Clinical trial NCT02417142
Conditions: Schizophrenia Schizoaffective Disorder
Sponsor: University of Massachusetts, Worcester
Start date: 2014-09-01; Completion date: 2020-07-01
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 24-week, randomized, double-blind, placebo-controlled trial of exenatide weekly injection (2mg per dose) as an adjunctive therapy in 70 schizophrenia subjects to examine exenatide's effects on negative symptoms and cognition.

Detailed description:
The specific aims include:

Primary aim:

1\. Examine the efficacy of exenatide weekly injection in improving negative symptoms as measured by the Scale for the Assessment of Negative Symptoms (SANS) total score.

Secondary aims:

1\. Examine the efficacy of exenatide in improving cognition as measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) composite score.

Tertiary/Exploratory aims:

1. Examine exenatide's effect on schizophrenia symptoms as measured by the Positive and Negative Syndrome Scale (PANSS) total score.
2. Examine the efficacy of exenatide in improving social function as measured by the Instrumental Activities of Daily Living Scale (IADL) and the Heinrich Carpenter Quality of Life Scale (QLS).
3. Examine exenatide's effect on neuro-protection as measured by the change in hippocampal volume.
4. Examine exenatide's effects on inflammatory markers including serum levels of high sensitivity C-reactive Protein (CRP), Interleukin 6 (IL-6), and tumor necrosis factor (TNF-α).
5. Examine the potential moderator role of baseline serum levels of C-reactive Protein (CRP), Interleukin 6 (IL-6), tumor necrosis factor (TNF-α), and baseline hippocampal volume for exenatide's effects on negative and cognitive symptoms.
6. Examine the potential mediator role of changes from baseline in serum levels of C-reactive Protein (CRP), Interleukin 6 (IL-6), tumor necrosis factor (TNF-α), and hippocampal volume for exenatide's effects on negative and cognitive symptoms.
7. Examine the efficacy of exenatide in reducing body weight and improving glucose metabolism as measured by fasting plasma glucose and HbA1c.
8. Examine the safety and tolerability of exenatide as measured by changes in the side effects questionnaire (SEQ, SEQabbrev), EKG and vital signs

Arms: arm 1: Exenatide 2mg subcutaneous injection, once weekly arm 2: Placebo
Interventions: intervention 1: Exenatide intervention 2: Placebo
Intervention descriptions: intervention 1: Exenatide SQ 2mg/week for 24 weeks. intervention 2: Placebo SQ 1x/week for 24 weeks.

Protocol documents:
Prot_002.pdf: 
 
 
 
 
 
 
 
 
 
 
Study Protocol 
The Effect of Adjunctive Exenatide Treatment on Psychopathology, Cognition and Metabolism in 
Patients with Schizophrenia 
PI: Xiaoduo Fan, MD, MPH 
Document Date: 11/30/2019 
Identifier: NCT02417142 
 
 
 
 
 
 
 
 
 
 
 
 
 


INSTRUCTIONS: 
 
1) 
Title 
     Exenatide weekly injection as an adjunctive treatment in patients with schizophrenia 
 
2) 
IRB Review History* 
N/A 
 
3) 
Objectives* 
This is a 24-week, randomized, double-blind, placebo-controlled trial of exenatide weekly 
injection (2mg per dose) as an adjunctive therapy in 70 schizophrenia subjects to 
examine exenatide’s effects on negative symptoms and cognition. 
Primary aim:  Examine the efficacy of exenatide weekly injection in improving negative 
symptoms as measured by the Scale for the Assessment of Negative Symptoms (SANS) total 
score.  
Secondary aims: Examine the efficacy of exenatide in improving cognition as measured by the 
MATRICS Consensus Cognitive Battery (MCCB) composite score.  
Tertiary/exploratory aims: 
1. Examine exenatide’s effect on schizophrenia symptoms as measured by the Positive 
and Negative Syndrome Scale (PANSS) total score. 
2. Examine the efficacy of exenatide in improving social function as measured by the 
Instrumental Activities of Daily Living Scale (IADL) and the Heinrichs Carpenter Quality 
of Life Scale (QLS).  
3. Examine exenatide’s effect on neuro-protection as measured by the change in 
hippocampal volume. 
4. Examine exenatide’s effects on inflammatory markers including serum levels of high 
sensitivity CRP, IL-6, and TNF-α. 
5. Examine the potential moderator role of baseline serum levels of CRP, IL-6, TNF-α, and 
baseline hippocampal volume for exenatide’s effects on negative and cognitive 
symptoms. 
6. Examine the potential mediator role of changes from baseline in serum levels of CRP, 
IL-6, TNF-α, and hippocampal volume for exenatide’s effects on negative and cognitive 
symptoms. 
7. Examine the efficacy of exenatide in reducing body weight and improving glucose 
metabolism as measured by fasting plasma glucose and HbA1c.  
8. Examine the safety and tolerability of exenatide as measured by changes in the 
side effects questionnaire (SEQ, SEQabbrev), EKG and vital signs 
4) 
Background* 
 
Negative symptoms and cognitive deficits in schizophrenia: Schizophrenia can be a devastating 
illness for patients, often producing life-long disability. Two major factors contributing to 


functional disability in schizophrenia are negative symptoms and cognitive impairment, which 
are the biggest obstacle to achieving an independent and productive lifestyle, with these deficits 
being refractory to current drug treatments. 
(1-3).   
 
Inflammation and negative symptoms:  Evidence of immune dysfunction and inflammation has 
been described in patients with schizophrenia (4-7).  A series of recent studies from our group 
have demonstrated abnormal patterns of immune activation, including elevated serum levels of 
IL-1β, IL-6, TNF-α, interferon-γ, increased nuclear factor-кB (NF-κB) activation and its mRNA 
expression in peripheral blood mononuclear cells (PBMC) in first episode schizophrenia patients 
(8, 9).  The findings from our group and others also support an altered immune function 
characterized by shifting from a Type 1 (cellular) to a Type 2 (humoral) immune response (10, 
11).  Several studies have suggested that the dysregulation of inflammatory and immunological 
processes is likely related to the manifestation of symptoms and treatment response of 
schizophrenia (12, 13).  We reported that specific markers for inflammation, including elevated 
blood levels of C-reactive protein (CRP) and white blood cell count (WBC), are associated with 
negative symptoms of schizophrenia (14, 15).   
 
Inflammation and cognition:  Considerable evidence links inflammation to cognitive impairment 
in non-schizophrenia populations (16).  Higher plasma levels of CRP and interleukin-6 (IL-6) 
have been associated with poorer cognitive performance at baseline and with a greater risk of 
cognitive decline over a 2-year follow-up period in well-functioning elders (17).  In the 
community-based Framingham study cohort, higher levels of IL-1 and TNF-α both were markers 
of future risk of Alzheimer disease in older individuals (18).  Further, it has been suggested that 
long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) offers some protection against 
the development of Alzheimer’s disease (19).  Inflammation is also associated with cognitive 
impairment in schizophrenia.  In a sample of 413 patients with schizophrenia, Dickerson et al. 
measured the levels of CRP, reported that those with CRP > 5 mg/mL had significantly lower 
cognitive scores than those with CRP < 5 mg/mL (20).  We recently found that schizophrenia 
patients with a TNF-α –308G/G genotype (N=83) had better executive function than those with 
G/A or A/A genotypes (N=31).   
 
Hippocampal volume loss in schizophrenia:  Studies have found evidence for a progressive loss 
of cortical tissue volume in the early phase of schizophrenia.  First episode patients have shown 
cortical volume reductions of 1% or more per year; these changes are thought to be most active 
during the first few years of the illness, with some leveling off of this degenerative process as 
the disease becomes chronic.  Progressive volume loss seems most pronounced in the frontal 
and temporal gray matter areas (21).  Reduced hippocampal volume has been consistently 
reported in both first episode psychosis and chronic schizophrenia (22-24).  Postmortem studies 
in schizophrenia patients have also demonstrated subtle anomalies in limbic structures, most 
consistently in the hippocampus (25).   
 


Hippocampal volume loss – in relation to cognitive deficits, negative symptoms and functional 
impairment in schizophrenia:  The hippocampus is a highly plastic brain region; new neurons 
are continuously produced in the dentate gyrus of the hippocampus throughout life.  The 
amount of neurogenesis correlates closely with the hippocampal function of learning and 
memory (26, 27).  Hippocampal pathology has been proposed to underlie clinical, cognitive and 
functional impairments in schizophrenia (28).  Progressive cortical loss is associated with more 
negative symptoms, cognitive decline and a more severe course of illness (21).  A significant 
inverse correlation between left hippocampal volume and negative symptoms of schizophrenia 
has been reported previously (29).  Studies also demonstrated a significant correlation between 
reduced hippocampal volume and cognitive deficits in patients with schizophrenia (30).  Further, 
a recent study reported that bilateral hippocampal increase occurs in a minority of patients 
following their first psychotic episode and is associated with good outcome across clinical, 
cognitive and functional domains (31).   
 
