 proportion and a Group 2 proportion (odds ratio of 0.231) when the sample size in each group is 64.  Reference: nQuery advisor 2.1  5 STUDY CONDUCT This study will be conducted in accordance with International Society for Pharmacoepidemiology (ISPE) Guidelines for Good Pharmacoepidemiology Practices (GPP) and applicable regulatory requirements.  5.1 Ethics Committee Review and Informed Consent 5.1.1 Ethics Committee Review The investigator must ensure that the required approvals from Ethics Committees, Independent Review Committees, Regulatory Authorities, and/or other local governance bodies are obtained before study initiation at the site.  5.1.2 Informed Consent In accordance with local regulations, subjects should provide either written or oral consent before enrollment into the study. Investigators must ensure that patients, or, in those situations where consent cannot be given by patients, their legally acceptable representatives, are clearly and fully informed about the purpose of the study, potential risks, the patient's rights and responsibilities when participating in this study. If local regulations do not require an informed consent document to be signed by the patient, the site staff should document key elements of the informed consent process in the patient's chart.  This study does not require that informed consent is obtained from patients. 5.2 Responsibilities within the Study The study shall be conducted as described in this approved protocol. All revisions to the protocol must be discussed with, and be prepared by BMS.  5.3 Confidentiality of Study Data The confidentiality of records that could identify patients within the database must be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).  For the purposes of protecting a patient's identity, a unique code will be assigned to each patient, such as a series of numbers and/or letters (for example, CA180330-0001-00001). The data that is recorded with the patient's assigned code is called "key-coded data". Key-coded study data will be managed by the sponsor and/or its delegates in a study-specific electronic database (the "study database"). Only the investigator and the site staff have access to the link between patient's assigned code and the patient's identity. However, in case of an audit or inspection, subject to local laws and regulations, government officials, IRB/EC representatives and sponsor representatives may access this information at the study site. If the study requires on-site monitoring, subject to local laws and regulations, sponsor representatives will also access the primary data source at the study site (see section 6.4). Data that could directly identify the patient will not be collected in the "study database".  5.4 Quality Control Power/Sample Size Representatives of BMS and/or its delegates must be allowed to visit all study site locations to assess the data quality and study integrity. On site, they will review study files and, if allowed by local laws and regulations, patient medical charts to compare them with source documents, discuss the conduct of the study with the investigator, and verify that the facilities remain acceptable.  In addition, the study may be evaluated by BMS internal auditors and government inspectors who must be allowed access to CRFs, source documents, other study files, and study facilities. BMS audit reports will be kept confidential.  The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, and promptly forward copies of inspection reports to BMS.  5.5 Database Retention and Archiving of Study Documents The investigator must retain all study records and source documents for the maximum period required by applicable regulations and guidelines, or institution procedures, or for the period specified by the sponsor, whichever is longer. The investigator must contact BMS prior to destroying any records associated with the study. Location of database and supporting documentation will be outlined in the final observational study report.  6 ADVERSE EVENT REPORTING The INSTITUTION/PRINCIPAL INVESTIGATOR must notify BMS with the related and non-related Serious Adverse Events (SAEs) and/or Pregnancies within 24 hours of becoming aware of the event.  The INVESTIGATOR must notify BMS with the related and non-related non-serious Adverse Events within 7 days of becoming aware of the event.  All Adverse Events and/or Serious Adverse Events must be reported to:  Bristol-Myers Squibb Company Global Pharmacovigilance FAX Number: 609-818-3804 or Email: WorldWide.Safety@bms.com  The INVESTIGATOR must notify BMS with all Adverse Events in aggregate in the Final Study Report (FSR).


This is what 20.0268 looks like:
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The objective of this study is to compare the long-term safety and efficacy of the Ahmed and the Baerveldt implants in patients who are undergoing aqueous shunt implant surgery for glaucoma. Eligible patients will be randomized. Outcome measures include intraocular pressure, visual acuity, visual field, number of glaucoma medications, glaucoma reoperations, and complications, including suprachoroidal hemorrhage, endophthalmitis, choroidal effusion, diplopia, corneal edema, and shunt/tube erosion. Background and Significance  Aqueous shunt devices have traditionally been reserved for treatment of only the most refractory glaucomas. However, more recent studies have reported favorable results in comparison with trabeculectomy in medically uncontrolled glaucomas at lower risk of filtration failure. Consequently, aqueous shunt devices have been used increasingly in glaucoma drainage surgery.  There are two principal designs of implant in common use, the Ahmed glaucoma valve implant (New World Medical, Los Ranchos, CA, USA and the Baerveldt implant (Advanced Medical Optics, Santa Ana, CA, USA).  Having both evolved from the Molteno, the Ahmed and Baerveldt devices have in common a tube portion that drains aqueous humor from the anterior chamber to a plate that is implanted on the equatorial sclera. The size of plate determines the surface area of the drainage bleb.  The Ahmed and Baerveldt implants differ in two major respects. Firstly, the plate surface area of the Baerveldt 350 implant is almost double that of the Ahmed (185 mm2). Secondly, the Ahmed has a flow-restrictor that limits early hypotony without the need for additional external ligation.  We propose a randomized prospective clinical trial comparing the long-term safety and efficacy of the Ahmed glaucoma valve implant (FP-7) with the 350-mm2 Baerveldt implant (101-350) for surgical control of secondary glaucoma and primary glaucoma in eyes that have undergone previous ocular surgery.  Objective  The objective of this study is to compare the long-term safety and efficacy of the Ahmed FP-7 implant and the 350-mm2 Baerveldt implant in patients who are undergoing aqueous shunt implant surgery. Patients who qualify for the study are randomized to receive either an Ahmed FP-7 or Baerveldt BG-101-350 implant.  Outcome discrimination between the two treatment groups will be made using typical measures of visual function (visual acuity and visual field), intraocular pressure, number of glaucoma medications, and glaucoma reoperations. Emphasis will also be placed on complication rates, including suprachoroidal hemorrhage, endophthalmitis, choroidal effusion, diplopia, corneal edema, and shunt/tube erosion.  Assignment  Since the purpose of this study is to compare the safety and efficacy of two surgical procedures used in the management of glaucoma, randomization techniques are used to assure an unbiased treatment assignment to patients.  Stratification:  Patients will be stratified by clinical center. At each Clinical Center, half of the patients will receive an Ahmed and half will receive a Baerveldt implant . Randomization takes place at the time the patient is enrolled in the study after informed consent is obtained.  Randomization:  A permuted variable block randomization scheme stratified by clinical center and type of glaucoma will be performed.  The following scenarios will constitute a failure in the ABC Study for the purposes of survival analysis:  - IOP > 21mmHG or < 6mmHg on 2 consecutive study visits at visits > 3 months  - IOP reduced by < 20% on 2 consecutive study visits at visits > 3 months  - Reoperation for glaucoma  - Loss of light perception vision  - Removal of implant for any reason  Clinical Procedures  Visual Acuity  Visual acuity is an important outcome variable in the ABC Study. Visual acuity is measured before pupil dilation, tonometry, gonioscopy, or any other technique that could affect vision. Refraction is performed prior to formal measurement of visual acuity by either technique at the Qualifying Assessment and at the annual follow-up visits. Snellen visual acuity is measured at the Qualifying Assessment and at every follow-up visit.  Subjective refraction must be performed at the Qualifying Assessment and at the annual follow-up visits in order to determine best-corrected visual acuity. It is permissible to use a phoropter or trial frame to determine best-corrected Snellen visual acuity.  Slit Lamp Biomicroscopy  Examination of the anterior segment using slit lamp biomicroscopy is performed at the Qualifying Assessment to document the preoperative status of the eye, and at all follow-up examinations to detect any changes in ocular status during the course of the study which may be attributable to the disease or treatment. Slit lamp biomicroscopy may be performed with any commercially available instrument, and it is used in a standard fashion starting anteriorly and working posteriorly. Standardizing subjective grading of lenticular opacities is difficult, if not impossible. However, it is expected that subjective grading by each investigator is relatively reproducible. Attempts will be made to compare subjective gradings between investigators.  Conjunctiva:  Eyes are examined carefully for tube or shunt erosion.  Cornea:  The cornea is examined at high magnification to evaluate the epithelium, stroma, and endothelium. The techniques of diffuse illumination, scleral scatter, and retroillumination may be used. Findings consistent with a diagnosis of the iridocorneal endothelial (ICE) syndrome, epithelial downgrowth, or fibrous downgrowth make the eye ineligible for the study. The presence of corneal epithelial or stromal edema is noted. Eyes are examined for the presence of tube-cornea touch.  An assessment is made of the position and length of the tube in the eye.  Anterior Chamber:  Before fluorescein instillation or pupillary dilation, the degree of anterior chamber cell and flare is determined. Eyes with vitreous in the anterior chamber are ineligible for the study if it is anticipated that a vitrectomy will be needed at the time of glaucoma surgery. Careful assessment of the anterior chamber depth is made postoperatively. If the anterior chamber is shallow, the central anterior chamber depth is measured relative to the corneal thickness. The appropriate gradation of > 3 CT, > 2 CT, > 1 CT, < 1 CT, or lens-cornea touch is documented.  Iris:  Before pupillary dilation, the pupillary iris is examined at high magnification for the presence of neovascularization. If rubeosis iridis is present, this should be documented.  Lens:  After pupillary dilation, the investigator assesses the lens and grades any cataract present as mild, moderate, or severe. In pseudophakic eyes, the presence of a posterior chamber or anterior chamber intraocular lens is documented. Aphakic eyes are excluded from the study.  Tonometry  Goldmann applanation tonometry is used to measure the intraocular pressure, except when irregular corneal astigmatism, corneal scarring, or corneal edema precludes accurate readings. In these cases, the Tono-Pen (Mentor) is used. The intraocular pressure is measured prior to pupillary dilation. Whenever possible, the intraocular pressure should be checked at the same time of the day as the Qualifying Assessment to minimize the effect of diurnal fluctuation The Tono-Pen (Mentor) is used in cases of corneal edema, corneal scarring, or irregular corneal astigmatism. The Tono-Pen probe tip is covered with a new Ocu-Film Tip Cover. The instrument is calibrated immediately prior to use, as described in the Mentor Tono-Pen Instruction Manual. The right eye is always tested first. A drop of 0.5% proparacaine is instilled. The patient is positioned in the sitting position and instructed to fix on a distant object. Tight-fitting neckwear is loosened, and the patient is instructed not to hold his or her breath. The Tono-Pen is activated by depressing the activation switch momentarily. The Tono-Pen is brought in contact with the patient's cornea lightly and briefly while holding the instrument perpendicular to the cornea. A click will sound and a digital intraocular pressure measurement will be displayed each time a valid reading is obtained. After four valid readings, a final beep sounds and the averaged measurement appears on the display, along with a single line denoting statistical reliability. Measurements are repeated until two successive readings are obtained within 1 mm Hg and both have a statistical reliability of 5%, indicating that the standard deviation of the valid measurements is 5% or less of the number displayed. The investigator records the last two successive measurements. After testing of the right eye is complete, the same technique is applied to testing of the left eye.  Pachymetry  Aqueous shunt implantation has been implicated in long-term damage to the cornea. In this study the position of the tube will be documented in relation to the cornea and the central corneal thickness monitored throughout the study.  Central corneal thickness will be measured in each eye, by ultrasound pachymetry. A minimum of 5 measurements will be taken and the lowest recorded.  Motility Evaluation  Diplopia is an important complication which may occur following glaucoma drainage implantation. The incidence of permanent restrictive strabismus associated with glaucoma drainage implantation is not precisely known, as this complication has not been studied prospectively. In order to address this issue, a formal motility evaluation is performed in all patients preoperatively and in those patients with diplopia at the 6 month follow-up visit or beyond. In addition, all patients will undergo a motility evaluation at the 1 year and 5 year follow-up visits. Transient diplopia following glaucoma drainage implantation is not uncommon. This study will focus on the incidence and nature of permanent restrictive strabismus associated with the glaucoma drainage implantation.  The cover-uncover and alternate cover tests are performed with the patient looking in primary gaze, as well as in upgaze, downgaze, left gaze, and right gaze. Motility evaluation is performed with the patient looking in the distance.  Any heterophorias or heterotropias are identified, and the deviation is measured with hand-held prisms. In patients who are unable to fixate for cover testing, the deviation may be measured by centering the corneal light reflexes with prism using the modified Krimsky method.  An estimate of restriction of abduction, adduction, elevation and depression of each eye is made using a 0 - 4 empirical grading scale.  Gonioscopy  Gonioscopy is performed with the patient sitting at the slit lamp using either a Zeiss type four-mirror gonioprism or Goldmann single- or three-mirror lens. A preoperative examination of the anterior chamber angle is essential to document neovascularization and peripheral anterior synechiae, to identify the presence of silicone oil in the angle and to identify an appropriate implantation site for the tube.  Ophthalmoscopy  A dilated fundus examination is performed at the Qualifying Assessment to determine the preoperative status of the eye, and at all postoperative follow-up examinations to detect any changes in ocular status produced by the disease or treatment. After pupil dilation with appropriate mydriatics, the optic nerve and posterior pole are examined at the slit lamp using a Hruby lens, fundus contact lens, or Volk 90 diopter, 78 diopter, or 60 diopter lens. A head-mounted indirect ophthalmoscope and hand held condensing lens (20 diopter or 28 diopter Nikon aspheric lens) is used to evaluate the retinal periphery.  At the Qualifying Assessment, particular attention is paid for signs of proliferative retinopathy, including retinal neovascularization, neovascularization of the disc, vitreous hemorrhage, or preretinal hemorrhage. At all postoperative follow-up visits, ophthalmoscopy is performed to evaluate for posterior segment complications, such as serous choroidal effusions, suprachoroidal hemorrhage, or hypotony maculopathy.  Perimetry  Visual field assessment is an important outcome measure in the ABC Study. Quantitative automated perimetry is performed using the Humphrey Field Analyzer. Visual field testing is performed before tonometry, gonioscopy, or any other technique that could affect vision. A visual field should be attempted in any eye that has sufficient vision to permit finger counting at two feet. Eyes with poor central vision may have an intact, off-center island of vision which may be measured with perimetry.  