Clinical trial NCT03922945
Conditions: Adolescent Obesity Obesity in Adolescence Adolescent Overweight
Keywords: weight loss obesity weight control
Sponsor: VIVUS LLC
Start date: 2019-05-02; Completion date: 2021-04-16
Enrollment: 223 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is being conducted to assess weight loss efficacy, as determined by changes in body mass index (BMI), and safety of VI-0521 (Qsymia®) or placebo, taken for 56 weeks accompanied by a lifestyle modification program in obese adolescents age 12-16 years.

Detailed description:

Arms: arm 1: Weeks 1-2: VI-0521 (Phentermine 3.75 mg + Topiramate 23 mg) oral capsule, once daily; Weeks 3-56: VI-0521 (Phentermine 7.5 mg + Topiramate 46 mg) oral capsule, once daily arm 2: Weeks 1-2: VI-0521 (Phentermine 3.75 mg + Topiramate 23 mg) oral capsule, once daily; Weeks 3-12: VI-0521 (Phentermine 7.5 mg + Topiramate 46 mg) oral capsule, once daily; Weeks 13-14: VI-0521 (Phentermine 11.25 mg + Topiramate 69 mg) oral capsule, once daily; Weeks 15-56: VI-0521 (Phentermine 15 mg + Topiramate 92 mg) oral capsule, once daily arm 3: Subjects will receive placebo oral capsule, once daily for up to 56 weeks
Interventions: intervention 1: VI-0521 oral capsule intervention 2: Placebo oral capsule intervention 3: Lifestyle Modification
Intervention descriptions: intervention 1: Phentermine/Topiramate intervention 2: Inactive drug intervention 3: The lifestyle modification includes physical activity, behavior change, reduced calorie diet advice, and family support. This intervention is applied to all treatment groups.

Protocol documents:
Prot_000.pdf: 
NCT03922945


INVESTIGATOR AGREEMENT PAGE 
VIVUS, Inc. 
Protocol Title: A Phase IV, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Design Study to Determine the Safety and Efficacy of VI-0521 in Obese 
Adolescents 
 
Version: Amendment #2, 21 June 2019 
 
I will provide copies of the protocol, any subsequent protocol amendments and access to all 
information provided by the sponsor to the study personnel under my supervision. I will discuss 
this material with them to ensure that they are fully informed about the investigational drug and 
the clinical trial protocol. 
I agree to conduct this clinical trial according to the attached protocol, except when mutually 
agreed in writing. I also agree to conduct this clinical trial in compliance with all federal, state 
and local regulations, Good Clinical Practice, and the Declaration of Helsinki, and the 
requirements of the appropriate Institutional Review Board/Independent Ethics Committee and 
any other institutional requirements. 
 
 
Principal Investigator: 
 
Date: 
 
Printed Name: 
 
Institution: 
 
Address: 
 
NCT03922945


1.0 
TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT PAGE ...................................................................................2 
1.0 
TABLE OF CONTENTS ..................................................................................................3 
2.0 
PROTOCOL SYNOPSIS ..................................................................................................6 
3.0 
LIST OF ABBREVIATIONS .........................................................................................11 
4.0 
BACKGROUND ..............................................................................................................14 
5.0 
STUDY OBJECTIVES ....................................................................................................15 
6.0 
STUDY DESIGN ..............................................................................................................15 
6.1 
Primary Efficacy Endpoints ...................................................................................16 
6.2 
Secondary Efficacy Endpoints ...............................................................................16 
6.3 
Exploratory Endpoints: ..........................................................................................17 
6.4 
Safety Endpoints ....................................................................................................17 
7.0 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................17 
7.1 
Inclusion Criteria ...................................................................................................17 
7.2 
Exclusion Criteria ..................................................................................................17 
7.3 
Subject Withdrawal ................................................................................................19 
8.0 
TREATMENT OF SUBJECTS ......................................................................................20 
8.1 
Study Treatment .....................................................................................................20 
8.2 
Allocation to Treatment .........................................................................................20 
8.3 
Breaking the Blind .................................................................................................20 
8.4 
Drug Supply ...........................................................................................................21 
8.4.1 
Formulation and Packaging ..................................................................21 
8.4.2 
Preparation and Dispensing ..................................................................22 
8.4.3 
Administration ......................................................................................22 
8.4.4 
Dose Reduction and/or Interruption During Trial Participation ...........22 
8.4.5 
Discontinuing Study Drug ....................................................................23 
8.4.6 
Compliance ...........................................................................................23 
8.4.7 
Drug Storage and Drug Accountability.................................................23 
8.5 
Concomitant Medications ......................................................................................24 
8.5.1 
Excluded Medications ...........................................................................24 
8.5.2 
Other Restricted Medications ................................................................24 
8.5.3 
Documentation of Concomitant Medication Use ..................................24 
8.6 
Treatment of Diabetes ............................................................................................25 
8.7 
Treatment of Elevated Blood Pressure ..................................................................25 
8.8 
Treatment of Hypothyroidism................................................................................25 
9.0 
STUDY PROCEDURES .................................................................................................26 
9.1 
Schedule of Visits ..................................................................................................26 
9.1.1 
Screening Visit (Visit 1, Up to – 4 Weeks) ...........................................26 
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9.1.2 
Baseline/Randomization (Visit 2, Week 0) ...........................................26 
9.1.3 
Treatment Week 4 Through Week 52 (Visits 3 Through 15) ...............27 
9.1.4 
Treatment Week 56, End of Study; Early Termination (Visit 16) ........28 
9.2 
Study Period ...........................................................................................................28 
10.0 
ASSESSMENT .................................................................................................................29 
10.1 
Weight Measurement .............................................................................................29 
10.2 
Waist Circumference Measurement .......................................................................29 
10.3 
Height and BMI .....................................................................................................30 
10.4 
Vital Signs ..............................................................................................................30 
10.5 
Physical Examinations and Tanner Staging ...........................................................30 
10.6 
Electrocardiograms ................................................................................................30 
10.7 
X-Ray of the Hand and Wrist ................................................................................31 
10.8 
DXA (Sub Study) ...................................................................................................31 
10.9 
Laboratory Tests ....................................................................................................31 
10.10 Oral Glucose Tolerance Test .................................................................................32 
10.11 CANTAB (Cambridge Neuropsychological Test Automated Battery) .................32 
10.12 IWQOL-Kids .........................................................................................................32 
10.13 PHQ-9: Modified for Teens ...................................................................................33 
10.14 Columbia Suicide Severity Rating Scale (C-SSRS) ..............................................33 
11.0 
ADVERSE EVENT REPORTING ................................................................................34 
11.1 
Adverse Events ......................................................................................................34 
11.1.1 
Severity Assessment .............................................................................34 
11.1.2 
Causality Assessment ............................................................................34 
11.1.3 
Abnormal Test Findings ........................................................................35 
11.1.4 
Mood or Depression Related Events .....................................................35 
11.1.5 
Serious Adverse Events or Serious Suspected Adverse Reactions .......35 
11.1.6 
Definition of Hospitalization ................................................................36 
11.2 
Eliciting Adverse Event Information .....................................................................37 
11.3 
Reporting Period ....................................................................................................37 
11.4 
Reporting Requirements ........................................................................................37 
11.4.1 
Serious Adverse Event Reporting Requirements ..................................37 
11.4.2 
Non-Serious Adverse Event Reporting Requirements ..........................38 
11.4.3 
Pregnancy ..............................................................................................38 
12.0 
STATISTICAL PLAN .....................................................................................................38 
12.1 
Statistical Analysis .................................................................................................38 
12.2 
Sample Size Determination ....................................................................................38 
12.3 
Analysis Populations ..............................................................................................39 
12.4 
Subgroups ..............................................................................................................39 
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12.5 
Statistical Methods .................................................................................................39 
12.5.1 
Analysis of the Primary Endpoint .........................................................39 
12.5.2 
Method for Prevention and Treatment of Missing Values ....................40 
12.5.3 
Analysis of the Secondary Endpoints ...................................................41 
12.6 
Safety Analysis ......................................................................................................41 
12.6.1 
Analysis of CANTAB ...........................................................................41 
12.6.2 
Analysis of Hand and Wrist X-Ray ......................................................41 
12.6.3 
Analysis of DXA ...................................................................................41 
12.6.4 
Adverse Events .....................................................................................42 
12.6.5 
Clinical Laboratory Tests ......................................................................42 
12.6.6 
Vital Signs and Other Safety Evaluations .............................................42 
12.7 
Interim Analysis .....................................................................................................42 
12.8 
Data Monitoring Committee ..................................................................................42 
13.0 
TRIAL TERMINATION CRITERIA ...........................................................................43 
14.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION ................................43 
15.0 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................43 
16.0 
ETHICAL CONSIDERATIONS ....................................................................................43 
16.1 
Institutional Review Board /Independent Ethics Committee .................................43 
16.2 
Ethical Conduct of the Clinical Trial .....................................................................44 
16.3 
Subject Information and Consent/Assent ...............................................................44 
17.0 
DATA HANDLING AND RECORD KEEPING ..........................................................44 
17.1 
Case Report Forms/Electronic Data Record ..........................................................44 
17.2 
Record Retention ...................................................................................................45 
18.0 
PUBLICATION PLAN ...................................................................................................45 
19.0 
REFERENCES .................................................................................................................46 
APPENDIX 1: SCHEDULE OF EVENTS ................................................................................47 
APPENDIX 2: BMI CONVERSION CHART ..........................................................................48 
APPENDIX 3: CDC CLINICAL GROWTH CHARTS7 .........................................................49 
APPENDIX 4: PHQ-9: MODIFIED FOR TEENS ...................................................................50 
APPENDIX 5: SAMPLE COLUMBIA SUICIDE SEVERITY RATING SCALE ...............51 
APPENDIX 6: IWQOL-KIDS ....................................................................................................63 
APPENDIX 7: FORMULAS FOR ESTIMATING CREATININE CLEARANCE .............64 
APPENDIX 8: SUMMARY OF CHANGES IN AMENDMENT #1 ......................................65 
APPENDIX 9: SUMMARY OF CHANGES IN AMENDMENT #2 ......................................67 
LIST OF FIGURES 
Figure 1. Schematic Diagram of Study Design .................................................................16 
Figure 2. Measuring Tape Position for Waist Circumference Assessments ......................29 
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2.0 
PROTOCOL SYNOPSIS 
Title of Clinical Study: 
A Phase IV, Multi-Center, Randomized, Double-Blind, Placebo-
Controlled, Parallel-Design Study to Determine the Safety and 
Efficacy of VI-0521 in Obese Adolescents 
Sponsor: 
VIVUS, Inc. (VIVUS) 
Phase of Development: 
4 
Indication: 
Weight management in obese adolescents 
Study Rationale: 
Obesity remains a major problem in pediatrics. National Health 
and Nutrition Examination Survey (NHANES) data indicate that 
18.5% of children and adolescents age 2 to 19 years and 20.6% 
of adolescents age 12 to 19 years met the definition of obesity in 
2015-2016. Obesity in childhood or adolescence increases the 
risk of adult obesity, type 2 diabetes mellitus, and dyslipidemia. 
VI-0521 (marketed as Qsymia® in the United States), a fixed 
dose combination of immediate-release (IR) phentermine 
(PHEN) and extended-release (ER) topiramate (TPM), was 
approved in July 2012 by the FDA as an adjunct to a reduced-
calorie diet and increased physical activity for chronic weight 
management in overweight and obese adults. 
Topiramate is used as an anticonvulsant in children as young as 
2 years, typically beginning at doses of 1–3 mg/kg/day and 
titrating as needed to 5–9 mg/kg/day. Adequate and well-
controlled studies of phentermine have not been conducted in 
children. 
Based on a previously completed PK study of obese adolescents 
(study OB-402), PK parameters in obese adolescent subjects 
were consistent with those observed in previous Phase 1 to 3 
studies conducted in adult obese subjects. 
This study is being conducted to assess the safety and efficacy of 
VI-0521, accompanied by a lifestyle modification program, in 
obese adolescents. 
Study Design: 
In this multicenter, randomized, double-blind, placebo-
controlled, parallel-design study, approximately 200 subjects 
will be enrolled at approximately 20 sites in the United States. 
Subjects will be randomly assigned in a 1:1:2 ratio to placebo, 
N=50; mid-dose (PHEN/TPM 7.5 mg/46 mg), N= 50; or top-
dose (PHEN/TPM 15 mg/92 mg), N=100 of VI-0521, to be 
taken orally once daily in the morning. Randomization will be 
stratified by age (12-14 vs 15-16 years old) and gender. The 
study will consist of a screening period of up to 28 days, 
followed by a 56-week treatment period. 
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Subjects will be instructed to follow a mild hypocaloric diet 
modification program representing a 500-calorie/day deficit and 
to implement a family-based lifestyle modification program for 
adolescents, as tolerated, throughout the study period. The 
lifestyle program will include physical activity, behavior change, 
and family support. The same lifestyle modification program, 
specific to this population, will be implemented across all sites. 
Study drug doses will be titrated according to the following 
schema. 
Group 
Treatment 
Dosage for 
PHEN/TPM 
(mg) 
Titration Dose for PHEN/TPM (mg) 
Weeks 
1-2 
Weeks 
3-4 
Weeks 
13-14 
Weeks 
15-16 
Placebo 
0/0 
0/0 
0/0 
0/0 
0/0 
VI-0521 Mid 
7.5/46 
3.75/23 
7.5/46 
7.5/46 
7.5/46 
VI-0521 Top 
15/92 
3.75/23 
7.5/46 
11.25/69 
15/92 
Subjects who are unable to tolerate the assigned dose may be 
treated at a reduced dose or may take a drug holiday as defined 
in the protocol. 
All subjects will return at approximately 4-week intervals for 
study assessments. All female subjects will undergo a pregnancy 
test at each visit. Subjects who discontinue the treatment during 
the study will be encouraged to remain on study (off study drug) 
for continued follow-up by attending all remaining visits and 
have all study-related procedures performed, and to return at the 
56-week time point for measurements and evaluations. For those 
who choose to completely withdraw from the study at any point, 
the end of study (Week 56) procedures should be completed. 
Study Objectives: 
The primary objectives are to evaluate the safety and efficacy of 
VI-0521 (PHEN/TPM 7.5 mg/46 mg and PHEN/TPM 
15 mg/92 mg doses) for the treatment of obesity in adolescents. 
The secondary objective is to characterize changes in obesity-
related risk factors. 
Duration of Treatment: 
The treatment period will be 56 weeks. 
Sample Size: 
Approximately 200 subjects 
Number of 
Sites/Locations: 
Approximately 20 sites in the United States 
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Study Population: 
Key Inclusion Criteria (see Section 7.1 for a complete list): 
• Aged ≥ 12 years and < 17 years at the time of screening; 
• BMI ≥ the 95th percentile, with documented history of 
failure to lose sufficient weight or failure to maintain 
weight loss in a lifestyle modification program; 
• If female, must be using adequate contraception, defined 
as double barrier methods, stable hormonal contraception 
plus single barrier method, tubal ligation, or abstinence. 
Study Population: 
Key Exclusion Criteria (see Section 7.2 for a complete list): 
• Type 1 diabetes; 
• Congenital heart disease; clinically significant ECG 
abnormality; 
• Physical exam, vital signs, or laboratory abnormality; 
clinically significant hepatic or renal disease; 
• Creatinine clearance (Schwartz formula) < 60 
mL/minute; 
• Clinically significant thyroid dysfunction as evidenced 
by signs, symptoms, or TSH > 1.5 x ULN; 
• Obesity of known genetic or endocrine origin; 
• History of bipolar disorder or psychosis, greater than one 
lifetime episode of major depressive disorder, depression 
of moderate or greater severity, or presence or history of 
suicidal behavior or active suicidal ideation; 
• Recent weight instability, or prior bariatric surgery; 
• History of glaucoma or increased intraocular pressure; 
• Current smoker or smoking cessation within 3 months of 
screening; 
• Currently taking or plan on taking any of following 
medications during the study: 
o Anticonvulsants used for treatment of seizure 
disorder, including barbiturates, benzodiazepines, 
GABA analogues, hydantoins, phenyltriazines, 
succinimides, and other agents (valproic acid and its 
derivatives, carbamazepine and its derivatives, 
zonisamide, and felbamate); 
o Tricyclic antidepressants, MAOIs, lithium, levodopa, 
and dopamine receptor agonists; 
o Carbonic anhydrase inhibitors; 
o Insulin, SFUs, GLP-1 agonists, SGLT-1, and SGLT-2 
inhibitors; 
NCT03922945


o Chronic systemic steroids (i.e. glucocorticoids, 
anabolic steroids) other than oral contraceptives; 
o Treatment for hyperactivity disorder; or 
o OTC, prescription medications, herbal agents and 
dietary supplements used with the intention to lose 
body weight. 
Study Drug Form and 
Strength: 
• Low-dose (for titration purposes only): One PHEN/TPM 
3.75/23 mg capsule administered daily 
• Mid-dose: One PHEN/TPM 7.5/46 mg capsule administered 
daily 
• ¾-dose (for titration purposes only): One PHEN/TPM 
11.25/69 mg capsule administered daily 
• Top-dose: One PHEN/TPM 15/92 mg capsule administered 
daily 
Study drug will be packaged into 2 types of kits; titration kits 
(blister cards) for use during the first 4 weeks of dosing and the 
first 4 weeks following up-titration for subjects randomized to 
the top-dose (Weeks 13-16), and treatment kits (bottles), for use 
once subjects have been titrated to their assigned dosage. 
Regimen/Administration: Each capsule of study drug will be taken orally in the morning, 
with or without food, and with water. 
Primary Efficacy 
Endpoints: 
The primary endpoint is the mean percent change in BMI from 
baseline to end of study (Week 56) 
Second Efficacy 
Endpoints: 
The secondary endpoints are: 
• Percent of subjects achieving a reduction ≥ 5%, ≥ 10% 
and ≥ 15% of baseline BMI at Week 56; 
• Change from baseline in waist circumference at Week 
56; 
• Change from baseline in fasting insulin and Whole Body 
Insulin Sensitivity Index (Matsuda) at Week 56; 
• Change from baseline in triglycerides and HDL-C at 
Week 56; 
• Change from baseline in blood pressure at Week 56. 
Exploratory Endpoints: 
Additional exploratory analyses will be conducted to evaluate 
effects of treatment on IWQOL-Kids questionnaire scores, 
changes in various glycemic and lipid markers, and change in 
BMI Z-score. 
Safety Evaluations and 
Oversight: 
Safety monitoring and tolerability will be assessed by evaluation 
of adverse events/serious adverse events, physical exams, vitals, 
cognitive function tests using the CANTAB, responses to PHQ-
9, C-SSRS, bone age (X-ray of the hand and wrist), DXA in a 
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subset (approximately 25 subjects each on the placebo and mid-
dose, and 50 subjects on the top-dose), and periodic monitoring 
of laboratory test results. 
An independent Data Monitoring Committee (DMC) will be 
established to evaluate accumulating trial data on a periodic 
basis and to assess the ongoing safety of the study. 
Statistical Methods: 
Analysis Populations: 
Randomized: This population will be comprised of all subjects 
who were initially randomized. This population will be used for 
summaries of subject disposition and baseline subject 
characteristics. 
Intent-to-treat (ITT)/Safety: This population will be comprised 
of all subjects who were initially randomized and received at 
least one dose of study drug. This will be the primary population 
for all summaries of subject disposition and baseline 
characteristics, efficacy analyses, and safety analyses for 
purposes of regulatory submissions. 
Comparisons in the primary endpoint of change from the 
baseline BMI between treatment groups will be assessed using a 
mixed effects model with repeated measures (MMRM) with 
factors of treatment, visit, treatment by visit interaction, baseline 
BMI value, age stratification, and gender stratification. 
Appropriate contrast will be applied for treatment comparisons 
at Week 56. The 3 comparisons of interest are 1) top-dose vs. 
placebo; 2) mid-dose vs. placebo; and 3) top-dose vs. mid-dose. 
Sensitivity analyses will be conducted to examine the impact of 
missing data on the robustness of statistical conclusions. 
In previous studies in adults, PHEN/TPM 7.5 mg/46 mg dose 
resulted in a placebo-subtracted BMI reduction of 2.4 units with 
a standard deviation of 2.9. Assuming a similar effect size, with 
enrollment of 200 subjects (100 randomized to the top-dose, 50 
randomized to the mid-dose, and 50 randomized to the placebo), 
the present study will have greater than 90% power to detect a 
significant difference in BMI reduction between the top-dose 
and the placebo, and approximately 80% power to detect a 
significant difference between the mid-dose group and the 
placebo. The above power calculation assumes very conservative 
differences between the active doses and placebo and a worst 
case 30% dropout rate. 
NCT03922945