Inflammation and hippocampal volume loss in schizophrenia:  Overwhelming evidence from 
animal studies indicates that activation of microglia and the subsequent release of pro-
inflammatory cytokines including IL-1β, TNF-α and IL-6 have negative effect on hippocampal 
neurogenesis.  Activated microglia and inflammatory cytokines may reduce cell proliferation, 
survival and function of new neurons in hippocampus (32).  The initial work demonstrating that 
classically activated microglia impair hippocampal neurogenesis was reported by Monje et al. 
(33) and Ekdahl et al. (34) following lipopolysaccharide (LPS) administration in rats.  Earlier 
post-mortem studies have shown the presence of microglial activation in the brains of patients 
with schizophrenia (35, 36).  More recent studies using positron emission tomography (PET) in 
live patients with schizophrenia further demonstrated microglia activation especially in temporal-
limbic gray matter (37, 38).  Microglia, a major source of various inflammatory cytokines and 
free radicals such as superoxide and nitric oxide in the brain, play a crucial role in apoptosis and 
the neurodegenerative process (39).  Negative symptoms and cognitive deficits in schizophrenia 
may in part be related to inflammation-induced reduction in adult hippocampal neurogenesis 
and volume loss. 
 
Anti-inflammatory treatment and hippocampal neurogenesis:  Administration of the microglia 
inhibitor, minocycline, blocked the LPS-induced decrease in new neuron survival in the 
hippocampus (34).  In another study, inflammatory blockade with indomethacin, a common 
nonsteroid anti-inflammatory drug, restores hippocampal neurogenesis after LPS-induced 
inflammation in rats (33).   Anti-inflammatory treatment may preserve hippocampal 
neurogenesis, therefore slow down or even reverse the hippocampal volume loss process in 
schizophrenia. 
 
Anti-inflammatory treatment in schizophrenia:  Muller et al. conducted a 6-week trial of celecoxib 
augmentation to amisulpride treatment in patients with first episode of schizophrenia, and found 
a significant therapeutic effect of celecoxib as measured by the PANSS total score and the 
negative symptom subscale score (40, 41).  Another commonly used anti-inflammatory agent, 
aspirin, was also studied in the schizophrenia population.  It was reported that aspirin as an 
adjuvant therapy to antipsychotic treatment reduced schizophrenia symptoms as measured by 


the PANSS total score (42).  A recent study also found minocycline, a second-generation 
tetracycline that exerts anti-inflammatory and antimicrobial effects, was associated with 
improvement in negative symptoms and executive function in early phase schizophrenia (43, 
44).  Despite the promise of potential benefit of celecoxib, aspirin and minocycline in 
schizophrenia treatment, there are both important scientific and safety issues to be addressed:  
Scientifically, it is unclear which brain target is engaged in anti-inflammatory treatment, and by 
which mechanism these anti-inflammatory drugs affect the target.  On the safety aspect, the 
adverse side effects related to these drugs limit their potential clinical therapeutic utility in the 
schizophrenia population. Celecoxib and other COX-2 inhibitors have been associated with an 
elevated risk of cardiovascular disease (45), which is a serious comorbid medical condition in 
patients with schizophrenia.  The cardio-protective non-selective COX inhibitor aspirin is 
arguably preferable.  However, it is well established that aspirin, especially used in a relatively 
high dosage, is associated with a significant risk for GI bleeding.  Tetracyclines are known to 
have side effects of pigmentation changes, pediatric tooth discoloration and photosensitivity 
reactions (46).   
GLP-1 and its analogues: Glucagon-like peptide-1 (GLP-1) is an endogenous 30-amino acid 
peptide hormone, which is secreted from the intestinal L-cells in response to ingested 
carbohydrate and fat.  It stimulates insulin secretion in a glucose-dependent manner and inhibits 
glucagon secretion from the pancreas.  Exendin-4 is a peptide agonist of GLP-1 receptor (GLP-
1R) that promotes insulin secretion.  Two longer-lasting GLP-1 analogues (exenatide - a 
synthetic exendin-4, and liraglutide) are two FDA-approved medications for diabetes treatment.  
In addition to glycemic control, treatment with GLP-1 analogues is also associated with 
moderate weight loss, and improvement in cardiovascular risk factors (47).  Given the overall 
favorable safety profile and weight effect, a low risk of hypoglycemia, and clinically meaningful 
improvements in HbA1c in various patient populations, the guidelines of the American 
Association of Clinical Endocrinologists (AACE) and the recently updated guidelines from the 
American Diabetes Association (ADA) assign exenatide and liraglutide a central role in the 
treatment of diabetes (48). 
Exenatide, a synthetic exendin-4, is available in two formulations: twice daily and once weekly.  
Exenatide twice daily is the first glucagon-like peptide-1 (GLP-1) receptor agonist approved for 
the treatment of type 2 diabetes.  Exenatide once weekly is the first glucose-lowering agent that 
is administered once per week.  This long-acting formulation contains the same active 
ingredient as exenatide twice daily, except that the exenatide is encapsulated in dissolvable 
microspheres.  
 
GLP-1 and inflammation: Recent evidence has shown that GLP-1 and analogues have anti-
inflammatory activity.  It has been shown that both activated microglia and activated astrocytes 
bind GLP-1 and that GLP-1 can prevent lipopolysaccharide (LPS)-induced increase in 
interleukin-1β (IL-1β) in these cells (49).  Other studies reported that exendin-4 can reduce 
monocyte adhesion to aortic endothelium in a model of atherosclerosis and prevent LPS-
induced cytokine and chemokine mRNA synthesis in both human and mouse monocytes (50, 
51). 
 


Recent clinical studies also have demonstrated that exenatide exerts a potent anti-inflammatory 
effect (52-54).  In a double-blinded, 16-week study with 23 patients with diabetes and 
inadequate glucose control, subjects were randomly assigned to receive exenatide (5µg twice 
daily for 4 weeks followed by 10µg twice daily for 12 weeks) or placebo; exenatide treatment 
significantly reduced oxidative stress and high sensitivity CRP (55).  In a more recent study, 24 
patients with diabetes were randomized to be on exenatide 10µg twice daily or placebo for 12 
weeks; the results showed that exenatide significantly decreased reactive oxygen species 
generation, NF-κB binding, the mRNA expression of TNF and IL-1β in PBMC, and serum levels 
of IL-6 (56).  In another study, patients with diabetes were treated with exenatide 2mg once 
weekly or 10µg twice daily for 30 weeks; in addition to improving glycemic control and lipids, 
both the once weekly and twice daily exenatide regimens significantly reduced serum levels of 
high sensitivity CRP (57). 
 
GLP-1 and neuro-protection:  GLP-1Rs are found in cerebral cortex, hippocampus, 
hypothalamus, and thalamus.  The distribution of GLP-1 receptors (GLP-1Rs) in the brain 
suggests they may play an important role in the regulation of neuronal activity.  In pre-clinical 
studies, GLP-1 and analogues protect motor activity, modulate long-term potentiation and 
synaptic plasticity, enhance neurogenesis, reduce apoptosis, protect neurons from oxidative 
stress, and reduce plaque formation in the brain in mouse models of Alzheimer disease, 
Parkinson disease, amyotrophic lateral sclerosis, stroke and other neurodegenerative diseases 
(58-60). 
 
GLP-1 and longer-lasting analogues cross the blood-brain barrier (BBB) by simple diffusion, a 
property that is of great importance in order to be effective in the brain (61).  In contrast, several 
neuro-protective growth factors such as nerve growth factor (NGF) and brain-derived 
neurotrophic factor (BDNF) do not cross the BBB, therefore have no effect in the brain if injected 
peripherally. 
 
GLP-1 and hippocampus:  Li et al. found that intraperitoneal treatment of exendin-4 in mice for 4 
weeks increases cell proliferation and neuroblast differentiation in the adult mouse hippocampal 
dentate gyrus (62).  Another study in mice demonstrated that intrahippocampal LPS injection 
induces cognitive decline via activation of NF-κB related inflammatory response; intraperitoneal 
treatment of exendin-4 reduces the inflammation and protects against cognitive impairment (63).  
A more recent study in mice reported that subcutaneous exendin-4 treatment presents traumatic 
brain injury induced changes in hippocampus gene expression and memory deficits (64).  These 
studies demonstrated that peripheral administration of exendin-4 can inhibit inflammation and 
preserve neurogenesis in the hippocampus. 
 
GLP-1 and cognition: In animal studies, treatment with GLP-1 analogues has been 
demonstrated to improve measures of cognitive function (65).  For example, Mice injected daily 
for 8 weeks with GLP-1 exhibited significant improvement in recognition index on an object 
recognition test, indicating enhanced learning and memory (66).  GLP-1R -/- knockout mice 


demonstrate impaired spatial learning and memory as shown by their performance in the Morris 
water maze task, longer time to completion, and poorer recall of landmarks.  They also 
performed poorly on an object recognition task, demonstrating inability to differentiate between 
familiar and novel objects (67). 
 