For the ABC Study, a 24-2 threshold test is performed in all patients using a size III white stimulus. Visual field testing may be performed with the Swedish Interactive Thresholding Algorithm (SITA) or full threshold strategy, but the same testing strategy must be used throughout the duration of the study. The pupil diameter should be 3 mm or greater before visual field testing is undertaken, and this may require pharmacologic dilation. Standardized refraction is performed to determine the patient's distance refraction and best-corrected visual acuity prior to visual field testing. The age appropriate plus lens is added to the distance refraction. Patient education is provided, and the instrument is set up for the test. The technician should monitor the patient during testing. Visual fields are performed preoperatively (within one month of enrollment in the study) and annually thereafter. Copies of all visual fields are faxed to the Statistical Coordinating Center for evaluation.  Surgical Procedures  Anesthesia:  The type of anesthesia is at the surgeon's discretion.  Conjunctival Flap:  An Ahmed FP-7 is used in all cases and implantation is performed in the superotemporal quadrant. A limbus-based or fornix-based conjunctival flap may be used depending on the surgeon's preference. Sufficient exposure is obtained in the superotemporal quadrant to permit placement of the Ahmed plate. A corneal traction suture or episcleral traction suture may be used to rotate the globe inferonasally to improve exposure.  Priming the Implant  A 28- or 30- gauge cannula is used to prime the Ahmed valve. Occlusion of the tube with a ligature is not permitted.  Attachment of Episcleral Plate:  The Ahmed plate is sutured to the sclera at a measured distance of 8 - 10 mm posterior to the limbus using the two fixation holes on the plate. The type of nonabsorbable suture used is of the surgeon's choice.  Preparation of Tube:  The tube is trimmed bevel-up to extend 2 to 3 mm into the anterior chamber.  Insertion of Tube into the Anterior Chamber:  A 23-gauge needle is used to enter the anterior chamber at the posterior limbus parallel to the iris plane. The Ahmed tube is inserted through this entry incision and should be well positioned in the anterior chamber away from the corneal endothelium and just above the iris. A 23-gauge needle produces an adequate entry incision for the tube without causing aqueous leakage around the tube.  Coverage of Tube:  A donor patch graft composed of donor sclera, donor cornea, or pericardium is used to cover the limbal portion of the tube. The suture selected to fixate the patch graft is of the surgeon's choice.  Conjunctival Closure:  Tenon's and conjunctiva are reapproximated to the limbus. The suture used for the conjunctival closure is determined by the surgeon in keeping with his or her usual practice.  Optional Viscoelastic Insertion  At the surgeons discretion, a viscoelastic of his or her choice may be inserted into the anterior chamber, especially if the anterior chamber shallows after balanced salt solution is inserted.  Intraoperative Medications:  The use of intraoperative medications is at the surgeon's discretion. Subconjunctival antibiotics and corticosteroids may be injected, and a cycloplegic-mydriatic drop and steroid-antibiotic ointment may be instilled at the conclusion of the case, as determined by the surgeon in keeping with his or her usual practice.  Baerveldt Implantation  Anesthesia:  The type of anesthesia is at the surgeon's discretion.  Conjunctival Flap:  A 350-mm2 Baerveldt is used in all cases and implantation is performed in the superotemporal quadrant. A limbus-based or fornix-based conjunctival flap may be used depending on the surgeon's preference.  Scleral Exposure:  Sufficient exposure is obtained in the superotemporal quadrant to permit placement of the Baerveldt plate. A corneal traction suture or episcleral traction suture may be used to rotate the globe inferonasally and improve exposure.  Insertion of Episcleral Plate:  The 350-mm2 Baerveldt plate may be positioned under or over the superior rectus and lateral rectus muscles, depending on the surgeon's usual practice. The implant is sutured to the sclera at a measured distance of 8 - 10 mm posterior to the limbus using the two fixation holes on the plate. The type of nonabsorbable suture used is of the surgeon's choice.  Occlusion of Tube:  The Baerveldt tube must be completely occluded in all cases in order to restrict aqueous flow to the plate until it becomes encapsulated. This is done to minimize the incidence of postoperative hypotony. The method of tube occlusion is left to the discretion of the surgeon. Ligation of the tube with a polyglactin suture near the tube-plate junction, ligation with a polypropylene suture which is inserted into the anterior chamber with the tube, or internal occlusion of the tube using a "rip-cord" technique have all been used effectively. A 30-gauge cannula is used to cannulate the end of the tube and confirm complete occlusion of the tube. Following tube occlusion, the surgeon may fenestrate the tube if desired. The method of tube fenestration is left to the discretion of the surgeon.  Preparation of Tube:  The tube is trimmed bevel-up to extend 2 to 3 mm into the anterior chamber.  Insertion of Tube into the Anterior Chamber:  A 23-gauge needle is used to enter the anterior chamber at the posterior limbus parallel to the iris plane. The Baerveldt tube is inserted through this entry incision and should be well positioned in the anterior chamber away from the corneal endothelium and just above the iris. A 23-gauge needle produces an adequate entry incision for the tube without causing aqueous leakage around the tube.  Coverage of Tube:  A donor patch graft composed of donor sclera, dura mater, or pericardium is used to cover the limbal portion of the tube. The suture selected to fixate the patch graft is of the surgeon's choice.  Conjunctival Closure:  Tenon's and conjunctiva are reapproximated to the limbus. The suture used for the conjunctival closure is determined by the surgeon in keeping with his or her usual practice.  Intraoperative Medications:  The use of intraoperative medications is at the surgeon's discretion. Subconjunctival antibiotics and corticosteroids may be injected, and a cycloplegic-mydriatic drop and steroid-antibiotic ointment may be instilled at the conclusion of the case, as determined by the surgeon in keeping with his or her usual practice.  Study Organization  Introduction  Multicenter clinical trials require an organizational structure that provides efficient operations and facilitates communication. The following resource centers work together in this study:  - Clinical Centers (CC)  - Statistical Coordinating Center (SCC)  - Safety and Data Monitoring Committee (SDMC)  - Steering Committee (SC)  Clinical Centers:  Each Clinical Center is responsible for screening potential study patients, enrolling an adequate number of eligible patients, and following the patients according to the protocol until the termination of the study. Each CC has one principal investigator. The responsibilities of the Clinical Centers are as follows:  - To assess the eligibility of patients for the ABC Study.  - To enroll an adequate number of patients in the study through informed consent.  - To manage each patient in accordance with the randomized assignment provided by the SCC.  - To examine patients using the techniques and schedules established for the study.  - To complete the proper forms and obtain visual fields and quality of life assessments at the appropriate follow-up visits.  - To respond promptly to requests made by the SCC.  - To maintain patient records for the ABC Study in an easily accessible and confidential manner.  - To obtain approval for the study and consent form from the local Institutional Review Board.  - To promote patient satisfaction and commitment to the trial.  - To provide representation at all meetings of the SC.  Statistical Coordinating Center  The Statistical Coordinating Center is located at the Department of Biostatistics at the Bascom Palmer Eye Institute. The SCC receives, edits, processes, analyzes, and stores all study data. The SCC coordinates the activities at the Clinical Centers and monitors adherence to the study protocol. The responsibilities of the SCC are listed below:  - To provide guidance in the development and implementation of the design of the primary study and ancillary studies.  - To confirm local IRB approval of the study and consent form before initiating participation of a CC.  - To verify eligibility of the patient and completion of the consent form prior to randomization.  - To randomize study patients.  - To review data received, process, and store all study data.  - To produce extensive monitoring reports for the SC and SDMC every six months and upon request.  - To assist in the preparation of manuscripts.  Safety and Data Monitoring Committee  The Safety and Data Monitoring Committee is responsible for the ethical conduct of the study. This committee oversees the informed consent process and major changes in the protocol. The SDMC reviews the accumulating data for evidence of adverse and beneficial treatment effects. This committee meets twice each year for the duration of the study. Telephone conferences will occur as needed. The responsibilities of the SDMC are as follows:  - To review the study design and study documents before the start of the study to identify any problems that may affect future data analysis or patient safety.  - To monitor adherence to the study protocol at each CC.  - To review treatment reports prepared by the SCC for evidence of adverse and beneficial treatment effects.  - To terminate the study if treatment benefits or treatment risks are so high for one treatment group that continuation of the trial is deemed unethical.  - To advise the SC on interpretation of study data.  - To recommend to the SC changes in study protocol based on periodic data analysis.  - To review and approve all publications and presentations.  - To determine when data collected in the study should be released to study investigators, study patients, the medical community, and the public.  Steering Committee  The Steering Committee is composed of the principal investigator from each Clinical Center. The SC provides leadership for the trial. This committee has overall responsibility for directing activities and formulating policy for the study. This committee meets twice each year for the duration of the study. Telephone conferences will occur as needed. The specific functions of the SC are as follows:  - To evaluate and approve operational procedures in the study, including the Manual of Procedures and data forms.  - To change procedures and resolve technical issues during the course of the trial.  - To review study progress and take steps to correct deficiencies, such as patient recruitment, adherence to protocol, or data collection procedures.  - To appoint and disband subcommittees needed for execution of the study.  - To review and approve ancillary studies.  - To collaborate in preparing manuscripts of study findings for publication.  - To review and approve all publications and presentations.  Policy Matters  The Ahmed vs. Baerveldt Comparison (ABC) Study requires that written consent be obtained from each patient enrolled in the study. The patient is requested to sign the consent form only after patient education is completed. The signed consent form is kept with the study records at the Clinical Center. A copy of the signed consent is given to the patient, and a second copy is sent to the Statistical Coordinating Center.  The principal investigator of each Clinical Center is responsible for obtaining approval for the study and consent form from the local Institutional Review Board. A copy of each Clinical Center's approved consent and documentation of IRB approval must be submitted to the Statistical Coordinating Center prior to beginning patient enrollment in the study. A copy of the consent form approved by the Institutional Review Board for the University of Miami School of Medicine and the Western IRB is provided in the investigator pack.  Policy of Confidentiality  Materials distributed for Steering Committee and Safety and Data Monitoring Committee meetings are confidential. Minutes from all study meetings are confidential. Access to a participant's record by any unauthorized individual is prohibited. Tabulations or listings which reveal the identity of individual study participants are confidential.  Clinical Center Procedures  Qualifying Assessment  The Qualifying Assessment establishes whether the patient satisfies ABC Study eligibility criteria. If the patient appears to be eligible for the study, the Clinical Center completes the Qualifying Assessment Form and Preoperative Form. Both forms are faxed to the Statistical Coordinating Center, along with a copy of the consent form. Informed consent is an eligibility criterion because it is an agreement by the patient to be randomized and complete follow-up in their treatment group. The SCC reviews each of the inclusion and exclusion criteria to ensure that the patient is eligible. It is vital to the scientific validity of the study that every eligible patient be offered enrollment.  Assignment of Patient Identification Number  Any patient who is confirmed by the Statistical Coordinating Center to meet the eligibility criteria and is enrolled in the study is assigned a patient identification number. The SCC provides a list of patient identification numbers to each Clinical Center. The patient identification number is a six digit, three letter code which is unique for each patient.  Randomization Procedure  Randomization takes place at the time the patient is enrolled in the study. After patient eligibility is confirmed and a patient identification number is provided, the Statistical Coordinating Center assigns treatment by saying, "Ahmed implant" or "Baerveldt implant". The Clinical Center then repeats the assigned treatment. The surgery date is the study entry date, and the dates for all postoperative follow-up visits are computed from this date.  The randomization schedule is constructed using a computer pseudo-random number generator. The allocation ratio is equal between the two treatment groups. The randomization is blocked by clinic and study stratum using a variable block design. This procedure ensures that there is an equal number of patients in each treatment group even early in the trial, and that the CC is not able to predict the next treatment assignment.  Schedule of Visits  All study investigators must be familiar with the schedule of visits to ensure that required data is collected and that future visits are scheduled within the appropriate time windows. The need for continued follow-up and timely visits should be stressed to the patient during the informed consent process and throughout the study. An appointment schedule is generated for each patient by the Statistical Coordinating Center and sent to the patient's Clinical Center. Time windows for follow-up visits are shown in Table 1. Table 2 summarizes the required data at each of the scheduled visits.  Statistical Coordinating Center Procedures  A master log is kept of each patient randomized in the ABC Study. An appointment schedule is made for each patient and sent to the patient's Clinical Center. When a data form is received at the Statistical Coordinating Center, it is processed for filing and data entry. Each form is data entered by a data entry clerk and then verified by double entry by the SCC Research Coordinator. Edit checks, such as missing data and out-of-range values, will be clarified within the CC.  The statistical package SPSS is used for data entry, management, and analysis. Each of the study's two statisticians has a personal computer and one more is dedicated to data entry. The Research Coordinator also has a personal computer to use for data management, study correspondence, reports, and manuscripts. Each computer, except the one dedicated to data entry, has access to the University of Miami's network for e-mail, Internet access, and data file transfer.  Data Security  The paper data forms for the ABC Study are kept in file cabinets in the Biostatistics facility in the McKnight Research Building. The building is locked and access is by card key entry. A security guard is present during working hours. The computer files for the study are kept on computers in the same location. These rooms are kept locked when not in use, and the study computer files are password-protected. The data is backed up weekly, and monthly backups are stored at a remote facility. Computer data files used for publication are saved and stored as separate files.  Data Forms  The data forms were designed to be self-explanatory. Their completion should not require reference to separate information manuals. The data forms contain information to be collected at a given point in time during the study. Information collected at another date is incorporated into a separate form. Data forms are faxed to the Statistical Coordinating Center for data entry. Forms will be reviewed periodically and revised as dictated by protocol changes. The various data forms are provided at the end of this section.


