Conditions: Obesity, Visceral Cardiovascular Diseases Fat Disorder
Keywords: Obesity Visceral Cardiovascular Disease Fat
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 235
Healthy volunteers: yes

Brief summary:
This study is a clinical study to investigate the efficacy of liraglutide compared to placebo in reducing visceral adiposity measured by MRI in overweight or obese subjects at high risk for cardiovascular disease after 40 weeks on-treatment.

Detailed description:
Obesity has long been recognized as a risk factor for all-cause mortality and morbidity, including the development of cardiovascular and metabolic diseases such as coronary artery disease, hypertension, insulin resistance, diabetes, and dyslipidemia. Obesity has recently been formally defined as a chronic disease characterized by pathophysiological processes that result in increased adipose tissue mass and can result in increased morbidity and mortality. Although the health risks associated with obesity are clear, there is an emerging appreciation that obesity per se, as defined by simple anthropometric measures such as waist circumference or body mass index (BMI), is neither necessary nor sufficient to promote cardiometabolic disease and atherosclerotic cardiovascular disease (ASCVD) risk. As a result, BMI alone is an insufficient marker of risk and may not accurately identify individuals at elevated risk for ASCVD. There is a pressing need to more accurately phenotype obesity to identify individuals at elevated risk for ASCVD that may benefit from more intensive preventive and therapeutic strategies

Arms:
arm 1: Drug: Liraglutide Active Drug

Other Names:

* Saxenda

Escalate the liraglutide (active) dose to 3.0 mg/day over a 4 week period following an initial dose of 0.6 mg/day and weekly dose escalation steps of 0.6 mg/day through subcutaneous injection. arm 2: Drug: Placebo (for Liraglutide at a concentration of 6.0 mg/mL) Placebo tablet manufactured to mimic Liraglutide at a concentration of 6.0 mg/mL

Other Names:

* Placebo
* Saline injection

Escalate the Placebo dose to 3.0 mg/day over a 4 week period following an initial dose of 0.6 mg/day and weekly dose escalation steps of 0.6 mg/day through subcutaneous injection.

Interventions: intervention 1: Liraglutide intervention 2: Placebo
Intervention descriptions: intervention 1: Liraglutide is administered once daily by subcutaneous injections with the pen-injector, either in the abdomen, thigh or upper arm. Injections can be done at any time of day irrespective of meals. Subjects will be instructed to escalate the liraglutide dose to 3.0 mg/day over a 4 week period following an initial dose of 0.6 mg/day and weekly dose escalation steps of 0.6 mg/day. intervention 2: Placebo is administered once daily by subcutaneous injections with the pen-injector, either in the abdomen, thigh or upper arm. Injections can be done at any time of day irrespective of meals. Subjects will be instructed to escalate the placebo dose to 3.0 mg/day over a 4 week period following an initial dose of 0.6 mg/day and weekly dose escalation steps of 0.6 mg/day.

Protocol document:
SAP_002.pdf: 
Published: 7/28/2020 12:46 PM 
 
 
Impact of Liraglutide 3.0 on Body Fat Distribution—Statistical Analysis Plan 
NCT 03038620 
July 28, 2020 
 


Published: 7/28/2020 12:46 PM 
 
 
Statistical Analysis Plan - Impact of Liraglutide 3.0 on Body Fat Distribution 
 
Important points: 
1. Modified intention-to-treat (mITT) which includes data from the full-analysis set of all 
participants who underwent randomization and had a follow-up endpoint assessment (full 
analysis set, FAS). 
2. Secondary analyses will be performed using per-protocol approach which includes data 
from the full-analysis set of all participants who underwent randomization, received at 
least one dose of study drug, and completed a final imaging visit at the planned study 
end; this is termed a “completers analysis”. 
3. Missing values will be imputed with the Monte Carlo Markov Chain method. Sensitivity 
analyses will be performed to determine the effect of missingness/imputation on the 
primary and secondary outcomes. 
 
Descriptive: 
1. Baseline characteristics of study population overall and stratified by treatment assignment 
2. Mean medication adherence as a percentage of drug taken/drug dispensed after 
randomization through final outcomes assessment.  
3. Proportion losing ≥ 5% body weight and ≥ 10% body weight in each group (and 
compared with p-value).  
4. Adverse events: a) most frequent (%), b) serious (%), rate of withdrawal in each group 
for adverse events 
 
Endpoints analysis: 
Note: All to be reported as mean ± standard deviation in each group with between group 
differences reported as placebo-adjusted difference with 95% confidence interval.  
1. Primary endpoint: Relative percent change in visceral adipose tissue volume 
2. Secondary endpoints 
a. Absolute change in visceral adipose tissue volume 
b. Relative percent change in body weight 
c. Absolute change in body weight 
d. Relative percent change in waist circumference 
e. Absolute change in waist circumference 
f. Relative percent change in total body adipose tissue volume 
g. Absolute change in total body adipose tissue volume 
h. Relative percent change in abdominal subcutaneous adipose tissue volume 
i. Absolute change in abdominal subcutaneous adipose tissue volume 


Published: 7/28/2020 12:46 PM 
 
j. Relative percent change in lower body subcutaneous adipose tissue volume 
k. Absolute change in lower body subcutaneous adipose tissue volume 
l. Relative percent change in liver fat percent 
m. Absolute change in liver fat percent 
n. Relative percent change in total body lean volume 
o. Absolute change in total body lean volume 
p. Relative percent change in total thigh muscle volume 
q. Absolute change in total thigh muscle volume 
r. Relative percent change in mean anterior thigh muscle fat infiltration percent 
s. Absolute change in mean anterior thigh muscle fat infiltration percent 
3. Subgroup analyses 
a. To be performed for the primary endpoint as well as selected secondary endpoints 
as below: 
i. Relative percent change in abdominal subcutaneous adipose tissue volume 
ii. Relative percent change in lower body subcutaneous adipose tissue 
volume 
iii. Relative percent change in liver fat percent 
iv. Relative percent change in total thigh muscle volume 
v. Relative percent change in mean anterior thigh muscle fat infiltration 
percent 
b. Age (stratified by median) 
c. Sex (M/F) 
d. Race (non-Hispanic black, non-Hispanic white, Hispanic) 
e. Body mass index (kg/m2) category (overweight 25-29.9, class I 30-34.9, class 
II/III ≥35) 
f. Sex-specific tertiles of total body fat (T1, T2, T3) 
g. Prediabetes (Y/N) 
4. Correlation between change in body weight, BMI, total body fat, and change in fat 
distribution for: 
a. Visceral adipose tissue 
b. Abdominal subcutaneous adipose tissue 
c. Lower body subcutaneous adipose tissue 
d. Liver fat 
e. Anterior thigh muscle fat infiltration 
5. “Responders” analysis 
a. Pre-specified analysis stratified by those who did vs. did not lose ≥4% body 
weight at week 16 of treatment to determine differential outcomes among 
“responders” vs. “non-responders” as outlined in the Liraglutide package insert. 
b. This analysis will be performed for the primary endpoint only.   
Statistical approach: 
1. For continuous endpoints, an analysis of covariance model will be used to analyze 
mean changes. The model will include treatment, sex, BMI stratification (<30, ≥30), 


Published: 7/28/2020 12:46 PM 
 
prediabetes status at baseline, interaction between BMI and prediabetes status strata 
as fixed effects, with the baseline value of the relevant variable as a covariate. 
2. For categorical endpoints, logistic regression will be used with the same fixed effects 
and covariates as the analysis of covariance model. 
3. Sensitivity analyses for primary endpoint 
Endpoint 
Type of analysis 
Description 
Relative percent change in 
visceral adipose tissue 
mITT 
Analysis of FAS with a valid 
non-imputed measurement at 
study end 
Relative percent change in 
visceral adipose tissue 
LOCF 
Same analysis as the primary 
applied to all randomized 
patients allowing for baseline 
carried forward for those 
without a post-baseline 
measurement 
Relative percent change in 
visceral adipose tissue 
MCMC 
Same analysis as the primary 
applied to all randomized 
patients allowing for 
imputation of missing 
observations using a 
modeling method 
FAS denotes full analysis set, defined as all participants who underwent randomization and had a 
follow-up endpoint assessment 
 
 
 
 

Prot_001.pdf: 
Official title: Impact of Liraglutide 3.0 on Body Fat Distribution, Visceral  
                     Adiposity, and Cardiometabolic Risk Markers In Overweight  
                     and Obese Adults at High Risk for Cardiovascular Disease 
 