Summary of GLP-1:  Activation of the GLP-1R has shown neurotrophic, neuroprotective, and 
functional and behavioral benefit under numerous physiological and pathophysiological 
paradigms in pre-clinical studies.  As GLP-1R stimulation has proven to be beneficial and well 
tolerated in diabetes treatment, it is reasonable to hypothesize that GLP-1 analogues including 
exenatide would likely be beneficial in human neurological or neuropsychiatric diseases.  
Several clinical trials are currently underway, testing GLP-1 analogues in mild cognitive 
impairment, Alzheimer disease and Parkinson disease (www.clinicaltrials.gov).  Based on the 
extensive evidence of its anti-inflammatory and neuro-protection effects, GLP-1 might be a 
potential novel treatment target for negative symptoms, cognitive deficits and metabolic 
problems in patients with schizophrenia.  GLP-1 analogues show great promise as a novel 
treatment for schizophrenia.  
  
 
5) 
Inclusion and Exclusion Criteria* 
 
Inclusion Criteria: 
1) age 18-65 years;  
2) diagnosis of schizophrenia or schizoaffective disorder;  
3) stable dose of the current antipsychotic drug for at least one month;  
4) well established compliance with outpatient treatment per treating clinician’s 
judgment;  
5) able to complete the cognitive assessment battery (must be English speaking);  
6) Female subjects will be eligible to participate in the study if they are of non-
childbearing potential or of child-bearing potential and willing to practice 
appropriate birth control methods during the study.   
 
Exclusion Criteria:  
1) inability to provide informed consent, or for individuals with a legal guardian, 
inability to provide assent or a lack of informed consent from the legal 
guardian 
2) current substance abuse  
3) Subjects who are not on a stable dose of an antipsychotic medication for at 
least a month prior to enrollment  
4) psychiatrically unstable per treating clinician’s judgment 
5) Uncontrolled medical condition including uncontrolled hypertension, diabetes, 
seizure disorder, severe cardiovascular, cerebrovascular, pulmonary, thyroid 
diseases, and gastroparesis. 
6) history of ketoacidosis 
7) currently taking insulin  
8) currently taking meglitinides (repaglinide and nateglinide) 


9) currently on  immunosuppressant medication regularly including oral steroids; 
topical and inhalant steroids are allowed 
10) currently on sulfonylurea drugs (e.g. glyburide) 
11) Current, active chronic infection (including tuberculosis, HIV and hepatitis), 
malignancy, organ transplantation, blood dyscrasia, central nervous system 
demyelinating disorder, and any other known autoimmune or inflammatory 
condition 
12) pregnant or breastfeeding. 
13) prisoners 
14) Exclusionary labs: eGFR < 35 ml/min 
Hematology (CBC) 
Leukocytes 
<2 or >17.5 x 103/mm3 
Platelets 
<75 or >700 x 103/mm3 
Comprehensive Metabolic Panel 
Sodium 
<1.1 times the lower limit (≤121.5) or >1.1 times upper limit 
(≥159.5) of the reference range 
Potassium 
<1.1 times the lower limit (≤3.15) or >1.1 times upper limit 
(≥5.83) of the reference range 
Glucose 
>2 times the upper limit (>198) of the reference range 
Blood Urea Nitrogen (BUN) 
>1.3 times upper limit (>29.9) of the reference range 
Creatinine 
>1.3 times upper limit (>1.69) of the reference range 
Total bilirubin 
>2 times the upper limit (>2.4) of the reference range 
Aspartate amino 
transferase (AST) 
>3 times upper limit (>120) of the reference range 
Alanine amino transferase 
(ALT) 
>3 times upper limit (>120) of the reference range 
Alkaline phosphatase 
(ALP) 
>3 times upper limit (>345) of the reference range 
Hemoglobin A1C 
Patients with a value ≥ 9.0% 
All exclusionary labs will be reviewed prior to administration of the study drug. 
 
We will continue our recruitment efforts to assure a meaningful representation of women and 
minority populations.  
 
Ages of subjects will range from 18-65 years. In recent years, there has been an increased use 
of antipsychotic agents in the younger population. The literature about antipsychotic treatment 
related to metabolic disturbances in children and adolescents is accumulating.  The proposed 
studies included in this application will focus on the adult schizophrenia population. Only 
individuals in the range of 18-65 years of age will be included.  
 
6) 
Study-Wide Number of Subjects* 
This is a single site study. We expect to enroll 110 subjects in this study with the 
goal of randomizing 70 subjects. 
 


7) 
Study-Wide Recruitment Methods* 
This is a single-site study being conducted solely at UMass Medical School. For 
information on how potential subjects will be recruited, see section 24 (“Recruitment 
Methods”).  
 
8) 
Study Timelines* 
The duration of an individual subject’s participation in the study will be 24 weeks. It is 
anticipated that 110 subjects will be enrolled, and 70 subjects will be randomized. This 
study received an extension to continue until our goal of 70 randomized patients is met. 
The investigators plan on completing primary analysis of the data within six months of 
the study’s completion.  
9) 
Study Endpoints* 
 
Primary Study Endpoint:   
 
Improvement in negative symptoms as measured by the Scale for the Assessment of Negative 
Symptoms (SANS) total score.  
 
Secondary Study Endpoint:  
Improvement in cognition as measured by the MATRICS Consensus Cognitive Battery (MCCB) 
composite score.  
 
Safety Endpoints: 
An EKG will be conducted at the beginning and end of the study to assess safety. Vital Signs 
including blood pressure will be collected at every visit.  Data on adverse events will be 
collected at every visit using the side effects questionnaires (SEQ and SEQabbrev) to assess 
safety and tolerability.  
 
10) Procedures Involved* 
 
This is a 24-week, randomized, double-blind, placebo-controlled trial of exenatide weekly 
injection (2mg per dose) as an adjunctive therapy in 70  schizophrenia subjects to 
examine exenatide’s effects on negative symptoms, cognition and potential moderators 
or mediators of exenantide’s effects on negative and cognitive symptoms. 
 
Informed consent will be obtained prior to the screening visit (see Section 30 “Consent 
Process”).  


 
Screening visit:  Fasting blood samples for glucose, insulin, HbA1c, lipid profile, comprehensive 
metabolic profile, CBC, high sensitivity CRP, eGFR and TNF-α will be obtained at the screening 
visit. Subjects will not receive study medication until all baseline labs have been completed, 
reviewed, and determined to fall within range.   Potential subjects will undergo a diagnostic 
evaluation. Psychiatric diagnosis will be determined using the Structured Clinical Interview for 
DSM-IV Axis I Disorders (SCID).  A medical evaluation, including weight, height, vital signs 
(heart rate, sitting, and standing blood pressures), a physical examination, and review of 
systems will be performed. The screening process includes a comprehensive review of medical 
history & evaluations, which is then reviewed by the PI before continuing with randomization. 
The study doctor discusses the patient’s medical history with the patient, completes a review of 
systems, a physical exam, assesses the patient’s overall health status, and reviews all available 
medical records, previous laboratory assessments and other relevant medical information in 
addition to the patient’s self-report. Based on all of the information gathered, the PI then 
assesses the patient’s eligibility for the study utilizing their clinical judgment. A urine pregnancy 
test will be performed on women of childbearing potential. Weekly reminders will be provided to 
the subject to use condoms or other appropriate birth control. The subjects will be given an 
appointment card for their next visit which will also provide a reminder for the use of appropriate 
birth control.  In addition, a urine drug screening, and a 12-lead EKG will be performed. The 
screening visit will take about 2 hours. While the study team plans to complete all assessments 
in one study visit, it is likely that due to symptoms of psychosis, including avolition, apathy and 
cognitive disturbances subject may have inconsistent behavior and variable tolerance to 
screening procedures and assessment batteries. In such cases the subject may be called for an 
additional visit to complete the remaining procedures or they will be completed in the following 
visit. Following the screening visit, the subjects’ primary care provider and/or psychiatrist will be 
notified of their participation in the study in order to adequately screen subjects, ensure that only 
eligible subjects are enrolled, and minimize subject risk. Ongoing subjects will be re-consented 
and informed of this notification during that time. 
 
Baseline visit: The baseline visit will take about 5 hours to complete. Eligible subjects will come 
to the clinic for the baseline visit.  Subjects will complete the clinical symptoms assessment, the 
extrapyramidal symptoms (EPS) assessment, and vital signs.  On a separate day, subjects will 
come to the UMass Imaging Center at the university campus, or UMass Memorial MRI & 
Imaging Center at Shields MRI Imaging Suite to complete the brain MRI scans.  Then the 
subjects will receive the study medication (either exenatide weekly injection (2mg per dose) or 
placebo injection).  The UMass research pharmacy is responsible for randomization and 
preparation of study medication.  The randomization is based on a double-blinded 1:1 ratio 
using permuted block randomization with randomly varying block size.  
 