This is what 21.1676 looks like:
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The most important cause of mortality amongst DM2 patients is cardiovascular disease. An early finding of cardiovascular disease in DM2 and obesity is diastolic dysfunction. Diastolic dysfunction is an independent predictor of mortality and has been shown to improve in patients on a low calorie diet. The improvement of diastolic function was associated with a reduction in triglyceride accumulation in the heart and liver. A relatively new widely prescribed therapeutic agent for DM2 patients is Liraglutide (Victoza®). Liraglutide is a Glucagon Like Peptide - 1 homologue that improves glucose homeostasis and reduces blood pressure and body weight. Next to the induction of weight loss, which is potentially beneficial for cardiac function, GLP-1 therapy might have a direct advantageous effect on the cardiovascular system. However, the effect of Liraglutide on cardiovascular function has not been investigated yet. The investigators hypothesize that treatment of DM2 patients with Liraglutide is associated with improvement of cardiovascular function and a reduction of triglyceride accumulation in end-organs. 1. INTRODUCTION AND RATIONALE  Type 2 diabetes mellitus is an endemic disease associated with obesity and a sedentary lifestyle. In the year 2025 the prevalence of DM2 patients worldwide is expected to be 334 million. In the year 2000 there were an estimated 2,9 million diabetes-related deaths worldwide. Especially cardiovascular disease contributes for a great deal to the high mortality rates. Diabetes patients have a two-fold excess risk for a wide range of vascular diseases, independently of other risk factors, making cardiovascular disease the leading cause of death of diabetes patients. Therefore, treatment of DM2 is focused on the prevention of cardiovascular disease and other diabetes related complications such as retinopathy, neuropathy and nephropathy. Unfortunately, despite lifestyle advises, glucose lowering therapy and co-treatment of other risk factors such as hypertension and dyslipidemia, complication rates remain high. Classical glucose lowering treatment strategies such as sulfonylurea derivatives and insulin ultimately can not control the disease, partly because they participate in the vicious cycle of increasing body weight and insulin resistance. A hopeful new therapeutic agent is the Glucagon Like Peptide -1 analogue Liraglutide. Next to its glucose lowering effect, it reduces body weight resulting in increased insulin sensitivity. The group of GLP-1 analogues are therefore widely prescribed nowadays. However, the effect on the cardiovascular system has not been investigated yet. Since cardiovascular disease is the major threat for the DM2 patient, the effect of this new drug on the cardiovascular system is a very important issue. Interestingly, a cardio-protective effect from Liraglutide can be expected on the basis of both the associated weight loss and because of a direct protective effect on the heart. The investigators hypothesize that treatment with Liraglutide improves cardiac function in DM2 patients. The pathogenesis of cardiovascular disease in DM2 is rather complex and multifactorial. Ultimately most patients develop myocardial infarction and / or heart failure. Often DM2 patients already have subclinical signs of cardiac dysfunction before DM2 is recognized, the main early sign being diastolic dysfunction. Diastolic dysfunction is a strong predictor of mortality. The subclinical characteristics of cardiac dysfunction are highly associated with a condition called the metabolic syndrome. The metabolic syndrome consists of the existence of three out of five of the following risk factors: 1. elevated waist circumference; 2. elevated triglycerides; 3. reduced HDL-C; 4. elevated blood pressure; 5. elevated fasting blood glucose including diabetic-range elevated blood glucose level. With these criteria most patients with diabetes meet the criteria for the metabolic syndrome. A key element in the pathogenesis of the metabolic syndrome might be ectopic fat deposition; the earliest sign of the syndrome being visceral adiposity. Next to visceral adiposity, there is significant deposition of ectopic fat stores in the liver, heart, skeletal muscle and kidney. Triglyceride accumulation in the cardiomyocyte is called myocardial steatosis. Studies performed by our group have proven that caloric restriction results in a reduction in myocardial steatosis and improvement of diastolic function. Hence, myocardial steatosis and associated cardiac dysfunction seem to be reversible as is the case for hepatic steatosis. The putative mechanism of steatosis resulting in cardiac dysfunction is thought to be explained by a phenomenon called lipotoxicity. Altered substrate metabolism and insulin resistance of cardiomyocytes may also play an important role in the pathogenesis of cardiac dysfunction in obesity and DM2. Systemic and cardiac insulin resistance was proven to be associated with increased production of toxic lipids such as diacylglycerol and ceramide. The ultimate treatment for obesity and diabetes related cardiac disease seems to be weight loss. However, lifestyle intervention programs have repeatedly been unsuccessful to have a sustained long term effect. Liraglutide is characterized as a long-acting, human GLP-1 analogue as it shows 97% homology with the amino acid sequence of human GLP-1. The phase 3a program for Liraglutide encompasses five clinical trials in which Liraglutide treatment was studied in each stage of the treatment cascade for type 2 diabetes mellitus. In five studies, Liraglutide was compared directly to standard treatment. The phase 3a clinical development program, included 3,978 exposed patients with DM2, investigated the efficacy and tolerability of Liraglutide 1.2 or 1.8 mg daily (n = 2735) as monotherapy and in combination with various oral antidiabetic drugs. The phase 3a studies showed HBA1C reductions of 1-1.5% and fasting plasma glucose reductions of 0,83 - 2,39 mmol/L. In addition, weight reduction was consistent: Liraglutide 1.8 mg as monotherapy was accompanied by a mean weight loss of 2.5 kg over a 52-week period. A substudy of two phase 3a trials showed that the weight loss caused by Liraglutide, is predominantly caused by a reduction in fat mass; the visceral fat compartment was reduced by 16% from baseline during 26 weeks of Liraglutide 1,2 mg daily. Recent experimental data suggest GLP-1 and its analogues to have direct effects on the heart. In studies on rat heart, the size of an infarct was diminished by more than 50% by an infusion of GLP-1. Post conditioning efficacy of GLP-1 was also demonstrated in an ex vivo rat heart. Exendin-4 was shown to diminish infarct size by approximately 56% and 39%, respectively, in rat global and pig focal models of heart ischemia. The GLP-1 receptor (GLP-1R) is present in the cardiomyocytes as well as in the endothelium and smooth muscle cells of myocardial vasculature. The cell death effector mechanisms targeted by the GLP-1R appear to be mitochondrial permeability transition and apoptosis. Animal studies have suggested myocardial contractility improvement after GLP-1 administration. For instance, dogs with dilated cardiomyopathy treated with GLP-1 for 48 h showed strong improvements in myocardial contractility and cardiac output. GLP-1 infusion was associated with increased myocardial glucose uptake, suggesting ameliorated insulin sensitivity of the cardiomyocytes. In a few small clinical studies, GLP-1 was infused to patients after PCI for approximately 72 h and to patients selected for elective coronary artery bypass grafting from 12 h before to 48 h after the surgery. The latter group showed an improved metabolic profile but no hemodynamic change. In contrast, a left ventricular ejection fraction (LVEF) increase from 29% to 39% was found in the former study, as well as in a study of 12 diabetic, overweight heart failure patients (New York Heart Association class III/IV, LVEF ≤ 40%), given GLP-1 infusion for 5 weeks: at the end of the treatment, these patients showed an increased LVEF, cardiac output, and improved scores in a life quality questionnaire. A number of laboratory studies have suggested a vasorelaxant effect of GLP-1. No pressor effect has been found associated with GLP-1 treatment in studies on diabetic patients. In fact, a decrease of both systolic and diastolic blood pressure values was noted in DM2 patients after an 82-week exenatide trial [33], in a manner correlated to weight loss. Recent experiments (unpublished data) have shown that the GLP-1 analogue exendin - 4 can protect against atherosclerosis and non-alcoholic steatohepatitis (NASH) in APOE 3 - Leiden.CETP mice on a western diet probably due to decreased hepatic CETP expression as well as reduced monocyte recruitment from the circulation to the vessel wall. In addition, hepatic steatosis was improved by a GLP-1 receptor agonist in mice. So far, no dedicated clinical studies have been performed to systematically study the effects of GLP-1 analogues on cardiovascular function. Given the consistency of the results from animal experiments and clinical observations, this area appears ripe for clinical studies. Beneficial effects on cardiovascular endpoints will be crucial to consolidate the therapeutic profile of Liraglutide. Although large scale studies on cardiovascular endpoints are underway, an attractive option is to perform small scale, short-term studies with advanced cardiovascular imaging techniques. Thereby gaining insight in what way GLP-1 therapy affects the cardiovascular system. Advanced cardiovascular magnetic resonance imaging and spectroscopy (MRI/S) enables to assess effects of interventions, in relatively small groups of patients in a limited period of time. As these cardiovascular parameters are strong and clinically relevant predictors of cardiovascular events, measurements of these parameters with MRI/S are worthwhile. Our research group has developed advanced cardiovascular MRI and MRS techniques and algorithms and gained extended experience in the field of DM2 related cardiac function and lipid metabolism.  2. RECRUITMENT AND SCREENING PROCEDURE OF STUDY POPULATION  Patients will be recruited from the outpatient clinics of the Leiden University Medical Center, general practitioners, local hospitals and by advertisement. Patients own physicists will be asked to point eligible patients to the opportunity of study participation. If interested, patients will be informed by the principal investigator. Patients will be given oral and written explanati¬on about the study. After a consideration time of two weeks, patients are asked to give written acknowl¬edgement of informed consent to participate. Then a medical screening will take place. Screening will be performed after an overnight fast of at least 12 hours. The screening will consist of a medical history, physical examination consisting of measurement of height, body weight, heart rate, blood pressure and examination of thorax and abdomen. Furthermore laboratory tests and rest-ECG will be performed. If the patient is eligible- and willing to participate in the study, and has signed the informed consent, the patient will be included. Informed consent must be obtained before any trial related activities take place. After inclusion in the study protocol, the patient's treating physician and general practitioner will be notified. Alt¬hough the patients are free to leave the study at any time, it will be attempted to recruit patients who are likely to continue the study to completion.  3. SAMPLE SIZE CALCULATION  Because of the absence of data on the effects of GLP-1 in DM2 patients without heart failure, it is hard to calculate the sample size needed to detect differences between myocardial function at 26 weeks between active treatment and controls. Clinically relevant differences and standard deviations of two studies were chosen to generate data for the sample size calculation. The data we used to incorporate the precision of MRI assessment of cardiac function was generated by a study performed by our group with pioglitazone vs metformin on cardiac function parameters. To estimate the effect of GLP-1 therapy on cardiac function, we only have data of a pilot study with eight DM2 patients with heart failure. Calculations for diastolic function parameters were based on the "early deceleration peak" and for systolic function on the basis of "ejection fraction". With a power of 90% and alfa = 0.05, groups varying from 9 to 17 patients will be needed. In a comparable trial the drop-out rate was 10%. Taken into consideration that the population studied will have a significant better systolic function than the heart failure patients studied by Sokos et al, differences may be smaller. In conclusion, investigators estimate to be able to detect a clinically relevant, significant result with 90% power and alfa = 0.05 with 25 patients in each group.  