NCT number:  NCT03038620 
Document date: August 24, 2018  


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STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
Impact of Liraglutide 3.0 on Body Fat Distribution, Visceral Adiposity, and 
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Cardiometabolic Risk Markers In Overweight and Obese Adults at High Risk for 
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Cardiovascular Disease 
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A Phase 4 randomized, double blinded, placebo controlled 46-week clinical trial 
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INVESTIGATOR-INITIATED TRIAL PROPOSAL 
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UNIVERSAL TRIAL NUMBER (UTN): U1111-1171-4812 
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CLINICALTRIALS.GOV REGISTRATION: PENDING 
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Principal Investigator: 
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Parag Joshi MD 
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Division of Cardiology 
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UT Southwestern Medical Center 
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5323 Harry Hines Blvd. 
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Dallas, TX 75390-8830 
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Correspondence to: 
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Parag Joshi MD 
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Assistant Professor of Medicine 
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University of Texas Southwestern Medical Center 
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5323 Harry Hines Blvd 
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Dallas Texas 75390-8830 
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Phone: (214) 645-1268 
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E-mail: Parag.Joshi@UTSouthwestern.eduTable of Contents: 
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1. Executive Summary………………………………………………………………………………4 
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2. Background and Significance…………………………………………………………………..7 
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3. Trial Rationale……………………………………………………………………………………..12 
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4. Objectives and Endpoints………………………………………………………………………12 
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5. Research Design and Methods………………………………………………………………...13 
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6. Statistical Considerations………………………………………………………………………16 
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7. Data Handling and Record Keeping…………………………………………………………..16 
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8. Ethics……………………………………………………………………………………………….17 
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9. Trial Schedule………………………………………………………………………………….....18 
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10. Trial Drugs and Materials…………………………………………………………………….....28 
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11. Concomitant Illnesses and Medications……………………………………………………..30 
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12. Subject Safety and Data Monitoring…………………………..………………………………31 
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13. Liability and Subject Insurance………………………………………………………………...33 
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14. Evaluability of Subjects………………………………………………………………………….34 
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15. Premature Termination of Trial…………………………………………………………………34 
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16. Publication Plan…………………………………………………………………………………...34 
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17. Key Personnel……………………………………………………………………………………..34 
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18. References………………………………………………………………………………………….35 
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Abbreviations: 
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ASCVD = atherosclerotic cardiovascular disease 
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BMI = body mass index 
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H1 MRS = proton magnetic resonance spectroscopy 
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SAT = subcutaneous adipose tissue 
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VAT = visceral adipose tissue 
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CLINCAL TRIAL EXECUTIVE SUMMARY: 
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Primary Objective: 
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To investigate the efficacy of liraglutide compared to placebo in reducing visceral adiposity 
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measured by MRI in overweight or obese subjects at high risk for cardiovascular disease after 
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40 weeks on-treatment. 
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136 
Secondary Objectives: 
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To compare liraglutide and placebo regarding the effect on: 
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• 
Changes in abdominal subcutaneous adipose tissue by MRI 
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• 
Changes in total fat mass by MRI 
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• 
Changes in fat-free mass by MRI 
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• 
Changes in lower body adipose tissue mass by MRI 
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• 
Changes in hepatic fat content by MRI 
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Changes in circulating blood biomarkers of cardiometabolic risk including markers of insulin 
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resistance, inflammation, lipids, and natriuretic peptides. 
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Trial Design: 
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This is a randomized, double-blind, parallel-group, placebo controlled, prospective clinical trial to 
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be conducted at a single center over 46 weeks (40 weeks on-treatment). There are two 
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treatment arms.  Patients will be randomized to liraglutide 3.0 administered once a day by 
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subcutaneous injection or matching placebo, in addition to a reduced-calorie diet and increased 
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physical activity.  All participants will be prescribed a 500 kcal per day deficit diet, based on 
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estimated 24-h energy expenditure.1  All participants will be instructed to maintain physical 
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activity at the recommended level of 150 minutes of moderate activity per week.  
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Trial Population: 
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Planned number of subjects to be screened:  356 (2:1 screen to randomization ratio) 
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Planned number of subjects to be treated in run-in period: 214 
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Planned number of subjects to be randomized/started on trial medication(s):178 
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Anticipated number of subjects to be studied: At least 128 completers  
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Number of trial sites: Single center 
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Sample Size: 
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This trial is powered to detect a clinically meaningful difference in the percent relative reduction 
164 
in VAT.  The estimates used in the sample size calculations below are derived from prior data 
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from the SCALE program.  Assuming a mean 8% relative reduction of VAT among placebo 
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treated subjects and an expected 16% relative reduction of VAT among liraglutide treated 
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subjects (with a standard deviation of 16%, based on data from [2]), we expect to require 128 
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total subjects (in a 1:1 trial drug:placebo randomization scheme) to achieve 80% power to 
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detect an 8% difference between groups at an alpha level of 0.05.  Assuming an estimated 28% 
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of subjects may withdraw trial medication during the trial, we expect a planned total of 178 
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patients will be randomized in order to achieve at least 128 completers of the full trial protocol. 
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Inclusion Criteria: 
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1. Age ≥ 35 years 
175 
2. Able to provide informed consent 
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3. BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 with metabolic syndrome 
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4. Metabolic syndrome as defined by at least three of the following:3   
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1) waist circumference > 102 cm (40 in) in men and 88 cm (35 in) in women 
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2) triglycerides > 150 mg/dL or on treatment for hypertriglyceridemia 
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3) HDL cholesterol < 40 mg/dL in men and < 50 mg/dL in women 
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4) blood pressure > 130/85 mmHg or on treatment for hypertension 
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5) fasting glucose > 100 mg/dL 
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Exclusion Criteria: 
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1. Treatment with GLP-1 receptor agonists (including liraglutide, exenatide or others as 
186 
become available for use), DPP-4 inhibitors or insulin within the last 3 months. 
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2. Receipt of any anti-obesity drug or supplement within 1 month prior to screening for this 
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trial. 
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3. Self-reported or clinically documented history of significant fluctuations (>5% change) in 
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weight within 3 months prior to screening for this trial. 
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4. History of diabetes mellitus (type 1 or 2) or on treatment with anti-diabetes medication. 
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5. History of chronic pancreatitis or idiopathic acute pancreatitis (current or prior history). 
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6. History of gallbladder disease (cholelithiasis or cholecystitis). 
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7. Chronic kidney disease stage III or greater (eGFR<60 mL/min). 
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8. Obesity induced by other endocrinologic disorders (e.g. Cushing Syndrome). 
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9. Current or history of treatment with medications that may cause significant weight gain, 
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within 1 month prior to screening for this trial, including systemic corticosteroids (except 
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for a short course of treatment, i.e., 7- 10 days), tri-cyclic antidepressants, atypical 
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antipsychotic and mood stabilizers (e.g., imipramine, amitryptiline, mirtazapine, 
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paroxetine, phenelzine, clorpromazine, thioridazine, clozapine, olanzapine, valproic acid 
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and its derivatives, and lithium). 
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10. Diet attempts using herbal supplements or over-the-counter medications within 1 month 
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prior to screening for this trial. 
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11. Current participation in an organized weight reduction program or within the last 1 month 
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prior to screening for this trial.  
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12. Participation in a clinical trial within the last 3 months prior to screening for this trial. 
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13. Familial or personal history of multiple endocrine neoplasia type 2 or familial medullary 
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thyroid carcinoma. 
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14. Personal history of non-familial medullary thyroid carcinoma. 
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15. History of Major Depressive Disorder within the last 2 years. 
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16. History of other severe psychiatric disorders, e.g., schizophrenia, bipolar disorder. 
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17. Any lifetime history of a suicide attempt. 
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18. A history of any suicidal behavior in the last month prior to randomization. 
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19. Surgery scheduled for the trial duration period, except for minor surgical procedures, at 
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the discretion of the Investigator. 
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20. Known or suspected hypersensitivity to trial product(s) or related product(s). 
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21. Known or suspected abuse of alcohol or narcotics. 
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22. Language barrier, mental incapacity, unwillingness or inability to understand. 
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23. Females of childbearing potential who are pregnant, breast-feeding or intend to become 
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pregnant or are not using adequate contraceptive methods. These include abstinence 
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and the following methods: diaphragm with spermacide, condom with spermacide (by 
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male partner), intrauterine device, sponge, spermacide, Norplant®, Depo-Provera® or 
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oral contraceptives.  
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Assessment of Efficacy Endpoints: 
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The following endpoints will be assessed at the end of 40 weeks of treatment: 
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Primary Endpoint:  
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• 
The liraglutide treatment effect on relative percent change from baseline in visceral adipose 
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tissue mass measured by MRI 
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Secondary Endpoints: Liraglutide treatment effect on: 
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• 
Relative percent change from baseline in body weight 
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• 
Absolute change from baseline in body weight 
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• 
Absolute change from baseline in visceral adipose tissue mass 
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• 
Relative percent change from baseline in abdominal subcutaneous adipose tissue mass 
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• 
Absolute change from baseline in abdominal subcutaneous adipose tissue mass 
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• 
Change from baseline in VAT/SAT ratio 
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• 
Relative percent change from baseline in total fat mass 
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• 
Absolute change from baseline in total fat mass 
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• 
Relative percent change from baseline in fat-free mass 
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• 
Absolute change from baseline in fat-free mass 
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• 
Relative percent change from baseline in lower body adipose tissue mass 
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• 
Absolute change from baseline in lower body adipose tissue mass 
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• 
Change from baseline in total fat/fat-free mass ratio 
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• 
Relative percent change from baseline in hepatic fat content 
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• 
Absolute change from baseline in hepatic fat content 
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• 
Relative percent change from baseline in biomarkers of cardiometabolic risk 
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- 
Markers of insulin resistance: fasting blood glucose, insulin, HOMA-IR 
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- 
Markers of inflammation: CRP 
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- 
Lipids: TG/HDL-C ratio  
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- 
Natriuretic peptides: NT-proBNP 
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• 
Absolute change from baseline in biomarkers of cardiometabolic risk 
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• 
Change from baseline in heart rate and blood pressure 
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• 
Change in waist circumference 
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Trial Products: 
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Liraglutide will be administered at a concentration of 6.0 mg/mL.  Liraglutide and placebo will be 
259 
supplied in a 3 mL pen-injector.  Subjects will follow a fixed dose escalation and in order to 
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reduce the level of side effects, liraglutide is gradually escalated up to the maintenance dose. 
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Subjects will be instructed to escalate the liraglutide (active or placebo) dose to 3.0 mg/day over 
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a 4 week period following an initial dose of 0.6 mg/day and weekly dose escalation steps of 0.6 
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mg/day. If subjects do not tolerate an increase in dose during dose-escalation, the Investigator 
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will have the option to delay the next dose escalation for approximately one week. 
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Trial Design Diagram 
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Trial Chart  
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BACKGROUND AND SIGNIFICANCE: 
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Section 1: Obesity and Cardiovascular Risk 
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Obesity has long been recognized as a risk factor for all-cause mortality4 and morbidity, 
281 
including the development of cardiovascular and metabolic diseases such as coronary artery 
282 
disease, hypertension, insulin resistance, diabetes, and dyslipidemia.5  Obesity has recently 
283 
been formally defined as a chronic disease characterized by pathophysiological processes that 
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result in increased adipose tissue mass and can result in increased morbidity and mortality.6  
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Although the health risks associated with obesity are clear, there is an emerging appreciation 
286 
that obesity per se, as defined by simple anthropometric measures such as waist circumference 
287 
or body mass index (BMI), is neither necessary nor sufficient to promote cardiometabolic 
288 
disease and atherosclerotic cardiovascular disease (ASCVD) risk. As a result, BMI alone is an 
289 
insufficient marker of risk and may not accurately identify individuals at elevated risk for 
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ASCVD.7  There is a pressing need to more accurately phenotype obesity to identify individuals 
291 
at elevated risk for ASCVD that may benefit from more intensive preventive and therapeutic 
292 
strategies. 
293 
 
294 
Section 2: Visceral adipose tissue as a key marker of CV Risk 
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It appears that risk for ASCVD and metabolic diseases varies substantially by distribution of 
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body fat, as well as by adipocyte size and function.  Excess intra-abdominal (i.e. visceral) 
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adipose tissue (VAT) may be a primary driver of the cardiometabolic complications of obesity8, 
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and ectopic fat linked to VAT may itself play a key contributory role.  An increase in VAT is 
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thought to reflect the relative inability of the subcutaneous adipose tissue depot to sufficiently 
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expand its clearance and storage capacity in response to caloric excess.9  Defects in adipocyte 
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maturation and differentiation10 cause adipocyte dysfunction, resulting in spillover of excess 
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triglycerides and promotion of ectopic fat deposition in the viscera, liver, heart, and skeletal 
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muscle.  The ensuing milieu of overactive lipolysis, altered glucose homeostasis, pro-
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inflammatory adipocytokine release, and endothelial dysfunction appears to be a primary cause 
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of the pathophysiological alterations observed in obesity related cardiometabolic disease. 
306 
 
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Although more simplistic anthropomorphic measures of abdominal obesity, such an increased 
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waist circumference, identify individuals at increased risk for atherosclerosis11 and mortality 
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Trial periods 
Scre
enin
g 
Run-
In 
Randomi
zation 
Dose escalation period/ 
Maintenance 
Maintenance/ 
End of 
treatment 
Follow-
up 
 
Weeks in relation to 
Visit 2 
(randomization) 
-4 
-2 
0 
1 
2 
3 
4-40 
42 
Visit number 
1 
2 
3 
4 
5 
6 
7-16 
17 
Liraglutide 
Scre
enin
g 
Run-
In 
0.6 mg 
 
1.2 mg 
 
1.8 mg  
2.4 mg  
3.0 mg 
 
No 
treatment  
Placebo 
Placebo 
 
Placebo 
 
Placebo 
 
Placebo 
 
Placebo 
 


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across different levels of BMI12, it is an imprecise surrogate for the VAT phenotype.  First, the 
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correlation between BMI, waist circumference, and VAT is highly variable among different racial 
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groups, prompting the American Diabetes Association and the International Diabetes Federation 
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to define different cutoffs for abnormal BMI and waist circumference, respectively, in Asian 
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populations.13,14  Second, waist circumference measurement includes both VAT and abdominal 
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subcutaneous adipose tissue (SAT) compartments.  These two depots are anatomically and 
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physiologically distinct, especially within the obese population, and are differentially associated 
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with markers of cardiometabolic risk.15  VAT, but not abdominal subcutaneous fat, has been 
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shown to associate with incident T2D and pre-T2D16, incident hypertension17, and alterations in 
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left ventricular structure and function18, and has also been linked to increased risk of developing 
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ASCVD and cancer.19  Medical treatments that reduce VAT mass may translate into improved 
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major adverse cardiac event (MACE)-free survival. 
321 
 
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Section 3: Liraglutide 3.0 
323 
GLP-1: Physiology and current literature  
324 
In response to a meal, GLP-1, an incretin hormone secreted from the L-cells in the lower gut, 
325 
stimulates endogenous insulin secretion in a glucose-dependent manner, decreases blood 
326 
glucagon levels, reduces gastric emptying and increases satiety.  GLP-1 reduces appetite in 
327 
lean and normal weight individuals, as well as in obese individuals, and has been shown to 
328 
reduce body weight. The combination of these mechanisms makes GLP-1 receptor stimulation 
329 
an attractive mechanism to investigate for weight management.   
330 
 
331 
Liraglutide 
332 
Liraglutide 3.0 mg (Saxenda®, Novo Nordisk, Bagsvaerd, Denmark) is a glucagon-like peptide 
333 
(GLP-1) receptor agonist indicated as an adjunct to a reduced-calorie diet and increased 
334 
physical activity for chronic weight management in adult patients with an initial body mass index 
335 
(BMI) of ≥30 kg/m2  (obese) or in patients with a BMI of ≥27 kg/m2  (overweight) in the presence 
336 
of at least one weight-related comorbid condition such as hypertension, type 2 diabetes mellitus, 
337 
or dyslipidemia. 
338 
 
339 
Compared to human GLP-1, liraglutide has a C16 fatty (palmitic) acid chain attached at position 
340 
26 (lysine) of the peptide, and has lysine at position 34 replaced by arginine. When 
341 
administered subcutaneously, these structural modifications result in a compound with 
342 
protracted kinetic properties suitable for once daily injection. The dose approved for use in the 
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United States for the chronic treatment of obesity is 3.0 mg injection once daily. This dose was 
344 
approved for use by the FDA based upon the results of a clinical trial which evaluated weight 
345 
change after 20 weeks using liraglutide 1.2, 1.8, 2.4 and 3.0 mg compared to placebo and open-
346 
label orlistat (Trial 1807).1 Those trials (a dose-ranging phase 2 and four phase 3 trials) included 
347 
5922 patients and demonstrated a consistent and clinically meaningful reduction in weight. 
348 
Liraglutide met the 5% mean placebo-corrected difference in weight loss as described in the 
349 
FDA 
draft 
weight 
management 
guidance 
350 
(http://www.fda.gov/downloads/Drugs/Guidances/ucm071612.pdf, accessed June 3, 2015).  The 
351 
safety and efficacy of Liraglutide was established in three 56-week, randomized, double blind, 
352 
placebo-controlled trials. In all studies, liraglutide was titrated to 3.0 mg daily during a 4-week 
353 
period. All patients received instruction for a reduced calorie diet (approximately 500 kcal/day 
354 
deficit) and exercise counseling (recommended increase in physical activity of minimum 150 
355 
mins/week) that began with the first dose of study medication and continued throughout the trial. 
356 
Study patients were either overweight defined as a BMI of 27 kg/m2 or greater in the presence 
357 