Follow-up visits (week 1-23):  These visits will take about one hour to complete. Subjects will 
come to the clinic weekly to receive the study medication injection (exenatide or placebo); 
possible side effects will be assessed weekly.  At week 6, 12, 18 visits, vital signs, the clinical 
symptoms assessment and the EPS assessment will be repeated; fasting blood samples for 
glucose, insulin, HbA1c, lipid profile, comprehensive metabolic profile, CBC, high sensitivity 


CRP, eGFR and TNF-α will be obtained. In the event that research staff are unable to obtain a 
subject’s blood sample at an indicated visit, subject’s blood will be drawn in a week’s time by a 
professional phlebotomist at UMass. In the event that a subject misses a visit where a routine 
blood draw is required, the subject will be scheduled to complete the routine blood draw prior to 
receiving the next dose of study medication.  Once the lab results have been reviewed and 
signed off by the PI, the subject will be scheduled for their next study visit and will resume 
receiving the study medication.  
 
Week 24 visit:  This visit will take about 5 hours. The week 24 visit consists of vital signs, and 
side effects assessment.  A 12-lead EKG will also be obtained during this visit.  The clinical 
symptoms assessment and the EPS assessment will be repeated.  Fasting blood samples for 
glucose, insulin, HbA1c, lipid profile, comprehensive metabolic profile, CBC, high sensitivity 
CRP, eGFR and TNF-α will be obtained. In the event that research staff are unable to obtain a 
subject’s blood sample at an indicated visit, subject’s blood will be drawn in a week’s time by a 
professional phlebotomist at UMass. On a separate day, subjects will come to the UMass 
Imaging Center at the university campus, or UMass Memorial MRI & Imaging Center at Shields 
MRI Imaging Suite to repeat the brain MRI scans. 
 
Clinical symptoms assessment:  The clinical symptoms assessment includes: The Scale for 
Assessment of Negative Symptoms (SANS), the Positive and Negative Syndrome Scale 
(PANSS), the Clinical Global Impression Scale (CGI), the Calgary Depression Scale for 
Schizophrenia (CDSS), the Heinrichs Carpenter Quality of Life Scale (QLS), the Instrumental 
Activities of Daily Living Scale (IADL), and the MATRICS Consensus Cognitive Battery (MCCB). 
  
Side effects/safety/EPS assessment:  Possible side effects related to exenatide treatment will 
be monitored during each visit.  Vital signs (blood pressure, pulse, temperature) and EPS will be 
evaluated at baseline, week 6, week 12, week 18 and week 24 using the Simpson-Angus Scale, 
the Barnes Akathisia Scale, and the Abnormal Involuntary Movement Scale (AIMS).   
 
Bioassay:  Routine blood tests (glucose, insulin, HbA1c, lipid profile, comprehensive metabolic 
profile, CBC, high sensitivity CRP, eGFR) will be performed at the UMass Core Lab.  Plasma 
levels of IL-6 and TNF-α will be measured using enzyme-linked immunosorbent assay (ELISA) 
(R & D Systems) by Quest Diagnostics.   
 
Structural MRI data acquisition, processing and analysis methods: To measure hippocampal 
volume at baseline and week 24, a structural MRI imagining examination will be performed at 
the UMass Advanced MRI facility on a Philips Achieva 3T system, or UMass Memorial MRI & 
Imaging Center at Shields MRI Imaging Suite on a GE 3T scanner.  Segmentation of brain 
structures from T1-weighted 3D structural MRI data and estimation of structure volumes will be 
performed using the Freesurfer toolkit, which is freely available to the research community 
(http://surfer.nmr.mgh.harvard.edu/). This suite of methods uses a probabilistic brain atlas for 


representation of spatial priors for brain labels (71). The current subcortical, cortical and white 
matter parcellation segmentation methods are fully automated. Each subject will result in a 
complete set of segmentations for volume and cortical surface. Each of these regions generates 
a volume; whole brain, cerebreum and white matter volumes are also available for normalization 
with respect to overall brain size.  
 
MRI Procedure: Anatomic acquisitions will include: (1) a T2/PD double echo fast spin echo 
sequence, (2) a multi-flip angle 3D spoiled gradient echo (MPRAGE  type) compatible with the 
UMASS/CANDI protocol, (3) an proton PRESS and single voxel MEscher-Garwood Point-
REsolved Spectroscopy Sequence (MEGA-PRESS) (TE:68msec, TR:2000msec) MRS scans 
from the ACC, (4) a diffusion scan sequence that uses a standard single shot, spin echo, echo 
planar acquisition with diffusion weighting gradient pulses comprised of 32 diffusion-encoding 
directions with an additional baselineT2 weighted image and (5) Echo Planar MRI (EPI) / 
Functional MRI (fMRI) scan will measure brain fluctuations while at rest. Total scan time will be 
approximately 60 minutes. Post-processing will be performed with standard software (LCModel, 
Freesurfer, and FSL) to quantify the MRS metabolites, and regional gray and white matter 
structural properties in the brain.  
 
A trained neuroradiologist associated with the MRI imaging center at University of 
Massachusetts Medical School will read the diagnostic MRI scans. In the event that there is a 
suspicious reading on the MRI the PI will be informed of this. The PI will share with the subject 
the findings and will facilitate in helping them determine what follow up care is needed and 
appropriate. 
 
It is possible that a subject may not complete the MRI scan in the study either because 
the subject is not interested in this component or because it may not be appropriate (for 
example, claustrophobia or implanted metal in the subject’s body). Only those subjects who 
qualify will complete the MRI scan throughout the study. 
 
11) Data and Specimen Banking* 
 
Extra blood samples will be collected for future research related to schizophrenia. We will store 
samples for future genetic testing. These samples will be labeled with a unique study ID code. 
Only members of the research team will be able to derive an individual’s identity from their study 
ID code. The key to the code is stored on secure server and can only be accessed through 
password-protected computer.  
 
Extra blood samples will be drawn at Biotech One, Suite 100 or at Community Health link and 
stored in a -80oF freezer, which is located in a locked room at Biotech One. 
 
While there are no definitive plans yet for use of these samples, the Principal Investigator plans 
to store these blood samples indefinitely after the study’s completion.  A log system will be put 
in place to ensure that only authorized research personnel have access to the samples. The PI 
will be held responsible for the safety and security of these samples. A separate IRB approval 
will be requested to utilize these stored samples in the future.  


 
12) Data Management* 
All data management will be conducted in the research offices of the Biotech One 
building. Standard data forms for the clinical rating scales will be used for this project. 
Individual notebooks will be maintained for each subject that will include signed consent, 
letter to halfway house, subject information sheets, raw data from clinical rating scales, 
laboratory measurements and a study timetable or flow sheet for that subject. A study 
database will be created using the REDCap system. The data will be stored on a secure 
server in the UMass HIPAA-compliant data center with daily backup. The database will 
be designed by the PI and maintained by the PI and the research staff. Data entry will be 
performed by research coordinators and will be reviewed by the research manager and 
the PI for accuracy. Access to the database will be restricted by password. All data will 
be stored safely for 5 years.  
There are no published data yet about exenatide’s effects on clinical symptoms and 
cognition in the schizophrenia population. This study is intended as an initial test of 
efficacy.  Repeated measures of clinical symptoms and cognitive performance will be 
analyzed in separate linear mixed models with fixed effects of visit, treatment group, 
baseline score, and visit x treatment and visit x baseline score interactions and random 
participant-specific intercepts and slopes.  Potential confounding variables will be 
included as covariates.  The effect of exenatide on 24-week change from baseline will be 
determined by the estimated regression coefficient of the visit x group interaction term. 
The sample of 60 evaluable subjects will have 80% power to detect an effect size of 0.74 
based on a two-tailed t-test at alpha = 0.05.   
 
13) Provisions to Monitor the Data to Ensure the Safety of Subjects* 
The PI and all key personnel involved in this study have completed the Collaborative IRB 
Training Initiative (CITI), a mandatory tutorial on the responsible conduct of human 
subject research. The tutorial and institutional policies and procedures governing the 
conduct of human subjects research are available on the UMass Medical School intranet 
website and may be accessed by the Investigator and key study personnel if questions 
arise. 
The PI will immediately report to the IRB any unanticipated problems or adverse events 
that occur during the conduct of the study, after study completion, or after subject 
withdrawal in accordance with adverse event and unanticipated problems reporting 
guidelines. 
Safety monitoring will have two components. The first will focus on change in psychiatric 
symptoms. Safety monitoring will also assess the incidence and severity of side effects 
and the frequency and reason for any medication changes and study medication 
discontinuation. The PI will discuss likely side effects of exenatide and potential risks of 
study procedures as part of the informed consent procedure. 


Investigators and research personnel who are trained and experienced at conducting 
assessments in persons with schizophrenia, will assess for deteriorating mental status 
and/or suicidal ideation.  Participants will meet with a study psychiatrist at each visit and 
have routine monitoring of psychiatric symptoms. The PI will be notified immediately if 
subject expresses suicidal ideation. The PI is a board certified psychiatrist and has the 
necessary training and experience to address such events. 
The PI can be contacted by phone at all times and the UMass Memorial Emergency Service is 
available for psychiatric and medical assessment of research subjects.  Female patients will be 
screened for pregnancy during enrollment by a urine pregnancy test.  
 