3.0 
LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse event 
ACE 
Angiotensin converting enzyme 
ADHD 
Attention-deficit/hyperactivity disorder 
ANCOVA 
Analysis of covariance 
ARB 
Angiotensin receptor blocker 
AST 
Aspartate transaminase 
ALT 
Alanine aminotransferase 
AUC 
Area under the curve 
BMC 
Bone mineral content 
BMD 
Bone mineral density 
BMI 
Body mass index 
oC 
Degrees Celsius 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practices 
CL 
Apparent clearances 
Cmax 
Maximum observed drug concentration 
CRF 
Case report form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DMC 
Data Monitoring Committee  
DXA 
Dual-energy X-ray absorptiometry 
ECG 
Electrocardiogram 
ER 
Extended-release 
oF 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
GABA 
Gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
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Abbreviation or Term 
Definition/Explanation 
GLP-1 
Glucagon-like peptide -1 
HbA1c 
Hemoglobin A1c 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
Human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
ITT 
Intent to treat 
IR 
Immediate-release 
IRB 
Institutional Review Board 
IWQOL-Kids 
Impact of Weight on Quality of Life-Kids 
IWRS 
Interactive Web Response System 
LDL-C 
Low-density lipoprotein cholesterol 
LOCF 
Last observation carried forward 
LSD 
Least significant difference 
MAOI 
Monoamine oxidase inhibitor 
MAR 
Missing at random 
MCMC 
Markov chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
m-ITT 
Modified intent to treat 
mmHg 
Millimeters of mercury pressure 
MMRM 
Mixed effect Model with Repeated Measures 
MNAR 
Missing not at random 
NHANES 
National Health and Nutrition Examination Survey 
OGTT 
Oral glucose tolerance test 
OTC 
Over-the-counter 
PA 
Posterior-anterior 
PHEN 
Phentermine 
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Abbreviation or Term 
Definition/Explanation 
PHQ 
Patient Health Questionnaire 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
sCr 
Serum creatinine 
SFU 
Sulfonylurea 
SGLT 
Sodium glucose transporter 
TBLH 
Total body less head 
Tmax 
Time to maximum concentration 
TPM 
Topiramate 
TSH 
Thyroid Stimulating Hormone 
TZD 
Thiazolidinedione 
ULN 
Upper limit of normal 
USA 
United States of America 
Vc/F 
Apparent volume of distribution 
WHO 
World Health Organization 
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4.0 
BACKGROUND 
Obesity remains a major problem in pediatrics. National Health and Nutrition Examination 
Survey (NHANES) data indicate that 18.5% of children and adolescents age 2 to 19 years and 
20.6% of adolescents age 12 to 19 years met the definition of obesity in2015-2016.1 Obesity in 
childhood or adolescence increases the risk of adult obesity, type 2 diabetes mellitus, and 
dyslipidemia.2,3,4 Although lifestyle changes and behavior modification programs have shown 
some benefit, these measures have not been widely adopted for the treatment of obesity in 
children. When intensive lifestyle modification is unsuccessful in reaching weight loss goals, 
adjunct pharmacotherapy may be warranted. Few weight loss drug therapies have been evaluated 
in children and currently there is only one FDA approved product (orlistat) to treat adolescent 
obesity. Additional pharmacotherapy options are needed in order to address pediatric obesity. 
VI-0521 (marketed as Qsymia® in the United States), a fixed dose combination of immediate-
release (IR) phentermine (PHEN) and extended-release (ER) topiramate (TPM), was approved in 
July 2012 by the Food and Drug Administration (FDA) as an adjunct to a reduced-calorie diet 
and increased physical activity for chronic weight management in overweight and obese adults. 
Mean weight loss of > 10% was achieved after one year of treatment in obese adults randomized 
to top-dose (PHEN/TPM 15 mg/92 mg) and > 8% in those randomized to mid-dose (PHEN/TPM 
7.5 mg/46 mg) of VI-0521. Weight loss was sustained over two years. In addition to weight loss, 
VI-0521 also resulted in significant reductions in blood pressure, improved glycemic parameters, 
increased HDL-C, and reduced triglycerides.5 The doses employed in this combination represent 
a fraction of those commonly prescribed as single agents for other indications. 
Topiramate is used as an anticonvulsant in children as young as 2 years, typically beginning at 
doses of 1–3 mg/kg/day and titrating as needed to 5–9 mg/kg/day.6 The 92 mg of topiramate in 
the top-dose of VI-0521 falls well within the dose range currently used in children. Adequate and 
well-controlled studies of phentermine have not been conducted in children. The top-dose of VI-
0521 contains roughly ½ of the maximum phentermine dose currently approved for use in adults. 
The single- and multiple-dose pharmacokinetics (PK) of topiramate and potential drug 
interactions between topiramate and phentermine in VI-0521 have been fully investigated in the 
adult population. The major route of elimination of phentermine and its metabolites is through 
the urine. Topiramate is not extensively metabolized and is primarily eliminated unchanged in 
the urine (approximately 70% of an administered dose). Previous population PK analyses 
demonstrated that creatinine clearance and body weight were the most important components 
describing the PK of phentermine and topiramate in VI-0521, that the PK parameters of 
phentermine and topiramate were dose proportional, and that no relationship was observed 
between PK parameters and age, gender, or body mass index (BMI) for either drug. 
By the time children reach adolescent age, their kidneys are fully developed and there is little 
variation in kidney function compared to adults. 
Based on the PK study of obese adolescents (study OB-402), plasma concentrations in obese 
adolescents were consistent with those observed in previous Phase 1 to 3 studies conducted in 
adult obese subjects. 
For phentermine, geometric means of individual posterior Bayes PK parameters (apparent 
clearance [CL/F] and apparent volume of distribution [Vc/F]) in obese adolescent subjects were 
within 10% of those previously assessed in obese adult subjects enrolled in Phase 2 and Phase 3 
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studies, and arithmetic means of area under the curve (AUC) and Cmax in obese adolescent 
subjects were within 10% of arithmetic means previously obtained based on rich concentration-
time profiles of phentermine under steady-state in obese adults. Medians of Tmax in adolescent 
subjects were within 11% of medians of Tmax observed in obese adults. 
For topiramate, geometric means of individual posterior Bayes CL/F were within 30% of those 
previously assessed in obese adult subjects enrolled in Phase 2 and Phase 3 studies, with higher 
CL/F values in the adolescent population. Geometric means of posterior Bayes Vc/F of TPM in 
obese adults and obese adolescents were similar. The higher CL/F values in adolescents are 
consistent with lower serum creatinine values in this population, but did not result in marked 
differences in exposure, as arithmetic means of AUC and Cmax of topiramate were within 12% of 
arithmetic means previously obtained based on rich concentration-time profiles of topiramate 
under steady-state in obese adults. Medians of Tmax in adolescent subjects were within 2% of 
medians of Tmax observed in obese adults. 
This study is being conducted to assess the safety and efficacy of VI-0521, accompanied by a 
lifestyle modification program, in obese adolescents. 
5.0 
STUDY OBJECTIVES 
The primary objectives are to evaluate the safety and efficacy of VI-0521 for the treatment of 
obesity in adolescents. The secondary objective is to characterize changes in obesity-related risk 
factors. 
6.0 
STUDY DESIGN 
In this multicenter, randomized, double-blind, placebo-controlled, parallel-design study, 
approximately 200 subjects will be enrolled at approximately 20 sites in the United States. 
Subjects will be randomly assigned in a 1:1:2 ratio to placebo, N= 50; mid-dose (PHEN/TPM 
7.5 mg/46 mg), N= 50; or top-dose (PHEN/TPM 15 mg/92 mg), N =100, of VI-0521, to be taken 
orally once daily in the morning. Randomization will be stratified by age (12-14 vs 15-16 years 
old) and gender. The study will consist of a screening period of up to 28 days, followed by a 56-
week treatment period. 
Subjects will be instructed to follow a mild hypocaloric diet modification program representing a 
500-calorie/day deficit and to implement a family-based lifestyle modification program for 
adolescents, as tolerated, throughout the study period. The lifestyle program will include 
physical activity, behavior change, and family support. The same lifestyle modification program, 
specific to this population, will be implemented across all sites. Study drug will be titrated as 
described in Section 8.4.1. 
Subjects who are unable to tolerate the assigned dose may be treated at a reduced dose level or 
may take a drug holiday as defined in Section 8.4.4. In addition, for growth monitoring, 
investigators will monitor rates of weight loss in treated subjects. For subjects with baseline BMI 
95-98th percentile, reduce study drug dosage when BMI is < 85th percentile or when weight loss 
exceeds an average of 2 lbs (0.9 kg) per week. For subjects with baseline BMI ≥ 99th percentile, 
reduce study drug when weight loss exceeds an average of 2 lbs (0.9 kg)/week. 
All subjects will return at approximately 4-week intervals for study assessments. All female 
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subjects will undergo a pregnancy test at each visit. Subjects who discontinue study drug during 
the study will be encouraged to remain on study (off study drug) for continued follow-up by 
attending all remaining visits and have all study-related procedures performed, and to return at 
the 56-week time point for measurements and evaluations. For those who choose to completely 
withdraw from the study at any point, the end of study (Week 56) procedures should be 
completed. 
Figure 1. Schematic Diagram of Study Design 
 
6.1 
Primary Efficacy Endpoints 
The primary endpoint is the mean percent change in BMI from baseline to end of study (Week 
56). 
6.2 
Secondary Efficacy Endpoints 
The secondary endpoints are: 
• Percent of subjects achieving a reduction ≥ 5%, ≥ 10% and ≥ 15% of baseline BMI at 
Week 56; 
• Change from baseline in waist circumference at Week 56; 
• Change from baseline in fasting insulin and Whole Body Insulin Sensitivity Index 
(Matsuda) at Week 56; 
• Change from baseline in triglycerides and HDL-C at Week 56; 
• Change from baseline in blood pressure at Week 56. 
VI-0521 (7.5 mg/46 mg) 
(N=100) 
VI-0521 (7.5 mg/46 mg) 
(N=50) 
Placebo 
(N=50) 
VI-0521 (15 mg/92 mg) 
Screening 
12 
Weeks 
~ 2 
Weeks 
44 
Weeks 
Randomization 
Week 12 Titration Point 
End of Study 
1 
1 
2 
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6.3 
Exploratory Endpoints: 
Additional exploratory analyses will be conducted to evaluate effects of treatment on Impact of 
Weight on Quality of Life-Kids (IWQOL-Kids) questionnaire scores, changes in various 
glycemic and lipid markers, and change in BMI Z-score. 
6.4 
Safety Endpoints 
Safety will be assessed by evaluation adverse events (AEs)/serious adverse events (SAEs); vital 
signs, laboratory parameters (screening, periodically during the study and end of study); 
electrocardiograms; physical examinations; cognitive function tests using the Cambridge 
Neuropsychological Test Automated Battery (CANTAB). All subjects will be screened for the 
presence and severity of depression using the PHQ-9: Modified for Teens (Appendix 4) and for 
suicidal/ideation using the Columbia Suicide Severity Rating Scale (C-SSRS) (Appendix 5: 
Sample Columbia Suicide Severity Rating Scale) and follow up assessments will be done at each 
visit after treatment has been initiated. Bone age (X-ray of the hand and wrist) will be evaluated 
at baseline and end of study or early termination. Effect on bone mineral density and bone 
mineral content, as evaluated by Dual-energy X-Ray Absorptiometry (DXA) will be performed 
at baseline, end of study or early termination, at selected sites. 
7.0 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
Inclusion Criteria 
To be eligible for enrollment into this study, each subject must meet all of the following criteria 
at screening: 
1. Provide written informed consent (of a parent or legal guardian) who will accompany the 
subject to all study visits; 
2. Provide written assent (of study subject); 
3. Be an adolescent ≥ 12 years and < 17 years of age with Tanner Staging of ≥ 2 at the time 
of screening; 
4. Have a BMI ≥ the 95th percentile of BMI for age and gender (see Appendix 3: CDC 
Clinical Growth Charts8), with documented history of failure to lose sufficient weight or 
failure to maintain weight loss in a lifestyle modification program; 
5. Be willing and able to comply with scheduled study visits, treatment plan, laboratory 
tests and other study procedures; 
6. If female, must be using adequate contraception, defined as double barrier methods, 
stable hormonal contraception plus single barrier method, tubal ligation, or abstinence. 
7.2 
Exclusion Criteria 
To be eligible for enrollment into this study, each subject must not meet any of the following 
criteria at screening (unless otherwise specified): 
1. Weight gain or weight loss of greater than 5 kg, use of a supervised fast or very low-
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calorie diet within the past 3 months; 
2. Treatment with phentermine, topiramate, lorcaserin, naltrexone HCl/bupropion HCl, any 
over-the-counter (OTC) or prescription or herbal agents and dietary supplements, teas or 
tinctures used with the intention to lose body weight within 3 months of screening; 
3. Any stimulants used for treatment of attention-deficit/hyperactivity disorder (ADHD) 
within 3 months of screening; 
4. Condition or disease interfering with metabolism, such as untreated hypothyroidism, 
Cushing’s syndrome; 
5. Pulmonary disorders (other than asthma not requiring continuous medication or sleep 
apnea-related disorders); 
6. Type 1 diabetes or any medical treatment with insulin, sulfonylureas (SFUs), glucagon-
like peptide-1 (GLP-1) agonists, sodium glucose transporter (SGLT-1) inhibitors, and 
SGLT-2 inhibitors; 
7. Congenital heart disease; 
8. Clinically significant arrhythmia or electrocardiogram (ECG) abnormality; 
9. Screening laboratory values as specified (tests may be repeated per investigator’s 
discretion): 
a. Bicarbonate 
< LLN 
b. AST and ALT 
> 3 x ULN 
c. HbA1c 
≥ 8.0 % 
d. Fasting glucose 
≥ 270 mg/dL 
e. Triglyceride 
≥ 400 mg/dL 
f. Creatinine clearance 
< 60 mL/minute (Schwartz Formula)7 (see Appendix 7: 
Formulas for Estimating Creatinine Clearance) 
g. TSH 
> 1.5 ULN 
10. Clinically significant hepatic or renal disease; 
11. Clinically significant thyroid dysfunction as evidenced by signs or symptoms of 
hypothyroidism, a thyroid stimulating hormone (TSH) > 1.5 x ULN, or use of thyroid 
hormone treatment that has not been stable for at least 3 months; 
12. Systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg or concurrent 
antihypertensive medication that has not been stable for 3 months; 
13. Any history of bipolar disorder or psychosis, greater than one lifetime episode of major 
depressive disorder, current depression of moderate or greater severity (PHQ-9 score of 
10 or more), presence or history of suicidal behavior or ideation with some intent to act 
on it; tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), lithium, 
levodopa, and dopamine receptor agonists; or allowed antidepressant use that has not 
been stable for at least 3 months; 
14. Use of chronic systemic glucocorticoid therapy (i.e. glucocorticoids, anabolic steroids) or 
any other steroid hormone therapy other than oral contraceptives, that has not been stable 
for at least 3 months; 
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15. Pregnancy or breastfeeding; 
16. Any history of eating disorders (e.g. bulimia; binge eating disorder; anorexia); 
17. Any history of laxative abuse; 
18. History of glaucoma, use of carbonic anhydrase inhibitors, history of increased 
intraocular pressure or any past or present use of medications to treat increased 
intraocular pressure; 
19. Prior bariatric surgery; 
20. Any history of nephrolithiasis; 
21. Any history of epilepsy, or requirement for anticonvulsants used for treatment of seizure 
disorder, including barbiturates, benzodiazepines, gamma-aminobutyric acid (GABA) 
analogues, hydantoins, phenyltriazines, succinimides, and other agents (valproic acid and 
its derivatives, carbamazepine and its derivatives, zonisamide, and felbamate); 
22. Positive urine drug screen; 
23. Current smoker or smoking cessation within 3 months of screening; 
24. Obesity of a known genetic or endocrine origin, such as Prader-Willi Syndrome; 
25. Known allergy or hypersensitivity to phentermine or topiramate or history of anaphylaxis 
to any drug; 
26. Use of any investigational medication or device for any indication or participation in a 
clinical study within 30 days prior to screening; or 
27. Other clinically significant medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with trial participation or investigational product 
administration or may interfere with the interpretation of trial results and, in the judgment 
of the investigator, would make the subject inappropriate for entry into this trial. 
7.3 
Subject Withdrawal 
Subjects are free to withdraw from the clinical trial or discontinue treatment at any time for any 
reason. 
The sponsor reserves the right to discontinue this trial at any time (see Section 13.0 on clinical 
trial discontinuation criteria). 
Subject participation in this clinical trial may be discontinued for any of the following reasons: 
• Occurrence of any medical condition or circumstance that exposes the subject to 
substantial risk and/or does not allow the subject to adhere to the requirements of the 
protocol; 
• Any serious adverse event (SAE), clinically significant adverse event (AE), severe 
laboratory abnormality, intercurrent illness, or other medical condition that indicates to 
the Investigator that continued participation is not in the best interest of the subject; 
• Subject's (or a parent’s or legal guardian’s) decision to withdraw; 
• Requires other medical treatment that is excluded by the protocol (see Section 8.5); 
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• Subject failure to comply with protocol requirements or study related procedures; or 
• Termination of the clinical trial by the sponsor, FDA, or other regulatory authorities. 
Withdrawn subjects will not be replaced. 
Subjects discontinued from treatment should be encouraged to remain in the trial off-treatment 
and to continue study visits at the scheduled intervals. Subjects who withdraw completely from 
the trial at any point should complete the end of study (Visit 16, Week 56) procedures. The date 
of last dose should be recorded. 
Every effort should be made to document subject outcome. For subjects who elect to withdraw 
from the trial without continuing study visits, the investigator should inquire about the reason for 
withdrawal, request that the subject return all unused investigational product(s), request that the 
subject return for a final visit (Section 9.1.4) and follow-up with the subject regarding any 
unresolved adverse events. 
At about the 56-week time point, withdrawn subjects who have not continued study visits should 
be asked to return to the site to obtain weight and height measurements at a minimum and, if 
possible, all the other tests and procedures (except physical examination and ECG) required for 
end of study visit. 
If a subject withdraws from the trial and also withdraws consent for disclosure of future 
information, no further evaluations will be performed and no additional data will be collected. 
The sponsor may retain and continue to use any data collected before such withdrawal of 
consent. 
8.0 
TREATMENT OF SUBJECTS 
8.1 
Study Treatment 
Eligible subjects will receive 56 weeks of treatment with either VI-0521, or matching placebo for 
daily use. 
8.2 
Allocation to Treatment 
Written informed consent will be obtained prior to the performance of any study-related 
procedures. Eligible subjects will be randomly assigned in a 1:1:2 ratio to placebo, mid-dose 
(PHEN/TPM 7.5 mg/46 mg) or top-dose (PHEN/TPM 15 mg/92 mg) of VI-0521. Randomization 
will be stratified by gender and age (12-14 vs 15-16 years old), and will be implemented using an 
Interactive Web Response System (IWRS). The sponsor, the subjects, and the study site will be 
blinded as to subject randomization. 
When a subject qualifies for randomization, site personnel will log into the IWRS to obtain a 
specific titration blister card or bottle number to dispense to the study subject. The subject will 
return the study drug at every clinic visit for drug accountability and will be dispensed with a 
new blister card/bottle for the next treatment period. 
8.3 
Breaking the Blind 
Study drug must not be unblinded during the study unless it is considered absolutely necessary 
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by the investigator for the management of an adverse event or other medical emergency. Under 
such conditions, investigators will first contact the medical monitor when deciding to unblind a 
subject and if unblinding is deemed medically necessary the identity of the study treatment may 
be obtained via the IWRS. Any subject whose treatment assignment has been unblinded must be 
withdrawn from the study. 
Investigators are also required to ensure that any potential SAEs are reported according to the 
requirements outlined in Section 11.1.5 and provide a written report to VIVUS or designee 
within 7 days to document the reason for unblinding. 
8.4 
Drug Supply 
Clinical supplies will be manufactured for VIVUS by 
 in 
accordance with current Good Manufacturing Practices (cGMP). All clinical supplies will be 
labeled with information required by national regulations. 
8.4.1 
Formulation and Packaging 
Sufficient quantities of VI-0521, phentermine and topiramate capsules will be supplied by the 
sponsor in blister cards and bottles and shipped to a designee at the study site. All clinical 
supplies will be labeled with information required by national and/or international regulations. 
Study drug will be packaged into 2 types of kits; titration kits (blister cards) for use during the 
first 4 weeks of study treatment and the titration period during study Weeks 13-16, and treatment 
kits (bottles), for use once subjects have been titrated to their assigned dose. 
Each titration kit contains 1 blister card for use during Weeks 1 through 4 of titration, with each 
card containing 4 columns of 8 capsules each. Each column on the blister card will be labeled 
with the week number (1 through 4) and will contain capsules with the dose specified for that 
week of treatment, as outlined in Table 1. Titration kits will consist of blister cards labeled with 
the study number, a unique kit number, storage instructions, and spaces for the subject number 
and initials. Treatment kits will consist of bottles, each containing 35 capsules of study 
medication at the treatment dosages shown in Table 1. Each kit will contain a single bottle 
labeled with the study number, a unique kit number, storage instruction, and spaces for the 
subject number and initials. 
Table 1: VI-0521 Dosage Strengths by Titration Week for Each Treatment Group 
Group 
Treatment Dosage for 
Phentermine/Topiramate 
(mg) 
Titration Dose for Phentermine/Topiramate (mg) 
Weeks 
1-2 
Weeks 
3-4 
Weeks 
13-14 
Weeks 
15-16 
Placebo 
0/0 
0/0 
0/0 
0/0 
0/0 
VI-0521 Mid 
7.5/46 
3.75/23 
7.5/46 
7.5/46 
7.5/46 
VI-0521 Top 
15/92 
3.75/23 
7.5/46 
11.25/69 
15/92 
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8.4.2 
Preparation and Dispensing 
Clinical supplies provided by the sponsor are to be dispensed only by or under the direct 
supervision of qualified investigators to subjects meeting the criteria for study entry and in 
accordance with this protocol. Randomization scheme will be followed by site staff for 
assignment of specific bottle to study subjects. No other preparation of clinical supplies is 
required of the study staff. 
8.4.3 
Administration 
Subjects will be instructed to take 1 capsule of study drug every morning with or without food, 
and with water. Subjects should stay hydrated by drinking plenty of water while in the study. 
Subjects will be reminded not to take study drug to school or work. Capsules are not to be 
broken or split apart in any manner. 
When dispensing titration kits, investigators should ensure that subjects understand that each 
blister card contains a 4-week supply of medication, and that the capsules must be taken in a 
specific order (i.e. Week 1 before Week 2, and Week 3 before Week 4). 
When dispensing study drug bottles, investigators should ensure that subjects understand that 
each bottle contains a 4-week supply of study drug, and that the capsules must be taken for the 
treatment period that the bottle is dispensed for. Instruction should also be provided that each 
bottle contains extra capsules that should only be taken should the next study visit be scheduled 
beyond 4 weeks after the previous visit. Investigators will also instruct subjects to return all 
study drug (blister card and the bottle, even if empty) to the site at each study visit. 
8.4.4 
Dose Reduction and/or Interruption During Trial Participation 
Dose reduction is an option for subjects who experience adverse events that are sufficiently 
severe to cause the subject to consider discontinuation or to cause the investigator concern about 
the subject’s ability to continue in the study. 
It should be recognized that caloric restriction resulting in rapid weight loss (independent of any 
specific drug mechanisms) carries the potential to negatively affect growth. Due to the potential 
of the study drug to cause significant weight loss which may affect growth in adolescents, 
investigators should actively monitor the subject’s rate of weight loss and growth (using height 
and weight), and implement a down-titration of study drug should rates of weight loss in a given 
subject exceed rates that are deemed safe. For subjects with baseline BMI 95-98th percentile, 
reduce study drug dosage when BMI is < 85th percentile or when weight loss exceeds an average 
of 2 lbs (0.9 kg) per week. For subjects with baseline BMI ≥ 99th percentile, reduce study drug 
when weight loss exceeds an average of 2 lbs (0.9 kg)/week. 
Dose reduction is implemented through the IWRS, and will be done without breaking the blind. 
Subjects assigned to the mid-dose may be reduced down to the low-dose and those assigned to 
the top-dose may be reduced down to the mid-dose, and if necessary, the low-dose in a blinded 
manner. Dose reduction is not an option for subjects who experience intolerable adverse events 
related to study medication during the first week of titration (Week 1) during the initial 
randomization; these subjects will be withdrawn from treatment. 
When dose reduction is not appropriate or when dose interruption may be required due to events 
unrelated to study treatment, subjects may temporarily discontinue from treatment (up to 7 days) 
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on one or more occasions. Dose interruptions longer than 7 days are possible with agreement 
from the medical monitor. All subjects undergoing dose interruptions for any duration may be 
titrated back up to the original dose level based on discretion of the investigator. If study drug 
has been discontinued for 2 weeks or more, a new titration kit should be ordered through IWRS 
to resume treatment. Subjects who have a drug holiday following dose reduction due to study 
medication intolerance will be retitrated to the dose specified for use after dose reduction. For 
subjects having a drug holiday due to events unrelated to treatment, attempts should be made to 
retitrate to the initial randomized dose. For treatment interruptions of less than 2 weeks, subjects 
may resume treatment by dosing every other day for the first week that treatment is resumed. 
If symptoms remain intolerable after dose reduction and drug holidays, subjects may be 
discontinued from treatment. Subjects discontinued from treatment will be encouraged to remain 
in the trial off-treatment and to continue to make study visits at the regularly scheduled intervals. 
The last date on which the subject is dosed with study medication should be recorded on the case 
report form (CRF). 
If the subject remains in the trial off-treatment, all study procedures should be continued for the 
duration of subject participation and they should be encouraged to return at the 56- week time 
point for measurements and evaluations. For those who choose to completely withdraw from the 
study at any point, the end of study (Week 56) procedures should be completed. 
8.4.5 
Discontinuing Study Drug 
Abrupt withdrawal of topiramate, a component of VI-0521, has been associated with seizures in 
individuals without a history of seizures or epilepsy. Subjects discontinuing VI-0521 should be 
gradually tapered by taking a dose every other day for 1 week prior to stopping treatment 
altogether. 
8.4.6 
Compliance 
Subject compliance with study drug will be assessed by counting capsules that are returned at 
each study visit. Subjects whose actual capsule consumption differs from their expected capsule 
consumption by more than 20% should be queried by site personnel about reasons for not using 
study drug as directed, and site personnel should plan any corrective action as necessary. 
Subjects who remain noncompliant with study drug dosing despite corrective action by site 
personnel may be withdrawn from the study. 
8.4.7 
Drug Storage and Drug Accountability 
All unused study drug must be stored in its packaging at controlled room temperature, 15 to 
25°C (59 to 77°F) with excursion to 30°C (86°F), in a dry, secure area. Access to drug storage 
areas should be limited to the investigator and designated staff involved with the study. All used 
and unused drug must be maintained at the study site and made available for audits by VIVUS 
personnel or their designee. 
It should be noted that phentermine, one component of the VI-0521 combination is a Schedule 
IV controlled substance. The investigator should take all appropriate measures to control access 
to and dispensing of study drug. 
The investigator must maintain records documenting the amount, condition, and date of delivery 
NCT03922945