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of at least one obesity related comorbidity or were obese defined as a BMI of 30 kg/m2 or 
358 
greater.  
359 
 
360 
These 3 trials included 4788 patients, of these 3122 were treated with liraglutide. Study 1 
361 
included 3,371 obese or overweight patients; study 2 included 635 patients with type 2 diabetes 
362 
mellitus with obesity or overweight; and study 3 included 422 obese and overweight patients 
363 
who also lost at least 5% of body weight with diet and exercise alone. The primary efficacy 
364 
endpoint in trials 1 and 2 was the mean percent change in body weight and the percentages of 
365 
patients achieving greater than or equal to 5% of weight loss from baseline through 56 weeks. 
366 
In study 3 there was an additional efficacy measure which was the percentage of patients not 
367 
gaining more than 0.5% of body weight from randomization. Patients treated with liraglutide 
368 
experienced a significant decrease in percent change (from baseline) in total body weight 
369 
ranging from -4.9 to -7.4% (least square mean). Over 50% of patients lost greater than 5% of 
370 
their baseline body weight and approximately 30% lost greater than 10% of their body weight. 
371 
These changes were significantly greater than weight loss seen in the placebo arms of these 
372 
three trials. In study 3 there were a statistically greater number of patients randomized to 
373 
placebo that gained at least 0.5% of their body weight at week 56. Liraglutide use was also 
374 
associated with a reduction in waist circumference, blood pressure and modest reductions in 
375 
total cholesterol, LDL and increase in HDL. Liraglutide was associated with an increase in heart 
376 
rate of approximately 2 beats per minute.  
377 
 
378 
Tolerability and Adverse Events 
379 
Treatment with liraglutide in prior obesity trials was generally well tolerated.  Approximately 70% 
380 
of patients randomized to liraglutide completed the trials on medication. The withdrawal rate 
381 
was approximately 8.5% in the liraglutide arms and 8.6% in the placebo treated patients. 
382 
Serious adverse events were relatively uncommon, but were more frequent in liraglutide-treated 
383 
subjects compared with placebo (4.2 vs. 2.4%).  GI side effects seen in the SCALE 
384 
Maintenance trial were common in patients taking liraglutide 3.0 mg. The frequency of nausea 
385 
was 47.6%, of diarrhea was 17.9%, of constipation was 26.9% and of vomiting was 16.5%. 
386 
Other less common AEs included dyspepsia (9.4%), abdominal pain (6.6%), abdominal 
387 
distension (6.1%), eructation (5.2%), and flatulence (5.2%).20  
388 
 
389 
There have been rare, spontaneous post-marketing reports of acute pancreatitis in patients 
390 
without a history of pancreatitis being treated with liraglutide.  In the obesity clinical trials, acute 
391 
pancreatitis was confirmed in 9 of 3291 liraglutide treated patients and 1 of 1843 placebo 
392 
treated patients. There were 3 additional cases of pancreatitis occurring in liraglutide treated 
393 
patients ranging 14 to 124 days after study discontinuation. A history of pancreatitis was an 
394 
exclusion criterion in clinical trials performed to date. If the investigator suspects acute 
395 
pancreatitis, all suspected drugs should be discontinued until confirmatory tests have been 
396 
conducted and appropriate treatment initiated.  
397 
 
398 
Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at 
399 
clinically relevant exposures in both genders of rats and mice. It is unknown whether liraglutide 
400 
causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as 
401 
human relevance could not be ruled out by clinical or nonclinical studies. Liraglutide is 
402 
contraindicated in patients with a personal or family history of MTC and in patients with Multiple 
403 
Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring 
404 
with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may 
405 


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have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring 
406 
with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors.  
407 
 
408 
Liraglutide and Body Composition 
409 
Body composition was measured in a sub-study of Trial 1807 which included 113 patients (92 
410 
completers) from 7 European centers using dual energy x-ray absorptiometry (DXA) and 
411 
computerized axial tomography (CT) scans.  Trial 18072 was a placebo-controlled 20 week trial 
412 
with open label orlistat, placebo and once daily injection of liraglutide. At 1 year liraglutide 3.0 
413 
mg recipients lost 5.8 kg (95% CI 3.7–8.0) more body weight than those on placebo and 3.8 kg 
414 
(1.6–6.0) more than those on orlistat (P<0.0001). In this body composition sub-study at week 
415 
20, mean total body fat mass was reduced between 5.0-6.9 kg with liraglutide, 4.4 kg with 
416 
placebo and 4.9 with orlistat. The percentage of body weight lost due to fat was 80-90% of the 
417 
total weight lost in the liraglutide treated group and 63% in the placebo group. The weight loss 
418 
and reduction in waist circumference with liraglutide was primarily due to reduction in fat mass 
419 
rather than lean body mass.  This sub-study also quantified the VAT and abdominal SAT mass 
420 
lost. Summary data from this body composition sub-study are presented in Table 1 and Figure 1 
421 
below:   
422 
 
423 
While there was a numerical trend for greater VAT mass loss in the liraglutide 3.0 mg group, this 
424 
study was underpowered to detect between group differences in absolute or relative VAT mean 
425 
mass lost. This initial work is a fundamental first step but has important limitations, including: 1) 
426 
lack of study subjects in the United States; patients enrolled in this study were exclusively 
427 
recruited from European centers including Belgium, Czech Republic, Denmark, Finland, 
428 
Netherlands, Spain, and Sweden; 2) there were very few subjects treated with 3.0 mg of 
429 
liraglutide (N=15); therefore this study was not only underpowered to detect clinically meaningful 
430 
differences in abdominal fat distribution, but also systematically underdosed; 3) the use of 
431 
ionizing radiation (with CT scans) limits the generalizability to other research projects that will 
432 
likely be conducted over long-term follow-up with repeat imaging; and 4) this study did not 
433 
directly quantify hepatic fat, a known correlate of insulin resistance and cardiometabolic risk.  
434 
We will address these limitations in the research proposed below. 
435 
 
436 
Table 1. Body composition assessed by DXA and CT in a subgroup of participants at 20 weeks 
437 


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438 
 
439 
Figure 1. Relative changes in Visceral and Abdominal Subcutaneous Fat Mass Assessed by CT 
440 
 
441 
Therefore, we believe there is an important and pressing need for extensive and detailed 
442 
phenotyping to further elucidate the impact of Liraglutide 3.0 mg on markers of body fat 
443 
distribution, visceral adiposity, and adverse cardiometabolic risk and its potential benefits on 
444 
long-term cardiovascular disease outcomes.  Our long term goal is to understand how VAT 
445 
contributes to cardiometabolic disease risk and to identify strategies to reduce the 
446 
cardiometabolic consequences of excess VAT.  Our objectives here are to elucidate the effect 
447 
of Liraglutide 3.0 on body fat distribution, visceral adiposity, and markers of cardiometabolic 
448 


P a g e  | 12 
 
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disease risk among overweight and obese adults at high risk for cardiovascular disease using 
449 
detailed circulating blood biomarker and imaging phenotyping. 
450 
 
451 
TRIAL RATIONALE: 
452 
The rationale of this project is to utilize adipose tissue imaging with minimal or no ionizing 
453 
radiation to investigate the potential beneficial effects of Liraglutide 3.0 mg on pathways 
454 
underlying excess cardiovascular disease risk related to visceral adiposity and an adverse 
455 
cardiometabolic phenotype.  We will achieve the scientific objectives of this application by 
456 
pursuing the following objectives with the following hypothesis: 
457 
 
458 
OBJECTIVES AND ENDPOINTS: 
459 
Hypothesis: 
460 
Liraglutide will decrease visceral adiposity, favorably alter body fat distribution, and improve the 
461 
cardiometabolic risk marker profile significantly better than placebo in overweight or obese 
462 
subjects at high risk for cardiovascular disease. 
463 
 
464 
Primary Objective:  
465 
To investigate the efficacy of liraglutide compared to placebo in reducing visceral adiposity in 
466 
overweight or obese subjects at high risk for cardiovascular disease after 40 weeks on-
467 
treatment. 
468 
 
469 
Secondary Objectives:  
470 
To compare liraglutide and placebo regarding the effect on: 
471 
• 
Changes in abdominal subcutaneous adipose tissue by MRI 
472 
• 
Changes in total fat mass by MRI 
473 
• 
Changes in fat-free mass by MRI 
474 
• 
Changes in lower body adipose tissue mass by MRI 
475 
• 
Changes in hepatic fat content by MRI 
476 
• 
Changes in circulating blood biomarkers of cardiometabolic risk including markers of insulin 
477 
resistance, inflammation, lipids, and natriuretic peptides. 
478 
 
479 
Endpoints: The following endpoints will be assessed at the end of 40 weeks of treatment: 
480 
 
481 
Primary Endpoint:  
482 
• 
The liraglutide treatment effect on relative percent change from baseline in visceral adipose 
483 
tissue mass measured by MRI. 
484 
 
485 
Secondary Endpoints: Liraglutide treatment effect on: 
486 
• 
Relative percent change from baseline in body weight 
487 
• 
Absolute change from baseline in body weight 
488 
• 
Absolute change from baseline in visceral adipose tissue mass 
489 
• 
Relative percent change from baseline in abdominal subcutaneous adipose tissue mass 
490 
• 
Absolute change from baseline in abdominal subcutaneous adipose tissue mass 
491 
• 
Change from baseline in VAT/SAT ratio 
492 
• 
Relative percent change from baseline in total fat mass 
493 
• 
Absolute change from baseline in total fat mass 
494 
• 
Relative percent change from baseline in fat-free mass 
495 
• 
Absolute change from baseline in fat-free mass 
496 


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• 
Relative percent change from baseline in lower body adipose tissue mass 
497 
• 
Absolute change from baseline in lower body adipose tissue mass 
498 
• 
Change from baseline in total fat/fat-free mass ratio 
499 
• 
Relative percent change from baseline in hepatic fat content 
500 
• 
Absolute change from baseline in hepatic fat content 
501 
• 
Relative percent change from baseline in biomarkers of cardiometabolic risk 
502 
- 
Markers of insulin resistance: fasting blood glucose, insulin, HOMA-IR 
503 
- 
Markers of inflammation: CRP 
504 
- 
Lipids: TG/HDL-C ratio  
505 
- 
Natriuretic peptides: NT-proBNP 
506 
• 
Absolute change from baseline in biomarkers of cardiometabolic risk 
507 
• 
Change from baseline in heart rate and blood pressure 
508 
• 
Change in waist circumference 
509 
 
510 
TRIAL DESIGN AND METHODS: 
511 
 
512 
Trial type: 
513 
This is a randomized, double-blind, parallel-group, placebo controlled, prospective clinical trial to 
514 
be conducted at a single center over 46 weeks (40 weeks on-treatment). There are two 
515 
treatment arms.  Patients will be randomized to liraglutide 3.0 administered once a day by 
516 
subcutaneous injection or matching placebo, in addition to a reduced-calorie diet and increased 
517 
physical activity.  All participants will be prescribed a 500 kcal per day deficit diet, based on 
518 
estimated 24-h energy expenditure.1  All participants will be instructed to maintain physical 
519 
activity at the recommended level of 150 minutes of moderate activity per week.  
520 
 
521 
Rationale for trial design: 
522 
This trial design will directly address the trial objectives by allowing determination of the effects 
523 
of Liraglutide on body fat distribution, visceral adiposity, and cardiometabolic risk markers 
524 
independent of a reduced calorie diet and increased physical activity among overweight and 
525 
obese adults at high cardiovascular disease risk. 
526 
 
527 
Trial population: 
528 
Planned number of subjects to be screened:  356 (2:1 screen to randomization ratio) 
529 
Planned number of subjects to be treated in run-in period: 214 
530 
Planned number of subjects to be randomized/started on trial medication(s):178 
531 
Anticipated number of subjects to be studied: At least 128 completers  
532 
Number of trial sites: Single center 
533 
 
534 
The anticipated screening failure rate of 40% and the anticipated drop-out rate at 40 weeks of 
535 
28% are based on reported rates from obesity and diabetes trials. 
536 
 
537 
Inclusion criteria: 
538 
1. Age ≥ 35 years 
539 
2. Able to provide informed consent 
540 
3. BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 with metabolic syndrome 
541 
4. Metabolic syndrome is defined as at least three of the following:3   
542 
1) waist circumference > 102 cm (40 in) in men and 88 cm (35 in) in women 
543 
2) triglycerides > 150 mg/dL or on treatment for hypertriglyceridemia 
544 
3) HDL cholesterol < 40 mg/dL in men and < 50 mg/dL in women 
545 