Any adverse effect reported to study personnel will be reviewed with the PI who will determine 
whether they are mild, moderate or serious.  Potentially serious adverse events will be reviewed 
by an external monitoring team to determine the likelihood (unlikely/possible/probable) that it is 
related to the study medication and whether it is safe for the subject to remain in the study.  
 
 
Continuous data and safety monitoring will be conducted by the PI. The monitoring will include 
all adverse events (AEs and SAEs) both expected and unexpected, enrollment, dropout rates 
and protocol deviations in addition to the results of special studies and laboratory tests that are 
conducted to ensure patient safety, subject interview and conduct, review of subject symptom or 
performance status, review of clinical test results, review of subject physical examination, review 
of all vital signs, diagnostic tests, and evaluations.  The investigator will report adverse events to 
the IRB in accordance with IRB guidelines.  
The PI will create a Data Safety Monitoring Board (DSMB) to independently oversee this clinical 
trial. The DSMB for this study will be composed of at least three people and will include a 
psychiatrist, an endocrinologist and a biostatistician who will be independent of the study group. 
The group will follow the NIH policy for data and safety monitoring and guidelines as published 
on http://www.nimh.nih.gov/research-funding/grants/nimh-policy-on-data-and-safety-monitoring-
in-extramural-investigator-initiated-clinical-trials.shtml.  Study data regarding subject enrollment, 
characteristics, symptoms, adverse events and serious adverse events will be submitted to the 
DSMB for review and analysis annually. The DSMB will review study data, the safety of study 
participants and conduct of the study. It will advise the PI on continuation of the study and 
provide reports to the IRB regarding recruitment of appropriate subjects and presence of 
adverse effects. 
An explicit stopping rule will be followed for a potentially serious psychiatric decompensation in 
order to further enhance patient safety: active subjects will be terminated from the study if they 
experience an increase in PANSS total score greater than or equal to 20 compared to their 
baseline score at any point during the study. 
Subjects will be terminated from the study if their eGFR falls below 30 ml/min at any point during 
the study. 
14) Withdrawal of Subjects* 
Subjects will be withdrawn from the study if they are determined to meet ineligibility criteria after 
enrollment. If subjects have laboratory results that meet the exclusionary criteria range during 
the study, the subject will have his/her labs repeated before being withdrawn from the study. 
 


The study medication will be stopped if a subject has a serious adverse event, but will not 
necessarily be stopped for exacerbation of psychiatric symptoms or any other adverse event. If 
the PI or co-investigator considers continuation of the study medication to be safe after a 
worsening of psychiatric symptoms, and the subject wishes to continue, the subject’s treating 
psychiatrist will be contacted and will make the final decision whether the subject will be allowed 
to continue taking study medication.  
 
Female subjects may be terminated from the study if they become pregnant at any time while 
participating in the study. Subjects who fail the urine screening for illegal drugs during the 
screening visit will be deemed a screen fail and terminated from the study.  We will not 
document the results from the urine drug screen in the patient study records. We will maintain a 
separate log of the reasons for screen fail. This log will have the counts of screen fails for 
various exclusion factors including current substance abuse. This log will have no subject 
information and will have no link to subject id.   
 
Subjects may also withdraw their consent from the study at any time for any reason, 
including: physical or emotional discomfort associated with taking the study medication, 
physical or emotional discomfort associated with performing study procedures, or 
inability to come in for required study visits.  
 
If at any time the study sponsor or research personnel at UMass decide to terminate the 
study, subjects’ consent will be withdrawn involuntarily.  
 
For subjects terminated or withdrawn from the study, they will be asked to have an “exit” 
visit. Vital signs, ECG, side effect assessment and routine blood tests (CBC, basic 
metabolic profile) will be performed during the visit. 
 
15) Risks to Subjects* 
Potential Side effects of Exenatide: 
1) Risk of Thyroid C-cell tumors. 
In both genders of rats, exenatide extended-release caused a dose-related and 
treatment-duration dependent increase in the incidence of thyroid C-cell tumors 
(adenomas and/or carcinomas) at clinically relevant exposures compared to 
controls. A statistically significant increase in malignant thyroid C-cell carcinomas 
was observed in female rats receiving exenatide extended-release at 25-times 
clinical exposure compared to controls and higher incidences were noted in 
males above controls in all treated groups at ≥ 2-times clinical exposure. The 
potential of exenatide extended-release to induce C-cell tumors in mice has not 
been evaluated. Other GLP-1 receptor agonists have also induced thyroid C-cell 
adenomas and carcinomas in male and female mice and rats at clinically relevant 
exposures. It is unknown whether exenatide will cause thyroid C-cell tumors, 
including medullary thyroid carcinoma (MTC), in humans, as the human 
relevance of exenatide extended-release-induced rodent thyroid C-cell tumors 
could not be determined by clinical or nonclinical studies. 
2) Acute Pancreatitis. 


Based on postmarketing data, exenatide has been associated with acute 
pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. 
3) Hypoglycemia 
The endocrine responses of exenatide treatment are glucose dependent. Exenatide by 
itself usually does not cause hypoglycemia. Hypoglycemia may occur if it is prescribed 
with other anti-diabetic medications such as sulfonylurea. Therefore, patients who are 
currently on sulfonylurea are excluded from the study. 
4) Kidney Problems 
There have been postmarketing reports of altered renal function with exenatide, 
including increased serum creatinine, renal impairment, worsened chronic renal failure 
and acute renal failure, sometimes requiring hemodialysis or kidney transplantation. 
Some of these events occurred in patients receiving one or more pharmacologic agents 
known to affect renal function or hydration status such as angiotensin converting 
enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or diuretics. Some events 
occurred in patients who had been experiencing nausea, vomiting, or diarrhea, with or 
without dehydration. Reversibility of altered renal function has been observed in many 
cases with supportive treatment and discontinuation of potentially causative agents, 
including exenatide. Exenatide has not been found to be directly nephrotoxic in 
preclinical or clinical studies. 
5) Allergic Reaction 
There have been postmarketing reports of serious hypersensitivity reactions (e.g. 
anaphylaxis and angioedema) in patients treated with exenatide. 
6) Common Side effects 
The most common side effects of exenatide include nausea, diarrhea, headache, 
vomiting, constipation, itching at the injection site, small bump at the injection site 
and indigestion. 
 
 
Common 
Less Common 
Rare 
Nausea, vomiting, 
diarrhea, injection site 
nodule, constipation, 
headache 
dyspepsia 
Pain in the stomach 
area (abdomen) 
 
Low blood sugar 
(shakiness, confusion, 
feeling jittery, 
weakness, drowsiness 
and dizziness, hunger, 
Shortness of breath, 
swelling of eyes, face, 
tongue, lips, throat, 


irritability and fast 
heartbeat) 
arms, hands, feet, 
ankles or lower legs. 
Lump or swelling in 
the neck, hoarseness, 
trouble breathing or 
swallowing, 
 
Risk of EKG testing: There are also small risks in using EKG equipment, such as skin 
irritation. However, all research members involved in EKG testing have experience in 
operating the machinery. 
Risk of Blood draws: The risks of having blood drawn include slight pain when the needle is 
inserted. Subjects may develop a harmless black and blue mark, and their arm may be sore. 
Occasionally, some people feel dizzy or lightheaded when blood is drawn. They may become 
sweaty, feel cold or tingly, and may faint or throw up. Risks that are possible but unlikely include 
infection, nerve damage, and puncturing an artery instead of a vein. Standard high quality 
clinical practice will be used to draw blood in order to avoid discomfort and infection. 
 
Risk of MRI scans: Risks of MRI are rare and limited mainly to the risks associated with the 
interactions between metal objects and the very strong magnetic field of the magnet.  One such 
potentially lethal interaction is the superheating of metal fragments in a patient’s body that result 
in high temperature internal burns.  Injury and death can also occur from metal objects being 
pulled at high speed into the center of the magnet field. There is the extremely low theoretical 
risk of oxygen depletion from the release of helium gas in the event that the magnet had to be 
emergently quenched (this being an occurrence that is on its own extremely rare).   
Claustrophobia while inside the magnet for the MRI assessments can potentially 
precipitate a panic attack in some subjects. Subjects with known claustrophobia will be 
excluded from this study.  
Some subjects report dizziness, mild nausea, headaches, a metallic taste, double vision, 
or seeing flashing lights while in the MRI scanner. These symptoms, if present, 
disappear shortly after leaving the MRI scanner. 
In rare cases, a very slight, uncomfortable tingling of the back can occur in the MRI 
scanner. The scan can be modified to prevent this if the subject notifies the technologist 
of this feeling. 
There is also a remote possibility that subjects’ confidentiality may be compromised. However, 
members of the research team will do everything in their power to maintain their confidentiality. 
The PI is responsible for oversight of the proposed studies.  
 
Risks of Genetic Testing: Since genetic information is unique to every subject there is a small 
chance that it can be traced back to the individual. However the risk of this happening is very 
small, but may grow in the future. The federal law called the Genetic Information 
Nondiscrimination Act (GINA), in general, makes it illegal for health insurance companies, group 
health plans, and most employers, except those with fewer than 15 employees, to discriminate 
based on an individual’s genetic information.  However, it does not protect against 
discrimination by companies that sell life insurance, disability insurance, or long-term care 


insurance. If the subject does not share information about the blood samples in this study, he or 
she will reduce this risk. 
 