4. USE OF CO-INTERVENTION  Patients should continue to use the oral glucose lowering medicament metformin during the study. For glycaemic control after initiation of the study drug, the current clinical guideline will be followed. However when glycaemic control is lost and insulin is needed, patients will be withdrawn from the study.  Excluded concomitant therapy: Insulin, thiazolidinediones, other GLP-1 analogues or DPP-IV inhibitors, fibrates, prednisone, cytostatic and antiretroviral therapy.  Permitted concomitant medication: any other medication required, including antihypertensive agents and incidental analgesic and antibiotic therapy.  Given the risk of hypoglycaemia, patients will be instructed how to recognize and manage a hypoglycaemic episode. Routine measurement of blood glucose by the study participants themselves will be necessary once a week.  Furthermore patients are asked not to change their diet or level of physical activity during the study period and adequate contraception is obligatory for study participation.  5. RANDOMISATION, BLINDING AND TREATMENT ALLOCATION  After the medical screening and mutual agreement of participation in the study, patients will be randomised by block randomisation, stratified 1:1 for gender. A randomisation schedule will be prepared by the research pharmacist who is employee at the Department of Clinical Pharmacy. Coded and sealed envelopes for each participant will be kept at the department of Radiology. In case of safety issues, the sealed envelopes are readily available to the principal investigator and project leader. In case of a serious adverse event - or a medical emergency requiring knowledge of the study medication - the randomisation code will be broken. In order to ensure that in medical emergencies, the study participation of the patient is apparent, each patient will receive a patient file in the electronic patient registry. In this personal file, the study number of the patient including the procedure for deblinding and notification of the investigators will be mentioned. When the whole study is completed the randomisation list will be provided to the principle investigator by the pharmacist.  6. STUDY PROCEDURES  Withdrawal of individual subjects: Patients can leave the study at any time for any reason if they wish to do so without any consequences. The responsible investigator can also withdraw a subject if continuing participation is in his opinion deleterious for the subject's well being. Patients can also be withdrawn in case of protocol violations and non-compliance. When a subject withdraws from the study, a medical examination will be performed. In case of withdrawal because of a severe or serious adverse event, appropriate laboratory tests or other special examinations will be performed. Finally patients can be withdrawn from study participation if an incidental finding at the MRI examination - for example a malignancy - influences the ratio of justification versus risks / benefits.  Specific criteria for withdrawal: Loss of glycemic control: if hyperglycemia persists despite maximum dosage of metformin and allowed concomitant medication, the patient will be withdrawn from study participation. Specific criteria can not be given, as the need for concomitant medication is dependent not only on blood sugar levels, but also on the patient's general condition, age, the capability of prevention of dehydration, etcetera. The decision of withdrawal will be made by the principal investigator in concordance with the project leader and other responsible investigators and on the basis of the clinical parameters.  Replacement of individual subjects after withdrawal: Patients will not be replaced after withdrawal.  Follow-up of subjects withdrawn from treatment: Follow-up of patients after withdrawal will be done by the treating physicist (general practitioner in most cases). Immediately after study withdrawal, the treating physicist will be updated on the patient's condition and laboratory results and whether the patient was in the control group or intervention group.  Premature termination of the study: In case of the incidence of three serious adverse events, the study will be terminated prematurely and an independent committee will be asked to investigate the safety of the trial. Furthermore, the investigators will prematurely terminate the study when the number of subjects withdrawn from the study exceeds the number used for sample size calculation, i.e. 16 individuals in total.  7. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS and SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS  Adverse events (AEs):  Adverse events are defined as any undesirable experience occurring to a subject during a clinical trial, whether or not considered related to the used medication or the infused drugs. All adverse events reported spontaneously by the subject or observed by the investigator or his/her staff will be recorded on the adverse event data collection form. The intensity of these adverse events will be graded by the investigator as follows:  - Mild: Discomfort noted but no disruption of normal daily activity  - Moderate: Discomfort sufficient to reduce or affect normal daily activity  - Severe: Inability to work or perform daily activity All adverse events will be actively queried by asking the question: "Have you had any complaints since the last time we talked/met?" at all visits. All adverse events will be followed until they have abated, or until a stable situation has been reached. Depending on the event, follow up may require additional tests or medical procedures as indicated.  The chronicity of the event will be classified by the investigator on a three-item scale as defined below:  - Single occasion: Single event with limited duration  - Intermittent: Several episodes of an event, each of limited duration  - Persistent: Event that remains indefinitely For each adverse event, the relationship to the used medication or infused drug (definite, probable, possible, unknown, definitively not) as judged by the investigator, will be recorded, as well as any actions undertaken in relation to the adverse event, will be recorded. The occurrence of an adverse event that is fatal, life-threatening, disabling or requires in-patient hospitalization, or causes congenital anomaly, will be described according to CHMP guidelines as (suspected) "serious" adverse events and will be notified in writing to the Medical Ethics Committee.  Furthermore, the investigators will copy Novo Nordisk when expediting SARs and SUSARs to competent authorities and will report all SARs related to Novo Nordisk product to Novo Nordisk. The submission to Novo Nordisk must however be within day 15 from the investigator getting knowledge about a valid case no matter local timelines for reporting to the authorities. All pregnancies in trial patients occurring during use of a Novo Nordisk product must be reported to Novo Nordisk.  Serious Adverse Events (SAEs):  A serious adverse event is any untoward medical occurrence or effect that at any dose:  - results in death;  - is life threatening (at the time of the event);  - requires hospitalisation or prolongation of existing inpatients' hospitalisation;  - results in persistent or significant disability or incapacity;  - is a congenital anomaly or birth defect;  - Any other important medical event that may not result in death, be life threatening, or require hospitalization, may be considered a serious adverse experience when, based upon appropriate medical judgement, the event may jeopardize the subject or may require an intervention to prevent one of the outcomes listed above.  The sponsor will report the SAEs to the accredited METC that approved the protocol, within 15 days after the sponsor has first knowledge of the serious adverse reactions.  SAEs that result in death or are life threatening should be reported expedited. The expedited reporting will occur not later than 7 days after the responsible investigator has first knowledge of the adverse reaction. This is for a preliminary report with another 8 days for completion of the report.  Suspected Unexpected Serious Adverse Reactions (SUSARs):  Unexpected adverse reactions are SUSARs if the following three conditions are met:  1. the event must be serious  2. there must be a certain degree of probability that the event is a harmful and an undesirable reaction to the medicinal product under investigation, regardless of the administered dose;  3. the adverse reaction must be unexpected, that is to say, the nature and severity of the adverse reaction are not in agreement with the product information as recorded in:  - Summary of Product Characteristics (SPC) for an authorised medicinal product;  - Investigator's Brochure for an unauthorised medicinal product. The sponsor will report expedited all SUSARs to the competent authorities in other Member States, according to the requirements of the Member States.  The expedited reporting will occur not later than 15 days after the sponsor has first knowledge of the adverse reactions. For fatal or life threatening cases the term will be maximal 7 days for a preliminary report with another 8 days for completion of the report.  SAEs need to be reported till end of study within the Netherlands, as defined in the protocol  8. STATISTICAL ANALYSIS  Primary and secondary study parameters:  The study endpoints will be analyzed according to intention-to-treat principles. All endpoint parameters are continuous variables. Data will be calculated as mean SD, median (percentile range) according to nature and distribution of the variable. Within group changes from baseline will be tested with independent paired t-test or Wilcoxon signed-rank test. Between group differences will be compared after 26 weeks between Liraglutide and control. The endpoints will be analyzed using a linear regression model, with gender, age, BMI and HBA1C as covariates. For the covariates age, BMI and HbA1c in the primary analysis the baseline value will be used. The dataset for the primary analysis will include data from all subjects with at least one post-baseline measurement. Analysis will be performed with SPSS. A 2-sided significance level of p < 0.05 will be applied.  9 REGULATION STATEMENT  The study will be conducted according to the principles of the "Declaration of Helsinki" (as amended in Tokyo, Venice and Hong Kong, Somerset West and Edinburgh) and in accordance with the Guideline for Good Clinical Practice (CPMP/ICH/135/95 - 17th July 1996).  10. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION  Handling and storage of data and documents:  Study participants are provided a study name of the letter "MV" followed by the number of enrolment (1-50). The study name is coupled to a randomly chosen seven - digit study number. The study number will be used to register the participant in the Electronic Patient Registry of the LUMC. This file will be used as the general patient record, as well as collection of routine laboratory measurements needed for clinical and study treatment. The MRI images will be filed under this registry so that anonymity will be safeguarded. The subject identification code list will be stored by the principal investigator and will only be accessible by the principal investigator and project leader. The data extracted from the study file in the Electronic Patient Registry and from the MRI images will be saved in an SPSS file. From this file the true identity of the study participants can not be discovered. The data will be stored for fifteen years. The blood samples will be frozen and stored anonymously using the above mentioned study name and study number. For ad hoc laboratory tests of inflammatory, endocrine and other biomarkers, blood samples will be kept for a maximum period of three years. The blood samples are solely accessible by the investigator team.  In order to ensure that in medical emergencies, the study participation of the patient is apparent, each patient will receive a patient file in the electronic patient registry. In this personal file, the investigator will mention the study number of the patient including the procedure for de-blinding and notification of the investigators. In this file, the signed Informed Consent form of the patient will be stored.  Public disclosure and publication policy: The data analysis will be performed by the investigators. Novo Nordisk has no role in data analysis and / or publication of the results of the trial in peer reviewed papers. The results of the study will be submitted to peer reviewed papers, also in case the hypothesis has not been proven.