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4) blood pressure > 130/85 mmHg or on treatment for hypertension 
546 
5) fasting glucose > 100 mg/dL 
547 
 
548 
Exclusion criteria: 
549 
1. Treatment with GLP-1 receptor agonists (including liraglutide, exenatide or others as 
550 
they become available), DPP-4 inhibitors or insulin within the last 3 months. 
551 
2. Receipt of any anti-obesity drug or supplement within 1 month prior to screening for 
552 
this trial. 
553 
3. Self-reported or clinically documented history of significant fluctuations (>5% 
554 
change) in weight within 3 months prior to screening for this trial. 
555 
4. History of diabetes mellitus (type 1 or 2) or on treatment with anti-diabetes 
556 
medication. 
557 
5. History of chronic pancreatitis or idiopathic acute pancreatitis (current or prior 
558 
history). 
559 
6. History of gallbladder disease (cholelithiasis or cholecystitis). 
560 
7. Chronic kidney disease stage III or greater (eGFR<60 mL/min). 
561 
8. Obesity induced by other endocrinologic disorders (e.g. Cushing Syndrome). 
562 
9. Current or history of treatment with medications that may cause significant weight 
563 
gain, within 1 month prior to screening for this trial, including systemic corticosteroids 
564 
(except for a short course of treatment, i.e., 7- 10 days), tri-cyclic antidepressants, 
565 
atypical antipsychotic and mood stabilizers (e.g., imipramine, amitryptiline, 
566 
mirtazapine, 
paroxetine, 
phenelzine, 
clorpromazine, 
thioridazine, 
clozapine, 
567 
olanzapine, valproic acid and its derivatives, and lithium). 
568 
10. Diet attempts using herbal supplements or over-the-counter medications within 1 
569 
month prior to screening for this trial. 
570 
11. Current participation in an organized weight reduction program or within the last 1 
571 
month prior to screening for this trial.  
572 
12. Participation in a clinical trial within the last 3 months prior to screening for this trial. 
573 
13. Familial or personal history of multiple endocrine neoplasia type 2 or familial 
574 
medullary thyroid carcinoma. 
575 
14. Personal history of non-familial medullary thyroid carcinoma. 
576 
15. History of Major Depressive Disorder within the last 2 years. 
577 
16. History of other severe psychiatric disorders, e.g., schizophrenia, bipolar disorder. 
578 
17. Any lifetime history of a suicide attempt. 
579 
18. A history of any suicidal behavior in the last month prior to randomization. 
580 
19. Surgery scheduled for the trial duration period, except for minor surgical procedures, 
581 
at the discretion of the Investigator. 
582 
20. Known or suspected hypersensitivity to trial product(s) or related product(s). 
583 
21. Known or suspected abuse of alcohol or narcotics. 
584 
22. Language barrier, mental incapacity, unwillingness or inability to understand. 
585 
23. Females of childbearing potential who are pregnant, breast-feeding or intend to 
586 
become pregnant or are not using adequate contraceptive methods. These include 
587 
abstinence and the following methods: diaphragm with spermacide, condom with 
588 
spermacide (by male partner), intrauterine device, sponge, spermacide, Norplant®, 
589 
Depo-Provera® or oral contraceptives.  
590 
 
591 
Withdrawal Criteria: 
592 
1. Participants may withdraw at will at any time. 
593 
- 
Informed consent may be withdrawn at any time. 
594 


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- 
Permission to follow up for endpoint determination may be withdrawn at any time 
595 
- 
This is distinguished from withdrawal of trial medication.  
596 
2. Participants can be withdrawn from the trial at the discretion of the Investigator due to 
597 
safety concerns of if judged to be non-compliant with the trial protocol. 
598 
3. Pregnancy or intention of becoming pregnant 
599 
4. If target treatment dose of the randomized product is not tolerated by the subject. 
600 
5. If the trial investigator suspects acute pancreatitis, the trial drug will be discontinued until 
601 
the confirmatory tests (clinically indicated laboratory and imaging) have been conducted 
602 
and appropriate treatment has been administered.  We anticipate confirmation within 72 
603 
hours. If acute pancreatitis is confirmed, the participant will be withdrawn from the trial.  
604 
If acute pancreatitis is not confirmed, the participant will resume the trial drug at the 
605 
same dose previously used before temporary discontinuation. 
606 
6. Temporary trial drug discontinuation criteria: 
607 
- 
Side effects to trial medication (until such side effects have resolved or have 
608 
been otherwise addressed) 
609 
- 
Acute illness requiring treatment or hospitalization 
610 
- 
The longest time that the subject can be off trial drug and still continue in the trial 
611 
is 4 weeks.  If the trial drug is discontinued for >72 hours, then the dosing 
612 
escalation regimen will be restarted at 0.6 mg daily and titrated up according to 
613 
prescribing information recommendations.  
614 
 
615 
Subject Replacement 
616 
Participants will not be replaced if they withdraw or become ineligible but they will be asked to 
617 
return at the end of the trial period to complete the follow-up imaging/laboratory testing and 
618 
analyzed in an intention to treat analysis. As up to a 28% drop-out rate is anticipated, enrolment 
619 
will account for expected drop-out to minimize loss to follow-up given that subjects will not be 
620 
replaced.  
621 
 
622 
Rationale for Trial Population 
623 
The trial population represents the target population for which liraglutide is approved for chronic 
624 
weight management in adult patients, with the additional inclusion criterion of a diagnosis of 
625 
metabolic syndrome. This important criterion has been selected to enrich the trial population 
626 
with participants with a high visceral adipose tissue burden in order to improve the statistical 
627 
power to observe a meaningful effect on visceral adipose mass and enrich the trial population 
628 
with individuals at high risk for cardiovascular disease. 
629 
 
630 
Imaging Assessments 
631 
The primary and secondary endpoints of visceral fat, abdominal subcutaneous fat, lower body 
632 
fat, liver fat, and total body fat and fat-free (lean) mass will be assessed using a Phillips 3T MRI 
633 
system utilizing a two point Dixon fat-water segmentation technique (Advanced MR Analytics, 
634 
Sweden).21  This MRI system has been extensively studied and validated in multiple cohorts,21-23 
635 
has excellent test/retest precision and reliability,24 and is rapid (<6 minutes) and therefore cost 
636 
effective.   
637 
 
638 
STATISTICAL CONSIDERATIONS: 
639 
 
640 
Sample Size Calculation: 
641 
This trial is powered to detect a clinically meaningful difference in the placebo-corrected relative 
642 
reduction in VAT.  The estimates used in the sample size calculations below are derived from 
643 


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prior data from the SCALE program.  Assuming a mean 8% relative reduction of VAT among 
644 
placebo treated subjects and an expected 16% relative reduction of VAT among liraglutide 
645 
treated subjects (with a standard deviation of 16%, based on data from [2]), we expect to require 
646 
128 total subjects (in a 1:1 trial drug:placebo randomization scheme) to achieve 80% power to 
647 
detect an 8% difference between groups at an alpha level of 0.05.  Assuming an estimated 28% 
648 
of subjects may withdraw trial medication during the trial, we expect a planned total of 178 
649 
patients will be randomized in order to achieve at least 128 completers of the full trial protocol. 
650 
 
651 
Placebo-corrected 
Effect Size 
Power 
 
80% 
85% 
90% 
 
Sample Size (Total N, 1:1 randomization) 
 
5% 
322 
368 
432 
8% 
128 
146 
170 
10% 
82 
92 
108 
 
652 
Statistical Methods: A formal statistical analysis plan will follow.  Briefly, baseline 
653 
characteristics between liraglutide and placebo treated groups will be compared using 
654 
appropriate parametric or non-parametric tests depending on the distribution of the data. The 
655 
primary outcome will be analyzed using an intention to treat analysis. Mean change in outcome 
656 
measurements will be compared between groups using the appropriate statistical test. 
657 
Outcomes will also be analyzed by subgroups including age (above/below median), sex, race 
658 
(non-Hispanic black, non-Hispanic white, and Hispanic), BMI category (overweight, class I 
659 
obese, class II/III obese), and prediabetes status (yes/no).  In order to minimize type II error in 
660 
subgroup analyses by race, we will attempt to ensure Hispanics comprise at least 25% of the 
661 
trial population.  A pre-specified analysis stratified by those who did vs. did not lose ≥4% body 
662 
weight at 16 weeks of treatment will be performed prior to unblinding to determine differential 
663 
outcomes among “responders” vs. “non-responders” as outlined in the package insert.  All 
664 
statistical tests are two-sided at a 5% significance level. 
665 
 
666 
Interim Analysis: No interim analysis will be performed. 
667 
 
668 
Missing Data: The preferred approach to missing data is to incorporate proactive standard 
669 
operating procedures to mitigate the likelihood of missingness. We will implement measures to 
670 
reduce missing data (both baseline and endpoint).  The statistical analysis plan will describe 
671 
analytical approaches to address missingness of data, including multiple imputation including 
672 
the last observation carried forward (LOCF) and mixed-effects model repeated measure 
673 
approaches. Sensitivity analyses will also be performed to determine the effect of missingness 
674 
on the primary and secondary outcomes. 
675 
 
676 
DATA HANDLING AND RECORD KEEPING: 
677 
Subjects will be assigned an identification code. A subject's name and code will be contained 
678 
within a small notebook and will be kept in a locked cabinet in the research coordinator's locked 
679 
office.  The research chart will contain personal health information and will be kept in locked file 
680 
cabinet in the research coordinator's locked office.  All other data on a computer will be de-
681 
identified with the subject's identification code.  Blood samples waiting for analysis will not be 
682 
labeled with the subject's name, but with the assigned identification code. The trial database will 
683 
be password protected. No data will be sent over the internet unless it is encrypted. All email 
684 
with subject-identifiable information will be password protected.  Only key personnel will have 
685 
access to the information in the trial database on an as-needed basis. Key personnel may not 
686 


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alter the data in the database or directly view all of it without specific cause and approval of the 
687 
PI. 
688 
 
689 
ETHICS: 
690 
 
691 
Informed Consent 
692 
Before screening takes place subjects will be provided with written and verbal information about 
693 
the trial and the procedures involved. Qualified site will ensure that subjects are fully informed 
694 
both verbally and in writing about the practical consequences of participating, of their rights and 
695 
responsibilities while participating in the trial as well as any possible advantages and 
696 
disadvantages in being treated with the trial products. Subjects will have the opportunity to ask 
697 
questions to a medically qualified person and have ample time to consider participation.  
698 
Subjects who wish to participate must give signed and dated informed consent. This must be 
699 
done prior to any trial related activities, i.e. procedures that would not have been performed 
700 
during normal management of the subject. It must be stated in the medical record that the 
701 
subject is participating in the current trial.  
702 
 
703 
Written informed consent will be obtained from each subject at entry into the trial. Informed 
704 
consent is obtained by the following process: 
705 
 
706 
• 
Subject reviews the trial consent form. 
707 
• 
PI or trial coordinator meets with the subject to review the consent, confirm subject’s  
708 
 
understanding, and answer any questions. 
709 
• 
Once the investigator is convinced that the subject verbally demonstrates understanding  
710 
 and agrees to the process, the consent is signed. Individuals authorized to obtain written 
711 
consent are the principal investigator, co-investigators, and assigned medical staff 
712 
specifically designated by the principal investigator to work on this project. 
713 
 
714 
The trial protocol will be submitted to the local IRB for approval before any trial activities will be 
715 
initiated.  The trial protocol will be conducted and maintain compliance with appropriate ethical 
716 
responsibility standards according to the Declaration of Helsinki and the International 
717 
Conference on Harmonization-Good Clinical Practice guidelines, as well as local institutional 
718 
review board standards and approval. The investigators will comply with all applicable 
719 
regulatory and legal requirements, ICH-GCP guidelines, and the Declaration of Helsinki in 
720 
obtaining and documenting the informed consent. 
721 
 
722 
The trial investigators take full responsibility to ensure quality assurance and proper 
723 
maintenance of all trial materials by periodic (biweekly) quality control checks of trial drug 
724 
storage and handling, electronic database materials, and measurement devices.  
725 
 
726 
Confidentiality 
727 
• 
Protection of subject privacy. All materials will be obtained for research purposes only, and 
728 
data will be kept in strict confidence.  Subjects will be assigned an identification code. A 
729 
subject's name and code will be contained within a small notebook and will be kept in a 
730 
locked cabinet in the research coordinator's locked office.  The research chart will contain 
731 
personal health information and will be kept in locked file cabinet in the research 
732 
coordinator's locked office.  All other data on a computer will be de-identified with the 
733 
subject's identification code.  Blood samples waiting for analysis will not be labeled with the 
734 
subject's name, but with the assigned identification code. 
735 