of all study drug received from the sponsor. In addition, all drug dispensed to study subjects 
during the course of the study must be recorded on the appropriate accountability forms. Subjects 
must be instructed to return all empty containers and all unused medication in its original 
packaging, and sites must make an accounting of drug use by each subject. No study drug, used 
or unused, may be discarded. All used and unused drug must be returned to the sponsor or 
designated representative upon completion of the study. 
8.5 
Concomitant Medications 
8.5.1 
Excluded Medications 
Subjects may not use any of the following medications during participation in this study. 
Subjects who develop a need for any of these medications must be discontinued from the study: 
• Anticonvulsants used for treatment of seizure disorder, including barbiturates, 
benzodiazepines, GABA analogues, hydantoins, phenyltriazines, succinimides, and other 
agents (valproic acid and its derivatives, carbamazepine and its derivatives, zonisamide, 
and felbamate); 
• Tricyclic antidepressants, MAOIs, lithium, levodopa, and dopamine receptor agonists; 
• Carbonic anhydrase inhibitors; 
• Insulin, sulfonylureas (SFUs), GLP-1 agonists, SGLT-1 inhibitors, and SGLT-2 
inhibitors; 
• Chronic systemic steroids (i.e. glucocorticoids, anabolic steroids) other than oral 
contraceptives; 
• Treatment for hyperactivity disorder; or 
• OTC, prescription medications, herbal agents and dietary supplements used with the 
intention to lose body weight. 
8.5.2 
Other Restricted Medications 
Subjects using hormone replacement therapy (estrogen, thyroid, or other) or allowed 
antidepressants must be on doses that have been stable for at least 3 months prior to screening. 
Subjects who develop symptoms indicative of hypothyroidism during the course of the study 
need not withdraw but should be evaluated and managed as indicated. 
Benzodiazepine and non-benzodiazepine sleep medications are permitted, provided that the 
dosage has been stable for at least 1 month prior to screening, and the frequency of use does not 
exceed twice a week. 
Subjects may not initiate any other organized weight loss program during their participation in 
this study. 
8.5.3 
Documentation of Concomitant Medication Use 
All concomitant medications, including OTC products and nutritional/herbal supplements, must 
be listed on the appropriate CRF at study entry. Any changes in concomitant medication use 
during the course of the study must also be noted on the appropriate CRF. 
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8.6 
Treatment of Diabetes 
Subjects who develop type 2 diabetes during the course of the study will be provided with blood 
glucose meters and supplies and will be provided appropriate usage instructions. They will be 
instructed to measure a fasting morning glucose daily and to record the results in the blood 
glucose and hypoglycemic event log. Diabetic subjects will bring their meters and logs to each 
visit. 
If concomitant antidiabetic therapy is determined necessary, metformin is suggested as the initial 
therapy for newly-emergent type 2 diabetes unless contraindicated in a specific subject. Insulin 
secretagogues, including SFUs and meglitinides, either alone or in combination with other 
medications, should be reserved for subjects who cannot achieve adequate control with other 
modes of treatment. Insulins and incretins are prohibited, and subjects requiring treatment with 
these medications must be discontinued from the trial. Subjects whose blood glucose cannot be 
adequately controlled with the concomitant treatments allowed in this trial should be maintained 
in the study but discontinued from treatment, and referred back to their primary healthcare 
provider for more intensive treatment (see Section 7.3). 
During treatment, subjects whose fasting blood glucose is less than 72 mg/dL on 2 or more 
occasions, or who experience any signs or symptoms associated with hypoglycemia, should have 
their antidiabetic therapy reevaluated. 
8.7 
Treatment of Elevated Blood Pressure 
For subjects whose blood pressure requires management, antihypertensive therapy should be 
initiated with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers 
(ARB). If these medications are already present, calcium channel blockers, beta-blockers, or 
thiazide diuretics may be added. 
Subjects whose blood pressure exceeds 140/90 mmHg on 3 consecutive visits and who have 
undergone dose increases or the addition of antihypertensive medications over each of 3 visits, 
should be discontinued from study drug and referred back to their primary healthcare provider 
for more intensive management. Subjects may continue attending study visits off study drug, and 
if blood pressure control is re-established without requiring excluded medications, subjects may 
be restarted on study drug. 
Subjects whose blood pressure drops below 110/70 mmHg, or who exhibit symptoms associated 
with low blood pressure during the trial should have their antihypertensive medications 
reevaluated. 
8.8 
Treatment of Hypothyroidism 
Individuals who experience rapid weight loss sometimes develop signs and/or symptoms of 
hypothyroidism with or without elevation of TSH. Subjects who develop symptoms of 
hypothyroidism need not be discontinued from study drug. These subjects should be assessed 
clinically and with appropriate laboratory testing (TSH, free T3, free T4). Subjects found to be 
hypothyroid may be considered for thyroid replacement therapy, as appropriate. 
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9.0 
STUDY PROCEDURES 
A schedule of study activities by visit is presented in Appendix 1. A detailed list of these 
activities is provided below. 
9.1 
Schedule of Visits 
9.1.1 
Screening Visit (Visit 1, Up to – 4 Weeks) 
Activities at the Screening visit are: 
• Obtain written parental informed consent and subject assent; 
• Obtain written parental informed consent and subject assent for DXA (at selected sites); 
• Obtain demographics (including age, gender, race, and ethnicity); 
• Obtain medical history (including contraception methods); 
• Assess inclusion/exclusion criteria; 
• Record concomitant medications; 
• Administer PHQ-9 and C-SSRS questionnaires; 
• Administer neurocognitive battery (CANTAB) familiarization session; 
• Obtain vital signs (blood pressure, heart rate, respiration rate, and temperature); 
• Obtain weight and waist circumference measurements; 
• Measure height and calculate BMI. If a subject does not meet the BMI criterion for 
inclusion into the study, no further screening procedures should be undertaken; 
• Obtain serum samples for blood chemistry panel, hematology panel, lipid panel, HbA1c, 
HIV, HCV, HBsAg, TSH; 
• Obtain urine sample for routine urinalysis, drug screen, and pregnancy test (female 
subjects); 
• Provide contraception/pregnancy counseling (female subjects); and 
• Schedule the Randomization visit within 4 weeks (± 3 days). 
9.1.2 
Baseline/Randomization (Visit 2, Week 0) 
Subjects eligible for treatment will be randomized and have study drug dispensed at visit 2. If a 
subject is found to be ineligible for participation due to laboratory values, the subject may be 
notified prior to visit 2. Activities at baseline are: 
• Confirm inclusion/exclusion criteria (Section 7.0); 
• Administer PHQ-9, C-SSRS, and IWQOL-Kids questionnaires; 
• Administer neurocognitive battery (CANTAB); 
• Obtain vital signs (blood pressure, heart rate, respiration rate, and temperature); 
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• Obtain weight and waist circumference measurements; 
• Measure height and calculate BMI; 
• Record any changes in concomitant medications; 
• Record any adverse events reported or observed; 
• Perform complete physical examination (include Tanner Staging); 
• Perform and evaluate 12-lead ECG; 
• Perform urine pregnancy test (female only); 
• Perform OGTT for all subjects eligible for participation by results of Visit 1 screening 
tests (a separate visit may be scheduled for the OGTT) and obtain blood sample for 
glucose and insulin at 2 hours following oral glucose load; 
• Conduct hand and wrist X-ray; 
• Conduct DXA measurement (if applicable); 
• Contact IWRS to randomize the subject. Dispense study drug and instruct the subject on 
the proper use of the study drug (Section 8.4.3); 
• Provide diet (a 500-calorie/day deficit)/lifestyle modification and 
contraception/pregnancy counseling (female subjects); and 
• Schedule the next study visit in 4 weeks (± 7 days). 
9.1.3 
Treatment Week 4 Through Week 52 (Visits 3 Through 15) 
• Obtain weight and waist circumference measurements; 
• Administer PHQ-9 and C-SSRS questionnaires; 
• Administer neurocognitive battery (CANTAB), Visit 6 only; 
• Obtain vital signs; 
• Measure height and calculate BMI; 
• Record any changes in concomitant medications; 
• Record any adverse events reported or observed; 
• Perform urine pregnancy test; 
• Collect study drug from previous visit, assess treatment compliance, and perform drug 
accountability; and dispense study medication and instruct the subject in the proper use of 
the study drug; 
• Obtain blood sample for chemistry panel (Visits 3, 4, and 9 only); 
• Obtain blood sample for hematology and lipids panel (Visit 9 only); 
• Obtain blood sample for HbA1c (Visits 5 and 11 only); 
• Provide diet (a 500-calorie/day deficit)/lifestyle modification and 
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contraception/pregnancy counseling (female subjects); and 
• Schedule the next study visit in 4 weeks (± 7 days). 
9.1.4 
Treatment Week 56, End of Study; Early Termination (Visit 16) 
The end of study visit will be performed for subjects completing the study or for subjects who 
are withdrawn from the study prior to completion of the study at the time of their treatment 
termination. For subjects who withdraw from the study prior to completion, the site will also 
attempt to contact the subject at or about the 56-week time point to obtain end of study 
assessments. 
Activities at the end of study visit include: 
• Administer PHQ-9, C-SSRS, and IWQOL-Kids questionnaires; 
• Administer neurocognitive battery (CANTAB); 
• Obtain vital signs; 
• Obtain weight and waist circumference measurements; 
• Measure height and calculate BMI; 
• Collect study drug from previous visit, assess treatment compliance, and perform drug 
accountability; 
• Obtain blood sample for chemistry, hematology, and lipids, panel; 
• Obtain blood sample for HbA1c; 
• Obtain urine sample for routine urinalysis and urine pregnancy test (female only); 
• Administer glucose load for OGTT and obtain blood sample for glucose and insulin at 
2 hours following oral glucose load (Section 10.10); 
• Perform complete physical examination (include Tanner Staging); 
• Perform and evaluate 12-lead electrocardiogram (ECG); 
• Conduct hand and wrist X-ray; 
• Conduct DXA measurement (if applicable); 
• Record any changes in concomitant medications; 
• Record any adverse events reported or observed; 
• Discontinue subject’s study participation. 
9.2 
Study Period 
The study period for each subject will begin when written informed consent is provided and will 
continue until Week 56 or early termination is completed. Sites should link the scheduling of 
visits to the baseline/randomization visit (Visit 2, Day 0). Visit windows are provided to allow 
subject and site scheduling convenience. However, every effort should be made to ensure that 
visits occur within these windows so that the overall treatment duration is 56 weeks for subjects 
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who complete all visits. In certain instances, adverse event information may be required for 
events occurring after the study period (Section 11.3). 
10.0 
ASSESSMENT 
10.1 
Weight Measurement 
Subject weight will be obtained at every study visit. Subjects should be weighed using a 
calibrated scale. The same scale should be used for each measurement, and measurements should 
be evaluated by the same site personnel at each visit, whenever possible. Subject weights should 
be obtained, whenever possible, under the same conditions (no shoes, clothing of similar weight) 
that were employed at the first (Screening) weigh-in. Subjects should be encouraged to complete 
their weigh-in visits in the morning. 
10.2 
Waist Circumference Measurement 
Waist circumference measurements will be taken using a measuring tape provided by the 
sponsor or designee, and should be obtained by the same individual, whenever possible, at every 
study visit. To measure the waist circumference, locate the top of the right iliac crest. Place the 
measuring tape in a horizontal plane (parallel to the floor) around the abdomen at the level of the 
top of the iliac crest as shown in Figure 2. 
Figure 2. Measuring Tape Position for Waist Circumference Assessments 
 