This is what 22.2441 looks like:
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With the increasing rates of child obesity and diabetes, innovative programs are needed that capture children's attention and permit behavior change messages to get through. Serious video games with their immersive stories offer one such promising alternative. "Escape from Diab" and "Nanoswarm: Invasion from Inner Space" are two video games guided in their design by four behavior change theories that were targeted at increasing fruit, vegetable and water intakes, and lowering sedentary behaviors, and have been shown to change these children's diet and physical activity practices in a pilot study with a relatively low risk sample. In light of this preliminary success, it is important to test the efficacy of these interventions on diabetes risks (i.e. fasting insulin) with higher risk children (which should increase the effect) and with a larger sample to learn how the games change behaviors using mediating variable analyses. A study with 444 high risk (85%tile<BMI<99%tile) 10 to 12 year old children is proposed. Children will be randomly assigned to treatment or control groups. The control group will be a wait-list control and receive the intervention at the end of the second post assessment. Video games are a promising low cost approach to intervention since the games have already been developed, and can be broadly disseminated by simply reproducing and distributing their DVDs. No study has appeared that tested the effects of theory based video games on diet and physical activity that was adequately powered to investigate mediating variables. Conducting the mediating variable analyses will inform the design of future video games and enhance their ability to promote health behavior change. While using video games for health promotion is controversial, this study will establish whether video games efficaciously change diabetes risks (especially insulin, diet and physical activity) among children. Youth obesity has risen dramatically over the past few decades. While most child obesity prevention programs have had little or no effect, serious video games offer promise of effective behavior change by immersing children in a story that engages them in behavior change procedures inserted in the game. "Escape from Diab" and "Nanoswarm: Invasion from Inner Space," (hereinafter called Diab and Nano), two epic video games designed to lower risks of T2D and obesity from these theory based procedures, changed diet behaviors in a small pilot trial in a lower risk group of children (see Approach). This project is to conduct an efficacy trial of Diab and Nano. Since change interventions have had effects primarily among the overweight and obese, implementing these video games in higher risk groups should attain larger effects. To assess their potential for minimizing T2D and obesity risk, the investigators will assess dietary intakes and PA. Glucose levels are tightly regulated (not likely amenable to change by a public health intervention), and impacting BMI requires a long duration intervention, but fasting insulin has been responsive over shorter intervals. Thus, the investigators will target decreasing fasting insulin as the primary outcome, both as reducing an important indicator of type 2 diabetes risk and as an objective indicator of behavior change. To assess mechanisms, this study will be powered to test for mediation effects.  The proposed research will be conducted in two phases, covering a 3 year period: implementation and evaluation phase of 2.5 years and an analysis phase of 0.5 years.  Specific Aim 1: Conduct an efficacy outcome evaluation randomized clinical trial with Diab and Nano.  Specific Aim 2: Conduct analyses of the efficacy evaluation of Diab and Nano.  The hypotheses to be tested include:  Hypothesis 1: Children playing Diab and Nano will decrease fasting insulin by, at least, 2μU/dl, increase FV intake by at least 1.0 servings/day, and increase MVPA by at least 10 min/day from baseline to up to 3 months post baseline.  Hypothesis 2: Child diet, MVPA and fasting insulin changes from playing Diab and Nano will not be moderated by demographic characteristics (e.g. gender, age, ethnic group).  Hypothesis 3: Child fasting insulin change will be mediated by changes in diet, PA and SB.  Hypothesis 4: Child diet and PA change outcomes will be mediated by changes in preferences and intrinsic motivation for FV and PA.  Research Strategy Approach Methods  1. Specific Aim 1. Conduct an efficacy trial with Diab and Nano. Data will be collected to test the efficacy of Diab and Nano on FV intake, PA, and type 2 diabetes risks. The effects on mediating, and of moderating, variables will be examined to explain the pathways of effect to enhance understanding of how serious videogames influence behavior change and it's maintenance.  1.1. Research Design. This efficacy trial will be conducted using a two group design (treatment (trt), control (ctl)) with randomization to group occurring after baseline assessment (to obviate observer bias), and three assessment periods (baseline, up to 3 months post baseline (immediate post) and 2 months post immediate post). There will be no assessment between games because the investigators' pilot indicated differences emerged only after both games were played. Parents and their children will come to the CNRC at each assessment point for measurement. Two weeks are allowed for each assessment period to permit obtaining the multiple days of diet and physical activity measurement. A two month follow up was selected because in the investigators' experience this is the longest period over which it is likely to detect behavior change maintenance post intervention and the analyses should emphasize predicting behavior change maintenance. The investigators are allowing for a three month intervention period. The briefest possible time to complete one of these games is 3 weeks each, or 6 weeks total (1.5 months). For example, during each session the child sets goals to change specific behaviors at specific meals/times on specific forthcoming days. These goals are distributed across one to five days after a session (depending on number of goal days and days selected by the child). The longest it would take a child to complete a game while likely retaining their immersion in the game story would be 45 days per game or 3 months. The database retains a record of sessions completed and goals attained to provide child feedback. Project staff will call the children if they did not complete a session within 2 days after an expected play date as indicated by email messages automatically sent at the completion of a session. We will schedule immediate post assessment for the treatment groups at the end of 18 completed sessions, and schedule control either at the end of completed sessions or 3 months (whichever comes first). Randomization to group will be achieved by sequentially entering names into a list with sequential positions on the list randomly assigned to group from a random number generator. Before study recruitment begins, 444 sequential IDs will be created and attached to a random number following a uniform distribution within a (0,1) interval generated in SAS by the study statistician. Each ID will have the same probability of being assigned any number within the interval. The IDs associated with the lowest and highest 222 random numbers will be assigned to the treatment and control groups, respectively.  1.2. Control Intervention. A wait list control group will be employed. Control group children will receive the intervention at the end of the 2 month post assessment.  1.3. Recruitment and Screening. The primary tool for recruiting children to participate in this project will be radio advertisements that target ethnic minority communities (African-American, Hispanic) with parents of children in the targeted age groups. The investigators have ample successful experience using this recruitment channel. Houston is the center of a large diverse metropolitan area of 5.6 million people (4th largest city in the US), approximately 15% of whom are African American, and 45% Hispanic. This is amply large to provide the sample needed. Listeners will be given a telephone number to call. A bilingual professional CNRC participant recruiter (Marilyn Navarrete) will receive those calls, answer questions, conduct a preliminary screen for target child: age, child speaks English, height, weight, brief medical history, access to a computer and the internet, and willingness to provide a blood sample, answer questions on the phone about diet, and wear an accelerometer for multiple days. Children passing the screen, or for whom passing is not clear, will be forwarded to a project staff who will answer any further parent questions, complete preliminary screening and schedule an appointment for baseline assessment. As back up, children will be recruited from a variety of other sources, including the CNRC participant data base (with names, ages, demographics and contact information on over 9800 children whose parents have indicated interest in their child participating in CNRC research projects), posters and fliers distributed around the Texas Medical Center (with over 95,000 employees), press release announcements by Baylor College of Medicine and presentations to area schools (public and private). The investigators recruited over 1600 children to participate in a PROP taste sensitivity epidemiology study using combinations of these methods, recruited 153 10-12 yo children for the pilot study, and have recruited thousands of other children across a broad variety of studies. To minimize barriers to participation, the child's transportation to and from each of the assessments will be paid by the grant, if necessary.  1.4. Cohort maintenance and tracking procedures for longitudinal study. Data will be collected in 25 waves of 17 or 18 children each. The waves are interdigitated to permit continuous use of staff for data collection. (The data collection team included in this budget can efficiently handle this number of participants, with overlap between waves.) Investigators will make every effort to obtain all data from each child in the 25 waves. At the baseline assessment, the investigators will obtain participant name, address, phone number, email address, and the name and phone number of two individuals likely to know how to contact the participant (in case of moving, etc). At each subsequent parent data collection period, this information will be updated. Reminder phone calls will be made and letters with "address correction requested" will be mailed out, if necessary, prior to follow up observations. Graduated monetary incentives will be provided to youth and parents who participate in each measurement. Flyers will also be mailed to the home address of record. If these techniques do not enable us to maintain contact with the family, the alternative contact individuals identified at the beginning of the study will be contacted. If this does not work, the investigators will submit the parent's name and address to a "FIND ANYBODY" website, where people can be located at minimal cost. All known avenues will be exhausted to contact the family to participate in follow up data collection activities. This comprehensive strategy should enable the investigators to maximize participation maintenance throughout the study.  1.5. Sample Size and Power. Intention to treat procedures will be followed. Based on standard deviations from previous studies, the standardized effects (differences/standard deviation) to be detected are 0.80 (MVPA), 0.78 (FV), and 0.02 (fasting insulin). Given a repeated measures analysis of covariance to control for baseline measures, one between groups factor (intervention, control), one within subjects factor (post 1, post 2), a correlation over time of 0.10, an alpha of 0.05, and 80% power, 400 participants are needed to detect a small standardized effect (=0.2). For the remaining hypotheses, power and sample size requirements are based on path analyses. Because of model complexity, there is no set standard for calculating sample size for structural equation/path models. Therefore, the sample size needed to assess the moderation and longitudinal mediation is based on (1) the rule of thumb, (2) the framework for power in covariance structure modeling, and (3) Monte Carlo simulation. It is recommended that there are 10-20 cases per estimated parameter, for realistic and ideal conditions, respectively. Given regression paths, variances, correlations, and auto-correlations, a model at three time points with two mediators, one outcome, and an intervention effect would have 36 parameter estimates. A final sample of 400 just exceeds the minimum 10:1 case-parameter ratio. Using MacCallum's SAS power analysis for covariance structures, a sample of 400, 10 variables, and 22 degrees of freedom, would provide 80% power to provide significant support for a model yielding good fit. The Monte Carlo simulation used 10,000 repetitions, 400 participants, normally distributed data, 10 variables (plus intervention by demographic interactions), and all path estimates in the hypothesized direction (magnitudes=0.17). Given acceptable (<5%) parameter and standard error bias and acceptable (0.91-0.98) coverage, the range of power for path estimates were 0.84-0.97. Given an anticipated 10% sample attrition over the 7 months of participation in the trial (based on experience), the investigators inflated the recruited sample to 444.  1.6. Intervention Implementation. Children will play the game at home. Each intervention child will be provided with a manual and emailed a download address. The child can email or call the project office if problems develop. A project intervention coordinator will be fully trained in how to implement the project, identify and correct common technical difficulties, and collect and manage data. The intervention coordinator will attend to and answer the emails and phone calls. The intervention coordinator will monitor game completion and inform data collection staff when children can be scheduled for immediate post game data collection. Each game session should take about 45 to 60 minutes to complete with an ability to go back and replay some of the mini-games.  1.7. Quality Assurance of the Intervention. During implementation of the efficacy trial, the intervention coordinator will monitor child use of game by organizing and reviewing email messages each time a child completes a session, answer call-in questions, repair minor malfunctions of hardware or software system, arrange for speedy repair of larger malfunctions, and record all the above.  