P a g e  | 18 
 
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• 
Database protection. The trial database will be password protected.  No data will be sent 
736 
over the internet unless it is encrypted.  All email with subject-identifiable information will be 
737 
password protected.  Only key personnel will have access to the information in the trial 
738 
database on an as-needed basis. Key personnel may not alter the data in the database or 
739 
directly view all of it without specific cause and approval of the PI. 
740 
• 
Confidentiality during adverse event reporting. Adverse event reports and annual summaries 
741 
will not include subject-identifiable material. Each will include the identification code only. 
742 
 
743 
Potential Benefits of the Proposed Research to Human Subjects and Others and 
744 
Importance of Knowledge to be Gained 
745 
• 
There is a potential direct benefit of the proposed research to trial participants.  
746 
• 
Knowledge gained from this project will likely lead to better understanding of obesity and 
747 
visceral adiposity in the general population and across ethnic minorities and women as well 
748 
as potentially lead to improved targets of therapies aimed at reducing cardiovascular 
749 
disease risk.  
750 
• 
The risks outlined in this proposal are reasonable for this societal benefit as it may lead to 
751 
improved care to reduce cardiovascular disease risk, the leading cause of morbidity and 
752 
mortality in the U.S.   
753 
 
754 
TRIAL SCHEDULE: 
755 
 
756 
Planned duration of recruitment period: 2.5 years 
757 
 
758 
Planned date for first subject (FPFV): January 2017 
759 
 
760 
Planned completion of the last subject (LPLV): 30 months from FPFV 
761 
 
762 
Planned completion of clinical trial report: 36 months from FPFV 
763 
 
764 
The end of the clinical trial is defined as the last visit of the last subject (LPLV). 
765 
 
766 
Trial Sites: 
767 
The trial will be conducted at three sites in Dallas, TX: 
768 
1. University Hospital Ambulatory Clinics (at Aston and St. Paul Professional Office 
769 
Buildings) 
770 
2. Clements University Hospital 
771 
3. Parkland Hospital and Ambulatory Clinics 
772 
 
773 
Visit Procedures: 
774 
Prior to the first trial visit, potential subjects will be identified by physician referral or media 
775 
advertisement and will be introduced to participation in the trial by one of the trial staff. If the 
776 
patient meets potential inclusion criteria, written informed consent will be obtained and the 
777 
subject will be scheduled for Visit 1.  
778 
 
779 
Subjects enrolled in the trial will be provided with a subject ID card, stating that they are 
780 
participating in a trial and whom to contact (site address, Investigator’s name and telephone 
781 
number) for further information, if necessary. The subjects will be reminded to show the card to 
782 
other health care providers, as applicable. The subjects will be instructed to return the card to 
783 
the Investigator at the last visit of the subject or destroy the card after the last visit 
784 


P a g e  | 19 
 
STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
 
785 
The Investigator will keep a subject screening log and a subject enrolment log. For screening 
786 
failures (subjects who have given informed consent but who do not meet the inclusion, 
787 
exclusion and/or randomization criteria and hence are not randomized), all data for completed 
788 
trial procedures will be recorded in the case record form (CRF), and the reason for exclusion 
789 
from the trial will be recorded on the screening failure form. The screening failure form will be 
790 
entered into the clinical database.  
791 
 
792 
793 
 
794 
 
795 
Table: Visit Schedule 
796 
Visit no. 
Time of Visit 
Visit Type 
1 
-4 weeks ± 5 days 
Screening 
2 
-2 weeks ± 3 days 
Run-In 
3 
Day 0, baseline 
Randomization 
4 
1 week ± 3 days 
Dose escalation 
5 
2 weeks ± 3 days 
Dose escalation 


P a g e  | 20 
 
STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
6 
3 weeks ± 3 days 
Dose escalation 
7 
4 weeks ± 3 days 
Dose escalation/maintenance 
8 
8 weeks ± 3 days 
Maintenance 
9 
12 weeks ± 3 days 
Maintenance 
10 
16 weeks ± 3 days 
Maintenance 
11 
20 weeks ± 3 days 
Maintenance 
12 
24 weeks ± 3 days 
Maintenance 
13 
28 weeks ± 3 days 
Maintenance 
14 
32 weeks ± 3 days 
Maintenance 
15 
36 weeks ± 3 days 
Maintenance 
16 
40 weeks ± 3 days 
End of treatment 
17 
42 weeks ± 3 days 
Observational Follow-up/End of trial 
 
797 
The total duration of the trial (for a subject completing the trial) will be up to 46 weeks and will 
798 
comprise a total of 17 visits. 
799 
 
800 
Table: Treatment of subjects 
801 
 
802 
Trial periods 
Scr
eeni
ng 
Run-
In 
Randomi
zation 
Dose escalation period/ 
Maintenance 
Maintenance
/ 
End of 
treatment 
Follow-up 
 
Weeks in relation to 
Visit 2 
(randomization) 
-4 
-2 
0 
1 
2 
3 
4-40 
42 
Visit number 
1 
2 
3 
4 
5 
6 
7-16 
17 
Liraglutide 
Scre
enin
g 
Run-
In 
0.6 mg 
 
1.2 mg 
 
1.8 mg  
2.4 mg  
3.0 mg 
 
No 
treatment 
Placebo 
Placebo 
 
Placebo 
 
Placebo 
 
Placebo 
 
Placebo 
 
 
803 
Table: Visit schedule with assessments 
804 
 
805 
 
Pri
or 
to 
Sc
re
eni
ng 
Vi
sit 
Sc
re
eni
ng 
Ru
n-
In 
Ra
nd
o
mi
zat
io
n 
Dose Escalation 
Maintenance Period 
En
d 
of 
Tr
eat
me
nt 
O
bs
er
va
tio
na
l 
Fo
llo
w-
up 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Informed 
consent 
X 
X 
(re
vie
w) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In/exclus
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


P a g e  | 21 
 
STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
ion 
criteria 
Randomi
zation 
criteria 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Withdra
wal 
criteria 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demogr
aphics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Age 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sex 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomi
tant 
illnesses/
Medical 
history 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomi
tant 
medicati
ons 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Measure
ments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood 
pressure 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Heart 
rate 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood 
glucose 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Triglyceri
des 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
HDL-
cholester
ol 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnan
cy test (if 
female) 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Waist 
circumfer
ence 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Hip 
circumfer
ence 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Visceral 
AT (MRI) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Abd 
subcutan
eous AT 
(MRI) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Total fat 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 


P a g e  | 22 
 
STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
mass 
(MRI) 
Total fat-
free 
mass 
(MRI) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Lower 
body AT 
(MRI) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Hepatic 
fat (MRI) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Laborat
ory 
tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting 
insulin 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CRP 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
NT-
proBNP 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Trial 
Related 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diet and 
physical 
activity 
counseli
ng 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug 
accounta
bility 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse 
events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
806 
At Visits 1, 3, and 16 the subject must attend the clinic in a fasting condition in the morning (i.e., 
807 
at least eight hours overnight fast without food and/or drink intake, except for water). 
808 
Background medication should be withheld on the day of the fasting Visits 1, 3, and 16 until 
809 
blood sampling has been done. At all other visits the background medication and trial product 
810 
should be taken as usual during the conduct of the trial.  
811 
 
812 
Trial product will be dispensed at visits 3 through 15. Subjects will be asked to bring all empty, 
813 
partly used and unused trial product at visits 4 through 16 for drug accountability. The 
814 
computerized randomization system should be contacted for trial product dispensing. If the 
815 
subject attends the clinic for a visit not described in the protocol, then an Unscheduled Visit 
816 
Form must be completed. The Unscheduled Visit Form should not be completed if the sole 
817 
purpose of the visit is trial product dispensing. If an unscheduled visit is made for the purpose of 
818 
dispensing trial products to the subjects then an unscheduled dispensing session must be 
819 
completed in the computerized randomization system. If it is not possible to attend the visit 
820 
within the visit window, the subjects should be called in for an Unscheduled Visit. 
821 
 
822 
In case a subject is being prematurely withdrawn from the trial before or at visit 16, the 
823 
Investigator will ensure that the procedures for the End of Treatment visit (Visit 16) are 
824 


P a g e  | 23 
 
STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
undertaken, if possible. The primary reason (adverse event, non-compliance with protocol or 
825 
other) for discontinuation will be specified in the CRF and a computerized randomization system 
826 
withdrawal session should be completed. Even if the subject is not able to attend a final visit, the 
827 
End of Trial Form (EOT) must be completed. 
828 
 
829 
Subjects that have discontinued the trial prematurely before Visit 16 will be asked to attend a 
830 
visit (Visit 16x) taking place 40 weeks after the randomization date. The purpose of this visit will 
831 
be recording of all outcome assessments if possible. If the subject is not willing to attend Visit 
832 
16x, it should be documented in the patient medical record that the subject has refused to 
833 
attend the visit. 
834 
 
835 
Visit 1 
836 
At Visit 1, the informed consent will be reviewed again for signature and participants will be 
837 
screened for eligibility in the trial. This will include interview assessment for inclusion and any 
838 
exclusion criteria and laboratory components of the metabolic syndrome.  Subjects that meet all 
839 
eligibility requirements to participate in the trial will then return for a Run-In visit (Visit 2). 
840 
 
841 
Subjects must give signed and dated informed consent prior to any trial-related activities 
842 
(including Visit 1). All subjects will be provided with a copy of the subject information and a copy 
843 
of their own signed and dated Informed Consent Form. 
844 
 
845 
The subjects will be allocated the unique lowest consecutive 6 digit subject number available 
846 
from the range of subject numbers. The subject number is composed of three digits unique for 
847 
each trial site and three digits for each enrolled subject at the trial site. The subject number is 
848 
maintained throughout the trial. The computerized randomization system will be activated to 
849 
register the subject as screened and the subject will be provided with a trial card indicating that 
850 
the subject is participating in a trial. 
851 
 
852 
The following will be recorded in the case record form (CRF). Expanded list of 
853 
comorbidities will be developed prior to FPFV: 
854 
• 
Age 
855 
• 
Sex 
856 
• 
Race/ethnicity 
857 
• 
Height 
858 
• 
Weight 
859 
• 
Waist Circumference 
860 
• 
Blood Pressure 
861 
• 
Medical history 
862 
• 
Concomitant medications 
863 
• 
Informed consent, signed and dated 
864 
 
865 
The following laboratory studies will be performed and recorded in the CRF when 
866 
resulted: 
867 
• 
Fasting blood glucose 
868 
• 
Fasting triglycerides 
869 
• 
Fasting HDL-cholesterol 
870 
• 
For females of childbearing potential, urine pregnancy test 
871 
 
872 
Visit 2 
873 


P a g e  | 24 
 
STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
Visit 2 will be the start of the 2-week Run-In phase during which time eligible participants will be 
874 
counseled on diet and physical activity to determine adherence to lifestyle recommendations. A 
875 
dietary diary will be recorded by the participants and returned to the trial coordinator at Visit 3. 
876 
Pedometers will be given to the participants to encourage adherence to physical activity 
877 
guidelines and will be returned at Visit 3.  
878 
 
879 
Counseling on Diet and Physical Activity 
880 
At Visit 2 subjects will receive dietary counseling by trial staff according to local standard and 
881 
placed on a hypo-caloric diet containing approximately 30% of energy from fat, approximately 
882 
20% of energy from protein, approximately 50% of energy from carbohydrates and an energy 
883 
deficit of approximately 500 kcal/day compared to the subjects’ estimated total energy 
884 
expenditure (TEE) (See Table below).  The hypo-caloric diet will be continued from 
885 
randomization through the treatment period. Counseling on diet and physical activity will be 
886 
provided at every trial visit.  All subjects will be instructed by trial staff to keep a 3-day diary of 
887 
food intake between Visits 2 and 3.  The 3-day food diaries will be used for counseling at each 
888 
trial visit. The subject’s dietary compliance and the average daily level of physical activity will be 
889 
recorded at each visit. The subject will be questioned whether they performed less than half an 
890 
hour, between half an hour and one hour or more than 1 hour of physical activity per day. An 
891 
increase in physical activity (recommended minimum 150 minutes/week) will be encouraged.  
892 
Subject compliance with the prescribed diet will be determined at the discretion of trial staff after 
893 
review of the 3-day food diaries. 
894 
 
895 
Calculation of estimated total energy expenditure 
896 
The TEE is calculated by multiplying the estimated Basal Metabolic Rate (BMR) (see Table) 
897 
with a Physical Activity Level (PAL) value of 1.325 
898 
 
899 
Total Energy Expenditure (TEE) (kcal/day) = BMR x 1.3 
900 
Table _ Equations for estimating basal metabolic rate (BMR) in kcal/day* 
901 
Sex 
Age 
BMR (kcal/day) 
Men 
18-30 years 
15.057 x actual weight in kg + 692.2 
 