Ensure that the subject is relaxed. Ensure that the tape is snug but does not indent or compress 
the skin, and make the measurement (in centimeters) at the end of a normal expiration. 
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10.3 
Height and BMI 
Height measurements (cm) and BMI will be determined by the site at every visit (see BMI Chart 
in Appendix 2). Height measurements should be made using a calibrated stadiometer without 
shoes, socks, or hats. At each study visit, 3 independent measurements of height should be made, 
and the median value from these measurements recorded on the eCRF. Height should be 
recorded to the nearest centimeter. The same stadiometer should be used for all visits for any 
given subject. Stadiometer should be calibrated, at least daily, if used, following the equipment’s 
manufacturer instructions and/or site SOP. 
If a subject does not meet the BMI criterion for inclusion into the study (see CDC Clinical 
Growth Chart8 in Appendix 3), no further screening procedures should be undertaken. 
10.4 
Vital Signs 
Vital signs (systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, 
temperature) will be assessed at each study visit. Subjects should be seated comfortably for at 
least 10 minutes prior to assessing vital signs. Heart rate and respiratory rate measurements 
should be made by counting events (heartbeats or breaths) for a period of 30 seconds and 
multiplying these values by 2 to obtain the rates per minute. A calibrated cuff should be 
employed for blood pressure measurements. Site staff should ensure at the Screening visit that 
the cuff size used is appropriate for the patient’s arm circumference. Overweight and obese 
subjects often require a larger cuff than is typically used for adults of normal size and weight. 
The same cuff should be used for the same subject across multiple visits when blood pressure is 
performed. The same person should perform all assessments for a given subject. 
10.5 
Physical Examinations and Tanner Staging 
A complete physical examination will be performed at baseline, and end of study or early 
termination visits. The physical examination will consist of an examination of the following 
systems: general appearance, skin, eyes, ears, nose, throat, neck (including thyroid), lymph 
nodes, chest, heart (including any auscultated cardiac murmurs), abdomen, extremities, and 
neurologic. Puberty maturation will be assessed using the Tanner Staging (also known as the 
Sexual Maturity Rating (SMR), a gender specific 5-point scale of secondary sexual 
characteristics. Boys are rated for genital development and pubic hair growth, and girls are rated 
for breast development and pubic hair growth. Tanner Staging should be conducted by site 
personnel who have been trained on the proper technique for these assessments, and sites should 
ensure that the same observer conducts all Tanner Staging evaluations for any given subject. 
10.6 
Electrocardiograms 
Twelve-lead ECG studies will be performed at baseline, and end of study or early termination 
visits. ECGs will be evaluated for clinically significant abnormalities that would prevent entry 
into the study, and for arrhythmias, conduction disturbances, or other clinically relevant changes 
between randomization and each of the subsequent evaluations. Parameters including heart rate, 
R-R, P-R, QT intervals, and QRS duration will be recorded. 
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10.7 
X-Ray of the Hand and Wrist 
An X-ray of the hand and wrist will be performed at baseline, and end of study or early 
termination visit to assess bone growth. Equipment and procedures used to obtain hand and wrist 
X-ray data will be standardized as described in a separate document. X-rays will be read at a 
central facility and the reader will be blinded. 
10.8 
DXA (Sub Study) 
A bone health sub-study will be conducted at selected sites in approximately 100 subjects 
(25 each on placebo and mid-dose, and 50 on top-dose) to assess the effect of Qsymia 
administration on bone health using Dual X-ray Absorptiometry (DXA). DXA scans of the 
posterior-anterior (PA) spine (lumbar), and total body less head (TBLH) will be performed at 
baseline and at the end of study or early termination. Equipment and procedures used to obtain 
DXA data will be standardized as described in a separate document. Sites involved in DXA 
measurement will be trained on these procedures prior to performing scans on study subjects. 
Scans will be read at a central facility and the reader will be blinded. 
The following enrollment criteria will apply: 
1) Both male and female will be eligible to participate; 
2) Subjects with a history of any non-traumatic fracture will not be eligible; 
3) Subjects with juvenile osteoporosis at baseline will not be eligible; and 
4) Subjects must meet manufacturer equipment specifications with regard to height and 
weight limitations. 
10.9 
Laboratory Tests 
Laboratory tests will be performed at a licensed, certified central testing laboratory identified by 
the sponsor. Laboratory tests will be used to determine eligibility for study participation, for 
safety monitoring and to determine which subjects may progress to later phases of the study. 
Subjects should be fasting for at least 8 hours prior to obtaining blood samples for analyses. 
Table 2 summarizes the clinical laboratory testing for the study. Laboratory tests required at each 
study visit are detailed in Section 9.0 and Appendix 1. 
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Table 2: Clinical Laboratory Tests 
Fasting blood chemistry 
Hematology 
Other 
• albumin 
• alkaline phosphatase 
• ALT 
• AST 
• GGT 
• bicarbonate 
• blood urea nitrogen 
• serum calcium 
• serum chloride 
• serum sodium 
• carbon dioxide 
• creatinine (and estimated 
creatinine clearance) 
• glucose 
• lactate dehydrogenase 
• serum phosphorus 
• serum potassium 
• total and direct bilirubin 
• total protein 
• uric acid 
• hemoglobin 
• hematocrit 
• red blood cell count 
• red blood cell indices 
• total white blood cell count 
• white blood cell differential 
(neutrophils, lymphocytes, 
monocytes, eosinophils, and 
basophils) 
• platelet count 
• thyroid stimulating hormone 
Urinalysis 
• midstream urinalysis with 
reflex microscopic evaluation 
• pregnancy test (all female 
subjects) 
Urine Drug Screen 
• cannabinoids 
• amphetamines 
• cocaine 
• barbiturates 
• benzodiazepine 
• opiates 
Lipid panel 
• total cholesterol 
• LDL-C 
• HDL-C 
• triglycerides 
Glycemic testing 
Serology 
• HbA1c 
• insulin 
• glucose  
• HBsAg 
• HCV 
• HIV 
10.10 Oral Glucose Tolerance Test 
An oral glucose tolerance test (OGTT) will be obtained at baseline (after results from screening 
visit indicate the subject may be eligible for participation), and at end of study or early 
termination for all subjects. 
The OGTT will use a 75 g oral glucose load; blood samples will be obtained at baseline and at 
2 hours post glucose load for evaluation of both glucose and insulin levels. 
10.11 CANTAB (Cambridge Neuropsychological Test Automated Battery) 
Cognitive function will be assessed using selected tests from the CANTAB including paired 
associates learning, pattern recognition memory, and spatial span. The CANTAB will be 
assessed at screening (familiarization session only), baseline, Week 16 (Visit 6), and end of 
study or early termination. 
10.12 IWQOL-Kids 
The Impact of Weight on Quality of Life-Kids (IWQOL-Kids) questionnaire (Appendix 6) is a 
27-item, self-administered instrument that will be completed at baseline, and end of study or 
early termination. 
The IWQOL-Kids is validated for use in adolescents aged 11-19 years old. This questionnaire is 
designed to evaluate the impact of excess weight on quality of life domains including physical 
mobility and comfort (Physical Comfort), how an individual feels about themselves and their 
body (Body Esteem), how an individual is treated in their social environment (Social Life), and 
the individual’s perception of what family members may think and feel about them (Family 
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Relations).9 Because this instrument is intended to be completed directly by study subjects, it is 
important that site personnel remain neutral and do not influence subject answers on this 
questionnaire in any way. Should subjects ask questions to site personnel regarding the meaning 
of specific items, site personnel should not interpret items for the subjects, rather, they should 
repeat items back to subjects as they are worded on the instrument. 
Site personnel must also recognize that the subject’s answers to this questionnaire reflect their 
perceptions and attitudes at the time the questionnaire is completed, and that missing answers 
cannot be queried at a later date. It is critical, therefore, that site personnel review questionnaires 
for completeness at the time they are initially filled out, and that any missing answers are 
completed before the subject leaves the office. 
10.13 PHQ-9: Modified for Teens 
The Patient Health Questionnaire for Adolescents (PHQ-9: Modified for Teens) (Appendix 4) is 
a 9-item, self-administered instrument for the assessment of depression in adolescents. 
Because this instrument is intended to be completed directly by study subjects, it is important 
that site personnel remain neutral and do not influence subject answers on this questionnaire in 
any way. Should subjects ask questions to site personnel regarding the meaning of specific items, 
site personnel should not interpret items for subjects, rather, they should repeat items back to 
subjects as they are worded on the instrument. Because this questionnaire assesses the subject’s 
level of depression over a specific time frame (the past 2 weeks), answers not completed by 
subjects at a given visit cannot be queried or filled in at a later date. Site personnel, therefore, 
must carefully review questionnaires for completeness before subjects leave the clinic, and 
assure that questionnaires are properly completed. 
The PHQ-9 questionnaire is being used to screen for and to assess the severity of any depression 
in study subjects. This questionnaire will be completed at every visit. Answers to the 
questionnaire may reveal evidence of significant depression, including the possibility of suicidal 
thoughts or plans. It is the responsibility of the investigator to evaluate subjects’ responses to 
these questionnaires carefully, and to perform any additional evaluation and management that is 
indicated, including referral to a mental health professional if necessary. The evaluation by the 
investigator will be guided by the standardized methods for the PHQ-9 that have been developed 
to provide information regarding diagnosis of depression, severity of symptoms, and treatment 
follow-up options. Investigators should document any such problems identified in study source 
documents using standard diagnostic criteria and terminology as provided in the standardized 
guidelines. It is expected that any randomized subject presenting with a PHQ-9 score of 15 or 
more should be treated and may require referral to a qualified mental health care professional. 
10.14 Columbia Suicide Severity Rating Scale (C-SSRS) 
The Columbia Suicide Severity Rating Scale is an 11-item clinician-administered assessment of 
both suicidal behavior (6 items) and suicidal ideation (5 items).10 Each of the items comprising 
this scale corresponds to a specific level, or severity of ideation or behavior, and is answered on 
a yes/no basis. This assessment will be administered to all subjects at screening in order to 
confirm the absence of suicidal behavior or ideation with at least some intent to act on it, and to 
document the pre-study status of all subjects included in the treatment program. Subsequently, 
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C-SSRS evaluations may be done at the investigator’s discretions to evaluate and aid in 
diagnosis of reported or suspected events of suicidality. All C-SSRS assessments must be 
administered by a trained staff member. If any test reveals suicidal behavior or ideation with 
some intent to act on it, then test results must be confirmed by a physician investigator prior to 
discharging the subject from the study visit (see Appendix 5). 
11.0 
ADVERSE EVENT REPORTING 
11.1 
Adverse Events 
Adverse events are defined as any untoward medical occurrences in subjects administered the 
study treatment, whether or not they have a causal relationship to the treatment. All observed or 
volunteered adverse events regardless of suspected causal relationship to the investigational 
product must be reported as described in the following sections. 
Investigator must pursue and obtain information adequate to describe adverse events, their 
severity and relationship to study treatment, and their outcomes. For adverse events with a causal 
relationship to the investigational product, follow-up by the investigator is required for up to 
28 calendar days after the last dose of study drug or until the events or their sequelae resolve or 
stabilize at a level acceptable to the investigator, and VIVUS concurs with that assessment. 
Investigators must also assess whether adverse events meet the criteria for classification as 
serious adverse events requiring immediate notification to VIVUS or its designated 
representative. 
11.1.1 
Severity Assessment 
Investigators will assess the severity of all adverse events using the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of each adverse event. For 
purposes of consistency, these intensity grades are defined as follows: 
• MILD: Does not interfere with the subject’s usual function; 
• MODERATE: Interferes to some extent with the subject’s usual function; or 
• SEVERE: Interferes significantly with the subject’s usual function. 
Note the distinction between the severity and the seriousness of an adverse event. A severe event 
is not necessarily a serious event. For example, a headache may be severe (interferes 
significantly with subject’s daily function) but would not be classified as serious unless it met 
one of the criteria for SAEs listed in Section 11.1.5. 
11.1.2 
Causality Assessment 
Investigators are required to provide an assessment of causality for all adverse events (serious 
and non-serious) observed during this study. This assessment will provide a determination of 
whether, in the investigator’s judgment, there exists a reasonable possibility that the 
investigational product caused or contributed to an adverse event. For this assessment, 
investigators must categorize the causality as either “related” or “not related”. For an adverse 
event to be considered “related” to the study treatment, there should be evidence that the event 
follows a reasonable temporal sequence from the administration of study treatment, or that the 
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event follows a known response pattern to the drug. Causality would be further confirmed by 
improvement in an adverse event upon stopping the study treatment and reappearance of the 
event upon rechallenge. 
11.1.3 
Abnormal Test Findings 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event. Any abnormal test result that is determined to be an error does not 
require reporting as an adverse event. 
The criteria for determining whether an abnormal objective test finding should be reported as an 
adverse event are as follows: 
• Test result is associated with accompanying symptoms; 
• Test result requires additional diagnostic testing or medical/surgical intervention; 
• Test result leads to a change in study dosing or discontinuation from the study, significant 
additional concomitant drug treatment, or other therapy; or 
• Test result is considered by the investigator or sponsor to represent a clinically significant 
finding. 
11.1.4 
Mood or Depression Related Events 
All subjects will be screened for the presence and severity of depression at screening using a 
validated survey instrument (PHQ-9) designed for assessment of depression in a primary care 
setting. The PHQ-9 is a self-administered, nine-item depression module based directly on the 
diagnostic criteria for major depressive disorder in DSM-V-TR. This questionnaire may be used 
at the investigator’s discretion at other times during the study to aid in diagnosis and evaluation 
of reported or suspected events of depression. 
Suicidality will also be assessed at each study visit using the C-SSRS (see Appendix 5). The C-
SSRS may also be used at the investigator’s discretion at unscheduled visits during the study to 
aid in evaluation and diagnosis of reported or suspected events of suicidality. Should this 
additional assessment indicate the presence any suicidal behavior, or suicidal ideation with any 
intent to act on it, study treatment will be stopped, and the investigator must provide appropriate 
referral to a mental health professional for additional assessment and management. Any such 
event must be reported to the Medical Monitor and to the sponsor within 24 hours. Subjects must 
be followed until resolution of these events. 
Any mood- or depression-related adverse events must be documented using standard diagnostic 
criteria and terminology. 
11.1.5 
Serious Adverse Events or Serious Suspected Adverse Reactions 
As defined in the Code of Federal Regulations (21 CFR 312.32), an adverse event or suspected 
adverse drug reaction is considered “serious” if, in the view of either the investigator or the 
sponsor, it results in any of the following outcomes: 
• Death; 
• A life-threatening adverse event (Note: An adverse event or suspected adverse reaction is 
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considered “life-threatening” if, in the view of either the investigator or sponsor, its 
occurrence places the subject in immediate risk of death. It does not include an adverse 
event or suspected adverse event that, had it occurred in more severe form, might have 
caused death. The determination of whether an adverse event is life-threatening can be 
based on the opinion of either the investigator or sponsor.); 
• Inpatient hospitalization or prolongation of existing hospitalization; 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; or 
• A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition. 
If either the sponsor or investigator believes that the event is serious, the event must be 
considered serious and evaluated by the sponsor for expedited reporting. 
11.1.6 
Definition of Hospitalization 
Adverse events reported from clinical trials that result in hospitalization or prolong an existing 
hospitalization are considered serious. Any initial admission (even if less than 24 hours) to a 
healthcare facility meets these criteria. 
Outpatient ambulatory surgical procedures (same-day surgeries) and routine emergency room 
treatment do not qualify as hospitalizations. Additionally, hospitalization in the absence of a 
precipitating clinical adverse event is not in itself an SAE. Examples include, but are not limited 
to any of the following: 
• Admission for treatment of a pre-existing condition not associated with the development 
of a new adverse event or with a worsening of the pre-existing condition (e.g., for work 
up of persistent pre-treatment abnormality); 
• Administrative admission (e.g., for yearly physical examination); 
• Optional admission not associated with a precipitating clinical adverse event (e.g., for 
elective cosmetic surgery); or 
• Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as adverse events. However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event. For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as the 
adverse event, and the resulting appendectomy should be recorded as treatment of the adverse 
event. 
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11.2 
Eliciting Adverse Event Information 
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the study subject. In addition, study subjects should be questioned by 
site personnel about adverse events at each clinic visit using a standard non-leading question, 
such as “Have you experienced anything new or different since your previous study visit?” 
Certain adverse events require prompt and specific action by the investigator in any clinical trial. 
11.3 
Reporting Period 
The reporting period for adverse events begins when the subject provides written informed 
consent and extends until 28 calendar days after the last day of study participation. All adverse 
events that occur during this period and are known to the investigator must be reported according 
to the requirements outlined in this protocol. 
11.4 
Reporting Requirements 
All adverse events will be reported on the adverse event page of the CRF. In addition, serious 
adverse events must also be reported on a separate SAE Form. For cases in which the same data 
are collected, the forms must be completed in a consistent manner. For example, the same 
adverse event term should be used on both forms. Adverse events should be reported using 
concise medical terminology on the CRFs as well as on the form for collection of serious adverse 
events or suspected adverse reactions information. 
11.4.1 
Serious Adverse Event Reporting Requirements 
If an SAE occurs, VIVUS or designee is to be notified within 1 business day of awareness of the 
event. In particular, if the SAE is fatal or life-threatening, notification to VIVUS or designee 
must be made immediately, irrespective of the extent of available adverse event information. 
This timeframe also applies to additional new information (follow-up) on previously reported 
SAE. 
In the event that the investigator does not become aware of the occurrence of an SAE 
immediately (e.g., if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 1 business day after learning of it and document the time 
of his/her first awareness of the adverse event. 
For all SAEs, the investigator is obligated to pursue and provide information to VIVUS or 
designee in accordance with the timeframes for reporting specified above. In addition, an 
investigator may be requested by VIVUS or designee to obtain specific additional follow-up 
information in an expedited fashion. This information may be more detailed than that captured 
on the adverse event CRF. In general, this will include a description of the SAE in sufficient 
detail to allow for a complete medical assessment of the case and independent determination of 
possible causality. Information on other possible causes of the event, such as concomitant 
medications and illnesses, must be provided. In the case of a subject death, a summary of 
available autopsy findings must be submitted as soon as possible to VIVUS or its designee. 
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11.4.2 
Non-Serious Adverse Event Reporting Requirements 
Non-serious adverse events are to be reported on the Adverse Event CRFs, which are to be 
submitted to VIVUS or its designee. 
11.4.3 
Pregnancy 
If any study subject becomes or is found to be pregnant while receiving the investigational 
product, the investigator must immediately discontinue study treatment and report the pregnancy 
to VIVUS or designee within 1 business day of learning of the pregnancy. 
The investigator will follow the pregnancy until completion or until pregnancy termination 
(i.e., elective pregnancy termination) and then notify VIVUS or designee of the outcome. The 
investigator will provide this information as a follow-up to the initial pregnancy report. 
For reported pregnancies that result in a live birth, the status of the newborn should be assessed 
at the time of birth. The status of an aborted fetus should be assessed by gross visual inspection, 
unless pre-abortion test findings are suggestive of a congenital anomaly. 
If pregnancy outcomes meet the criteria for classification as SAEs (i.e., stillbirth, neonatal death, 
or congenital anomaly), the investigator should follow the procedures for reporting SAEs. 
Similarly, any pregnancy outcomes that are considered to be adverse events should be reported 
as such on the appropriate CRF. However, pregnancy in itself need not be reported as an adverse 
event if there is no associated adverse outcome. 
For reporting purposes, ectopic pregnancies should be reported as SAEs, but because the fetus is 
not potentially viable, they need not be reported as a pregnancy. 
12.0 
STATISTICAL PLAN 
12.1 
Statistical Analysis 
Detailed methodology for summary and statistical analyses of the data collected in this clinical 
trial will be documented in a Statistical Analysis Plan (SAP). This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoints 
definition and/or its analysis will also be reflected in a protocol amendment. Additional statistical 
analyses other than those described in this section may be performed if deemed appropriate and 
included in the plan. The SAP will be finalized and signed prior to the finalization of the 
database. 
12.2 
Sample Size Determination 
In previous studies in adults, VI-0521 mid-dose (PHEN/TPM 7.5 mg/46 mg) resulted in a 
placebo-subtracted BMI reduction of 2.4 units with a standard error approximately 0.16 units and 
a within treatment standard deviation of 2.9. A very conservative estimate of the treatment 
difference between the mid-dose and placebo would be 2 units of BMI which represents more 
than 2 standard errors below what was observed before. If we enroll 200 subjects (50 placebo, 
50 mid-dose, and 100 top-dose), we will have at least 90% power to detect a statistically 
significant difference between the top-dose (PHEN/TPM 15 mg/92 mg) and the placebo because 
we could assume that the top-dose will have a higher effect size than the mid-dose. This 
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calculation assumes that there will be an approximately 30% dropout rate. This sample size will 
also provide approximately 80% power to detect a statistically significant difference between the 
mid-dose and placebo. 
12.3 
Analysis Populations 
Three different analysis populations will be used for analysis of data from this study, as 
described below: 
• Randomized: This population will be comprised of all subjects who were initially 
randomized. This population will be used for summaries of subject disposition and 
baseline subject characteristics. 
• Intent-to-treat (ITT)/Safety: This population will be comprised of all subjects who were 
initially randomized and received at least one dose of study drug. This will be the primary 
population for all summaries of subject disposition and baseline characteristics, efficacy 
analyses, and safety analyses for purposes of regulatory submissions. 
• Modified Intent-to Treat (m-ITT): This population will be comprised of all randomized 
study subjects who receive study treatment and return for at least one post-randomization 
assessment of height and weight. This population will be used for the analysis of all 
efficacy variables for all other purposes, including but not limited to publications, 
presentations, and robustness of sensitivity of analyses. 
12.4 
Subgroups 
BMI change will be tabulated by age and gender. Additionally, further exploratory subgroup 
analyses of the primary efficacy endpoints may include evaluation by race and/or other 
subgroups deemed medically and/or scientifically important. 
12.5 
Statistical Methods 
12.5.1 
Analysis of the Primary Endpoint 
The primary endpoint for this study is the mean % change in BMI from baseline to end of study 
(Week 56). 
Comparisons in the primary endpoint of change from the baseline BMI between treatment 
groups be assessed for the ITT population using a mixed effects model with repeated measures 
(MMRM) with factors of treatment, visit, treatment by visit interaction, baseline BMI value, age 
stratification, and gender stratification. Appropriate contrast will be applied for treatment 
comparisons at Week 56. The pairwise comparisons of interest are top-dose vs. placebo, and 
mid-dose vs. placebo, and top-dose vs. mid-dose. The primary null hypothesis will be that there 
is no treatment difference between any VI-0521 treatment groups and the placebo in the percent 
change from baseline to Week 56 in BMI. An appropriate contrast will be used for the 
comparisons at Week 56. The family-wise type 1 error for the comparisons will be controlled by 
Fisher’s protected least significant difference (LSD) method at the 0.05 significance level: 
placebo, mid-dose, and top-dose will be first compared for overall difference in the percent 
change from baseline in BMI. Once the overall difference is significant at the 0.05 significance 
level, the above 3 pairwise comparisons will be conducted using Fisher’s LSD method at the 
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0.05 significance levels. The order for comparisons of interest is top-dose vs. placebo, mid-dose 
vs. placebo, and top-dose vs. mid-dose. Due to the fact that only three treatments are compared, 
the above procedure strongly controls the family-wise type 1 error.11 
12.5.2 
Method for Prevention and Treatment of Missing Values 
For subjects who discontinue treatment prior to trial completion, every attempt will be made to 
have them continue with clinic visits and study assessments. Particular attention will be given to 
collecting Week 56 assessments of weight and height, regardless of when subjects discontinued 
treatment. 
The above MMRM method used for the analysis of the primary endpoint has an inherent 
mechanism for imputing missing data. Therefore, MMRM is applied to the m-ITT population 
with the observed data without imputation. The following sensitivity analyses may be considered 
to explore the impact of missing data on the conclusion of the primary analysis. The details of 
the sensitivity analyses will be included in the statistical analysis plan. 
The first sensitivity analysis is using a multiple imputation method based on the monotonic 
missing pattern under the assumption of missing at random (MAR). The intermittent missing 
data will be imputed using multiple imputation MCMC (Markov chain Monte Carlo) procedure. 
The second sensitivity analysis is also using multiple imputation, however, under the assumption 
of missing not at random (MNAR) to explore the validity of MAR using pattern-mixture model: 
1) For subjects who discontinue study participation prior to Week 56 and do not have 
follow-up visit, the missing data will be imputed using the observed data from the 
subjects in the same arm who discontinue the study treatment but have the primary 
endpoint measurement in the follow up visit using a regression method. The intermittent 
missing data will be imputed using multiple imputation MCMC procedure. an ANCOVA 
model using a similar mixed procedure (without the repeated measures) as the primary 
analysis will be applied to these multiple-imputed % change in BMI at Week 56 with 
treatment, baseline BMI value as a covariate, and age and gender as stratification factors. 
The results of ANCOVA analysis on the multiple imputed datasets will be combined and 
summarized. 
2) Tipping point analyses: Subjects from the treatment arm who drop out the study will have 
their unobserved efficacy data imputed by the observed data from completers in the same 
arm using the multiple imputation method based on the monotonic missing pattern under 
the assumption of missing at random (MAR) with the resulting imputed values further 
worsened by an amount δ. Subjects who drop out the study from the control arm will be 
assumed to exhibit the same evolution of the disease as the completers in control arms 
and their values will be imputed by the multiple imputation method based on the 
monotonic missing pattern under the assumption of missing at random (MAR) above 
without the addition of δ. Sensitivity analysis may be performed for a range of δ to find a 
“tipping point” value of δ at which study conclusions start to change. When δ=0 the 
missing data are assumed to be MAR. When δ > 0, the missing data are assumed to be 
MNAR. 
The third sensitivity analysis is the last observation carried forward (LOCF). For those subjects 
who discontinue study participation prior to Week 56, the last observed weight and height will be 
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used to derive the change in BMI. 
Similar analyses will be performed for the primary endpoint for the m-ITT population. 
12.5.3 
Analysis of the Secondary Endpoints 
If both the mid- and top-doses are shown to be statistically significantly better than placebo for 
the primary endpoint using the Fisher’s LSD procedure, then the secondary endpoints will be 
tested in a stepwise way to preserve the familywise type 1 errors. Details of the stepwise testing 
procedure for secondary efficacy endpoints will be described in a prospective SAP. 
Percent of subjects achieving a reduction ≥ 5% from baseline in BMI at Week 56 will be 
analyzed using a logistic regression, with treatment, age and gender stratification as the main 
effect and baseline BMI value as a covariate at the 0.05 significance level. The adjusted odds 
ratios between the top-dose and placebo and between the mid-dose and placebo will be 
calculated together with their 95% confidence intervals. The p-values for the comparisons will 
also be generated. 
The percent of subjects achieving a reduction ≥ 10% and ≥ 15% from baseline in BMI at 
Week 56 will be analyzed similarly. 
Secondary efficacy endpoints that are continuous variables will be analyzed by a similar MMRM 
model as for the primary endpoint where the baseline BMI value will be replaced by the baseline 
value of the corresponding endpoint as a covariate. 
The above analyses will be conducted for both the ITT and m-ITT populations. 
12.6 
Safety Analysis 
All safety analyses will be done for the ITT population. Safety data will be summarized for all 
treatment groups. 
Safety will be assessed by an evaluation of adverse events (each study visit); laboratory 
parameters (screening, periodically during the study and end of study); electrocardiograms; 
physical examinations (screening, end of study); PHQ-9: Modified for Teens (see Appendix 4), 
C-SSRS, and vital signs, at each study visit). Descriptive statistics will be generated for the 
questionnaire data. 
12.6.1 
Analysis of CANTAB 
CANTAB will be scored according to its instructions. The scores will be summarized by 
treatment descriptively. 
12.6.2 
Analysis of Hand and Wrist X-Ray 
Changes from baseline to Week 56 in hand and wrist X-ray will be evaluated. Differences 
between treatment groups will be evaluated using methods similar to those used to evaluate other 
continuous variables. 
12.6.3 
Analysis of DXA 
In the subset of subjects treated at sites where DXA scans are being done, mean changes from 
NCT03922945