16) Potential Benefits to Subjects* 
There may be no direct benefits to taking part in this study. However, exenatide may have a 
beneficial role in improving the psychopathology profile and cognition in patients with 
schizophrenia.  
 
The results of this study may also lead to an increased understanding of how exenatide might 
affect psychiatric symptoms, cognition and metabolic profile in individuals suffering from 
schizophrenia. 
 
17) Vulnerable Populations* 
Adults suffering from schizophrenia comprise the subject population for this study. Due 
to the nature of the disease, some subjects may exhibit some level of cognitive 
impairment. Thus, individuals interested in participating in the study must be evaluated 
for capacity to provide informed consent by a research coordinator. Subjects must score 
100% on a true-false questionnaire consisting of important questions relating to the 
study procedure in order to participate. 
 
Pregnant women, children, and neonates are excluded from participating in the study.    
18) Multi-Site Research* 
This is not a multi-site study.  
19) Community-Based Participatory Research* 
          N/A 
20) Sharing of Results with Subjects* 
During the informed consent process, members of the research team will ask for 
subjects’ permission to have their blood test and electrocardiogram (ECG) results sent to 
their primary care provider or treating psychiatrist for safety purposes. Results from the 
urine drug test will not be included. Clinically significant lab tests, EKG readings, and 
MRI findings will be relayed to the subject’s primary care provider to ensure their safety. 
We will also ask for subject’s permission to share clinically significant MRI findings with 
his primary care provider. If the subject’s PCP or treating psychiatrist contacts the PI 
regarding his/her lab or EKG results then the subject’s PCP or treating psychiatrist will 
consult with the PI and if they both agree then the subject may continue in the study.  
The letter to share EKG, labs findings with the subject’s PCP or treating psychiatrist is 
used only to communicate results after the subject is enrolled in the study. It is not used 
as a recruitment tool. 
Subjects will be informed if their results from a treatment efficacy assessment or 
diagnostic blood test warrant termination from the study. If a subject becomes pregnant 


at any point during the study or fails the drug screening urine test, their health care 
providers will not be notified. Results from these tests will, however, remain part of the 
subject’s study record indefinitely. 
 
21) Setting 
Potential subjects will be recruited from UMass health care facilities and the local 
community. Research procedures will be conducted at the Clinical Research Unit in 
Biotech One, Suite 100, Community Healthlink, and the Clinical Research Center 
located in the Ambulatory Care Center at 55 Lake Avenue North, Worcester, MA.   
MRI scans will take place at the MRI imaging suite at the University of Massachusetts 
Medical School’s main campus.  
We were informed on 8/23/2017 that the MRI machine at the UMass site would be 
inoperative until early November due to scheduled maintenance. The MRI scans serve 
as study assessments, and are not related to patient safety. As we have ongoing 
subjects that require scans during this time, we established temporary services with 
UMass Memorial’s MRI & Imaging Center at Shields MRI Imaging Suite on 214 
Shrewsbury Street, Worcester MA 01604 to complete scans for subjects while the 
original MRI machine undergoes maintenance.   
22) Resources Available 
All research personnel have completed CITI training and are aware of Good Clinical 
Practices (GCP). The PI is a senior psychiatrist who specializes in schizophrenia 
treatment and research. Both the Principal Investigator and Co-Investigator each have 
more than 10 years of experience working with individuals suffering from schizophrenia 
and substance abuse. 
 
The study coordinator (i.e. research assistant) will be involved in activities such as 
reviewing study procedures with each subject, obtaining informed consent, data-entry, 
and blood sample collection. The study coordinator will also be responsible for 
administering questionnaires and conducting assessments. The study coordinator is 
certified in phlebotomy, and has completed sufficient training in order to obtain informed 
consent, conduct study assessments, enter data, etc. 
 
The PI will be held responsible for oversight of the study procedure. The PI and Co-
Investigator will also be responsible for identifying AEs and SAEs and for terminating a 
subject if their physical and/or mental health is compromised as a result of the study 
treatment.  
Research nurses who are qualified registered nurses (RN) may be involved in study activities 
such as administering Exenatide injections and completing questionnaires and other study 
assessments. 
The PI will discuss individual roles with each member of the research team once the 
study commences. 
 


The PI can be contacted by phone and the UMass Memorial Emergency Service is 
available for psychiatric and medical assessment of research subjects.  
 
23) Prior Approvals 
        We have received IBC approval for all of our studies on 10/30/2015. The IBC 
approval letter has been uploaded.  
24) Recruitment Methods 
Potential subjects will be recruited from Community Health Link (CHL, 72 Jacques 
Avenue) and the Ambulatory Psychiatry Clinic (located at 26 Queen Street & UMass 
Hahnemann Campus). Members of the study team will be stationed at these sites to 
help facilitate recruitment. All research staff will have access to electronic medical 
records of patients at these outpatient departments. CHL is the largest, multi-service, 
private, non-profit mental health organization in central Massachusetts with 5,000 
outpatients over 18 years of age.  CHL cares for many with severe and persistent mental 
illness.  Approximately 1,000 individuals are diagnosed with schizophrenia or 
schizoaffective disorder, and 700 with bipolar disorder.  Dr. Fan is Director of the 
schizophrenia specialty clinic and the early psychosis clinic at CHL.  Currently CHL has 
about 200 active schizophrenia patients. The Ambulatory Psychiatric Clinic serves 
patients aged 18 and up. The clinic handles more than 40,000 visits per year. Patients 
come from a wide range of socioeconomic backgrounds.  
Due to the patient population at this site, the research team will have access to many 
eligible patients. Both the PI and Co-Investigator also have extensive connections with 
several clinicians working at CHL, which will streamline recruitment efforts. Frequent 
communication with other clinicians at CHL will provide the basis for recruitment for this 
study. 
Subjects will also be recruited from two inpatient psychiatric clinics at University campus, 
8 East and PTRC, as well as Emergency Mental Health services. All research personnel 
(study coordinator(s), Co-Investigator, and PI) will have access to the electronic medical 
records of patients residing in these units. This is necessary in order to have immediate 
access to patients’ medical records once they are admitted to these clinics and to 
expedite the recruitment process. Subjects will also be recruited (using electronic 
medical records) from the Outpatient Psychiatry Clinic located at 26 Queen Street. In the 
event that the research team identifies a potential candidate for the study, the research 
team will contact the patient's clinician regarding the individual's study eligibility. If the 
clinician believes his or her patient would be a good candidate for the study, the clinician 
will provide information (via study fliers, brochures, etc.) on how to contact the research 
team, or if the subject provides a verbal permission to be contacted to his/her clinician 
the research team will reach out to the patient. Members of the research team will not 
contact prospective subjects directly. Utilizing this method of recruitment will allow the 
researchers to access more potential subjects.  
In situations where an individual’s attending physician or psychiatrist is the referral 
source, the attending doctor will initiate the study discussion with the eligible individual. If 
the individual expresses interest and agrees to be contacted by a member of the study 
team, the study coordinator or one of the investigators will follow-up with the potential 
subject.  


In addition, a permission to contact form will be administered to potential subjects in both 
inpatient and outpatient care settings by treating clinicians or research staff. This form 
allows patients to provide their name, contact information, and permission to be 
contacted by a member of our research team to discuss the study further. 
Due to difficulties in recruiting patients in this population, we propose sending out a letter 
to eligible study participants. A research staff member will screen for eligible study 
patients in advance. The letter will be generic; simply notifying the patient that he/she 
may receive a telephone call after 7 days of receipt of that letter from a member of the 
UMass Psychotic Disorders Program. We believe this will give sufficient time for patients 
to have received our letter.  The letter will also provide the PI contact information in case 
any patient wishes to decline participation or discuss the study prior to talking with a 
research staff member. We will make note of any patient declining to participate at this 
stage so that all staff are aware not to recruit these patients. The letter will be signed by 
Dr. Xiaoduo Fan who is the PI for the study and also the Director of the Schizophrenia 
Clinic within Community Healthlink. Additionally the Community Healthlink logo has been 
appropriately placed at the top of the letter head to provide familiarity to patients who will 
be receiving this letter. 
Advertisements will be utilized in the form of fliers and brochures, as well as a 
description on the Psychotic Disorders Program website, to increase access to potential 
participants. IRB-approved text will also be submitted to selected local newspapers and 
magazines in order to broaden our recruitment efforts in the local community. In addition, 
we will be utilizing the internet and various forms of social media to advertise the study. 
Ads containing IRB-approved language will be posted on various websites such as 
Craigslist, Facebook, Twitter, etc. Each ad will also contain information on other studies 
being conducted by the Principal Investigator (again, only language that has been 
approved by the IRB will be included in these advertisements). A multi-study tear away 
flier will be used including IRB-approved text about this study, as well as other IRB-
approved text detailing other IRB approved studies. The shell of the multi-study flier as 
well as the text specific to this study has been submitted for approval. A program 
business card will also be used including contact information that potential participants 
can call and see if they may be eligible for one of our studies. The business card will not 
include study specific language. Also, we will be using the Conquering Diseases 
Volunteer Database Docket #H-12562 as a recruitment tool. All aforementioned modes 
of advertisement have been approved by the IRB, and any advertisements in the future 
will consist only of IRB-approved language. We will also have a secure lock box 
available in the Community Healthlink (CHL) Outpatient waiting area with permission to 
contact forms for those who are interested to leave their contact information to be 
reached in the future. The key to the lock box will remain with the research staff at all 
times. The following instructions will be posted on the box for potential subjects to read: 
“If you are interested in being contacted to learn more about our studies, please provide 
your contact information on one of the forms below and put the form in the secure lock 
box at CHL so that we may contact you to tell you more about the studies and see if you 
are eligible.”     
If an individual appears eligible and expresses interest in participating, the study 
coordinator will initiate the screening process. The screening process is described in 
Section 10 “Procedures Involved”. 
The study will be advertised via IRB-approved fliers and brochures which will be placed 
at strategic locations at CHL and across the UMass Medical School campus. The study 
will also be advertised via fliers and brochures at local homeless shelters, various group 