1.8. Child data collection procedure. Project data collection staff will be blinded to group. For data collected on PDAs or iPads, children will be logged into the PDA using a user name and password; questions will appear on the screen one at a time, and participant will be prompted to select an answer. Program will not progress until an answer has been selected, which minimizes, if not effectively eliminates, missing values. Actual names and corresponding user names, passwords, and codes will be stored in a separate location to maintain confidentiality. Some process evaluation data (e.g. log on rates, progression through game, time spent on certain activities, goal attainment) will be automatically collected during the intervention and emailed to a secure central server at the end of each session. Other process evaluation data will be collected and maintained by interviewers. Three 24hrDR will be conducted using ASA24-Kids, web-based dietary data collection software. Accepted procedures will be followed. To optimize use of trained data collectors and equipment (e.g. accelerometers) children will participate in 25 groups/cohorts/waves of approximately 17-18 children each staggered over 2.5 years. The importance of these waves are to continuously use highly trained staff over long time intervals while insuring minimal overlap in use of limited equipment (e.g. accelerometers, PDAs). These time intervals are not precise. Some children will finish gameplay before the time allowed, and brought in for data collection out of sync with the wave to ensure that immediate post data collection occurs soon after game-play. Seasonal and other holidays will lengthen some of these time intervals. Unanticipated, yet not unexpected, cataclysmic events, e.g. hurricanes, other severe weather, will also play havoc with neatly planned schedules. The investigators have allowed some flexibility in anticipation of such events. Starting each wave with 18 children provides enough flexibility in time at the end to allow us to complete data collection for this trial and thoroughly conduct data editing and analyses.  1.9. Parent data collection procedure. Parent data will be collected by PDAs and questionnaires, where necessary, in English or Spanish. Parents will select their preferred language prior to baseline. To maintain confidentiality, parents will be assigned a unique user number. The master list of actual and user names will be kept in a locked room at CNRC.  1.10. Incentives. Incentives will be provided for child participation in data collection. Graduated incentives are utilized to enhance the likelihood youth and parents will participate in all data collection points. Because of the required blood draws, child incentives are: $60 for baseline assessment; $65 for immediate post assessment; and $70 for 2-month follow up. Participants will receive a healthy snack in light of their needing to fast prior to data collection. Parents/legal guardians will also receive graduated incentives for participating in interviews as follows: $20 for the immediate post-intervention questionnaire and $25 for the 2-month post questionnaire.  2. Measures. Outcome variables are those which should change as a result of the intervention. Mediating variables are those which provide component mechanisms by which the intervention produces its outcome: changes in mediating variables should be correlated with changes in outcome. Moderating variables are those for which the outcomes may vary. Confounding variables minimize the desired differences across the experimental conditions. Process evaluation determines whether the intervention was delivered and worked as designed.  2.1. Blood Related Variables. Since several intervention studies have impacted diabetes risk factors, but not any of the various derivatives of ht and wt, the investigators believe it is important to measure both fasting insulin and glucose. Since fasting glucose is tightly regulated the investigators do not expect to impact it, but we will monitor it. Several studies have had beneficial impact on fasting insulin including the recently completed HEALTHY study for which the investigators were a participating site.  2.2. FV Intake. Food frequency questionnaires (FFQ) are a standard method of diet assessment among adults. FFQs, however, have demonstrated problems in reliability of assessment among children 10-12 years.  2.3. Physical Activity. Physical activity will be assessed using the latest Actigraph GT3X accelerometer.  2.4. Anthropometrics. Body mass index (BMI; kg/m2) is the national criterion for the definition of overweight and obese among children and adolescents. Participant's height will be measured to the nearest 0.1 cm twice using a stadiometer (Shorr Height Measuring Board; Olney, MD) and the mean of the two recordings calculated. Body weight will be measured to the nearest 0.1 kg twice using a calibrated scale (Seca Research Model scales; Vogel and Halke, Hamburg, Germany) and the mean of the two recordings calculated. BMI will then be computed as well as the participants' age and gender specific BMI z-score which will be obtained from the CDC web site. Waist circumference will be assessed using a Figure Finder tape (Novel Products, Inc., Rockton, IL), because central adiposity has been independently associated with an increased risk of developing the metabolic syndrome. Triceps skinfold will be assessed, using a Lange caliper, since it correlated highest with DEXA assessed percent body fat. Standardized procedures for assessing these variables twice during each measurement period with the mean of the two recordings used in analyses will be used. To assess inter-rater reliability a second, independent data collector (not aware of the initial assessments) will repeat ten percent of all measurements.  2.5. FV, W preferences, self efficacy, and intrinsic motivation. Preferences, self efficacy, and intrinsic motivation are the most commonly reported significant influences on dietary intake. Preferences are the extent to which a person enjoys eating a group of foods. Self efficacy is the confidence one has in being able to overcome barriers to doing a behavior. Intrinsic motivation is the extent to which someone does a behavior to please oneself versus please others. Items to assess preferences, self efficacy, and outcome expectations for the targeted behavior change (increasing FV consumption to five or more servings and W to eight servings a day) will be obtained from measures developed and tested by this team.  2.6. PA Psychosocial Variables. Similar to diet, PA preferences/enjoyment, self efficacy, intrinsic motivation and home equipment availability have been demonstrated to influence children's physical activity, and will be assessed in this study.  2.7. Energy Balance Knowledge. The investigators are developing a measure of Energy Balance Knowledge. Energy Balance is a complex set of ideas requiring a person/child to know that foods are sources of calories; physical activities burn calories; different levels of calories are associated with different food intakes and portion sizes; calories expended are associated with different kinds of activities, intensity of effort and duration; the level of calories at balance for the respondent; etc. The investigators are developing items and honing the tool to make it appropriate for 10-12 year old children.  2.8. Transportation/immersion/liking. Transportation (also called "immersion") is "a distinct mental process, an integrative melding of attention, imagery and feeling", which can "draw" people into a story, "lose" themselves, or capture their complete attention. Immersion should enhance a participant's attention to the behavior change procedures inserted in the game. Recent work has led to new validated measures of immersion in game play. This is a 33 item questionnaire with a 5 category response scale from strongly disagree to strongly agree. In addition, standard questions used in the pilot trial in regard to whether the children liked the game will be employed. All these questions will be applied to each game.  2.9. Social desirability. Social desirability of response reflects giving answers that are socially acceptable or expected and has been observed in regards to self-report in both adults and children, including the investigators' pilot study. Because this may bias responses, thereby affecting the validity of the study, it will be assessed using the 9-item "Lie Scale" from the Revised Children's Manifest Anxiety Scale, which has a yes/no response format, and "lie" score determined by summing the "yes" responses. The instrument has shown good reliability and validity in children across a variety of ethnic groups, including the pilot study. This instrument will be programmed into the PDA and completed at baseline by the students.  2.10. Demographics. Parents will be asked to provide marital status, current employment status, race/ethnicity, number of children living in the home, highest educational level in household, and annual household income, as part of the informed consent form.  2.11. Parent reported Home FV availability and accessibility. A strong predictor of consumption of FV in the home is whether FV are in the home and easily accessible. The investigators GIMME 5 curriculum changed home FV availability; validity correlations of parent report with home observations were high (r=0.55).  2.12. Process Evaluation. A thorough process evaluation for each component of the intervention will be conducted. Process evaluation concerns the documentation of delivery of a program, factors that influence its delivery and factors resulting from program delivery. The investigators will assess: recruitment of participants, maintenance of participation, context of implementation, implementation (fidelity and dose), reach, barriers to implementation, exposure to program, initial use of program materials/tasks, continued use of the program, materials/tasks, and contamination. Much of the implementation and exposure assessments will be documented using web collected data records of Diab and Nano components. Diab and Nano have been programmed to automatically monitor and record log on and goals attained, as youth navigate and play the game. The process data will be emailed to the Intervention Coordinator after each session and stored in the project data base.  3. Specific Aim 2. Conduct analyses of the efficacy evaluation of Diab and Nano. 3.1. Data management. Code books will be created for all variables. Electronic data files will be created in which to enter and store data using latest available software. Any data entered by hand will be double entered and reviewed to minimize data entry errors. Data sets will be backed up nightly on the BCM secure server. Any hard copies of data generated by this study will be kept in a locked room at CNRC.  3.2. Partial or missing data. The longitudinal analysis models in this proposal handle available-data analyses. Available-data methods are more efficient because they incorporate the partial information obtained from those who dropout. During statistical analysis, the issue of missing data will be addressed. The investigators will apply imputation procedures for the missing responses following dropout, such as multiple imputation, in which each missing value is replaced with several plausible values. Several statistical procedures are now available to address issues related to missing or partial data. Little's likelihood ratio test will be used to test whether the data are missing completely at random.  3.3. Testing Hypotheses. Field and range checks will be conducted. Distributional characteristics will be assessed and outliers checked. Prior to inferential procedures, extensive descriptive statistical analyses of the outcome and predictor variables will be conducted. Standard descriptive statistics including means, standard deviations, ranges, box plots, histograms, and frequencies will be calculated where appropriate. Normalizing transformations will be explored as appropriate. Bivariate association will be evaluated using Pearson correlations (or Spearmann correlations, depending on distributional characteristics), scatter plots and contingency tables. Tests will be conducted of differences between those included vs. excluded, treatment vs. control, and those completing all data collection and those not. Analyses and presentation of data will be in accordance with the CONSORT guidelines with the primary comparative analysis being conducted on an intention-to-treat basis with due emphasis placed on confidence intervals for the between arm comparisons. Descriptive statistics will be used to ascertain imbalance between arms at baseline. A mixed model approach to account for the repeated measures among children will be conducted to test hypothesis 1: (H1) Children playing Diab and Nano will increase their FV intake by at least 1.0 servings/day, increase MVPA by at least 10 min/day, and decrease fasting insulin by 2 μU/dl, as compared to the control group. The mixed model will allow for investigating the correlation of the repeated measures over time. The model will contain time, a within subjects factor (post 1, post 2), and study group, a between subjects factor (intervention, control), and control for the baseline outcome. Separate models will be used for each set of dependent variables (fasting insulin, FV intake, PA). The analysis of variance portion of the model will contain main effects for time and group, as well as a time by group interaction. A significant group main effect will indicate a difference in the outcome after the intervention. The model will control for potential confounding variables (e.g., demographic characteristics, duration of game play, immersion, number of sessions completed). A longitudinal path model will be used to test hypotheses 2, 3, and 4: (H2) Child diet, MVPA and fasting insulin changes from playing Diab and Nano will not be moderated by demographic characteristics. To test this hypothesis, interactions of demographic characteristics (gender, age, ethnic/racial groups, SES) with group will be included in a longitudinal mediation model. The magnitude of moderation will be determined from the standardized regression coefficient. (H3) Child fasting insulin change will be mediated by changes in diet and PA. (H4) Child diet and PA change will be mediated by changes in preferences and outcome expectancies for FV and PA. Path models, a special case of structural equation models, utilize a series of steps to test the mediational processes that involve tests of added components, omitted paths, and assumption of stationarity (levels of the variable remain unchanged over time), as well as estimating the effects of the mediators. Because of the longitudinal model, the autoregressive effects are modeled as lags where baseline measures are predictors of post 1 measures and post 1 measures are predictors of post 2 measures, thus the temporal order is preserved. The ultimate goal is to identify the most parsimonious model that exhibits acceptable fit, evaluated using the same indication as for general structural equation models. Because there is no one standard for determining the fit of the model, a range of fit statistics, based on Hu and Bentler's criteria, will be used to assess model fit. The indicators and acceptable criteria include: the model chi-square goodness of fit (with a p value > 0.15), the root mean square error of approximation (with a value <0.05 indicative of good fit and <0.08 of acceptable fit), the comparative fit index and the non-normed fit index (with >.90 indicating acceptable fit). Because the model fit indices are influenced by sample size, the values of the standardized residuals (< 2.58 acceptable), the proportion of variance explained by the indicators, and model modification indices will also be used to evaluate the fit of the model. To assess mediation, the total, direct, and indirect effects of the intervention on the outcome will be evaluated. To test the statistical significance of the mediation with three time points, only the indirect effect of the intervention on the outcome at post 2 through the mediators at post 2 will be used to assess the mediated changes in FV and PA. Because of the sample size and model complexity, mediation analyses will be conducted for FV and PA separately.  4. Timeline. The proposed research will encompass 3 years, divided into two phases: implementation (2.5 yrs), and analysis (0.5 yrs). Although any individual's experience in the project will cover approximately 7 months (including a maximum of 3 months for game play), the investigators will need to efficiently use staff and equipment by using a rolling enrollment across 2.5 years and allow for data analysis in last half year.