baseline to Week 56 in bone mineral density (BMD) and bone mineral content (BMC)-Z scores 
will be evaluated. The mean change in BMD and BMC will be summarized descriptively as a 
continuous variable. 
12.6.4 
Adverse Events 
Adverse events will be coded using a MedDRA coding dictionary. The number and percentage 
of subjects who reported at least one adverse event in each system organ class and preferred term 
category, and the total number and percentage of subjects with any AE over all system organ 
classes will be summarized by treatment group. 
Subsets of AEs that are considered serious or required discontinuation of the study medication 
will be summarized separately and listed by subject. 
12.6.5 
Clinical Laboratory Tests 
A summary of observed values and change from baseline will be presented for all laboratory 
parameters with numerical measures using descriptive statistics. Shift tables displaying low-
normal-high at baseline versus low-normal-high at end of study in a 3-by-3 contingency table 
will be provided. For selected laboratory parameters, scatter plots of baseline versus Week 56 
results, will be produced by treatment group. 
A laboratory value that is above or below normal range will be considered an abnormal value. 
For selected laboratory parameters, threshold limits of clinical concern will be defined as 
multiplicative factors of the normal ranges. The list of multiplicative factors for each laboratory 
parameter will be included in the Statistical Analysis Plan. The frequency and percentage of 
subjects with laboratory results above or below the normal range and threshold limits at each 
scheduled assessment or any time during the treatment will be summarized by treatment group. 
12.6.6 
Vital Signs and Other Safety Evaluations 
Mean blood pressures, heart rate, respiration, rate and temperature, obtained at each visit, will be 
summarized and plotted by treatment group. Medications, other than study medication, taken 
during the study will be considered as concomitant medications. They will be summarized by 
treatment group according to the preferred terms, using the World Health Organization (WHO) 
Drug Dictionary. 
12.7 
Interim Analysis 
No interim analysis is planned. 
12.8 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) with multidisciplinary representation will 
be established to evaluate accumulating trial data on a periodic basis and to assess the ongoing 
safety of the study for the subjects enrolled and to be enrolled. As a result, following each data 
review, the DMC will make a recommendation to the sponsor regarding continuation, revision, 
or termination of the study. Details related to DMC responsibilities, authorities, and procedures 
will be documented in the DMC charter, which will be finalized by the DMC prior to the first 
DMC data review meeting. 
NCT03922945


13.0 
TRIAL TERMINATION CRITERIA 
Premature termination of this clinical trial may occur because of a regulatory authority decision, 
change in opinion of the institutional review board (IRB)/independent ethics committee (IEC), 
drug safety problems, or at the discretion of VIVUS. In addition, VIVUS retains the right to 
discontinue this study at any time. 
If a clinical trial is prematurely terminated or discontinued, VIVUS will promptly notify the 
investigator. After notification, the investigator must contact all participating subjects within 
2 − 3 days. As directed by VIVUS, all study materials must be collected and all CRFs completed 
to the greatest extent possible. 
14.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
Data generated by this clinical trial must be available for inspection by the FDA, by the sponsor 
or a designate acting on behalf of the sponsor, by applicable foreign health authorities, and by the 
IRB or IEC as appropriate. At a subject’s request, medical information may be given to their 
personal physician or other appropriate medical personnel responsible for their welfare. 
Subject medical information obtained during the course of this study is confidential and 
disclosure to third parties other than those noted above is prohibited. 
15.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
During trial conduct, VIVUS or its designee will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practice (GCP) are being followed. The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate. The 
investigator and institution will allow VIVUS monitors or its agents and appropriate regulatory 
authorities direct access to source documents to perform this verification. 
The study site and study-related documents may be subject to review by the IRB/IEC, and/or to 
quality assurance audits performed by VIVUS or its agents, and/or to inspection by appropriate 
regulatory authorities. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
16.0 
ETHICAL CONSIDERATIONS 
16.1 
Institutional Review Board /Independent Ethics Committee 
Regulations require that an IRB/IEC oversee all investigational drug clinical trials. This board or 
committee, the makeup of which must conform to local and regional regulations, will approve all 
aspects of the trial, including the protocol, advertising and written informed consent form (ICF) 
to be used prior to initiation of the trial. It is the responsibility of the investigator to have 
prospective approval of the clinical trial protocol, protocol amendments, informed consent forms, 
and other relevant documents, e.g., advertisements, if applicable, from the IRB/IEC. All 
correspondence with the IRB/IEC should be retained in the investigator file. Copies of IRB/IEC 
NCT03922945


approvals should be forwarded to VIVUS or its designee. 
Amendments to the protocol must be reviewed and approved by VIVUS and the IRB/IEC prior 
to implementation. The only circumstance in which an amendment may be initiated prior to 
IRB/IEC approval is where the change is necessary to eliminate apparent immediate hazards to 
the subjects. In that event, the investigator must notify the IRB/IEC and VIVUS in writing within 
5 working days after the implementation. 
The investigator is responsible for keeping the IRB/IEC advised of the progress of the study and 
of any changes made to the protocol as deemed appropriate. 
16.2 
Ethical Conduct of the Clinical Trial 
The clinical trial will be performed in accordance with the protocol, International Conference on 
Harmonization Good Clinical Practice (ICH GCP) guidelines, and applicable local regulatory 
requirements and laws. 
16.3 
Subject Information and Consent/Assent 
The informed consent form and any changes to the informed consent form during the course of 
the trial must be agreed to by VIVUS and the IRB/IEC and must be in compliance with ICH 
GCP, local regulatory requirements, and legal requirements. 
The investigator or designee(s) must ensure that each clinical study subject is fully informed 
about the nature and objectives of the clinical trial and possible risks associated with 
participation. The investigator or designee(s) will obtain written informed consent from each 
subject before any trial-specific activity is performed. The informed consent form used in this 
clinical trial, and any changes made during the course of the trial, must be prospectively 
approved by both the IRB/IEC and VIVUS before use. The original signed copy of the informed 
consent form must be maintained by the investigator and is subject to inspection by a 
representative of VIVUS, their representatives, auditors, the IRB/IEC and/or regulatory agencies. 
A copy of the signed informed consent form will be given to the subject. 
Parental consent and/or subject assent will be obtained according to IRB/IEC guidelines. 
17.0 
DATA HANDLING AND RECORD KEEPING 
17.1 
Case Report Forms/Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or an 
electronic data record or both, depending on the data collection method used in this clinical trial. 
A CRF is required and should be completed for each included subject. The completed original 
CRFs are the sole property of VIVUS and should not be made available in any form to third 
parties, except for authorized representatives of VIVUS or appropriate regulatory authorities, 
without written permission from VIVUS. 
It is the investigator's responsibility to ensure completion and to review and approve all CRFs. 
CRFs must be signed by the investigator or by an authorized staff member. These signatures 
serve to attest that the information contained on the CRFs is true. At all times, the investigator 
NCT03922945


has final personal responsibility for the accuracy and authenticity of all clinical and laboratory 
data entered on the CRFs. Subject source documents are the physician's subject records 
maintained at the study site. In most cases, the source documents will be the hospital's or the 
physician's chart. In cases where the source documents are the hospital or the physician's chart, 
the information collected on the CRFs must match those charts. 
In some cases, the CRF may also serve as the source document. In these cases, VIVUS and the 
investigator must prospectively document which items will be recorded in the source documents 
and for which items the CRF will stand as the source document. A CRF is required and should 
be completed for each randomized subject. The completed original CRFs are the sole property of 
VIVUS and should not be made available in any form to third parties, except for authorized 
representatives of VIVUS or appropriate regulatory authorities, without written permission from 
VIVUS. 
17.2 
Record Retention 
To enable evaluations and/or audits from regulatory authorities or VIVUS, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient information 
to link records, e.g., CRFs and hospital records), all original signed informed consent forms, 
copies of all CRFs, SAE forms, source documents, and detailed records of treatment disposition. 
The records should be retained by the investigator according to ICH, local regulations, or as 
specified in the Clinical Trial Agreement, whichever is longer. 
If the investigator relocates, retires, or for any reason withdraws from the study, VIVUS should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another investigator, another institution, or to VIVUS. The investigator must obtain VIVUS’ 
written permission from VIVUS before disposing of any records prior to completion of the 
required/stipulated retention period. 
18.0 
PUBLICATION PLAN 
Publication of study results is addressed in the Clinical Trial Agreement with each site. 
All information and data, including the terms of this protocol, and all data, clinical results, and 
research conducted hereunder concerning VIVUS’s products and operations including VIVUS 
patent applications, formulas, manufacturing processes, basic scientific data, and formulation 
information that has been supplied by VIVUS and not previously published are considered 
confidential by VIVUS and will remain the sole property of VIVUS. The investigator 
understands and agrees that said proprietary and/or confidential information disclosed to or 
produced by him/her there under is highly valuable to VIVUS and will be used exclusively by 
the Investigator in accomplishing this clinical trial and will not be used for any other purposes. 
NCT03922945


19.0 
REFERENCES 
1. Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of Obesity among Adults and 
Youth: United States, 2015–2016. NCHS data brief, no 288. Hyattsville, MD: National 
Center for Health Statistics; (2017). 
2. Steinberger J., Daniels S. R. Obesity, insulin resistance, diabetes, and cardiovascular risk in 
children: an American heart association scientific statement from the atherosclerosis, 
hypertension, and obesity in the young committee (council on cardiovascular disease in the 
young) and the diabetes committee (council on nutrition, physical activity, and metabolism) 
Circulation. 2003;107(10):1448–1453. 
3. Mary Ann Liebert, Inc./Genetic Engineering News. "Childhood obesity linked to increased 
risk of adult cardiovascular and metabolic disorders." ScienceDaily. ScienceDaily, 19 
November 2010. https://www.sciencedaily.com/releases/2010/11/101119120845.htm 
4. Juonala M, Magnussen CG, Berenson GS et al. Childhood adiposity, adult adiposity and 
cardiovascular risk factors. N Engl J Med 2011;365:1876–85. 
5, Qsymia (VI-0521) Investigator Brochure. 12 (5 Oct 2018) ed. Mountain View, CA: 
VIVUS, Inc.. 
6. Topamax (topiramate) tablets. [Package Insert]. Titusville, NJ: Janssen Pharmaceuticals, 
Inc.; 2018. 
7. Schwartz GJ, Work DF. Measurement and Estimation of GFR in Children and Adolescents. 
Clin J Am Soc Nephrol 2009; 4:1832-1843. 
8. CDC Clinical Growth Chart. http://www.cdc.gov/growthcharts/html_charts/bmiagerev.htm 
9 . Kolotkin RL, Zeller M, Modi AC, et al. Assessing Weight-Related Quality of Life in 
Adolescents. Obesity (Silver Spring, MD). 2006;14(3):448-457. 
10. Posner, Brent, Lucas, et al. Columbia-Suicide Severity Rating Scale (C-SSRS) 
https://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4306s1-01-CU-
Posner_files/frame.htm 
11. Hayter, A.J. The maximum familywise error rate of Fisher's least significant difference test. 
Journal of the American Statistical Association. 1986; 81, 1001-1004. 
NCT03922945


APPENDIX 1: SCHEDULE OF EVENTS 
 
Screening 
Baselinea 
(+ 3 days) 
Treatment (± 1 Week) 
Study Weeks→ 
Screen 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56/ET 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, Waist Circumference, Height, and BMI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam (include Tanner Staging) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
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 
PHQ-9/C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
DXA (selected sites only) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Chemistry (Fasting) 
X 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
Hematology/Lipids 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
TSH, HIV, HCV, HBsAg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hand and Wrist X-ray (bone age assessment) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
OGTTb 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Cognitive Battery (CANTAB) 
Xc 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
IWQOL-Kids 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Diet/Lifestyle Counseling 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Contraception/Pregnancy Counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense Study Drug 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Drug Accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Schedule Next Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
a Baseline can occur up to 4 weeks from Screening. 
b Blood sample at 2 hours post glucose load 
c Familiarization session only
NCT03922945


APPENDIX 2: BMI CONVERSION CHART 
Weight 
(lb) 
110 
115 
120 
125 
130 
135 
140 
145 
150 
155 
160 
165 
170 
175 
180 
185 
190 
195 
200 
205 
210 
(kg) 49.9 
52.2 
54.5 
56.8 
59.1 
61.4 
63.6 
65.9 
68.2 
70.5 
72.7 
75.0 
77.3 
79.5 
81.8 
84.1 
86.4 
88.6 
90.9 
93.2 
95.5 
Height 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(in) 
(cm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
55 
139.7 
26 
27 
28 
29 
30 
31 
33 
34 
35 
36 
37 
38 
40 
41 
42 
43 
44 
45 
46 
48 
49 
56 
142.2 
25 
26 
27 
28 
29 
30 
31 
33 
34 
35 
36 
37 
38 
39 
40 
41 
43 
44 
45 
46 
47 
57 
144.8 
24 
25 
26 
27 
28 
29 
30 
31 
32 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
58 
147.3 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
59 
149.9 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
43 
60 
152.4 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
61 
154.9 
21 
22 
23 
24 
25 
26 
27 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
62 
157.5 
20 
21 
22 
23 
24 
25 
26 
27 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
38 
63 
160.0 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
28 
29 
30 
31 
32 
33 
34 
35 
36 
36 
37 
64 
162.6 
19 
20 
21 
22 
22 
23 
24 
25 
26 
27 
28 
28 
29 
30 
31 
32 
33 
34 
34 
35 
36 
65 
165.1 
18 
19 
20 
21 
22 
23 
23 
24 
25 
26 
27 
28 
28 
29 
30 
31 
32 
33 
33 
34 
35 
66 
167.6 
18 
19 
19 
20 
21 
22 
23 
23 
24 
25 
26 
27 
27 
28 
29 
30 
31 
32 
32 
33 
34 
67 
170.2 
17 
18 
19 
20 
20 
21 
22 
23 
24 
24 
25 
26 
27 
27 
28 
29 
30 
31 
31 
32 
33 
68 
172.7 
17 
17 
18 
19 
20 
21 
21 
22 
23 
24 
24 
25 
26 
27 
27 
28 
29 
30 
30 
31 
32 
69 
175.3 
16 
17 
18 
18 
19 
20 
21 
21 
22 
23 
24 
24 
25 
26 
27 
27 
28 
29 
30 
30 
31 
70 
177.8 
16 
16 
17 
18 
19 
19 
20 
21 
22 
22 
23 
24 
24 
25 
26 
27 
27 
28 
29 
29 
30 
71 
180.3 
15 
16 
17 
17 
18 
19 
20 
20 
21 
22 
22 
23 
24 
24 
25 
26 
27 
27 
28 
29 
29 
72 
182.9 
15 
16 
16 
17 
18 
18 
19 
20 
20 
21 
22 
22 
23 
24 
24 
25 
26 
27 
27 
28 
29 
73 
185.4 
15 
15 
16 
17 
17 
18 
19 
19 
20 
20 
21 
22 
22 
23 
24 
24 
25 
26 
26 
27 
28 
74 
188.0 
14 
15 
15 
16 
17 
17 
18 
19 
19 
20 
21 
21 
22 
23 
23 
24 
24 
25 
26 
26 
27 
75 
190.5 
14 
14 
15 
16 
16 
17 
18 
18 
19 
19 
20 
21 
21 
22 
23 
23 
24 
24 
25 
26 
26 
NCT03922945


APPENDIX 3: CDC CLINICAL GROWTH CHARTS8 
 
Male 
Female 
 
 
Male 
Female 
Age 
(in months) 
95th Percentile 
BMI Value 
95th Percentile 
BMI Value 
 
Age 
(in months) 
95th Percentile 
BMI Value 
95th Percentile 
BMI Value 
143.5 
24.1 
25.2 
 
182.5 
27.0 
28.3 
144.5 
24.2 
25.3 
 
183.5 
27.0 
28.3 
145.5 
24.3 
25.3 
 
184.5 
27.1 
28.4 
146.5 
24.4 
25.4 
 
185.5 
27.1 
28.5 
147.5 
24.5 
25.5 
 
186.5 
27.2 
28.5 
148.5 
24.6 
25.6 
 
187.5 
27.3 
28.6 
149.5 
24.6 
25.7 
 
188.5 
27.3 
28.7 
150.5 
24.7 
25.8 
 
189.5 
27.4 
28.7 
151.5 
24.8 
25.9 
 
190.5 
27.4 
28.8 
152.5 
24.9 
26.0 
 
191.5 
27.5 
28.8 
153.5 
24.9 
26.0 
 
192.5 
27.6 
28.9 
154.5 
25.0 
26.1 
 
193.5 
27.6 
29.0 
155.5 
25.1 
26.2 
 
194.5 
27.7 
29.0 
156.5 
25.2 
26.3 
 
195.5 
27.7 
29.1 
157.5 
25.3 
26.4 
 
196.5 
27.8 
29.2 
158.5 
25.3 
26.5 
 
197.5 
27.9 
29.2 
159.5 
25.4 
26.5 
 
198.5 
27.9 
29.3 
160.5 
25.5 
26.6 
 
199.5 
28.0 
29.3 
161.5 
25.5 
26.7 
 
200.5 
28.0 
29.4 
162.5 
25.6 
26.8 
 
201.5 
28.1 
29.5 
163.5 
25.7 
26.9 
 
202.5 
28.1 
29.5 
164.5 
25.8 
26.9 
 
203.5 
28.2 
29.6 
165.5 
25.8 
27.0 
 
204.5 
28.3 
29.6 
166.5 
25.9 
27.1 
 
205.5 
28.3 
29.7 
167.5 
26.0 
27.2 
 
206.5 
28.4 
29.8 
168.5 
26.0 
27.3 
 
207.5 
28.4 
29.8 
169.5 
26.1 
27.3 
 
208.5 
28.5 
29.9 
170.5 
26.2 
27.4 
 
209.5 
28.5 
29.9 
171.5 
26.3 
27.5 
 
210.5 
28.6 
30.0 
172.5 
26.3 
27.6 
 
211.5 
28.7 
30.0 
173.5 
26.4 
27.6 
 
212.5 
28.7 
30.1 
174.5 
26.5 
27.7 
 
213.5 
28.8 
30.2 
175.5 
26.5 
27.8 
 
214.5 
28.8 
30.2 
176.5 
26.6 
27.8 
 
215.5 
28.9 
30.3 
177.5 
26.6 
27.9 
 
216.5 
29.0 
30.3 
178.5 
26.7 
28.0 
 
217.5 
29.0 
30.4 
179.5 
26.8 
28.1 
 
218.5 
29.1 
30.4 
180.5 
26.8 
28.1 
 
219.5 
29.1 
30.5 
181.5 
26.9 
28.2 
 
220.5 
29.2 
30.6 
 
NCT03922945


APPENDIX 4: PHQ-9: MODIFIED FOR TEENS 
NCT03922945


APPENDIX 5: SAMPLE COLUMBIA SUICIDE SEVERITY RATING 
SCALE 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Baseline 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; 
Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J. 
 