31-60 years 
11.472 x actual weight in kg + 873.1 
 
≥60 years 
11.711 x actual weight in kg + 587.7 
Women 
18-30 years 
14.818 x actual weight in kg + 486.6 
 
31-60 years 
8.126 x actual weight in kg + 845.6 
 
≥60 years 
9.082 x actual weight in kg + 658.5 
Revised WHO equations25 
 
902 
Visit 3 
903 
At Visit 3, participants will be randomized to liraglutide or placebo injection in a 1:1 fashion. 
904 
Randomization will be implemented using a computerized randomization system by an 
905 
independent party at UT Southwestern. Subjects will have trial products supplied according to 
906 
randomization and will be instructed in administration of daily injections of liraglutide/ placebo. 
907 
Injections can be done at any time of day irrespective of meals. However, it is preferable that 
908 
liraglutide/ placebo be injected during the same overall time period on a day to day basis. The 
909 
injection site does not have to be kept consistent throughout the trial. The trial products 
910 
dispensed will cover the dose escalation period. Subjects will follow a fixed dose escalation. The 
911 
dose will be gradually escalated to 3.0 mg starting with 0.6 mg and with a dose level increment 
912 
of 0.6 mg every 7 days.  
913 
 
914 


P a g e  | 25 
 
STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
If the subject is not eligible for randomization, the subject is considered a screening failure and 
915 
the the subject will be registered as a screening failure in the computerized randomization 
916 
system.  
917 
 
918 
At this visit, they will undergo all baseline anthropometric, imaging, and laboratory assessments. 
919 
 
920 
The following will be recorded in the CRF: 
921 
• 
Age 
922 
• 
Sex 
923 
• 
Race/ethnicity 
924 
• 
Weight 
925 
• 
Height 
926 
• 
Concomitant medications 
927 
• 
Blood Pressure 
928 
• 
Pulse 
929 
• 
Waist Circumference 
930 
• 
Hip Circumference 
931 
• 
Visceral adipose tissue mass 
932 
• 
Abdominal subcutaneous adipose tissue mass 
933 
• 
Total fat mass 
934 
• 
Total fat-free mass 
935 
• 
Lower body adipose tissue mass 
936 
• 
Hepatic fat content 
937 
• 
Laboratory tests, including 
938 
- 
Markers of insulin resistance: fasting blood glucose, insulin  
939 
- 
Markers of inflammation: CRP 
940 
- 
Lipids: TG/HDL-C ratio,  
941 
- 
Natriuretic peptides: NT-proBNP 
942 
 
943 
Visits 4-7 
944 
At Visits 4-7, subjects will follow a dose escalation regimen and trial staff will monitor for AEs 
945 
and ensure adherence to diet and exercise recommendations. Subjects will follow a fixed dose 
946 
escalation. The dose will be gradually escalated to 3.0 mg starting with 0.6 mg and with a dose 
947 
level increment of 0.6 mg every 7 days. 
948 
 
949 
Visits 8-15 
950 
Visits 8-15 are the maintenance phase of the trial. Subjects will attend visits with trial staff every 
951 
4 weeks to ensure adherence to the trial protocol, monitor for AEs, monitor for non-adherence to 
952 
trial medication, and monitor adherence to diet and exercise recommendations. 
953 
 
954 
Visit 16 
955 
Visit 16 is the final visit during the maintenance phase during which follow-up imaging and 
956 
laboratory studies will be assessed in addition to assessments done during Visits 8-15. All 
957 
remaining doses of trial medication will be collected at this visit and returned to Novo Nordisk. 
958 
No further trial drug will be administered after this visit.  
959 
 
960 
The following will be recorded in the CRF: 
961 
• 
Weight 
962 


P a g e  | 26 
 
STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
• 
Height 
963 
• 
Concomitant medications 
964 
• 
Blood Pressure 
965 
• 
Pulse 
966 
• 
Waist Circumference 
967 
• 
Hip Circumference 
968 
• 
Visceral adipose tissue mass 
969 
• 
Abdominal subcutaneous adipose tissue mass 
970 
• 
Total fat mass 
971 
• 
Total fat-free mass 
972 
• 
Lower body adipose tissue mass 
973 
• 
Hepatic fat content 
974 
• 
Laboratory tests, including 
975 
- 
Markers of insulin resistance: fasting blood glucose, insulin  
976 
- 
Markers of inflammation: CRP 
977 
- 
Lipids: TG/HDL-C ratio,  
978 
- 
Natriuretic peptides: NT-proBNP 
979 
Visit 17 
980 
Visit 17 will be an observational follow-up visit during which subjects will be monitored for AEs.  
981 
At the End of Trial visit (Visit 17) the Investigator or delegate will provide counseling on the 
982 
management of weight control and follow-up medical care. 
983 
 
984 
Assessments for efficacy 
985 
Weight will be recorded to the nearest 0.1 kg using calibrated scales.  Weight will be measured 
986 
in a fasting state with an empty bladder, without shoes and only wearing light clothing. Height 
987 
without shoes will be recorded at Visit 1. BMI will be calculated as follows: BMI = weight 
988 
(kg)/height (m2) 
989 
 
990 
Systolic and diastolic blood pressure will be measured at all visits  
991 
• 
The auscultatory method should be used to measure blood pressure. 
992 
• 
The patient should avoid caffeine, smoking, physical activity for 30 minutes prior to 
993 
measurement. 
994 
• 
Remove all clothing over the covered arm. 
995 
• 
The same sphygmomanometer should be used throughout the trial. 
996 
• 
The measurement should be taken in the seated position with legs uncrossed, back 
997 
and arm supported. 
998 
• 
Subject should rest in a sitting position for 5 minutes prior to the first blood pressure 
999 
being taken. 
1000 
• 
The measurement should be in the upper arm with a stethoscope at the elbow 
1001 
crease over the brachial artery. 
1002 
• 
The same arm should be used for blood pressure measurements at all trial visits. 
1003 
• 
The size of the cuff should be appropriate.  The bladder of the cuff should encircle at 
1004 
least 80% of the arm circumference and the width of the cuff is at least 40% of the 
1005 
arm circumference. 
1006 
• 
The cuff placement must be preceded with palpation of the brachial artery and the 
1007 
antecubital fossa.  The midline of the cuff bladder must be placed over the location of 
1008 
the arterial pulsation.  The lower edge of the cuff should be 2 to 3 cm above the 
1009 
antecubital fossa to allow for stethoscope placement. 
1010 


P a g e  | 27 
 
STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
• 
The cuff should be inflated to at least 30 mm above the point at which the radial 
1011 
pulse disappears.  The pulse should be then reduced at 2 or 3 mm/sec. 
1012 
• 
Korotkoff sounds should be used to measure blood pressure using standard 
1013 
techniques.  The measurement should be taken with the precision to the nearest 2 
1014 
mmHg. 
1015 
• 
There should be no talking during the measurement. 
1016 
• 
Two reliable measurements at intervals of at least 2 minutes should to be performed.  
1017 
In case there is a greater than 5 mmHg difference between the first and second 
1018 
reading of the diastolic blood pressure, one additional reading should be obtained.   
1019 
 
1020 
The resting heart rate will be recorded at all trial visits using the following methodology: 
1021 
• The pulse will be recorded after resting for five minutes in a sitting position.  
1022 
• The pulse will be counted for 30 seconds and recorded as beats per minute. The pulse 
1023 
will be measured using direct palpation.  
1024 
• Exercise, alcohol, nicotine, and coffee should be avoided 30 minutes preceding 
1025 
measurement. 
1026 
• Heart rate will be measured while the patient is seated in a comfortable position with 
1027 
legs uncrossed. 
1028 
 
1029 
The laboratory analyses for efficacy and safety will be outsourced to a Central Laboratory 
1030 
unless otherwise specified. Descriptions of assay methods, instrumentation and procedures for 
1031 
obtaining samples, handling and storage of samples will be described in a trial specific 
1032 
laboratory manual provided by the Central Laboratory. 
1033 
 
1034 
Samples will be coded with the intention that the subject’s identity will remain encrypted but 
1035 
information such as age, sex, race, health information and response to liraglutide will be 
1036 
correlated. The samples will only be used in relation to the present trial. Novo Nordisk and its 
1037 
representatives and/or regulatory authorities, may have access to this information. However, the 
1038 
subject’s identity will not be revealed. 
1039 
 
1040 
Laboratory analysis results will be sent to the Investigator after visits during which laboratory 
1041 
studies are obtained. All laboratory reports must be dated and signed by the Investigator on the 
1042 
day of evaluation. If a result is outside the normal range, the Investigator will judge whether the 
1043 
abnormality is clinically significant or not. The signed laboratory report is retained at the 
1044 
Investigator site as source documentation. Any abnormal, clinically significant result identified at 
1045 
screening visit 1 will be recorded as a concomitant illness. 
1046 
 
1047 
Ascertainment of clinical safety endpoints 
1048 
At each visit trial staff will review criteria for withdrawal and AEs/SAEs with the subject.  There 
1049 
will not be external independent event adjudications for the adverse cardiovascular endpoints of 
1050 
death, MI or stroke. The Investigator will identify adverse cardiovascular events.  These adverse 
1051 
events of interest include death, all cause and cardiovascular deaths, nonfatal myocardial 
1052 
infarction and nonfatal stroke.  These will be defined prospectively and identified by the 
1053 
Investigator.  These events will not undergo external independent event adjudication.  These 
1054 
endpoints will be investigator identified using a priori criteria.  
1055 
 
1056 
Ascertainment of diet/physical activity 
1057 
At each visit the trial staff will review diet and physical activity compliance with the subject.  
1058 
Subjects not meeting trial standards will be encouraged to adjust their behavior to adhere to trial 
1059 


P a g e  | 28 
 
STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
requirements. Subjects not meeting requirements after 2 attempts at correction may be subject 
1060 
to withdrawal from the trial at the discretion of the Investigator. 
1061 
 
1062 
Subject Compliance:  
1063 
At each visit the trial staff will review trial medication compliance with the subject.  At the 
1064 
prescribed visits, the subject will return used or partly used trial products including all empty 
1065 
packaging materials.  The investigator will assess the amount of return trial product and 
1066 
compare it to what was dispensed to estimate the subject's compliance with trial medication.  If 
1067 
noncompliance is identified, the investigator will counsel the patient on the importance of trial 
1068 
medication compliance.  Consistent failure to be compliant with trial medication or other trial 
1069 
protocols could ultimately lead to subject withdrawal from the trial. 
1070 
 
1071 
End of trial treatment strategy 
1072 
Following the end of the treatment, all trial drug treatment will be discontinued and the trial drug 
1073 
collected. Subjects will be advised with regards to the best possible post-trial treatment options 
1074 
for their weight management and metabolic syndrome. These treatments will be at the 
1075 
discretion of the local Investigator. Unblinding will occur at LPLV and after ascertainment of 
1076 
primary and secondary endpoints. 
1077 
 
1078 
 
1079 
Premature discontinuation 
1080 
If the trial subject opts for early trial termination, he/she will be asked to attend a premature trial 
1081 
discontinuation visit at the time of discontinuation. The purpose of this visit will be to assess 
1082 
body weight, occurrence of AEs and discuss end of trial imaging studies. The PI will offer end of 
1083 
trial imaging to assess for the primary and secondary efficacy endpoints if the subject has 
1084 
completed at least 40 weeks of trial treatment. Every effort will be made to assess for AE and 
1085 
SAEs during the trial for all patients including those prematurely withdrawing from the trial.  
1086 
 
1087 
TRIAL DRUGS AND MATERIALS: 
1088 
Treatment with liraglutide or placebo will be blinded to the subjects and investigators throughout 
1089 
the trial. 
1090 
 
1091 
Trial medication(s) / devices(s) 
1092 
The administration of liraglutide/ placebo will be as outlined above. 
1093 
The following trial products will be supplied by Novo Nordisk, Denmark. 
1094 
• 
Liraglutide 6.0 mg/mL, 3 mL pen-injector for subcutaneous injection 
1095 
• 
 Placebo 3 mL pen-injector for subcutaneous injection 
1096 
 
1097 
Liraglutide will be available at a concentration of 6.0 mg/mL.  Liraglutide and placebo will be 
1098 
supplied in a 3 mL  pen-injector .  Correct dosing is achieved by using the dose counter and the 
1099 
dose pointer to see how many mg to select. The subject will hear a “click” every time they turn 
1100 
the dose selector. The dose will not be set by counting the number of clicks the subject hears. 
1101 
Dosing with the liraglutide/ placebo pen-injector is controlled by turning the dose selector until 
1102 
the dose indicator shows the relevant dose (0.6, 1.2, 1.8, 2.4 or 3.0 mg, respectively or 
1103 
placebo). Therefore, the dose level (injection volume) of liraglutide or placebo is open labeled. 
1104 
 