This is what 23.1096 looks like:
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Cutaneous leishmaniasis is a worldwide disease, endemic in 88 countries, that has shown an increasing incidence over the last two decades. So far, pentavalent antimony compounds have been considered the treatment of choice, with a percentage of cure of about 85%. However, the high efficacy of these drugs is counteracted by their many disadvantages and adverse events. Previous studies have shown nitric oxide to be a potential alternative treatment when administered topically with no serious adverse events. However, due to the unstable nitric oxide release, the topical donors needed to be applied frequently, making the adherence to the treatment difficult. The electrospinning technique has allowed the production of a multilayer transdermal patch that produces a continuous and stable nitric oxide release. The main objective of this study is to evaluate this novel nitric oxide topical donor for the treatment of cutaneous leishmaniasis.  A double-blind, randomized, double-masked, placebo-controlled clinical trial, including 620 patients from endemic areas for leishmaniasis in Colombia was designed to investigate whether this patch is as effective as meglumine antimoniate for the treatment of cutaneous leishmaniasis but with less adverse events. Subjects with ulcers characteristic of cutaneous leishmaniasis will be medically evaluated and laboratory tests and parasitological confirmation performed. After checking the inclusion/exclusion criteria, the patients will be randomly assigned to one of two groups. During 20 days Group 1 will receive simultaneously meglumine antimoniate and placebo of nitric oxide patches while Group 2 will receive placebo of meglumine antimoniate and active nitric oxide patches. During the treatment visits, the medications will be administered daily and the presence of adverse events assessed. During the follow-up, the research group will visit the patients at days 21, 45, 90 and 180. The healing process of the ulcer, the health of the participants, recidivisms and/or reinfection will also be assessed. The evolution of the ulcers will be photographically registered. In the case that the effectiveness of the patches is demonstrated, a novel and safe therapeutic alternative for one of the most important public health problems in many countries will be available to patients. BACKGROUND  Cutaneous Leishmaniasis (CL) is a worldwide disease that is endemic in 88 countries [1] . It is estimated that 1.5 million people suffer from CL annually and that more than 350 million are at risk of contracting the infection [2-4]. In America, 60,000 new cases of CL are reported annually [5], being endemic in 20 of its 22 countries and in 2 islands of the Caribbean [2]. Currently, CL has affected more than 500 U.S. Army soldiers serving in Iraq [6]. In the Andean region, the incidence of Leishmaniasis has been increasing dramatically over the last two decades; reaching more than 14,000 cases per year from 1996-98 [7]. In Colombia 6,500 cases have been reported [8]. The increase in the reported cases of CL in Colombia has been related to factors such as migration, deforestation, the multiplication of illicit plantations, the armed political conflict and the behavioral changes of the vector. The main strains of Leishmania in Colombia are L. panamensis, L. brazilensis, L. infantum and L. guyanensis, which are distributed throughout the entire national territory, predominantly in the rural areas [10]. CL is caused by intracellular protozoan parasites of the genus Leishmania [1] and is transmitted to humans through the bite of a small percentage of the species of phlebotomus and lutzomyia sandflies classified to date [10]. In the digestive system of the sandflies, this dimorphic parasite presents an extracellular flagellated form called a promastigote, which upon its release in the host blood, is phagocytized by the macrophage, losing its flagella and turning into an amastigote [12]. Dogs, rodents and didelphidae are the natural hosts of the parasite while man is an incidental host [11]. This zoonosis has suffered an interesting urbanization phenomenon, changing from an eminent rural entity affecting mainly men of an active age, to a disease that is affecting all people, especially children [8,9]. The characteristic lesions of this disease are ulcers that heal spontaneously over a period of three months to a year, depending on the isolate, and that leave a flat, atrophic and depigmented scar [13-15]. The CL, especially the one produced by L. brazilensis can evolve into mucocutaneous Leishmaniasis (MCL), which has a worse prognosis owing to the deforming character of its lesions [16]. The spontaneous cure of these lesions allows for the acquisition of partial resistance to reinfection, which could explain the higher pathogenicity observed in the children and young adult population [9]. Previous studies have shown a higher incidence of CL and a poor response to treatment in the children population [17]. The program of epidemiological vigilance in Colombia requires that the probable cases of CL (identified by ulcer features and by the patient's origin) be confirmed by microscopic direct examination of a secession sample obtained from the ulcer, if these are negative, by biopsy of the wound. Once confirmed, the cases must be notified to the Local Health Secretary using clinical-epidemiological records. This institution, in charge of the epidemiological vigilance, studies the sources of transmission and distributes the medication to the people affected. Currently, various aspects are considered when treating CL, among which, the risk of developing MCL, the grade, localization, number, size, evolution and persistence of the lesions, are the most important [18]. For more than 60 years, the pentavalent antimony compounds: sodium stibogluconate, (Pentostan®, produced by Glaxo-Wellcome) and meglumine antimoniate, (Glucantime®, produced by Sanofi-Aventis) have been considered the treatments of choice for this disease [19]. Studies made in Colombia reported a percentage of cure of 85%, using meglumine antimoniate [20,21]. Despite the fact that the efficacy of these drugs is high, they present many disadvantages such as parenteral administration, and, reversible secondary effects such as nausea, vomiting, muscular and abdominal pain, cardiac problems, a rise in the concentration of hepatic aminotransferases, and chemical pancreatitis [21,22]. Additionally, the adherence to the treatment is affected by its duration (several weeks) and its availability by the restriction in its distribution. Therapeutic alternatives of second line have been proposed; amphotericin B and pentamidine have been used with excellent results, nevertheless their high cost, little availability, the necessity to hospitalize the patients for their administration and the severity of their secondary effects have limited their use [23,24]. In the last decade new treatments for CL have been developed, using oral agents such as mefloquine, itraconazole, miltefosine, paromomycin, ketoconazole, allopurinol and dapsone, however, they have not shown enough evidence of their effectiveness [19,21,25,26]. In an effort to develop a topical treatment for CL, paromomycin has been used in different preparations. However, rates of curation achieved with this medication have not been higher than conventional treatments, even when compared with placebo [27,28]. In several studies, in vitro and in vivo, it has been demonstrated that nitric oxide (NO) is effective to eliminate various strains of Leishmania in its amastigote form [29-35]. The production of NO from the oxidation of L-arginine caused by the inducible nitric oxide synthase (iNOS) constitutes one of the most important defense mechanisms of the macrophages [36], in which two oxidative forms of defense against Leishmania have been identified. During the first phase of infection, in response to the phagocytosis process, some promastigotes are eliminated due to the release of the superoxide ion, a process which is catalyzed by the NADPH oxidase [29]. Those promastigotes that survive this defense mechanism evolve into amastigotes, activating the production of IL-12 in the macrophages and promoting the presentation of the antigens of Leishmania [29] to the T helpers 1 lymphocytes that enhance the cytotoxic activities of the macrophages toward the intracellular parasites via the interferon gamma (INFγ) and the tumor necrosis factor alpha (TNFα) by promoting the production of NO catalyzed by iNOS [31-33]. A recent study shows a higher activity of iNOS in the macrophages of subjects infected with CL, suggesting a vital role of NO in the immunological activity against Leishmania [34]. In Studies with rodents resistant to Leishmania infection (C57BL/6), where L. major, L. chagasi or L. donovani were inoculated, the application of iNOS inhibitors like NG-monomethyl-L-arginine (L-NMMA) caused a higher rate of survival and virulence of the parasites in macrophages [33,35,37,38]. After inoculating L. major in mice with the genetic susceptibility to develop infections with Leishmania (BALB/C), no activity of iNOS was observed. However, the application of IL-12, was able to control the infection by activating iNOS [31]. In humans, several clinical trials have been realized with topical treatments containing NO donors [39,40]. In Ecuador, our group developed and tested a NO generating topical cream with S-nitroso-N-acetylpenicillamine (SNAP), evidencing a beneficial effect in the management of this type of ulcers with no reports of any serious adverse event. Nevertheless, due to the unstable nitric oxide release, the cream had to be applied frequently (4 times a day) making the adherence to the treatment difficult [39]. In Syria, another group used potassium nitrate acidified with salicylic acid and ascorbic acid for the topical treatment of L. tropica [40]. In vitro, this NO generating mixture destroyed the amastigotes and promastigotes of Leishmania; however, in vivo, the study of 40 patients presented inconsistent results, reducing the size of the ulcer in 28% of the subjects and healing only 12%. The discrepancy in these results is believed to be due to the technique used to obtain the NO. The acidification of nitrite produces an instant blast of NO, but its release is not maintained over a long period of time [40]. The difficulty of controlling the liberation of NO has created the necessity of looking for new techniques to regulate its release. The nanofiber polymers produced by the electrospinning technique have been studied in order to guarantee the constant release of pharmaceuticals on the lesion. In the electrospinning process, a high voltage is used to create an electrically charged jet of polymer solution, which dries and solidifies to leave behind a dry polymer fiber [41]. As this jet travels through the air, the solvent evaporates leaving behind a charged fiber that can be electrically deflected and collected on a metal screen [42,43]. Fibers with a variety of cross sectional shapes and sizes are produced from different polymers. With this technique, the encapsulation or entrapment of several pharmaceuticals, enzymes and proteins has been successful. In a previous study, nanofiber patches were successfully used as releasing vehicles of tetracycline hydrochloride. The release of tetracycline was constant for a period of 5 days [41;43]. Using the same model, a multilayer transdermal patch has been produced, in which nitrite is bound to an ion exchange resin (DOWEX) and electrospun into a polyurethane nanofibers layer. A solution containing Waterlock® superabsorbent and polyurethane is electrospun on top of the nitrite-DOWEX layer. The ascorbic acid entrapped in the polyurethane solution is electrospun onto a third layer, with another layer of Waterlock® superabsorbent and polyurethane as the fourth and final one. Upon hydration, this Nitric Oxide Releasing Patch (NOP) produces a stable release of 3.5 µmol of NO during 12 hrs [41,44,45]. In a pilot study, developed in Landazuri, Santander, Colombia, a placebo-controlled clinical trial was conducted with 35 patients who presented 68 ulcers produced by L. panamensis. Using the NOP, a 65% improvement was observed in the treated ulcers, with only a 25% improvement in the placebo group (p=0.001). In this pilot study the unique adverse event described was pruritus in the area where the patch was applied (unpublished data). Taking into account the wide distribution of CL, the changes in its form of transmission and the difficulty related with the availability of medication, this study proposes to investigate whether the NO donor transdermal patch, produced by electrospinning is, at least, as effective as the meglumine antimoniate for the treatment of CL, with less adverse events and a lower cost, constituting therefore an effective therapeutic alternative. In case that the effectiveness of the NOP is demonstrated in this study, a novel and safe therapeutic alternative of easy access and higher adherence for one of the most important public health problems in our country will be made available.  OBJECTIVES  General Objective  To evaluate the effectiveness and safety of NOP in the treatment of CL compared with meglumine antimoniate (Glucantime®).  Specific objectives  1. To evaluate the healing rate of CL ulcers using a NOP compared with the plan of treatment with meglumine antimoniate recommended by the health ministry.  2. To identify adverse events associated with the application of NOP and compare them with the ones produced by the treatment with meglumine antimoniate.  3. To identify and compare the recidivisms that may occur with both NOP and meglumine antimoniate.  4. To advance in the search of a therapeutic alternative for CL in Colombia.  DESIGN  Double blind, randomized, double-masked, placebo-controlled clinical trial, comparing nitric oxide releasing patches with meglumine antimoniate.  SAMPLE SIZE  The sample was calculated according to the arccosine formula using a power of 80% and a type 1 error of 0.05%. Assigning a successful rate of 85% for meglumine antimoniate and 75% for NOP, 558 patients will be needed. After adjustment for a loss rate of 5%, the total of patients that must be recruited is 620 (310 patients per treatment group).  POPULATION  The population will be composed from two regions of Colombia. The first one is an endemic zone in Santander, Colombia, located between the Magdalena Valley and the East Mountain Range, which includes the municipalities of Landazuri, El Carmen, San Vicente, El Playon and Rionegro. The second region is an endemic zone in North Tolima, which includes the municipalities of Chaparral, San Antonio, Libano, Falan, Palocabildo and Mariquita.  SELECTION OF THE PATIENTS  Inclusion Criteria  1. Men and women between 18 and 50 years old  2. Cutaneous ulcers of more than two weeks of evolution  3. Positive parasitological diagnosis for CL  4. Patients that voluntarily agree to participate in the study and sign the informed consent.  5. Disposition to attend all the visits punctually (initial, treatment and follow-up)  6. Acceptation of not using any other treatment for CL while in the study  Exclusion Criteria  1. Pregnant women  2. Presence of any condition or disease that compromises the patient immunologically (i.e. diabetes, cancer, etc.) or, any other, that, based on the judgment of the researcher, could alter the course of CL.  3. Diffuse CL or more than five active lesions.  4. Mucocutaneous leishmaniasis (no lesion must be located less than 2 cm from the nasal, uro-genital, and/or anal mucous membranes or from the edge of the lips).  5. Visceral leishmaniasis  6. Complete or incomplete treatment with antimony compounds in the last three months.  7. Patients with history of hepatic, renal or cardiovascular disease.  8. Mentally or neurologically disabled patients that are considered not fit to approve their participation in the study.  