Disclaimer: 
This scale is intended for use by trained clinicians. The questions contained in the Columbia-
Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the 
presence of suicidality depends on clinical judgment. 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia 
Suicide History Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center 
for the Neuroscience of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 
Riverside Drive, New York, NY, 10032. (Oquendo M.A., Halberstam B. & Mann J. J, Risk factors 
for suicidal behavior: utility and limitations of research instruments. In M.B. First [Ed.] 
Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 
1051 Riverside Drive, New York, New York, 10032; inquiries contact 
posnerk@childpsych.columbia.edu 
NCT03922945


SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” 
section. If the answer to question 2 is “yes”, answer questions 3, 4 and 5.  
Lifetime - 
Time He/She Felt 
Most Suicidal 
1. Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall 
asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
Frequency of Ideation: ______ 
If yes, describe:  
Yes 
No 
  
 
2. Non-Specific Active Suicidal Thoughts 
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g. “I’ve 
thought about killing myself”) without general thoughts of ways to kill oneself/associated 
methods, intent, or plan during the assessment period. 
Have you actually had any thoughts of killing yourself? 
Frequency of Ideation: ______ 
If yes, describe: 
Yes 
No 
  
 
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to 
Act 
Subject endorses thoughts of suicide and has thought of at least one method during the 
assessment period. This is different than a specific plan with time, place or method details 
worked out (e.g. thought of method to kill self but not a specific plan). Includes person 
who would say, “I thought about taking an overdose but I never made a specific plan as 
to when, where or how I would actually do it…..and I would never go through with it”. 
Have you been thinking about how you might do this? 
Frequency of Ideation: ______ 
If yes, describe: 
Yes 
No 
  
 
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on 
such thoughts, as opposed to “I have the thoughts but I definitely will not do anything 
about them”. 
Have you had these thoughts and had some intention of acting on them? 
Frequency of Ideation: ______ 
If yes, describe: 
Yes 
No 
  
 
5. Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject 
has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? 
Do you intend to carry out this plan? 
Frequency of Ideation: ______ 
If yes, describe: 
Yes 
No 
  
 
 
NCT03922945


INTENSITY OF IDEATION 
Ideation Type 
 
 
Type # (1-5)  
 
Description of Ideation 
Baseline 
Most Common Ideation: _____ ________________________________ 
Most Severe Ideation: _____ ________________________________ 
Lifetime – 
Time He/She Felt 
Most Suicidal 
The following features should be rated with respect to both most common and most severe types of 
ideation. Ask about time he/she was feeling the most suicidal. Only rate most common if most severe 
and most common are different. 
Most 
Common 
Most 
Severe 
Frequency 
How many times have you had these thoughts? 
1. Less than once a week 
2. Once a week 
3. 2-5 times in week 
4. Daily or almost daily 
5. Many times each day 
____ 
____ 
Duration 
When you have the thoughts how long do they last? 
1. Fleeting - few seconds or minutes 
2. Less than 1 hour/some of the time 
3. 1-4 hours/a lot of time 
4. 4-8 hours/most of day 
5. More than 8 hours/persistent or continuous 
____ 
____ 
Controllability 
Could /can you stop thinking about killing yourself or wanting to die if you want to? 
1. Easily able to control thoughts 
2. Can control thoughts with little difficulty 
3. Can control thoughts with some difficulty 
4. Can control thoughts with a lot of difficulty 
5. Unable to control thoughts 
0. Does not attempt to control thoughts 
____ 
____ 
Deterrents 
Are there things - anyone or anything (e.g. family, religion, pain of death) - that stopped you from 
wanting to die or acting on thoughts of committing suicide? 
1. Deterrents definitely stopped you from attempting suicide 
2. Deterrents probably stopped you 
3. Uncertain that deterrents stopped you 
4. Deterrents most likely did not stop you 
5. Deterrents definitely did not stop you 
0. Does not apply; wish to die only 
____ 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to 
end the pain or stop the way you were feeling (in other words you couldn’t go on living with this 
pain or how you were feeling) or was it to get attention, revenge or a reaction from others? Or 
both? 
1. Completely to get attention, revenge or a reaction from others. 
2. Mostly to get attention, revenge or a reaction from others. 
3. Equally to get attention, revenge or a reaction from others and to end/stop the pain. 
4. Mostly to end or stop the pain (you couldn’t go on living with the pain or how you were 
feeling). 
5. Completely to end or stop the pain (you couldn’t go on living with the pain or how you were 
feeling). 
____ 
____ 
NCT03922945


SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types)  
Lifetime 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. 
Behavior was in part thought of as method to kill oneself. Intent does not have to be 100%. If 
there is any intent/desire to die associated with the act, then it can be considered an actual suicide 
attempt. There does not have to be any injury or harm, just the potential for injury or harm. If 
person pulls trigger while gun is in mouth but gun is broken so no injury results, this is considered 
an attempt. 
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from 
the behavior or circumstances. For example, a highly lethal act that is clearly not an accident so 
no other intent but suicide can be inferred (e.g. gunshot to head, jumping from window of a high 
floor/story). Also, if someone denies intent to die, but they thought that what they did could be 
lethal, intent may be inferred. 
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life? 
Did you want to die (even a little) when you_____? 
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself 
(like to relieve stress, feel better, get sympathy, or get something else to happen)? (Self-Injurious 
Behavior without suicidal intent) 
If yes, describe: 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes  
No 
  
 
 
 
 
 
 
 
 
Total # of 
attempts 
____ 
 
 
 
 
 
 
 
 
 
Yes  
No 
  
 
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the potentially self-
injurious act (if not for that, actual attempt would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this 
becomes an attempt rather than an interrupted attempt. Shooting: Person has gun pointed toward 
self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they 
pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is 
grabbed and taken down from ledge. Hanging: Person has noose around neck but has not yet 
started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or 
something stopped you before you actually did anything? 
If yes, describe: 
Yes  
No 
  
 
 
 
 
 
 
Total # of 
interrupted 
____ 
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but stops themselves before 
they actually have engaged in any self-destructive behavior. Examples are similar to interrupted 
attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped 
yourself before you actually did anything? 
If yes, describe:  
Yes  
No 
  
 
 
Total # of 
aborted 
____ 
NCT03922945


Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything 
beyond a verbalization or thought, such as assembling a specific method (e.g. buying pills, 
purchasing a gun) or preparing for one’s death by suicide (e.g. giving things away, writing a 
suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such 
as collecting pills, getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe:  
Yes  
No 
  
 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period?  
Yes  
No 
  
 
Completed Suicide: 
Yes  
No 
  
 
 
NCT03922945


Answer for Actual Attempts Only 
Most Recent 
Attempt 
Date: 
Worst/Most 
Lethal Attempt 
Date: 
Initial/First 
Attempt 
Date: 
Actual Lethality/Medical Damage: 
0. No physical damage or very minor physical damage (e.g. 
surface scratches). 
1. Minor physical damage (e.g. lethargic speech; first-
degree burns; mild bleeding; sprains). 
2. Moderate physical damage; medical attention needed 
(e.g. conscious but sleepy, somewhat responsive; second-
degree burns; bleeding of major vessel). 
3. Moderately severe physical damage; medical 
hospitalization and likely intensive care required (e.g. 
comatose with reflexes intact; third-degree burns less 
than 20% of body; extensive blood loss but can recover; 
major fractures). 
4. Severe physical damage; medical hospitalization with 
intensive care required (e.g. comatose without reflexes; 
third-degree burns over 20% of body; extensive blood 
loss with unstable vital signs; major damage to a vital 
area). 
5. Death 
Enter Code 
______ 
Enter Code 
______ 
Enter Code 
______ 
Potential Lethality: Only Answer if Actual 
Lethality=0 
Likely lethality of actual attempt if no medical damage (the 
following examples, while having no actual medical damage, 
had potential for very serious lethality: put gun in mouth and 
pulled the trigger but gun fails to fire so no medical damage; 
laying on train tracks with oncoming train but pulled away 
before run over). 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause 
death 
2 = Behavior likely to result in death despite available 
medical care 
Enter Code 
______ 
Enter Code 
______ 
Enter Code 
______ 
 
NCT03922945


COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; 
Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J. 
 
Disclaimer: 
This scale is intended for use by trained clinicians. The questions contained in the Columbia-
Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the 
presence of suicidality depends on clinical judgment. 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia 
Suicide History Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center 
for the Neuroscience of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 
Riverside Drive, New York, NY, 10032. (Oquendo M.A., Halberstam B. & Mann J. J, Risk factors 
for suicidal behavior: utility and limitations of research instruments. In M.B. First [Ed.] 
Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 
1051 Riverside Drive, New York, New York, 10032; inquiries contact 
posnerk@childpsych.columbia.edu 
NCT03922945


SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” 
section. If the answer to question 2 is “yes,” answer questions 3, 4 and 5. 
Since Last Visit 
1. Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall 
asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
Frequency of Ideation: ______ 
If yes, describe: 
Yes 
No 
  
 
2. Non-Specific Active Suicidal Thoughts 
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g. “I’ve 
thought about killing myself”) without general thoughts of ways to kill oneself/associated 
methods, intent, or plan during the assessment period. 
Have you actually had any thoughts of killing yourself? 
Frequency of Ideation: ______ 
If yes, describe: 
Yes 
No 
  
 
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to 
Act 
Subject endorses thoughts of suicide and has thought of at least one method during the 
assessment period. This is different than a specific plan with time, place or method details 
worked out (e.g. thought of method to kill self but not a specific plan). Includes person 
who would say, “I thought about taking an overdose but I never made a specific plan as 
to when, where or how I would actually do it…..and I would never go through with it”. 
Have you been thinking about how you might do this? 
Frequency of Ideation: ______ 
If yes, describe: 
Yes 
No 
  
 
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on 
such thoughts, as opposed to “I have the thoughts but I definitely will not do anything 
about them”. 
Have you had these thoughts and had some intention of acting on them? 
Frequency of Ideation: ______ 
If yes, describe: 
Yes 
No 
  
 
5. Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject 
has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? 
Do you intend to carry out this plan? 
Frequency of Ideation: ______ 
If yes, describe: 
Yes 
No 
  
 
 
NCT03922945


INTENSITY OF IDEATION 
Ideation Type 
 
 
Type # (1-5)  
 
Description of Ideation 
Most Common Ideation: _____ _______________________________ 
Most Severe Ideation: _____ _______________________________ 
Since Last Visit 
The following features should be rated with respect to both most common and most severe types of 
ideation experienced since last visit. Only rate most common if most severe and most common are 
different. 
Most 
Common 
Most 
Severe 
Frequency 
How many times have you had these thoughts? 
1. Less than once a week 
2. Once a week 
3. 2-5 times in week 
4. Daily or almost daily 
5. Many times each day 
____ 
____ 
Duration 
When you have the thoughts how long do they last? 
1. Fleeting - few seconds or minutes 
2. Less than 1 hour/some of the time 
3. 1-4 hours/a lot of time 
4. 4-8 hours/most of day 
5. More than 8 hours/persistent or continuous 
____ 
____ 
Controllability 
Could /can you stop thinking about killing yourself or wanting to die if you want to? 
1. Easily able to control thoughts 
2. Can control thoughts with little difficulty 
3. Can control thoughts with some difficulty 
4. Can control thoughts with a lot of difficulty 
5. Unable to control thoughts 
0. Does not attempt to control thoughts 
____ 
____ 
Deterrents 
Are there things - anyone or anything (e.g. family, religion, pain of death) - that stopped you from 
taking your life or acting on thoughts of committing suicide? 
1. Deterrents definitely stopped you from attempting suicide 
2. Deterrents probably stopped you 
3. Uncertain that deterrents stopped you 
4. Deterrents most likely did not stop you 
5. Deterrents definitely did not stop you 
0. Does not apply; wish to die only 
____ 
____ 
NCT03922945


Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to 
end the pain or stop the way you were feeling (in other words you couldn’t go on living with this 
pain or how you were feeling) or was it to get attention, revenge or a reaction from others? Or 
both? 
1. Completely to get attention, revenge or a reaction from others. 
2. Mostly to get attention, revenge or a reaction from others. 
3. Equally to get attention, revenge or a reaction from others and to end/stop the pain 
4. Mostly to end or stop the pain (you couldn’t go on living with the pain or how you were 
feeling). 
5. Completely to end or stop the pain (you couldn’t go on living with the pain or how you were 
feeling). 
____ 
____ 
 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last Visit 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. 
Behavior was in part thought of as method to kill oneself. Intent does not have to be 100%. If 
there is any intent/desire to die associated with the act, then it can be considered an actual 
suicide attempt. There does not have to be any injury or harm, just the potential for injury or 
harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, this 
is considered an attempt. 
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically 
from the behavior or circumstances. For example, a highly lethal act that is clearly not an 
accident so no other intent but suicide can be inferred (e.g. gunshot to head, jumping from 
window of a high floor/story). Also, if someone denies intent to die, but they thought that 
what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life? 
Did you want to die (even a little) when you_____? 
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to 
relieve stress, feel better, get sympathy, or get something else to happen)? (Self-Injurious 
Behavior without suicidal intent) 
If yes, describe: 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes  
No 
  
 
 
 
 
 
 
 
 
 
Total # of 
attempts 
____ 
 
 
 
 
 
 
 
Yes  
No 
  
 
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the potentially self-
injurious act (if not for that, actual attempt would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, 
this becomes an attempt rather than an interrupted attempt. Shooting: Person has gun pointed 
toward self, gun is taken away by someone else, or is somehow prevented from pulling 
trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: 
Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose 
Yes  
No 
  
 
 
 
 
 
NCT03922945


around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or 
something stopped you before you actually did anything? 
If yes, describe: 
 
Total # of 
interrupted 
____ 
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but stops themselves 
before they actually have engaged in any self-destructive behavior. Examples are similar to 
interrupted attempts, except that the individual stops him/herself, instead of being stopped by 
something else. 
Has there been a time when you started to do something to try to end your life but you 
stopped yourself before you actually did anything? 
If yes, describe: 
Yes  
No 
  
 
 
Total # of 
aborted 
____ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything 
beyond a verbalization or thought, such as assembling a specific method (e.g. buying pills, 
purchasing a gun) or preparing for one’s death by suicide (e.g. giving things away, writing a 
suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself 
(such as collecting pills, getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
Yes  
No 
  
 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes  
No 
  
 
Completed Suicide: 
Yes  
No 
  
 
 
NCT03922945


Answer for Actual Attempts Only 
Most Recent 
Attempt 
Date: 
Worst/Most 
Lethal Attempt 
Date: 
Initial/First 
Attempt 
Date: 
Actual Lethality/Medical Damage: 
0. No physical damage or very minor physical damage 
(e.g. surface scratches). 
1. Minor physical damage (e.g. lethargic speech; first-
degree burns; mild bleeding; sprains). 
2. Moderate physical damage; medical attention needed 
(e.g. conscious but sleepy, somewhat responsive; 
second-degree burns; bleeding of major vessel). 
3. Moderately severe physical damage; medical 
hospitalization and likely intensive care required (e.g. 
comatose with reflexes intact; third-degree burns less 
than 20% of body; extensive blood loss but can 
recover; major fractures). 
4. Severe physical damage; medical hospitalization with 
intensive care required (e.g. comatose without reflexes; 
third-degree burns over 20% of body; extensive blood 
loss with unstable vital signs; major damage to a vital 
area). 
5. Death 
Enter Code 
______ 
Enter Code 
______ 
Enter Code 
______ 
Potential Lethality: Only Answer if Actual 
Lethality=0 
Likely lethality of actual attempt if no medical damage (the 
following examples, while having no actual medical 
damage, had potential for very serious lethality: put gun in 
mouth and pulled the trigger but gun fails to fire so no 
medical damage; laying on train tracks with oncoming train 
but pulled away before run over). 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause 
death 
2 = Behavior likely to result in death despite available 
medical care  
Enter Code 
______ 
Enter Code 
______ 
Enter Code 
______ 
 
NCT03922945


APPENDIX 6: IWQOL-KIDS 
The subject will answer questions based on what best applies to them in the past seven days. Each 
question contains five response options: “always true”, “usually true”, “sometimes true”, “rarely true”, 
and “never true”, scaled from 1 to 5, respectively. 
Physical Comfort 
1. Because of my weight I avoid using stairs whenever possible. 
2. Because of my weight it is hard for me to bend over to tie my shoes or to pick something up off the floor. 
3. Because of my weight it is hard for me to move around. 
4. Because of my weight it is hard for me to fit into seats in public places (e.g. movie theaters, desks at school, 
and booths in restaurants). 
5. Because of my weight my knees or ankles hurt. 
6. Because of my weight it is hard for me to cross my legs. 
Body Esteem 
7. Because of my weight I am ashamed of my body. 
8. Because of my weight I don’t like myself very much. 
9. Because of my weight I try not to look at myself in mirrors or in photographs. 
10. Because of my weight I have a hard time believing compliments that I receive from others. 
11. Because of my weight I am lacking in self-confidence. 
12. Because of my weight I avoid activities that involve wearing shorts or a bathing suit. 
13. Because of my weight it is very difficult for me to buy clothing. 
14. Because of my weight I don’t like to change my clothes or undress in front of others. 
15. Because of my weight I am embarrassed to try out for activities at school. 
Social Life 
16. Because of my weight people tease me or make fun of me. 
17. Because of my weight people talk about me behind my back. 
18. Because of my weight people avoid spending time with me. 
19. Because of my weight people stare at me. 
20. Because of my weight I have trouble making or keeping friends. 
21. Because of my weight people don’t think I’m very smart. 
Family Relations 
22. Because of my weight family members treat me differently from the way they treat other people. 
23. Because of my weight family members talk about me behind my back. 
24. Because of my weight one or more people in my family reject me. 
25. Because of my weight my parents aren’t proud of me. 
26. Because of my weight family members make fun of me. 
27. Because of my weight family members don’t want to be seen with me. 
NCT03922945


APPENDIX 7: FORMULAS FOR ESTIMATING CREATININE 
CLEARANCE 
Creatinine clearance in adolescent boys and girls should be calculated based on height (HT) and 
serum creatinine (sCr) using the Schwartz formula (refs) as noted below.7 
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏= [0.70 × 𝐻𝐻𝐻𝐻(𝑐𝑐𝑐𝑐)]
𝑠𝑠𝑠𝑠𝑠𝑠 (𝑚𝑚𝑚𝑚
𝑑𝑑𝑑𝑑)
 
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔= [0.55 × 𝐻𝐻𝐻𝐻(𝑐𝑐𝑐𝑐)]
𝑠𝑠𝑠𝑠𝑠𝑠 (𝑚𝑚𝑚𝑚
𝑑𝑑𝑑𝑑)
 
NCT03922945


APPENDIX 8: SUMMARY OF CHANGES IN AMENDMENT #1 
Amendment #1 (05 October 2018) 
Rationale: 
This protocol amendment is being implemented to clarify or revise several inconsistencies that 
had been noted in the original version. This amendment does not involve substantive changes to 
the subject population or additional study procedures, and is not expected to have any impact on 
the safety of study subjects. Specific changes are noted by section in the following table. 
 
Section and/ 
or Item 
Changes Effected 
Header 
Updated protocol version and version date. 
Title Page 
Added new line for Amendment 1 and version date. 
Investigator Signature 
Page 
Updated protocol version and version date. 
Section 1.0: Table of 
Contents 
Updated Table of Contents 
Section 2.0: Protocol 
Synopsis – Study 
Objectives 
Text deleted: “…VI-0521 (PHEN/TPM 7.5 mg/46 mg and PHEN/TPM and 15 mg/92 
mg doses) for...” 
Section 7.2: Exclusion 
Criteria #14 
Text deleted: “Any history of any eating disorders (e.g. bulimia; binge eating disorder; 
anorexia);” 
Section 8.4.1: 
Formulation and 
Packaging 
Revised: “…during the first 4 weeks of study treatment and the first 4 weeks following 
up-titration for subjects randomized to the top-dose (titration period during study 
Weeks 13-16), and treatment kits (bottles), for use once subjects have been titrated to 
their assigned dose.” 
Section 8.4.3: 
Administration 
Revised: “…should the next study visit be scheduled after Week 4beyond 4 weeks 
after the previous visit. Investigators will…” 
Section 9.1: Screening 
Visit (Visit 1, Up to – 4 
Weeks) 
Added: “Administer neurocognitive battery (CANTAB) familiarization session” 
Section 9.1.3: 
Treatment Week 4 
Through Week 52 
(Visits 3 Through 15) 
Revised: “Administer neurocognitive battery (CANTAB), Visit 36 only;” 
Section 9.2: Study 
Period 
Revised: “…Sites should link the scheduling of visits to the baseline/randomization 
visit (Visit 2, Day 0). … so that the overall treatment duration is 56 daysweeks for 
subjects… 
Section 10.10: Oral 
Glucose Tolerance Test 
Revised: “An oral glucose tolerance test (OGTT) will be obtained at baselineVisit 2 
(after results from Visit 1screening visit indicate the subject …” 
NCT03922945


Section and/ 
or Item 
Changes Effected 
Section 10.11: 
CANTAB (Cambridge 
Neuropsychological 
Test Automated 
Battery) 
Revised: “An oral glucose tolerance test (OGTT) will be obtained at baselineVisit 2 
(after results from Visit 1screening visit indicate the subject …” 
Section 10.12: IWQOL-
Kids 
Revised: “… is a 27-item, self-administered instrument that will be completed at 
baseline (Visit 2), Visit 9 (Week 28) and end of study (Visit 16 at Week 56 or early 
termination).” 
Appendix 1: Schedule 
of Events 
Updated CANTAB test to add familiarization test to Screening and moved test at 
Week 4 to Week 16. 
Text added to “Contraception/Pregnancy Counseling” 
Added “Schedule Next Visit” 
Added footnote c. 
Appendix 1: Schedule 
of Events 
Updated CANTAB test to add familiarization test to Screening and moved test at 
Week 4 to Week 16. 
Text added to “Contraception/Pregnancy Counseling” 
Added “Schedule Next Visit” 
Added footnote c. 
Section 19.0: 
References 
Updated References #1, #3, #5, #6. 
Appendix 1: Schedule 
of Events 
Updated CANTAB test to add familiarization test to Screening and moved test at 
Week 4 to Week 16. 
Text added to “Contraception/Pregnancy Counseling” 
Added “Schedule Next Visit” 
Added footnote c. 
NCT03922945


APPENDIX 9: SUMMARY OF CHANGES IN AMENDMENT #2 
Amendment #2 (21 June 2019) 
Rationale: 
This protocol amendment is being implemented to clarify or revise several inconsistencies that 
had been noted in the previous version. This amendment does not involve substantive changes to 
the subject population or additional study procedures, and is not expected to have any impact on 
the safety of study subjects. Specific changes are noted by section in the following table. 
Section and/ 
or Item 
Changes Effected 
Header 
Updated protocol version and version date. 
Title Page 
Updated current and previous protocol version and version date. 
Investigator Signature 
Page 
Updated protocol version and version date. 
Section 1.0: Table of 
Contents 
Updated Table of Contents 
Section 2.0: Protocol 
Synopsis – Study 
Rational 
Text updated: “Obesity remains a major problem in pediatrics. National Health and 
Nutrition Examination Survey (NHANES) data indicate that 17.018.5% of children 
and adolescents age 2 to 19 years and 20.520.6% of adolescents age 12 to 19 years 
met the definition of obesity in 2011–20142015-2016….” 
Section 2.0: Protocol 
Synopsis – Study 
Design 
Text revised: “…Randomization will be stratified by age (12-14 vs 15-1716 years old) 
and gender....” 
Section 2.0: Protocol 
Synopsis – Study 
Population: Key 
Exclusion Criteria 
Text added: “…History of bipolar disorder or psychosis, greater than one lifetime 
episode of major depressive disorder, depression of moderate or greater severity...” 
Section 4.0: 
Background 
Text updated: “Obesity remains a major problem in pediatrics. National Health and 
Nutrition Examination Survey (NHANES) data indicate that 17.018.5% of children 
and adolescents age 2 to 19 years and 20.520.6% of adolescents age 12 to 19 years 
met the definition of obesity in 2011–20142015-2016….” 
Section 6.0: Study 
Design 
Text revised: “…Randomization will be stratified by age (12-14 vs 15-1716 years old) 
and gender....” 
Section 7.2: Exclusion 
Criteria #9-27 
Updated numbering. 
Section 7.2: Exclusion 
Criteria #13 
Text added: “Any history of bipolar disorder or psychosis, greater than one lifetime 
episode of major depressive disorder, current depression of moderate or greater 
severity...” 
Section 8.2: Allocation 
to Treatment 
Text revised: “…Randomization will be stratified by gender and age (12-14 vs 15-
1716 years old), and...” 
Section 11.3: Reporting 
Period 
Text revised: “The reporting period for adverse events begins when the subject 
provides written informed consent and extends until 28 calendar days after the last 
dose of the investigational product is administeredday of study participation....” 
NCT03922945


Section and/ 
or Item 
Changes Effected 
Appendix 1: Schedule 
of Events 
Revised table header and footer. 
 