1105 
Liraglutide or placebo is administered once daily by subcutaneous injections with the pen-
1106 
injector, either in the abdomen, thigh or upper arm. Injections can be done at any time of day 
1107 
irrespective of meals. However, it is preferable that liraglutide be injected during the same 
1108 


P a g e  | 29 
 
STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
overall time period on a day to day basis. Subjects will be instructed to perform an air shot 
1109 
before the first injection with the pen-injector. For further information, please see the direction 
1110 
for use (DFU) for the liraglutide pen-injector. These DFUs will be provided together with the trial 
1111 
product. The Investigator or trial staff will instruct subjects in how to inject liraglutide or placebo, 
1112 
and will ensure that the subjects are familiar with the DFU. It will be documented in the subject’s 
1113 
research record that the subject has been instructed in the use of the pen-injector. 
1114 
 
1115 
Subjects will follow a fixed dose escalation and in order to reduce the level of side effects, 
1116 
liraglutide is gradually escalated up to the maintenance dose. Subjects will be instructed to 
1117 
escalate the liraglutide (active or placebo) dose to 3.0 mg/day over a 4 week period following an 
1118 
initial dose of 0.6 mg/day and weekly dose escalation steps of 0.6 mg/day. 
1119 
If subjects do not tolerate an increase in dose during dose-escalation, the Investigator will have 
1120 
the option to delay the next dose escalation for approximately one week. All subjects must be at 
1121 
the target dose 3.0 mg or placebo at the latest 8 weeks after randomization. 
1122 
 
1123 
Dose escalation schedule: 
1124 
Week 
Dose (mg) 
0 
0.6 
1 
1.2 
2 
1.8 
3 
2.4 
4 and beyond 
3.0 
 
1125 
After reaching the target dose, 3.0 mg liraglutide or placebo dose and dosing frequency should 
1126 
not be changed at any time during the treatment period. If any dose is missed by the subject up 
1127 
to and including 3 consecutive days it will be documented in the research record and the 
1128 
Investigator will discuss the importance of treatment compliance with the subject. After a 
1129 
potential discontinuation up to 3 days the subject must be re-initiated on trial drug on target 
1130 
dose 3.0 mg liraglutide or placebo. Missed doses for more than 3 consecutive days will be 
1131 
discussed with the PI and it will be up to Investigator’s judgment if the subject can continue on 
1132 
target dose or should be withdrawn. 
1133 
 
1134 
It is always important that the Investigator emphasizes to subjects the necessity of compliance 
1135 
with regard to taking trial drug as described in the protocol. It is the responsibility of the 
1136 
Investigator to access the subject’s overall compliance throughout the trial and subjects deemed 
1137 
to be non-compliant subjects may be withdrawn at the Investigator’s discretion. If subjects do 
1138 
not tolerate the target dose, they will be withdrawn from the trial.  If the Investigator suspects 
1139 
acute pancreatitis, all suspected drugs will be discontinued until confirmatory tests have been 
1140 
conducted. If tests reveal that a subject does not have acute pancreatitis, the subject can 
1141 
remain in the trial with re-initiation of titration until the target dose is reached. 
1142 
 
1143 
Packaging and Labelling of Trial Medication(s) 
1144 
All trial products will be packed and labeled by Novo Nordisk and provided in non-subject 
1145 
specific boxes.  Labeling will be in accordance with local law and trial requirements. 
1146 
 
1147 
Storage and Drug Accountability of Trial Medication(s) 
1148 
The Investigator must keep track of all received, used, partly used and unused trial products by 
1149 
the use of the drug accountability module in the computerized randomization system. 
1150 
 
1151 


P a g e  | 30 
 
STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
Store in a refrigerator (2°C to 8°C). Do not store in the freezer or directly adjacent to the 
1152 
refrigerator cooling element. Do not freeze liraglutide/ placebo and do not use liraglutide/ 
1153 
placebo if it has been frozen. Liraglutide/ placebo should not be used if it does not appear clear 
1154 
and colorless. After first use of the liraglutide/ placebo pen, the product can be stored for  30 
1155 
days at room temperature (+15°C to +30°C)/(59°F to 86°F) or in a refrigerator (+2°C to 
1156 
+8°C)/(+36°F to +46°F). Keep the pen cap on when liraglutide/ placebo pen is not in use in 
1157 
order to protect from light. Liraglutide/ placebo should be protected from excessive heat and 
1158 
sunlight. Always remove the injection needle after each injection and store the liraglutide/ 
1159 
placebo pen without an injection needle attached. This prevents contamination, infection, and 
1160 
leakage. It also ensures that the dosing is accurate. No trial product which has exceeded the 
1161 
expiry date must be used. 
1162 
 
1163 
The Investigator will ensure the availability of proper storage conditions and record and evaluate 
1164 
the temperature. The temperature will be recorded and evaluated on a daily basis (working 
1165 
days) using as a minimum a calibrated min/max thermometer. A log to document the 
1166 
temperature must be kept. Storage facilities will be checked frequently (at least once every 
1167 
working day). 
1168 
 
1169 
No trial product(s) should be dispensed to any person not enrolled in the trial and the 
1170 
computerized randomization system should always be updated when dispensing trial product(s). 
1171 
Returned trial product(s) (partly used or unused including empty packaging material) must be 
1172 
stored separately from non-allocated trial product(s) until the monitor has performed drug 
1173 
accountability. The monitor will be responsible for retrieval of trial products from the site. 
1174 
Destruction of trial products will be done according to local laws and will be recorded on a 
1175 
Destruction Form, which will be signed by the person responsible for destruction, as agreed with 
1176 
the monitor. 
1177 
 
1178 
Randomization and Blinding 
1179 
Trial participants and investigators will be blinded to treatment allocation throughout the trial.   
1180 
 
1181 
Randomization Scheme: 
1182 
Participants will be randomly assigned using a computerized randomization code generated by 
1183 
UT Southwestern. 
1184 
 
1185 
Breaking of Blinded Codes 
1186 
Blinding codes will be broken at the end of the trial. Blinding codes will only be broken before 
1187 
the end of trial if a subject develops a serious adverse event requiring knowledge of the 
1188 
treatment allocation. At such time, the subject will be considered to have completed the trial and 
1189 
will not undergo any further trial treatment but may be asked to undergo assessment of trial 
1190 
endpoints when feasible.  Whenever a code is broken, the person breaking the code must print 
1191 
the Code Break Confirmation generated by the computerized randomization system, record the 
1192 
reason, and sign and date the document. If the subject should be withdrawn following a code 
1193 
break, a withdrawal session should be completed in the computerized randomization system. 
1194 
 
1195 
CONCOMITANT ILLNESSES AND MEDICATIONS 
1196 
All concomitant illnesses and medications will be recorded in the CRF and assessed as AEs or 
1197 
not AEs. If a subject is prescribed a medication meeting criteria for withdrawal/exclusion, the 
1198 
subject will have the opportunity to decide whether to take such medication and withdraw from 
1199 
the trial or not take it and continue the trial.   
1200 


P a g e  | 31 
 
STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
SUBJECT SAFETY AND DATA MONITORING 
1201 
ADVERSE EVENTS: 
1202 
Definitions 
1203 
 
1204 
Adverse Event (AE): 
1205 
An AE is any undesirable medical event occurring to a subject in a clinical trial, whether or not 
1206 
related to the trial product(s). This includes events reported from the first trial related activity 
1207 
after the subject has signed the informed consent and until post treatment follow-up period as 
1208 
defined in the protocol. The following should not be recorded as AEs, if recorded as medical 
1209 
history/concomitant illness on the CRF at screening: 
1210 
• Pre-planned procedure, unless the condition for which the procedure was planned has    
1211 
worsened from the first trial related activity after the subject has signed the informed consent 
1212 
• Pre-existing conditions found as a result of screening procedures 
1213 
 
1214 
Clinical Laboratory Adverse Event: 
1215 
A clinical laboratory AE is any clinical laboratory abnormality regarded as clinically significant 
1216 
i.e. an abnormality that suggests a disease and/or organ toxicity and is of a severity, which 
1217 
requires active management, (i.e. change of dose, discontinuation of trial product, more 
1218 
frequent follow-up or diagnostic investigation). 
1219 
 
1220 
Serious Adverse Event (SAE): 
1221 
A serious AE is an experience that at any dose results in any of the following: 
1222 
• Death 
1223 
• A life-threatening experience (an event in which the subject was at risk of death at the time of 
1224 
the event. It does not refer to an event which hypothetically might have caused death if it was 
1225 
more severe) 
1226 
• In-patient hospitalisation or prolongation of existing hospitalization 
1227 
• A persistent or significant disability/incapacity 
1228 
• A congenital anomaly/birth defect 
1229 
• Important medical events that may not result in death, be life-threatening*, or require 
1230 
hospitalization may be considered an SAE when, based upon appropriate medical judgement, 
1231 
they may jeopardize the subject and may require medical or surgical intervention to prevent one 
1232 
of the outcomes listed in this definition. 
1233 
• Suspicion of transmission of infectious agents must always be considered an SAE  
1234 
 
1235 
Note: The term life-threatening in the definition of serious refers to an event in which the patient 
1236 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
1237 
might have caused death if it was more severe. 
1238 
 
1239 
Serious Adverse Drug Reaction (SADR):  
1240 
An adverse drug reaction (ADR) is an adverse event for which a causal relationship 
1241 
(Possible/Probable relation) between the trial drug and the occurrence of the event is 
1242 
suspected. The ADR should be classified as serious if it meets one or more of the seriousness 
1243 
criteria.  
1244 
 
1245 
Suspected Unexpected Serious Adverse Reaction (SUSAR):  
1246 
An SAE which is unexpected and regarded as possibly or probably related to the trial product by 
1247 
the investigator. 
1248 
 
1249 


P a g e  | 32 
 
STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
Non-Serious Adverse Event: 
1250 
A non-serious AE is any AE which does not fulfil the definition of an SAE. 
1251 
 
1252 
Severity Assessment Definitions: 
1253 
• Mild: Transient symptoms, no interference with the subject’s daily activities 
1254 
• Moderate: Marked symptoms, moderate interference with the subject’s daily activities 
1255 
• Severe: Considerable interference with the subject’s daily activities, unacceptable 
1256 
 
1257 
Relationship to trial medication Assessment Definitions: 
1258 
• Probable: Good reasons and sufficient documentation to assume a causal relationship 
1259 
• Possible: A causal relationship is conceivable and cannot be dismissed 
1260 
• Unlikely: The event is most likely related to an etiology other than the trial product 
1261 
• Suggested to specify the reference document (eg: USPI, CCDS) in the protocol which is 
1262 
agreed upon with NN, for evaluation of expectedness 
1263 
 
1264 
Outcome Categories and Definitions: 
1265 
• Recovered: Fully recovered or by medical or surgical treatment the condition has returned to 
1266 
the level observed at the first trial related activity after the subject signed the informed consent 
1267 
• Recovering: The condition is improving and the subject is expected to recover from the event. 
1268 
This term should only be used when the subject has completed the trial 
1269 
• Recovered with sequelae: As a result of the AE, the subject suffered persistent and     
1270 
significant disability/incapacity (e.g. became blind, deaf, paralyzed). Any AE recovered with 
1271 
sequelae should be rated as an SAE 
1272 
• Not recovered 
1273 
• Fatal – this term is only applicable if the subject died from a condition related to the reported 
1274 
AE. Outcomes of other reported AEs in a subject before he/she died should be assessed 
1275 
according to the state of the event at the time of death. An AE with fatal outcome must be 
1276 
reported as an SAE. 
1277 
• Unknown 
1278 
 
1279 
Collection, Recording and Reporting of Adverse Events 
1280 
All events meeting the definition of an adverse event will be collected and reported from the first 
1281 
trial related activity after the subject has signed the informed consent and until the end of the 
1282 
post-treatment follow-up period as stated in the protocol.  
1283 
 
1284 
Plan for reporting both anticipated and unanticipated adverse events: 
1285 
Each subject will be evaluated for any adverse events.  Any event that is reported to either the 
1286 
principal investigator or his designated research associates by the subject or medical staff 
1287 
caring for the subject and which meets the criteria will be documented as such.  Any event that 
1288 
is reported will then generate an adverse event report, which will be submitted to the safety 
1289 
officer, local IRB, Novo Nordisk, and FDA. The report will include a description of the event, 
1290 
when and how it was reported, as well as any official chart records or documentation to 
1291 
corroborate the event or the reporting of the event. All adverse events will be graded as mild, 
1292 
moderate, or severe.  All unexpected fatal or life-threatening suspected adverse reactions 
1293 
represent especially important safety information and will be reported to FDA as soon as 
1294 
possible but no later than 7 calendar days following the sponsor’s initial receipt of the 
1295 
information. Any severe and/or unanticipated adverse event will be reported to the safety officer, 
1296 
local IRB, Novo Nordisk, and FDA within 24 hours of knowledge of the event.  At a minimum, 
1297 
the investigator will copy NN when expediting SARs or SUSARs to health authorities and will 
1298 