STUDY DEVELOPMENT  Logistic Phase  This phase will last 4 months and will include the following activities:  1. Training of the personnel that will participate in the study.  2. Acquisition of the materials required for the development of the project.  3. Elaboration of flyers, promotional and educative material, procedures manual and case report forms (CRFs).  4. Treatment randomization. The treatment randomization will be realized by the epidemiologist of the Cardiovascular Foundation of Colombia. This randomization will be done in blocks in order to keep the size of the treatment groups similar, to avoid long sequences of the same treatment and to balance when possible some of the bias inherent to the simple randomization process. Additionally, this randomization in blocks will facilitate the execution of interim analyses.  Recruitment Phase  This phase will take 22 months. In the selected municipalities, the health personnel that work in hospitals and health centers will receive training regarding the disease and the study methodology. Simultaneously an epidemiological focus study will be done with the leaders of the community and the health personnel to identify the geographic and demographic conditions with the purpose of developing strategies for the recruitment of possible cases of leishmaniasis. Subsequently, the subjects that present active ulcers with more than 2 weeks of evolution, with or without parasitological confirmation of CL, will be invited by the health promoters to attend the screening visit (Table 1).  Screening Visit  During this visit a complete clinical history will be elaborated and data about antecedents of leishmaniasis obtained (administered treatment, localization, number of lesions, etc). A full medical evaluation will be realized based on universally accepted techniques. The inclusion/exclusion criteria will be applied and the selected candidates informed about the study after which they will sign an informed consent. For those subjects with ulcers of more than two weeks of evolution without parasitological diagnosis a direct test will be performed by the parasitologist. If the first direct test is negative, it will be repeated up to three times; after which, in case of negative results, a biopsy will be performed. In case leishmaniasis is not confirmed the patient will be remitted to the original health center.  Initial Visit  The included patients will be randomly assigned in one of two groups. A culture in Novy-Nicole-McNeal (NNN) medium will be taken for strain identification and a blood sample withdrawn from the antecubital vein for hepatic enzymes, creatinine, and pancreatic amylase determination. During this visit, a complete medical evaluation will be performed, the ulcer will be measured and a picture will be taken. Before taking the picture, a graduated rule will be placed next to the ulcer along with a sticker marked with the identification code of the participant, and the date of the visit. The first NOP (active or placebo) will be applied covering the lesion and the first shot of meglumine antimoniate (active or placebo) administered. The patients will receive information on how not to damage the patches and how to identify and report adverse events. To help the patients to do so, they will receive a diary to register them. The two groups randomly composed will be divided as follows:  Group 1: During 20 days this group will receive simultaneously intramuscular (IM) meglumine antimoniate (Glucantime® 20 mg/kg/day with a maximum dose of 3 ampules per day); and a NOP placebo.  Group 2: During 20 days this group will receive simultaneously placebo of IM meglumine antimoniate (5-15cc/day) and an active NOP.  Treatment Visits  The patients will visit the health center daily during 20 days to receive both the NOP (placebo or active) and meglumine antimoniate (placebo or active). Daily, the subjects and their adherence to the treatment will be assessed and the data collected. If any adverse event is detected, the patient will be referred immediately to the medical staff who will make an evaluation and report it to the adverse event committee that will take the final decision in each case.  Follow-up visits  This phase will last 10 months. During the follow-up, the patients will be seen by the research group in 4 opportunities. The first visit will take place the day after the end of the treatment (day 21) in which new blood samples will be taken for biochemical determinations. The second, third and fourth visits will be realized on day 45, 90 and 180 respectively. During these visits the healing process of the ulcer, the presence of recidivisms and/or reinfection and the health of the participants will be assessed. The evolution of the ulcers will be photographically registered.  The maximum and minimum diameters of the ulcer will be measured using a graduated ruler, and the induration using the ballpoint pen technique. The ulcer and induration areas will be calculated separately, and then registered in the CRF. The evaluation of the clinical response will be based on the ulcer showing the least improvement.  1. Complete clinical response: Complete reepithelization of the ulcer and disappearance of the induration.  2. Clinical Improvement: Reduction of more than 50% of the ulcer and the induration areas in relation to the last clinical evaluation.  3. Absence of clinical response: Increase or reduction of less than 50% of the ulcer and the induration areas in relation to the last clinical evaluation.  4. Therapeutic failure:  1. Increase in the size of the ulcer by more than 50% in relation to the last clinical evaluation  2. Presence of the ulcer three months after the beginning of the treatment.  3. Reactivation: Appearance of a lesion on the edge or in the center of the scar, with positive parasitological diagnosis, after a period of complete reepithelization.  4. Affection of the mucous membranes: Presence of affections of the mucous membranes during the treatment, at the end of it or in the follow-up visits.  5. Reinfection: Activation of an ulcer in an area different from the original lesion.  For subjects whose treatment will have been considered a failure the code will be broken and they will be remitted to their original health center to look for another therapeutic approach.  Procedures  Physical Examination  A complete physical examination will be realized and vital signs will be measured.  Blood Samples Withdrawn  Blood samples will be withdrawn from the antecubital vein to perform the following biochemical analyses:  1. Creatinine by spectrophotometry  2. Alanine transaminase (ALT) by spectrophotometry  3. Aspartate transaminase (AST) by spectrophotometry  4. Pancreatic amylase by spectrophotometry  Sampling Technique for the Direct Test of CL  A direct test is performed to confirm the presence of cells with amastigotes in a dermis scrape[46,47]; the sample must be, in so far as it is possible, free of blood, cellular detritus or pus. If the patients present several lesions, the sample must be taken from the one with the shortest time of evolution, the biggest induration area and/or the least purulent discharge. If the lesion has a scab it must be removed to improve the quality of the sample. The sample can be taken from the active edge or from the bottom of the ulcer. When the sample is taken from the active edge asepsis must be realized with alcohol at 70% and hemostasis then performed using the first and second fingers to make sure that there is no blood in the sample. A small incision of about 3mm in length and depth is made with a scalpel in the active edge parallel to the edge of the ulcer. With the sharp side of the scalpel, a scrape is done in the dermic wall of the incision to obtain tissue. The extracted material is extended on two microscope slides. The sample is dried at room temperature, and then fixed with methanol and stained with Giemsa, Wright or Field. Using immersion oil the sample is observed under a microscope with a 100X lens, the presence of amastigotes of Leishmania assessed and their structure verified (nucleus, kinetoplast and cell membrane). If the sample is taken from the center of the lesion the same hemostatic technique must be used, the scab removed, and the bottom of the ulcer well cleaned using the sharp side of the scalpel to prevent the presence of cellular detritus and/or purulent material. This procedure must be continued until the granulomas are seen at the bottom. With the same technique used to process the samples from the active edge the presence of amastigotes of Leishmania is verified.  Technique for the sampling of cultures  The sample for the culture may be obtained by suctioning the ulcer active edge or by extracting a fragment of tissue which is then macerated in a phosphate-buffered saline solution (PBS) with antibiotics (1000 UI of crystalline penicillin per cc), before it is put in the culture medium. A tuberculin syringe with a thin needle (26G), containing 0.3 cc of PBS solution with antibiotics is used in the suction technique. Previous asepsis of the ulcer with alcohol at 70%, a needle is introduced into the dermis and through rotating movements a small amount of tissue is macerated by the needle bevel during about a minute, after which it is suctioned into the syringe. The sample is deposited in aseptic conditions into a NNN culture medium and incubated at 26ºC during 4 weeks [46,47]. Every week a drop is extracted from the culture medium and placed between two slides to be observed under a microscope. In case that promastigotes are not found, the cultures are rejected as negative [46]. The strains are identified by species using the monoclonal antibodies developed by Dr. Diane Mc Mahon Pratt [48,49].  Evaluation and management of adverse events  During the treatment and the follow-up visits, the patients will be asked about adverse events. Each adverse event will be classified by the physician as serious or non-serious(Table 2 and 3). A serious adverse event should meet one or more of the following criteria:  1. Death  2. Life-threatening (i.e., immediate risk of death)  3. In-patient hospitalization or prolongation of existing hospitalization  4. Persistent or significant disability/incapacity The presence of a serious adverse event that puts the patient's life at risk and/or requires immediate medical or surgical procedure will call for the discontinuation of the treatment and the initiation of the pertinent medical management of the patients. The investigator will notify the Adverse Event Committee (AEC) of the FCV of any serious adverse event within 24 hours of learning about it.  A non serious adverse event will be classified as follows:  1. Mild: The patients are aware of their symptoms and/or signs, but those are tolerable. They do not require medical intervention or specific treatment.  2. Moderate: Patients present troubles that interfere with their daily activities. They require medical intervention or specific treatment.  3. Severe: The patients are unable to work or to attend their daily activities. They require medical intervention or specific treatment.  The possible relationship between the adverse events and the tested medication will be classified by the investigator on the basis of his/her clinical judgment and the following definitions:  1. Definitely related: Event can be fully explained by the administration of the tested medication.  2. Probably related: Event is most likely to be explained by the administration of the tested medication rather than other medications or by the patient's clinical state.  3. Possibly related: Event may be explained by the administration of the tested medication or other medications or by the patient's clinical state.  4. Not related: Event is most likely to be explained by the patient's clinical state or other medications, rather than the tested one.  All the events will be reported to the AEC that, depending on their criteria, will decide for the continuity or the withdrawal of the patient from the study and therefore the breaking of the code.  Although the project has been designed to minimize the inherent risks, any adverse event related to the study medications will be carefully evaluated by the AEC and the costs generated by the required treatment will be covered by the study.  Data analysis phase  This phase will last 6 months. After completing all the data entry to the CFR, the results will be audited and the detected errors evaluated and corrected by the person in charge. The information will be entered in two different databases by two different people and the records will be compared to detect any discrepancy. The original CFR will be used to correct any mistake in the database.  For the statistical analysis, Stata 8.0 will be used. The descriptive analysis will be composed of medians and proportions according to the nature of the variables, with its respective 95% confidence intervals. As a dispersion measurement the standard deviation will be calculated. The distribution of the variables will be studied using the Shapiro-Wilk test. To detect any difference between the groups, a T-test or a Wilcoxon test will be performed according to its distribution. The categorical variables will be compared using the Chi2 test or the exact Fisher's test. If required, a model of multiple logistic regressions or a covariance analysis will be done.  Two interim analyses will be performed when 35% and 70% of the calculated sample is collected, with the objective of determining the differences in effectiveness and safety between the treatments.  Endpoints  At the end of the study two endpoints will be evaluated:  1. Successful Treatment:  1. Complete reepithelization three months after the beginning of the treatment.  2. Absence of reactivation and affections of the mucous membranes during the 6 months of the study.  2. Treatment Failure:  1. Incomplete reepithelization three months after the beginning of the treatment.  2. Increase in the size of the ulcer by more than 50% in relation to the last clinical evaluation  3. Reactivation and/or affections of the mucous membranes during the 6 months of the study.  Final Report  At the end of the study the results will be evaluated and discussed and a final report presented to COLCIENCIAS, entity that is sponsoring the project. The relevant results will be published in both, national and international journals, and presented in congresses and scientific meetings.  ETHICAL ASPECTS  This study will be conducted in accordance with the Declaration of Helsinki and with the Colombian legislation as per the Resolution 8430/93 from the Ministry of Health. Prior to the admission of the patients in the study, the objectives and the methodology will be explained and the informed consent obtained. The study was approved by the Research Ethic Committee of the Cardiovascular Foundation of Colombia (Act# 105/January 28/2005). The right to confidentiality of the patients will be maintained in all the phases of the study.  COMPETING INTERESTS  Non Financial competing interests  The authors of this manuscript declare that they have no competing interests, including political, personal, religious, ideological, academic, intellectual, or any other competing interests.  Financial competing interests  We have not received in the past five years reimbursements, fees, funding or salary from any organization that may in any way gain or lose from the publication of this manuscript, either now or in the future. We don't hold any stocks or shares in an organization that may in any way gain or lose financially from the publication of the manuscript, either now or in the future. We don't hold or are currently applying for any patents relating to the content of the manuscript. We have not received reimbursements, fees, funding or salary from an organization that holds or has applied for patents relating to the content of the manuscript.

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