NCT03922945

SAP_001.pdf: 
 CONFIDENTIAL 
 
 
 
Statistical Analysis Plan 
 
VIVUS, Inc. 
OB-403 
 
 
 
Document Version: Final 1.1 
Document Date: April 01, 2021 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan  
Sponsor Name: Vivus, Inc. 
Sponsor Protocol ID: OB-403 
 
 
 
 CONFIDENTIAL 
 
 
Page 2 of 29 
Table of Contents 
1. 
Source Documents ............................................................................... 8 
2. 
Protocol Details .................................................................................... 8 
2.1 
Study Objectives ............................................................................... 8 
2.2 
Overall Study Design .......................................................................... 8 
2.3 
Sample Size and Power .................................................................... 10 
3. 
Efficacy and Safety Variables ................................................................ 10 
3.1 
Primary Efficacy Endpoints ................................................................ 10 
3.2 
Secondary Efficacy Endpoints ............................................................ 10 
3.3 
Exploratory Endpoints ...................................................................... 10 
3.4 
Safety Endpoints ............................................................................. 10 
3.5 
DXA (Sub Study) ............................................................................. 11 
4. 
Analysis populations ........................................................................... 11 
4.1 
Randomized .................................................................................... 11 
4.2 
Safety ............................................................................................ 11 
4.3 
Intent-to-treat (ITT) ........................................................................ 12 
4.4 
Modified Intent-to-treat (mITT) ......................................................... 12 
4.5 
Special Subpopulations ..................................................................... 12 
5. 
DATA Handling ................................................................................... 12 
5.1 
Time Points and Visit Windows ........................................................... 12 
Table 1 
Definition of Visit Windows ..................................................... 13 
5.2 
Handling of Dropouts, Missing Data, and Outliers ................................. 13 
6. 
Statistical Methods ............................................................................. 14 
6.1 
General Principles ............................................................................ 14 
6.2 
Subject Disposition and Data Sets Analyzed ........................................ 15 
6.3 
Protocol Deviations .......................................................................... 16 
6.4 
Demographics and Other Baseline Characteristics ................................. 16 
6.4.1 
Medical History ................................................................................................................... 17 
6.4.2 
Prior and Concomitant Medications ................................................................................... 17 
6.5 
Measurements of Treatment Compliance ............................................. 18 
6.6 
Efficacy .......................................................................................... 18 
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6.6.1 
Primary Efficacy Analysis ..................................................................................................... 18 
6.6.2 
Secondary Efficacy Analysis ................................................................................................ 19 
6.6.3 
Sensitivity Analysis .............................................................................................................. 20 
6.6.4 
Subgroup Analysis ............................................................................................................... 21 
6.6.5 
Exploratory Analysis ............................................................................................................ 21 
6.7 
Safety ............................................................................................ 22 
6.7.1 
CANTAB ............................................................................................................................... 22 
6.7.2 
PHQ-9 .................................................................................................................................. 23 
6.7.3 
C-SSRS.................................................................................................................................. 24 
6.7.4 
Hand and Wrist X-Ray ......................................................................................................... 24 
6.7.5 
DXA ...................................................................................................................................... 24 
6.7.6 
Adverse Events .................................................................................................................... 24 
6.7.7 
Laboratory Evaluations ....................................................................................................... 26 
6.7.8 
Vital Signs ............................................................................................................................ 27 
6.7.9 
Electrocardiograms ............................................................................................................. 27 
6.7.10 
Physical Examination ........................................................................................................... 27 
6.8 
Interim Analysis .............................................................................. 27 
6.9 
Data Monitoring Committee ............................................................... 28 
7. 
Changes in Planned Analysis ................................................................ 28 
8. 
Data Issues ....................................................................................... 28 
9. 
References ........................................................................................ 29 
 
 
 
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Reviewers 
The following reviews of the SAP were conducted: 
 
Version History  
Version # 
Description of Changes 
Version Date 
Final 1.0 
Original Version 
01Sept2020 
1.1 
Updates to Sections 5.2 and 6 
07Jan2021 
 
 
 
 
 
Name and Title  
Role 
Version Last 
Reviewed 
Company/ 
Organization 
 
 
Lead Statistician 
Final 1.1 
 
 
 
Peer Review 
Statistician 
Final 1.1 
 
 
 
Lead Programmer 
Final 1.0 
 
 
 
Medical Writer 
Final 1.1 
 
 
 
Sponsor 
Final 1.1 
Vivus 
 
 
Sponsor 
Final 1.1 
Vivus 
 
 
Sponsor 
Final 1.1 
Vivus 
 
 
QC Reviewer 
Final 1.1 
 
 
 
Biostatistician 
Final 1.1 
 
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Glossary of Abbreviations 
Abbreviations pertain to the SAP only (not the TFLs). 
Abbreviation 
Term 
AE 
Adverse event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BMD 
bone mineral density 
BMC 
bone mineral content 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CI 
Confidence Interval 
CRF 
Case report form 
C-SSRS 
Columbia Suicide Severity Rating Scale  
DXA 
Dual-energy X-Ray Absorptiometry 
ECG 
Electrocardiogram 
ET 
Early Termination 
HR 
Heart Rate 
LSD 
protected Least Significant Difference  
ITT 
Intention-to-treat 
IWQOL-Kids 
Impact of Weight on Quality of Life-Kids 
LOCF 
Last observation carried forward 
MAR 
missing at random 
MCMC 
Markov chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention-to-treat 
MMRM 
Mixed Effects Model with Repeated Measures  
MNAR 
missing not at random  
PHQ-9  
Patient Health Questionnaire-9  
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAEs 
Treatment–Emergent AEs  
TFLs 
Tables, Figures and Listings 
 
 
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STATISTICAL ANALYSIS PLAN AMENDMENT 1 
Not applicable. 
 
 
 
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1. Source Documents 
The Statistical Analysis Plan (SAP) was written based on the following 
documentation: 
Document 
Date 
Version 
Protocol 
24 Aug 2017 
Original 
Protocol Amendment #1 
05 Oct 2018 
Amendment # 1 
Protocol Amendment #2 
21 Jun 2019 
Amendment # 2 
<e>CRF 
17 Sep 2019 
3.0 
DMC Charter 
27 Feb 2020 
1.0 
DMC Charter Amendment 
NA 
NA 
2. Protocol Details 
2.1 Study Objectives 
The primary objectives are to evaluate the safety and efficacy of VI-0521 for the 
treatment of obesity in adolescents. The secondary objective is to characterize 
changes in obesity-related risk factors. 
2.2 Overall Study Design 
In this multicenter, randomized, double-blind, placebo-controlled, parallel-design 
study, approximately 200 subjects will be enrolled at approximately 20 sites in the 
United States. Subjects will be randomly assigned in a 1:1:2 ratio to placebo, N= 50; 
mid-dose (PHEN/TPM 7.5 mg/46 mg), N= 50; or top-dose (PHEN/TPM 15 mg/92 mg), 
N =100, of VI-0521, to be taken orally once daily in the morning. Randomization will 
be stratified by age (12-14 vs 15-16 years old) and gender. The study will consist of 
a screening period of up to 28 days, followed by a 56-week treatment period. 
Subjects will be instructed to follow a mild hypocaloric diet modification program 
representing a 500-calorie/day deficit and to implement a family-based lifestyle 
modification program for adolescents, as tolerated, throughout the study period. The 
lifestyle program will include physical activity, behavior change, and family support. 
The same lifestyle modification program, specific to this population, will be 
implemented across all sites. Study drug will be titrated according to the following 
schema. 
 
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Subjects who are unable to tolerate the assigned dose may be treated at a reduced 
dose level or may take a drug holiday as defined in the protocol. In addition, for 
growth monitoring, investigators will monitor rates of weight loss in treated subjects. 
For subjects with baseline BMI 95-98th percentile, reduce study drug dosage when 
BMI is < 85th percentile or when weight loss exceeds an average of 2 lbs (0.9 kg) 
per week. For subjects with baseline BMI ≥ 99th percentile, reduce study drug when 
weight loss exceeds an average of 2 lbs (0.9 kg)/week. 
All subjects will return at approximately 4-week intervals for study assessments. All 
female subjects will undergo a pregnancy test at each visit. Subjects who discontinue 
study drug during the study will be encouraged to remain on study (off study drug) 
for continued follow-up by attending all remaining visits and have all study-related 
procedures performed, and to return at the 56-week time point for measurements 
and evaluations. For those who choose to completely withdraw from the study at any 
point, the end of study (Week 56) procedures should be completed. 
  
Group 
Treatment Dosage 
for 
PHEN/TPM (mg) 
Titration Dose for PHEN/TPM (mg) 
Weeks 
1-2 
Weeks 
3-4 
Weeks 
13-14 
Weeks 
15-16 
Placebo 
0/0 
0/0 
0/0 
0/0 
0/0 
VI-0521 Mid 
7.5/46 
3.75/23 
7.5/46 
7.5/46 
7.5/46 
VI-0521 Top 
15/92 
3.75/23 
7.5/46 
11.25/69 
15/92 
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2.3 Sample Size and Power 
In previous studies in adults, VI-0521 mid-dose (PHEN/TPM 7.5 mg/46 mg) resulted 
in a placebo-subtracted BMI reduction of 2.4 units with a standard error 
approximately 0.16 units and a within treatment standard deviation of 2.9. A very 
conservative estimate of the treatment difference between the mid-dose and placebo 
would be 2 units of BMI which represents more than 2 standard errors below what 
was observed before. If we enroll 200 subjects (50 placebo, 50 mid-dose, and 100 
top-dose), we will have at least 90% power to detect a statistically significant 
difference between the top-dose (PHEN/TPM 15 mg/92 mg) and the placebo because 
we could assume that the top-dose will have a higher effect size than the mid-dose. 
This calculation assumes that there will be an approximately 30% dropout rate. This 
sample size will also provide approximately 80% power to detect a statistically 
significant difference between the mid-dose and placebo. 
3. Efficacy and Safety Variables 
3.1 Primary Efficacy Endpoints 
• 
The mean percent change in BMI from baseline to end of study (Week 56). 
3.2 Secondary Efficacy Endpoints 
• 
Percent of subjects achieving a reduction ≥ 5%, ≥ 10% and ≥ 15% of baseline 
BMI at Week 56;  
• 
Change from baseline in waist circumference at Week 56;  
• 
Change from baseline in fasting insulin and Whole Body Insulin Sensitivity Index 
(Matsuda) at Week 56;  
• 
Percent change from baseline in triglycerides and HDL-C at Week 56;  
• 
Change from baseline in blood pressure at Week 56.  
3.3 Exploratory Endpoints 
• 
Evaluate effects of treatment on Impact of Weight on Quality of Life-Kids (IWQOL-
Kids) questionnaire scores. 
• 
Changes in various glycemic and lipid markers.  
• 
Change in BMI Z-score. 
3.4 Safety Endpoints 
Safety will be assessed by evaluating adverse events (AEs)/serious adverse events 
(SAEs); vital signs, laboratory parameters (screening, periodically during the study 
and end of study); electrocardiograms; physical examinations; cognitive function 
tests using the Cambridge Neuropsychological Test Automated Battery (CANTAB). All 
subjects will be screened for the presence and severity of depression using the PHQ-
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9: Modified for Teens and for suicidal/ideation using the Columbia Suicide Severity 
Rating Scale (C-SSRS) and follow up assessments will be done at each visit after 
treatment has been initiated. Bone age (X-ray of the hand and wrist) will be evaluated 
at baseline and end of study or early termination. Effect on bone mineral density and 
bone mineral content, as evaluated by Dual-energy X-Ray Absorptiometry (DXA) will 
be performed at baseline, end of study or early termination, at selected sites. 
3.5 DXA (Sub Study) 
A bone health sub-study will be conducted at selected sites in approximately 100 
subjects (25 each on placebo and mid-dose, and 50 on top-dose) to assess the effect 
of VI-0521 administration on bone health using Dual X-ray Absorptiometry (DXA). 
DXA scans of the posterior-anterior (PA) spine (lumbar), and total body less head 
(TBLH) will be performed at baseline and at the end of study or early termination. 
Equipment and procedures used to obtain DXA data will be standardized as described 
in a separate document. Sites involved in DXA measurement will be trained on these 
procedures prior to performing scans on study subjects. Scans will be read at a 
central facility and the reader will be blinded. 
The following enrollment criteria will apply:  
1) Both male and female will be eligible to participate;  
2) Subjects with a history of any non-traumatic fracture will not be eligible;  
3) Subjects with juvenile osteoporosis at baseline will not be eligible; and 
4) Subjects must meet manufacturer equipment specifications with regard to height 
and weight limitations.  
4. Analysis populations 
4.1 Randomized 
This population will be comprised of all subjects who were initially randomized. This 
population will be used for summaries of subject disposition and baseline subject 
characteristics.  
4.2 Safety 
This population will be comprised of all subjects who were initially randomized and 
received at least one dose of study drug. This will be the primary population for all 
summaries of subject disposition and baseline characteristics, and safety analyses 
for purposes of regulatory submissions. The safety population is based on the 
treatments actually received. 
 
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4.3 Intent-to-treat (ITT) 
This population will be comprised of all subjects who were initially randomized and 
received at least one dose of study drug. This will be the primary population for all 
summaries of efficacy analyses for purposes of regulatory submissions. The ITT 
population is based on the randomized treatments. 
4.4 Modified Intent-to-treat (mITT) 
This population will be comprised of all randomized study subjects who receive study 
treatment and return for at least one post-randomization assessment of height and 
weight. This population will be used for the analysis of all efficacy variables for all 
other purposes, including but not limited to publications, presentations, and 
robustness of sensitivity of analyses.  
4.5 Special Subpopulations 
BMI change will be tabulated by age and gender. Additionally, further exploratory 
subgroup analyses of the primary efficacy endpoints may include evaluation by race 
and/or other subgroups deemed medically and/or scientifically important. 
5. DATA Handling 
5.1 Time Points and Visit Windows 
Day 0 (Visit 2) is defined as the Baseline/Randomization visit, is also the first day of 
treatment. Relative days are calculated as (assessment date – Day 1 date).  The day 
prior to Day 0 is Day -1.  
The following visit windows defined in Table 1 will be used for the by-visit analyses 
of the primary endpoint, the secondary and other endpoints. All other analyses will 
use the nominal study visit as defined in the Study Schedule and eCRF. 
If there are multiple visits (scheduled or unscheduled) within a visit window, the 
measurement closest to the target day of the visit will be used in the analysis. If the 
measurements are equally distant to the target day, then the later one will be used 
in the analysis. If both scheduled and unscheduled visits fall within the same visit 
window, the scheduled visit will be used for analysis. 
 