P a g e  | 33 
 
STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
report all SARs related to NN product to the local NN affiliate safety department.  All other 
1299 
adverse events will be reported in a timely fashion to the safety officer, local IRB, Novo Nordisk, 
1300 
and FDA preferably within 2 weeks of the date of the event.  All adverse events will be 
1301 
summarized annually and submitted to the local IRB, Novo Nordisk, and FDA.  Any action 
1302 
resulting in a temporary or permanent suspension of this trial (e.g. FDA actions, IRB actions, or 
1303 
actions by the investigators or co-investigators) will be reported to the appropriate Novo Nordisk 
1304 
program official. 
1305 
 
1306 
Follow-up of Adverse Events 
1307 
Periodic reviews of adverse events and safety issues will be performed during the trial as listed 
1308 
below: 
1309 
 
1310 
Safety reviews. The principal investigators (SM, IN) will review the safety and progress of this 
1311 
trial on a weekly basis.   
1312 
 
1313 
Annual review. The principal investigators (SM, IN) will review this protocol on a continuing 
1314 
basis for subject safety and include results of the review in the annual progress reports 
1315 
submitted to the safety officer, local IRB, and Novo Nordisk. 
1316 
 
1317 
Pregnancy 
1318 
Pregnant and breast-feeding females cannot participate in the trial because they may expose 
1319 
the unborn child to risks.  If participants can become pregnant, a pregnancy test will be done 
1320 
from a urine sample, and it must be negative before they can be a part of this trial.  If they do 
1321 
become pregnant during this trial, they must inform the researchers immediately and their 
1322 
participation in the trial will be discontinued. Novo Nordisk will receive a report of any pregnancy 
1323 
in the trial subject that occurs during the use of a NN product. The investigator must follow the 
1324 
pregnancy until the pregnancy outcome and the newborn infant is one month of age. The 
1325 
investigator must report information about the pregnancy, pregnancy outcome, and health of the 
1326 
newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
1327 
newborn infant. 
1328 
 
1329 
At a minimum the following details will be reported - Trial name - Patient identification (e.g. 
1330 
subject number, initials, sex, age) - Event (Preferably diagnosis) - Drug - Reporter - Causality – 
1331 
Outcome. These details will be reported to Novo Nordisk Inc. safety department. 
1332 
 
1333 
Precautions/Over-dosage 
1334 
Certain precautions will be taken by the PI and trial staff based on prior data and experience. 
1335 
These include: 
1336 
1. Injection Site Reaction 
1337 
Approximately 1-10/100 subjects developed pain, bruising, irritation, itching and/or rash 
1338 
at the injection site in the previous LEAD and SCALE clinical trials.  A similar incidence 
1339 
of these injection site reactions will be expected in this clinical trial.  Safety text regarding 
1340 
these reactions and the possibility of anaphylactic shock will be included in the informed 
1341 
consent and as part of site and investigator training.   
1342 
 
1343 
2. Calcitonin Monitoring 
1344 
Calcitonin levels will not be routinely monitored during the trial.  
1345 
 
1346 
Possible Side-Effects 
1347 


P a g e  | 34 
 
STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
As with any drug, allergic reactions to the drug in this study are possible.  Liraglutide may cause 
1348 
some, all or none of the side-effects listed below that have been reported in patients previously. 
1349 
• 
More frequent (>10%):  nausea, diarrhea, constipation, and vomiting;  
1350 
• 
Less common (1-10%):  dyspepsia, abdominal pain, abdominal distension, eructation,  
1351 
            flatulence; and  
1352 
• 
Rarely (<1%):  gallbladder disease, acute pancreatitis 
1353 
All adverse effects are reversible with discontinuation of the medication. 
1354 
 
1355 
Data and Safety Monitoring Committee (DSMC): 
1356 
1. Parag Joshi MD 
1357 
2. Steven P. Marso MD 
1358 
3. James de Lemos MD 
1359 
4. Darren McGuire MD MHSc 
1360 
The DSMC will meet biannually by telephone/teleconference and distribute a report to the IRB 
1361 
at the completion of each meeting. 
1362 
 
1363 
LIABILITY AND SUBJECT INSURANCE: 
1364 
During and following a subject’s participation in the trial, the primary investigators (IN and SM) 
1365 
and UT Southwestern Medical Center will provide adequate medical care to the study subject 
1366 
for any study-related adverse events, including clinically significant laboratory values related to 
1367 
the study. This medical care for study subjects will be provided regardless of their insurance 
1368 
status. 
1369 
 
1370 
Novo Nordisk carries product liability insurance for its products.  Sponsor-investigator agrees to 
1371 
indemnify Novo Nordisk in accordance with the written contract executed between the parties 
1372 
for this study. Generally, however, Novo Nordisk assumes no liability in the event of negligence 
1373 
of the sponsor-investigator conducting the trial, or by persons for whom the sponsor-investigator 
1374 
is responsible. 
1375 
 
1376 
EVALUABILITY OF SUBJECTS: 
1377 
The following analysis sets are defined: 
1378 
 
1379 
Full analysis set (FAS) 
1380 
All randomized subjects exposed to at least one dose of the trial product and with at least one 
1381 
post-baseline assessment of any efficacy endpoint will be included. Subjects in the FAS will be 
1382 
analyzed according to intention to treat (primary) and per-protocol (secondary). The requirement 
1383 
of a post-baseline observation is in alignment with the FDA recommendations. 
1384 
 
1385 
Safety analysis set 
1386 
All randomized subjects who have been exposed to at least one dose of trial product. Subjects 
1387 
in the safety analysis set will be analyzed “as treated”. 
1388 
 
1389 
PREMATURE TERMINATION OF TRIAL: 
1390 
The trial will be prematurely terminated for the following reasons only: 
1391 
1. A serious threat to the safety of trial participants occurs that cannot be addressed in any 
1392 
other manner than trial termination. 
1393 
2. Funding is withdrawn from the trial. 
1394 
3. The local IRB withdraws approval for the trial. 
1395 


P a g e  | 35 
 
STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
 
1396 
PUBLICATION PLAN: 
1397 
It is expected that this trial will generate 1 or more scientific abstracts that will be presented at 
1398 
scientific meetings and 1 or more manuscripts that will be published in peer review journals. For 
1399 
each publication there will be a first and senior author and a responsible writing group. This 
1400 
subgroup will be responsible for driving the publication process forward. The manuscript will be 
1401 
forwarded to Novo Nordisk for review prior to publication. Novo Nordisk will be allowed 10 
1402 
working days to review the manuscript and provide feedback. The investigators retain the right 
1403 
to publish results independent of findings and will not need Novo Nordisk permission prior to 
1404 
publication and or presentation of data.  
1405 
 
1406 
KEY PERSONNEL: 
1407 
Sponsor: UT Southwestern Medical Center, Dallas, TX 
1408 
Clinical sites: UT Southwestern Medical Center (Ambulatory and Inpatient sites) and Parkland 
1409 
Hospital (Ambulatory and Inpatient sites) 
1410 
 
1411 
Primary Investigator:  
1412 
Parag Joshi MD 
1413 
 
1414 
Data and Safety Monitoring Committee (DSMC): 
1415 
5. Parag Joshi MD 
1416 
6. Steven P. Marso MD 
1417 
7. James de Lemos MD 
1418 
8. Darren McGuire MD MHSc 
1419 
 
1420 
Trial coordinator: Bienka Milton MPH, BS 
1421 
 
1422 
Statistician: Colby Ayers, MS 
1423 
 
1424 
REFERENCES: 
1425 
1. 
Astrup A, Rossner S, Van Gaal L, et al. Effects of liraglutide in the treatment of obesity: a 
1426 
randomised, double-blind, placebo-controlled study. Lancet 2009;374:1606-16. 
1427 
2. 
Astrup A, Carraro R, Finer N, et al. Safety, tolerability and sustained weight loss over 2 
1428 
years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond) 2012;36:843-54. 
1429 
3. 
Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic 
1430 
syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific 
1431 
Statement. Circulation 2005;112:2735-52. 
1432 
4. 
Berrington de Gonzalez A, Hartge P, Cerhan JR, et al. Body-mass index and mortality 
1433 
among 1.46 million white adults. N Engl J Med 2010;363:2211-9. 
1434 
5. 
Despres JP. Body fat distribution and risk of cardiovascular disease: an update. 
1435 
Circulation 2012;126:1301-13. 
1436 
6. 
Garvey WT, Garber AJ, Mechanick JI, et al. American association of clinical 
1437 
endocrinologists and american college of endocrinology position statement on the 2014 
1438 
advanced framework for a new diagnosis of obesity as a chronic disease. Endocr Pract 
1439 
2014;20:977-89. 
1440 
7. 
Morkedal B, Vatten LJ, Romundstad PR, Laugsand LE, Janszky I. Risk of myocardial 
1441 
infarction and heart failure among metabolically healthy but obese individuals: HUNT (Nord-
1442 
Trondelag Health Study), Norway. J Am Coll Cardiol 2014;63:1071-8. 
1443 


P a g e  | 36 
 
STU122015-044, Joshi, Form A, Mod_8, 08-24-18 (2) 
Version 4.1 | November 1, 2016 
 
 
 
8. 
Despres JP, Lemieux I, Bergeron J, et al. Abdominal obesity and the metabolic 
1444 
syndrome: contribution to global cardiometabolic risk. Arterioscler Thromb Vasc Biol 
1445 
2008;28:1039-49. 
1446 
9. 
McLaughlin T, Lamendola C, Liu A, Abbasi F. Preferential fat deposition in 
1447 
subcutaneous versus visceral depots is associated with insulin sensitivity. J Clin Endocrinol 
1448 
Metab 2011;96:E1756-60. 
1449 
10. 
McLaughlin T, Sherman A, Tsao P, et al. Enhanced proportion of small adipose cells in 
1450 
insulin-resistant vs insulin-sensitive obese individuals implicates impaired adipogenesis. 
1451 
Diabetologia 2007;50:1707-15. 
1452 
11. 
See R, Abdullah SM, McGuire DK, et al. The association of differing measures of 
1453 
overweight and obesity with prevalent atherosclerosis: the Dallas Heart Study. J Am Coll Cardiol 
1454 
2007;50:752-9. 
1455 
12. 
Cerhan JR, Moore SC, Jacobs EJ, et al. A pooled analysis of waist circumference and 
1456 
mortality in 650,000 adults. Mayo Clin Proc 2014;89:335-45. 
1457 
13. 
Alberti KG, Zimmet P, Shaw J. The metabolic syndrome--a new worldwide definition. 
1458 
Lancet 2005;366:1059-62. 
1459 
14. 
Hsu WC, Araneta MR, Kanaya AM, Chiang JL, Fujimoto W. BMI cut points to identify at-
1460 
risk Asian Americans for type 2 diabetes screening. Diabetes Care 2015;38:150-8. 
1461 
15. 
Neeland IJ, Ayers CR, Rohatgi AK, et al. Associations of visceral and abdominal 
1462 
subcutaneous adipose tissue with markers of cardiac and metabolic risk in obese adults. 
1463 
Obesity (Silver Spring) 2013;21:E439-47. 
1464 
16. 
Neeland IJ, Turer AT, Ayers CR, et al. Dysfunctional adiposity and the risk of 
1465 
prediabetes and type 2 diabetes in obese adults. JAMA 2012;308:1150-9. 
1466 
17. 
Chandra A, Neeland IJ, Berry JD, et al. The relationship of body mass and fat 
1467 
distribution with incident hypertension: observations from the dallas heart study. J Am Coll 
1468 
Cardiol 2014;64:997-1002. 
1469 
18. 
Neeland IJ, Gupta S, Ayers CR, et al. Relation of regional fat distribution to left 
1470 
ventricular structure and function. Circulation Cardiovascular imaging 2013;6:800-7. 
1471 
19. 
Britton KA, Massaro JM, Murabito JM, Kreger BE, Hoffmann U, Fox CS. Body fat 
1472 
distribution, incident cardiovascular disease, cancer, and all-cause mortality. J Am Coll Cardiol 
1473 
2013;62:921-5. 
1474 
20. 
Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight loss 
1475 
with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized 
1476 
study. Int J Obes (Lond) 2013;37:1443-51. 
1477 
21. 
Borga M TE, Romu T, Rosander J, Fitzpatrick J, Leinhard OD, Bell JD. Validation of a 
1478 
fast method for quantification of intra-abdominal and subcutaneous adipose tissue for large-
1479 
scale human studies. . NMR Biomed 2015;In Press. 
1480 
22. 
Schaudinn A, Linder N, Garnov N, et al. Predictive accuracy of single- and multi-slice 
1481 
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