homes, bus stops, and grocery stores in the Central Massachusetts area. We will also 
advertise at various private practice clinics, local hospitals, mental healthcare facilities, 
peer support centers, and club houses in the Worcester area. We will also distribute 
IRB-approved fliers and brochures to selected locations in the broader Central 
Massachusetts area, including towns surrounding the Greater Boston area.    
To improve our recruitment efforts, we would like to host Lunch and Learns with the 
clinicians and staff at CHL, UMass Medical School, and various private practice clinics in 
the Worcester and Greater Boston area. During the Lunch and Learn, we will provide 
information to the attendees regarding the purpose and general procedures of this 
research study, and how potential subjects can be referred for this study. Referrals will 
be handled as stated earlier in Section 24. We will only use IRB approved material and 
text for these Lunch and Learn sessions. 
We will also be using a “Service Provider” letter to improve recruitment. This letter will be 
sent from the PI to psychiatric patient care workers in the Worcester and Greater Boston 
area. The letter will contain information about our research program, a list our ongoing 
research studies, and the study team’s contact information.  If the recipient has a 
potential subject they would like to refer for this study, they will inform the study team 
using the contact information in the letter. The study team will confirm with the recipient 
that the potential subject has expressed interest in this research study, and the study 
team will follow-up with the potential subject.  
Subjects will be compensated for their participation after each study visit. Subjects will be paid 
$15 for screening visit, $20 for the baseline visit, $10 each for week 1 to 11, week 13 to 17, and 
week 19 to 23; $25 each for week 6, 12, 18 and 24 visit. Subjects will receive retention material 
in the form of a pen with our study team information upon randomization in the study. An image 
of the pen has been uploaded to the eIRB site.  Subjects will also receive retention material in 
the form of a water bottle upon completion of their week 12 visit. Subject will have two MRI 
scans and will be compensated $30 per MRI scan for a total of $60 Thus, if a subject completes 
the study, they will be paid a total of $395 over the course of 24 weeks.  
 
In an effort to improve recruitment and completion rates of our subjects, we would like to offer 
taxi vouchers or additional travel compensation of $10 for select patients, on a case by case 
basis, for certain study visits. 
 
25) Local Number of Subjects 
A total of 110 subjects are expected to be enrolled, with the goal of randomizing 70 of those 
subjects.  
 
26) Confidentiality 
Data will be obtained in study binders in a locked room located at Biotech One, Suite 
100. Participant data will be coded to protect privacy. Each participant will be assigned a 
unique identification number.  The list of participant names and identification numbers 
will be kept separate from the database. Only members of the research team will be able 
to derive an individual’s identity from their study ID code. The key to the code is stored 
on secure server and can only be accessed through password-protected computer. All 
hard copies of research records will be kept in separate locked files. Access to the 
computerized data system is carefully protected by a secured password entry system. 


Access to participants' data will be restricted to project investigators on a need to know 
basis. Data entry will be performed by the study coordinator and will be reviewed by the 
research manager and the PI for accuracy. Access to the database will be restricted by 
password.  
The secure lock box that will be used for recruitment purposes will only be accessed by 
the research staff assigned to this study. The research staff will be responsible for 
securely collecting the contents of the lock box on a weekly basis and transporting them 
to a secure location where the confidential information will be safely stored at Biotech 
One, Suite 100. The keys to the lock box will remain with the study coordinator at all 
times in a secure location.  
Stored blood samples for future research use will be drawn at Biotech One, Suite 100, 
and stored in a -80F, which is located in a locked room at Biotech One. A log system will 
be put in place to ensure that only authorized research personnel have access to the 
samples. The PI will be held responsible for the safety and security of these samples. 
27) Provisions to Protect the Privacy Interests of Subjects (HIPAA) 
Identifiable health information from a subject’s medical record will be collected by 
members of the research team. This information will only be used for purposes related 
to the study and will not be used to identify the subject in any way by non-members of 
the research team. 
Results from study assessments, study questionnaires, blood tests, and psychiatric 
evaluations will only be made available to the research team. The research team will 
send a subject’s lab, electrocardiogram (ECG) and clinically significant MRI results to 
their primary care providers or their treating psychiatrist.  
Subjects who do not receive treatment through the UMass Memorial Healthcare system 
will be asked to sign a protected health information release form. This form will serve 
two purposes. First, the release form will allow the research staff to gather information 
on a given subject’s medical record from their primary care doctor or psychiatrist 
(residing outside of the UMass Memorial Healthcare system) in order to determine 
study eligibility. Second, the form will also enable research staff to send laboratory and 
EKG results to the subject’s primary care doctor or treating psychiatrist. 
Subjects are free to contact the research team regarding study related questions at any 
point while they are a participant in the study. Subjects are encouraged to confide in the 
research team if they are at all concerned or unsure about specific aspects of the study. 
Each subject must also score 100% on a brief true-false questionnaire designed to 
ensure that the subject understands the study procedure and is aware of their rights as 
a study participant. Subjects may contact the PI by phone if they have questions 
regarding the study.  
 
28) Compensation for Research-Related Injury 
If the subject is injured as a direct result of his or her participation in the study, there will 
be no compensation provided by the research team. No funds have been set aside. In 
the unlikely event of injury, subjects or their insurance will be responsible for coverage. 


29) Economic Burden to Subjects 
Exenatide will be provided for study subjects at no cost. All medical tests, blood tests, 
and study assessments will also be conducted at no additional cost for each subject. 
Subjects will otherwise continue to pay for their routine medical care in the usual way. 
30) Consent Process 
A potential subject who expresses interest in the study will be met by the study 
coordinator at Biotech One, Suite 100 or Community Healthlink and verify that the 
patient is interested in participating, understands that participation is voluntary, and 
understands that declining participation will not affect his or her treatment at the facility. 
The PI, Co-Investigator, and study coordinator(s) will clearly explain the study 
procedure, risks and benefits of participating (including potential risks involving the study 
medications), and other aspects of the study that are of interest to each subject. 
Specifically, the study coordinator will review logistical aspects of the study (study 
timeline, study visit procedures, etc.), while the PI or Co-Investigator will provide 
information on the study medications. Individuals who express interest will be evaluated 
by the study coordinator for capacity to provide informed consent. We have developed a 
questionnaire consisting of approximately 10 true-false questions about important 
aspects of the study procedures, potential risks, the subject’s right to end participation at 
any time or to speak to a patient advocate, etc. Subjects must score a 100% to 
participate in the study. Subjects who are judged to be competent will then be asked to 
sign the study consent form. In addition, prior to starting the study medication, the PI or 
Co-Investigator will meet with each subject to review the risks of taking the study 
medication, as well as which medications should be avoided while taking exenatide. In 
addition, potential participants will also be asked if they would like us to notify their 
primary care physician or their psychiatrist of their participation in the study. 
Many of our potential subjects live in supported living/group home facilities that are 
staffed with individuals who offer day to day support for these subjects. These staff 
members are also involved in patient care. As such, we would like to notify a potential 
subject’s supported living/group home staff of the subject’s participation in this study. 
The study team will ask all potential subjects if they live in a supported living/group home 
facility, and if so, the study team will ask permission to notify the staff at the subject’s 
supported living/group home facility. 
We want to enroll a diverse patient population with different levels of cognitive function 
and varied levels of schizophrenia symptom severity. If the subject lacks the capacity to 
provide informed consent, then the subject’s authorized legal guardian will be present for 
the consent process. Potential participants and guardians are encouraged to read the 
consent form and ask questions. After providing a detailed overview of the study, the 
study coordinator will present the questionnaire consisting of approximately 10 true-false 
questions about important aspects of the study procedures, potential risks, the subject’s 
right to end participation at any time or to speak to a patient advocate, etc. to the subject 
and the subject’s authorized legal guardian. Participants are further encouraged to solicit 
input from significant others and/or care providers, if appropriate. To minimize coercion, 
the consent form has language that clearly spells out that participation in the study is 
voluntary and refusal to participate will not affect a person's health/mental health care. 
Subjects and their authorized legal guardians will be required to sign both the informed 
consent form and the true-false questionnaire form if they agree to participate. We will 
explain the study in a language understandable to the subject and obtain his or her 


assent. Subject will be particularly closely monitored. Subject will be withdrawn if they 
appear unduly distressed. 
The consent process will take place at Community Health Link or at Biotech One, Suite 
100. Research personnel will follow HRP-090.  
All currently enrolled subjects will be informed of the most recent modification and at 
their next study visit they will be “re-consented” to the recent changes to the consent 
form. 
 
 
31) Process to Document Consent in Writing 
Subjects will review the informed consent document with a study coordinator or the PI. 
Subjects will give their consent by signing the informed consent document. Each subject 
will receive a paper copy of the signed consent form.  
Standard Operating Procedures HRP-090 (Informed Consent Process for Research) and 
HRP-091 (Written Documentation of Consent) will be followed. 
 
32) Drugs or Devices 
Subjects will be given weekly injections of exenatide (2mg per dose) or placebo for 24 
weeks as an adjunctive therapy. The medication will be administered by the PI or the co-
investigator, or a medically qualified designate such as a registered nurse. The UMass 
research pharmacy is responsible for randomization and preparation of study 
medication. 
 
The use of exenatide in this study does not constitute an IND. It is exempt under Section 5 of 
the Drug Worksheet (HRP-306): 
• 
The drug is lawfully marketed in the United States 
• 
The research is not intended to be reported to the FDA as a well-controlled study in 
support of a new indication for use nor intended to be used to support any other 
significant change in the labeling for the drug  
• 
The research is not intended to support a significant change in the advertising for the 
product  
• 
The research does not involve a route of administration or dosage level or use in a 
patient population or other factor that significantly increases the risks or decreases the 
acceptability of the risks associated with the use of the drug product 
• 
The research is conducted in compliance with the marketing limitations described in 21 
CFR 312.7).  
Please see attached email from the FDA.  In addition, the endocrine responses of exenatide 
treatment are glucose-dependent, which explains the low risk of hypoglycemia with exenatide in 
both diabetic or non-diabetic patient populations (Kendall et al., 2005, Aviles-Olmos et al., 
2013), as well as healthy volunteers (Khoo et al., 2010). Therefore the PI feels that it will not 
affect their acceptability. 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Diabetologia 53:139-143. 
 
 
 
 
 


 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
(SAP) 
 
 
 
The Effect of Adjunctive Exenatide Treatment on Psychopathology, Cognition and Metabolism 
in Patients with Schizophrenia 
 
PI: Xiaoduo Fan, MD, MPH 
 
Document Date: 11/30/2019 
 
Identifier: NCT02417142 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Participants 
Adult outpatients with schizophrenia or schizoaffective disorder were recruited from the UMass 
Memorial Healthcare System an in Central Massachusetts. Psychiatric diagnosis was determined 
using the Structured Clinical Interview for DSM-IV (SCID). Other inclusion criteria included: 1) 
age 18-65 years; 2) stable dose of the current antipsychotic drug for at least one month; 3) well 
established compliance with outpatient treatment per treating clinician’s judgment; 4) able to 
complete the cognitive assessment battery (must be English speaking); 5) female subjects will be 
eligible to participate in the study if they are of non-childbearing potential or of child-bearing 
potential and willing to practice appropriate birth control methods during the study. Exclusion 
criteria were: 1) inability to provide informed consent, or for individuals with a legal guardian, 
inability to provide assent or a lack of informed consent from the legal guardian; 2) current 
substance abuse; 3) Subjects who are not on a stable dose of an antipsychotic medication for at 
least a month prior to enrollment; 4) psychiatrically unstable per treating clinician’s judgment; 5) 
Uncontrolled medical condition including uncontrolled hypertension, diabetes, seizure disorder, 
severe cardiovascular, cerebrovascular, pulmonary, thyroid diseases, and gastroparesis; 6) 
history of ketoacidosis; 7) currently taking insulin; 8) currently taking meglitinides (repaglinide 
and nateglinide); 9) currently on immunosuppressant medication regularly including oral 
steroids; topical and inhalant steroids are allowed; 10) currently on sulfonylurea drugs (e.g. 
glyburide); 11) current, active chronic infection (including tuberculosis, HIV and hepatitis), 
malignancy, organ transplantation, blood dyscrasia, central nervous system demyelinating 
disorder, and any other known autoimmune or inflammatory condition; 12) pregnant or 
breastfeeding; 13) prisoners; 14) estimated glomerular filtration rate (eGFR) < 35 ml/min. The 
study was approved by the institutional review board of the University of Massachusetts Medical 
School and followed the Good Clinical Practice guideline. 
 
Procedures 
 
Baseline visit: Eligible subjects came to the clinic for the baseline visit. Fasting blood samples 
for glucose, insulin, HbA1c, lipid profile, comprehensive metabolic profile, CBC, high 
sensitivity C-reactive protein (hsCRP), and tumor necrosis factor α (TNF-α) were obtained. The 
subject completed the clinical symptoms assessment, the extrapyramidal symptoms (EPS) 
assessment, and vital signs. Then the subject received the study medication (either exenatide 
2mg or placebo weekly injection).  The randomization was based on a double-blinded 1:1 ratio 
using permuted block with randomly varying block size. 
 
Follow-up visits (week 1-24): Subjects came to the clinic weekly to receive the study 
medication injection; possible side effects were assessed weekly. At week 6, 12, 18, 24 visits, 
vital signs, the clinical symptoms assessment and the EPS assessment were repeated; fasting 
blood samples for glucose, insulin, HbA1c, lipid profile, comprehensive metabolic profile, CBC, 
hsCRP, and TNF-α were obtained.   
 
Clinical symptoms assessment: The clinical symptoms assessment included: The Scale for 
Assessment of Negative Symptoms (SANS), the Positive and Negative Syndrome Scale 
(PANSS), the Clinical Global Impression Scale (CGI), the Calgary Depression Scale for 
Schizophrenia (CDSS), the Heinrichs Carpenter Quality of Life Scale (QLS), the Instrumental 


Activities of Daily Living Scale (IADL), and the MATRICS Consensus Cognitive Battery 
(MCCB). 
  
EPS assessment: The EPS scales included: the Simpson-Angus Scale, the Barnes Akathisia 
Scale, and the Abnormal Involuntary Movement Scale (AIMS).   
 
Bioassay: Routine blood tests (glucose, insulin, HbA1c, lipid profile, comprehensive metabolic 
profile, CBC, hsCRP) were performed at the UMass Core Lab. Insulin immunometric assays 
were performed using an Immulite Analyzer (Diagnostic Product Corporation, Los Angeles, CA) 
with an intra-assay coefficient of variation of 4.2–7.6%. Fasting plasma glucose was measured 
with a hexokinase reagent kit (A-gent glucose test, Abbott, South Pasadena, CA). Glucose assays 
were run in duplicate, and the intra-assay coefficient of variation ranged from 2 to 3%. The 
homeostatic model assessment of insulin resistance (HOMA-IR) was calculated by the following 
formula: [fasting serum insulin concentration (μIU/mL) × fasting plasma glucose concentration 
(mmol/L)]/22.5. Hemoglobin A1C (HbA1c) was measured with high performance liquid 
chromatography using an automated analyzer (normal range 4.5–6.5%) (SmithKline, Van Nuys, 
CA). Fasting total plasma cholesterol and triglyceride levels were measured enzymatically, and 
the HDL cholesterol fraction was measured after precipitation of low-density lipoprotein (LDL) 
and very-low-density lipoprotein (VLDL) with dextran sulfate magnesium. LDL levels were 
determined by the direct LDL reagents (Roche Diagnostics, Indianapolis, IN). Plasma levels of 
IL-6 and TNF-α were measured by a commercially available enzyme-linked immunosorbent 
assay (R&D Systems, Minneapolis, MN, USA). Serum levels of hsCRP were measured via a 
high-sensitivity latexenhanced immunonephelometric assay on a BN II analyzer. 
 
Statistical analysis: Statistical analysis was performed using SPSS (version 24.0, IBM Corp, 
Armonk, NY, USA). Descriptive statistics were performed to summarize demographic and 
clinical characteristics of the study sample. Group comparisons were performed using 
independent samples t test for continuous variables and the Fisher exact test or Chi-square test 
for categorical variables. The outcome measures were repeated at different time points. 
Therefore, analysis of repeated measures using mixed models was performed to compare the 
change over time in outcome measures between the two treatment groups while controlling for 
potential confounding variables. The mixed model approach does not require subjects to have the 
same number of study visits or measurements and uses all available data instead of eliminating 
subjects with missing data, resulting in unbiased estimates of the model parameters when data 
are missing at random. Further, for those who completed 24-week treatment, analysis of 
covariance (ANCOVA) was used to compare change scores from baseline to week 24 between 
the two treatment groups controlling for potential confounding variables. For all analyses, a P 
value less than 0.05 (two-tailed) was used for statistical significance.