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Table 1 
Definition of Visit Windows 
Visit 
Visit time 
(Week) 
Acceptable visit 
window 
Study Day Analysis Visit Window 
Range 
1 Screening 
Screening 
-28 days from 
baseline 
NA 
2 Baselinea 
Week 0 
±3 days 
Day -27 to Day 2 
3 Treatment 
Week 4 
±1 week 
Day 3 to Day 41(Week 6)  
4 Treatment 
Week 8 
±1 week 
Day 42 to Day 69(Week 10) 
5 Treatment 
Week 12 
±1 week 
Day 70 to Day 97(Week 14) 
6 Treatment 
Week 16 
±1 week 
Day 98 to Day 125(Week 18) 
7 Treatment 
Week 20 
±1 week 
Day 126 to Day 153(Week 22) 
8 Treatment 
Week 24 
±1 week 
Day 154 to Day 181(Week 26) 
9 Treatment 
Week 28 
±1 week 
Day 182 to Day 209(Week 30) 
10 Treatment 
Week 32 
±1 week 
Day 210 to Day 237(Week 34) 
11 Treatment 
Week 36 
±1 week 
Day 238 to Day 265(Week 38) 
12 Treatment 
Week 40 
±1 week 
Day 266 to Day 293(Week 42) 
13 Treatment 
Week 44 
±1 week 
Day 294 to Day 321(Week 46) 
14 Treatment 
Week 48 
±1 week 
Day 322 to Day 349(Week 50) 
15 Treatment 
Week 52 
±1 week 
Day 350 to Day 377(Week 54) 
16 End of Study/ETb 
Week 56/ET 
±1 week 
Day 378 to Day 398(Week 57) 
a Baseline Visit (Visit 2) can be scheduled up to 4 weeks from Screening. 
b. ET = Early Termination 
5.2 Handling of Dropouts, Missing Data, and Outliers 
For subjects who discontinue treatment prior to study completion, every attempt will 
be made to have them continue with clinic visits and study assessments. Particular 
attention will be given to collecting Week 56 assessments of weight and height, 
regardless of when subjects discontinued treatment. 
Missing data will not be imputed for safety analyses. The safety evaluations will be 
performed on observed data only. 
For the MMRM (mixed effects model with repeated measures) method used for the 
primary analysis on the primary endpoint, the retrieved dropouts will be used to 
impute missing data for subjects who discontinue the study prematurely. If there are 
no sufficient retrieved dropouts, then the wash-out imputation method will be 
applied.  
The following sensitivity analyses will be considered to explore the impact of missing 
data on the conclusion of the primary analysis. 
The first sensitivity analysis is using a multiple imputation method based on the 
monotonic missing pattern under the assumption of missing at random (MAR). The 
intermittent missing data will be imputed using multiple imputation MCMC (Markov 
chain Monte Carlo) procedure.  
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The second sensitivity analysis is also using multiple imputation, however, under the 
assumption of missing not at random (MNAR) to explore the validity of MAR using 
pattern-mixture model:  
1) For subjects who discontinue study participation prior to Week 56 and do not have 
follow-up visit, the missing data will be imputed using the observed data from the 
subjects in the same arm who discontinue the study treatment but have the 
primary endpoint measurement in the follow up visit using a regression method. 
The intermittent missing data will be imputed using multiple imputation MCMC 
procedure. An ANCOVA (analysis of covariance) model using a similar mixed 
procedure (without the repeated measures) as the primary analysis will be applied 
to these multiple-imputed % change in BMI at Week 56 with treatment, baseline 
BMI value as a covariate, and age and gender as stratification factors. The results 
of ANCOVA analysis on the multiple imputed datasets will be combined and 
summarized.  
2) Tipping point analyses: Subjects from the treatment arm who drop out the study 
will have their unobserved efficacy data imputed by the observed data from 
completers in the same arm using the multiple imputation method based on the 
monotonic missing pattern under the assumption of MAR with the resulting 
imputed values further worsened by an amount δ. Subjects who drop out the 
study from the control arm will be assumed to exhibit the same evolution of the 
disease as the completers in control arms and their values will be imputed by the 
multiple imputation method based on the monotonic missing pattern under the 
assumption of MAR above without the addition of δ. Sensitivity analysis may be 
performed for a range of δ to find a “tipping point” value of δ at which study 
conclusions start to change. When δ=0 the missing data are assumed to be MAR. 
When δ > 0, the missing data are assumed to be MNAR.  
The third sensitivity analysis is the last observation carried forward (LOCF). For those 
subjects who discontinue study participation prior to Week 56, the last observed 
weight and height will be used to derive the change in BMI.  
Similar analyses will be performed for the primary endpoint for the mITT population. 
6. Statistical Methods 
6.1 General Principles 
All data processing, summarization and analyses will be performed using SAS 
Environment / Version 9.3 (or later) of the SAS statistical software package. 
The following principles will be applied to all TFLs unless otherwise stated: 
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Principle 
Value 
Significant tests 
Two-sided and use a 5% significance level. 
Treatment group labels 
and order presented 
Placebo 
VI-0521 Mid 
VI-0521 Top 
Tables 
Data in summary tables presented by treatment group, 
assessment and visit (where applicable).  
Listings 
All data collected presented by treatment group, site, 
subject, and visit (where applicable), unless otherwise 
specified.  
Descriptive summary 
statistics for continuous 
variables 
Number of observations (N), mean, standard deviation 
(SD), minimum, median and maximum.  
Descriptive summary 
statistics for categorical 
variables 
Frequency counts and percentages [n (%)]. 
Denominator for 
percentages 
Number of subjects in the pertinent analysis population, 
unless stated otherwise in table shells. 
Include “Missing” as 
category 
Demographics and Other Baseline Characteristics only 
Display for 0 percentages 
Blank 
Display to one more 
decimal place than 
collected value 
Mean 
Median 
Minimum 
Maximum 
Display to two more 
decimal places than 
collected value 
Standard Deviation 
Confidence Interval 
Limit of precision for 
displays 
3 decimal places 
Date Format 
DDMMMYYYY 
6.2 Subject Disposition and Data Sets Analyzed 
Subject disposition will be listed and summarized by treatment group and overall and 
will include the number and percentage of subjects: 
• 
Screened; 
• 
Randomized; 
• 
Not randomized; 
• 
Randomized and not treated; 
• 
Treated; 
• 
Included in each study population (Safety, ITT, mITT, DXA Substudy); 
• 
Completed all study visits; 
• 
Completed all study visits on study drug; 
• 
Randomized but discontinue study drug and discontinue from all study visits and 
procedures; 
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• 
Randomized but discontinue study drug but continue with all study visits and 
procedures; and 
• 
Randomized but discontinue from the study and returned for the Week 56 weight 
measurement. 
For subjects who are not randomized, randomized subjects who discontinue study 
drug but continue in the study, and randomized subjects who discontinue study drug 
and study participation, a summary regarding reason of discontinuation will also be 
provided. 
A summary of patient enrollment by site will also be provided by treatment group 
and overall for the Safety population.   
6.3 Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design 
or procedures defined in the protocol. Protocol deviations for the study include, but 
are not limited to, the following: 
• 
Failure to meet inclusion/ exclusion criteria; 
• 
Non-compliance of protocol guidelines; 
• 
Inability to adequately complete study assessments per protocol, etc. 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol deviation. The Sponsor will determine if a protocol deviation will result in 
withdrawal of a subject. 
All protocol deviations and deviation categories will be listed and summarized for the 
Safety population. 
6.4 Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be listed and summarized by treatment 
group and overall for randomized, Safety and DXA substudy populations. Standard 
descriptive statistics will be presented for the continuous variables of: 
• 
Age at screening (years) 
• 
weight (kg) 
• 
height (cm) 
• 
body mass index (kg/m2) 
• 
Waist Circumference (cm) 
• 
Fasting insulin 
• 
Whole Body Insulin Sensitivity Index (Matsuda) 
• 
Triglycerides 
• 
HDL-C 
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• 
Systolic Blood Pressure (mmHg) 
• 
Diastolic Blood Pressure (mmHg) 
The total counts and percentages of subjects will be presented for the categorical 
variables of: 
• 
Age at screening (12-14 years, 15-16 years) 
• 
Gender 
• 
Race 
• 
Ethnicity 
• 
BMI categories ≥95th to <99th, and ≥99th percentile) 
No formal tests of statistical significance will be performed on the demographic and 
baseline data.   
Other baseline measurements, such as vital signs, ECG, will be summarized by 
treatment group with the post-baseline measurements. 
6.4.1 Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 21.3 (or a later version if updated during the study).  All medical 
history will be listed, and the number and percentage of subjects with any medical 
history will be summarized for Safety population by system organ class (SOC) and 
preferred term (PT) for each treatment group and overall.   
6.4.2 Prior and Concomitant Medications 
Medications received prior to or concomitantly with study drug treatment will be 
coded by 
 using the WHO Drug Global Dictionary, Version September 2018 
(or a later version if updated during the study), Anatomical Therapeutic Chemical 
(ATC) Classification codes.  
Medications, other than study medication, taken within 30 days prior to screening 
will be considered as prior medications; while those taken during the study will be 
considered as concomitant medications.  
If a medication cannot be classified as “prior” or “concomitant” after applying 
imputation rules for missing/incomplete dates, it will be classified as concomitant. 
Prior medications and concomitant medications will be listed and summarized 
together for Safety population. 
The number and percentage of subjects using each medication will be displayed 
together with the number and percentage of subjects using at least one medication 
within each therapeutic class (ATC-Level 2), chemical subgroup (ATC-Level 4), and 
preferred term. 
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6.5 Measurements of Treatment Compliance 
Percentage compliance is calculated as: 
100 * actual capsules taken/expected capsules taken 
Where actual capsules taken is defined as (total number of capsules dispensed – total 
number of capsules returned) and expected taken is defined as the number of 
capsules prescribed per day times the number of days taken for study treatment. 
Percentage compliance will be summarized descriptively by treatment group for the 
Safety population. 
The number and percentage of compliant subjects will be presented for the Safety 
population, where compliant is defined as percentage compliance between 80.0% 
and 120.0% inclusive. The following percentage compliance categories will also be 
presented:  
• 
<80.0% 
• 
80% to 120% 
• 
>120.0% 
6.6 Efficacy 
6.6.1 Primary Efficacy Analysis 
The primary endpoint for this study is the mean % change in BMI from baseline to 
end of study (Week 56).  
For subjects who discontinue treatment prior to trial completion, every attempt will 
be made to have them continue with clinic visits and study assessments. Particular 
attention will be given to collecting Week 56 assessments of weight and height, 
regardless of when subjects discontinued treatment. These retrieved dropouts will be 
used to impute missing data using multiple imputation method for the primary 
analysis for subjects who discontinue the study prematurely and are missing follow-
up observations. This is based on the assumption that the group that best reflects 
what happened to the non-retrieved dropouts at week 56, are the retrieved dropouts. 
For patients who terminate the treatment early but decide to stay in the study and 
have all the data after being off treatment, those data will be used to impute the 
missing data off-treatment. For any patient who terminates the treatment and study 
prematurely and permanently, if the patient has the final measurement at Week 56, 
the measurement will be used for analyses at Week 56. The missing data between 
the last available measurement and Week 56 will be imputed by interpolation for 
analyses. 
If there are no sufficient retrieved dropouts, the washout imputation method will be 
applied. This imputation method will only impute the time point at Week 56 for the 
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active treatment arms using multiple imputation regression with randomization strata 
and baseline BMI as the predictors. This approach ignores any post-baseline changes 
in the BMI values when predicting missing Week 56 values and will impute all patients 
similar to an average placebo patient. For patients in placebo arm, missing data at 
any time point will be imputed assuming MAR mechanism. The variables used as 
explanatory variables for imputation include Randomization strata and baseline BMI. 
After such imputation, comparisons in the primary endpoint of change from the 
baseline BMI between treatment groups be assessed for the ITT population using a 
mixed effects model with repeated measures (MMRM) with factors of treatment, visit, 
treatment by visit interaction, baseline BMI value, age stratification, and gender 
stratification. Appropriate contrast will be applied for treatment comparisons at Week 
56. The pairwise comparisons of interest are top-dose vs. placebo, and mid-dose vs. 
placebo, and top-dose vs. mid-dose. The primary null hypothesis will be that there is 
no treatment difference between any VI-0521 treatment groups and the placebo in 
the percent change from baseline to Week 56 in BMI. An appropriate contrast will be 
used for the comparisons at Week 56. The family-wise type 1 error for the 
comparisons will be controlled by Fisher’s protected least significant difference (LSD) 
method at the 0.05 significance level: placebo, mid-dose, and top-dose will be first 
compared for overall difference in the percent change from baseline in BMI. Once the 
overall difference is significant at the 0.05 significance level, the above 3 pairwise 
comparisons will be conducted using Fisher’s LSD method at the 0.05 significance 
levels. The order for comparisons of interest is top-dose vs. placebo, mid-dose vs. 
placebo, and top-dose vs. mid-dose. Due to the fact that only three treatments are 
compared, the above procedure strongly controls the family-wise type 1 error. 
6.6.2 Secondary Efficacy Analysis 
If both the mid- and top-dose are shown to be statistically significantly better than 
placebo for the primary endpoint using the Fisher’s LSD procedure, then the 
secondary endpoints will be tested in a stepwise way to preserve the familywise type 
1 errors.  
Starting from top-dose of VI-0521 treatment, hypothesis tests for secondary efficacy 
endpoints will be based on null hypotheses that assume no a priori differences 
between placebo and top-dose treatment. 
A closed or sequential testing procedure will be used for testing the key secondary 
efficacy variables.  With this hierarchical procedure, the key secondary efficacy 
variables will only be tested if the primary efficacy analysis is statistically significant. 
Analyses will be carried out for the key secondary variables. 
Within the key secondary variables, the statistical significance level will be adjusted 
using the Hochberg method, controlling the familywise error rate at 5%. Correlation 
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analysis will be implemented among the key secondary variables to ensure the 
conditions required for Hochberg procedure are satisfied. All endpoints have to be 
statistically significant in favor of top-dose VI-0521 treatment compared to placebo, 
after the Hochberg adjustment, in order for the next set in the hierarchy to be tested.  
The testing is only stopped when all of the alpha is ‘exhausted’.  The sequential 
testing will stop at the first endpoint set where top-dose VI-0521 treatment does not 
demonstrate statistical superiority over placebo.   
The above process will be repeated on mid-dose of VI-0521 treatment. 
Percent of subjects achieving a reduction ≥ 5% from baseline in BMI at Week 56 will 
be analyzed using a logistic regression, with treatment, age and gender stratification 
as the main effect and baseline BMI value as a covariate at the 0.05 significance 
level. The adjusted odds ratios between the top-dose and placebo, between the mid-
dose and placebo, and between the top-dose and mid-dose will be calculated together 
with their 95% confidence intervals. The p-values for the comparisons will also be 
generated.  
The percent of subjects achieving a reduction ≥ 10% and ≥ 15% from baseline in 
BMI at Week 56 will be analyzed similarly.  
Secondary efficacy endpoints that are continuous variables (change from baseline in 
waist circumference, fasting insulin, whole body insulin sensitivity index (Matsuda), 
triglycerides, HDL-C, and systolic and diastolic blood pressure) will be analyzed by a 
similar MMRM model as for the primary endpoint where the baseline BMI value will 
be replaced by the baseline value of the corresponding endpoint as a covariate.  
The above analyses will be conducted for both the ITT and mITT populations. 
6.6.3 Sensitivity Analysis 
The MMRM method used for the analysis will be applied to the mITT population with 
the observed data without imputation. The following sensitivity analyses will also be 
considered to explore the impact of missing data on the conclusion of the primary 
analysis. 
The first sensitivity analysis is using a multiple imputation method based on the 
monotonic missing pattern under the assumption of MAR. The intermittent missing 
data will be imputed using multiple imputation MCMC procedure.  
The second sensitivity analysis is also using multiple imputation, however, under the 
assumption of MNAR to explore the validity of MAR using pattern-mixture model:  
1) For subjects who discontinue study participation prior to Week 56 and do not have 
follow-up visit, the missing data will be imputed using the observed data from the 
subjects in the same arm who discontinue the study treatment but have the primary 
endpoint measurement in the follow up visit using a regression method. The 
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intermittent missing data will be imputed using multiple imputation MCMC procedure. 
An ANCOVA model using a similar mixed procedure (without the repeated measures) 
as the primary analysis will be applied to these multiple-imputed % change in BMI at 
Week 56 with treatment, baseline BMI value as a covariate, and age and gender as 
stratification factors. The results of ANCOVA analysis on the multiple imputed 
datasets will be combined and summarized.  
2) Tipping point analyses: An additional sensitivity analysis using a 2-way tipping-
point strategy will be conducted on the primary endpoint to explore the influence of 
missing data from active treatment and placebo arms on the overall conclusion from 
statistical inference. In this approach, a wide spectrum of assumptions regarding the 
magnitude of missingness (from less conservative to more conservative) is proposed 
for replacing missing data. All subjects who drop out the study will have their 
unobserved efficacy data imputed by the observed data from completers in the same 
arm using the multiple imputation method based on the monotonic missing pattern 
under the assumption of MAR with the resulting imputed values further worsened by 
an amount δ. Scenarios where dropouts on active arms have worse outcomes than 
dropouts on placebo will be included. The analysis finds a ‘tipping’ point from among 
these assumptions under which the study conclusions shift from being favorable to 
the active treatments to being unfavorable. After such a tipping point is determined, 
clinical judgment can be applied as to the plausibility of the assumptions underlying 
this tipping point. The tipping point can be identified while the result is no longer 
statistically significant. 
The third sensitivity analysis is the LOCF. For those subjects who discontinue study 
participation prior to Week 56, the last observed weight and height will be used to 
derive the change in BMI.  
Similar analyses will be performed for the primary endpoint for the mITT population. 
6.6.4 Subgroup Analysis 
BMI change will be tabulated by age and gender. Additionally, further exploratory 
subgroup analyses of the primary efficacy endpoints may include evaluation by race 
and/or other subgroups deemed medically and/or scientifically important. 
6.6.5 Exploratory Analysis 
IWQOL-Kids will be analyzed by a similar MMRM model as for the primary endpoint 
where the baseline BMI value will be replaced by the baseline value of the 
corresponding endpoint as a covariate to evaluate effects of treatment on Impact of 
Weight on Quality of Life-Kids (IWQOL-Kids) questionnaire scores. 
Change from baseline will be presented for various glycemic, lipid markers and BMI 
Z-score parameters with numerical measures using descriptive statistics. BMI Z-score 
will be calculated as [(BMI/M)L-1]/(L*S) where L, M and S values are available in 
percentile data files. 
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6.7 Safety 
All safety analyses will be done for the Safety population. Safety data will be 
summarized for all treatment groups.  
Safety will be assessed by an evaluation of adverse events (each study visit); 
laboratory parameters (screening, periodically during the study and end of study); 
electrocardiograms; physical examinations (screening, end of study); PHQ-9: 
Modified for Teens, C-SSRS, and vital signs (at each study visit). Descriptive statistics 
will be generated for the questionnaire data. 
6.7.1 CANTAB 
Cognitive testing will include CANTAB Paired Associates Learning (PAL), Pattern 
Recognition Memory (PRM) and Spatial Span (SSP) and will be collected at Screening, 
Baseline, Week 16 and Week 56 for each treatment assignment. The tasks will 
evaluate effects on episodic memory, visual pattern recognition memory and working 
memory capacity, respectively. The key outcome measures to be included in the 
analysis are described in Table 2.  
For each key CANTAB outcome measure, descriptive summary statistics (n, mean, 
median, standard deviation, minimum and maximum) for change from baseline will 
be reported for visits at Week 16 and Week 56 across all treatment groups (Placebo, 
Mid-dose and Top-dose of VI-0521) and stratification factors for age and gender. Line 
graphs of mean change from baseline to Week 16 and Week 56 by treatment groups 
and stratification factors will also be produced.  
Mixed effects models with repeated measures will be used to generate least squares 
means and standard errors for change from baseline to Weeks 16 and 56 for each 
treatment group, controlling for stratification factors age and gender and baseline 
performance for each CANTAB outcome measure. 
The standardized mean difference (effect size) between placebo and each treatment 
group will be calculated using the least squares mean change from baseline to Week 
16 and Week 56 estimates and the pooled standard deviation of change across both 
treatment and placebo groups. 
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Table 2 CANTAB Key outcome measures 
CANTAB  
Task 
Key Outcome 
Measure (code) 
Description 
Cognitive Domain 
/ Direction of Effect 
PAL  
Total Errors Adjusted  
(PALTEA)  
The number of times the subject 
chose the incorrect box for a 
stimulus on assessment problems, 
plus an adjustment for the 
estimated number of errors they 
would have made on any problems, 
attempts and recalls they did not 
reach. This measure allows you to 
compare performance on errors 
made across all subjects regardless 
of those who terminated early 
versus those completing the final 
stage of the task 
Episodic memory/ 
Lower is better  
PAL  
First Attempt Memory 
Score 
(PALFAMS)  
The number of times a subject 
chose the correct box on their first 
attempt when recalling the pattern 
locations. Calculated across all 
assessed trials 
Episodic memory/ 
Higher is better 
 
PRM 
Percent Correct 
Immediate  
(PRMPCI) 
The number of correct patterns 
selected by the subject in the 
immediate forced-choice condition, 
expressed as a percentage 
Visual pattern 
recognition memory/ 
Higher is better 
PRM 
Percent Correct Delayed 
(PRMPCD) 
The number of correct patterns 
selected by the subject in the 
delayed forced-choice condition, 
expressed as a percentage 
Visual pattern 
recognition memory/ 
Higher is better 
SSP 
Forward Span Length 
(SSPFSL) 
The longest sequence of boxes 
successfully recalled by the 
subject. Applicable to Forward 
variants only 
Working Memory 
Capacity/ 
Higher is better 
SSP 
Reverse Span Length  
(SSPRSL) 
The longest sequence of boxes 
successfully recalled by the 
subject. Applicable to Reverse 
variants only 
Working Memory 
Capacity/ 
 
 
6.7.2 PHQ-9 
The PHQ-9 questionnaire will be completed at every study visit. 
The mean change in PHQ-9 score from baseline to Week 56, along with the 
percentage of subjects with at least 1 PHQ-9 score indicative of depression of 
moderate or greater severity (PHQ-9 score of 10 or more), the percentage of subjects 
with at least 1 PHQ-9 score indicative of major depression (Kroenke), and the 
percentage of subjects with at least 1 positive answer to question 9 relating to suicidal 
ideation will be presented by treatment group. A listing of all subjects presenting with 
any of the outcomes listed above, or a PHQ-9 score of 15 or more will be provided.  
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6.7.3 C-SSRS 
For each item of the C-SSRS, counts and percentages will be presented by treatment 
group and in total summarizing the number of yes responses at each study visit. In 
addition, a composite measure will be summarized at each study visit that includes 
the following C-SSRS items: Active suicidal ideation with some intent to act without 
specific plan, Active suicidal ideal with specific plan and intent, Actual attempt, 
Engaged in non-suicidal non-injurious behavior, Interrupted attempt, Aborted 
attempt, Preparatory acts or behavior, and Suicidal behavior. The baseline 
distribution of responses to the C-SSRS will also be presented. 
6.7.4 Hand and Wrist X-Ray 
Changes of bone age from baseline to Week 56 in hand and wrist X-ray will be 
evaluated. Differences between treatment groups will be evaluated using methods 
similar to those used to evaluate other continuous variables. 
6.7.5 DXA 
In the subset of subjects treated at sites where DXA scans are being done, mean 
changes from baseline to Week 56 in bone mineral density (BMD) and bone mineral 
content (BMC)-Z scores will be evaluated. The mean change in BMD and BMC will be 
summarized descriptively as a continuous variable. 
6.7.6 Adverse Events 
All adverse events (AEs) recorded on the eCRF will be coded using the MedDRA 
dictionary Version 21.1 (or a later version if updated during the study) and classified 
as either pre-treat AEs or treatment – emergent AEs (TEAEs) as follows: 
• 
Pre-treat AEs are events that start prior to the date of first dose of study 
treatment. 
• 
TEAEs are events with start date on or after the date and time of first dose of 
study treatment and up to 28 days after date and time of last dose of study 
treatment or events with start date and time prior to the date and time of first 
dose of study treatment whose severity worsens on or after the date and time of 
first dose of study treatment.  
All AE data will be listed by treatment group.  Treatment-emergence status will be 
flagged in the listing. In addition, corresponding listings of serious AEs (SAEs), AEs 
leading to discontinuation of study treatment and AEs resulting in death will be 
produced. 
Summary tables of TEAEs by treatment group will be produced for the Safety 
population. 
The severity of all AEs is recorded as mild, moderate, or severe.  If severity is missing 
for a TEAE, it will be considered severe only in the overall category in the summary 
tables.  
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The relationship between an AE and study treatment is assessed as Related or Not 
Related by the investigator.   
An overview table will summarize the number and percentage of subjects with at 
least one of the following TEAEs, where subjects with more than one TEAE in a 
particular category are counted only once in that category: 
• 
Any TEAE  
• 
Any TEAE by severity (mild, moderate, severe) 
• 
Drug-related TEAE  
• 
TEAE leading to dose reduction 
• 
Drug-related TEAE leading to dose reduction 
• 
TEAE leading to study treatment discontinuation  
• 
Treatment-emergent SAE  
• 
Drug-related Treatment-emergent SAE  
• 
Treatment-emergent SAE leading to death; 
• 
Drug-related Treatment-emergent SAE leading to death  
• 
Treatment-emergent SAE leading to treatment discontinuation  
The number and percentage of subjects reporting each TEAE will be summarized by 
System Organ Class (SOC) and Preferred Term (PT) for the Safety population.  Tables 
will be sorted alphabetically by SOC.  PTs will be sorted by descending overall total.  
The following summaries will be produced: 
• 
TEAEs by SOC and PT 
• 
Drug-related TEAEs by SOC and PT 
• 
TEAEs by maximum severity by SOC and PT 
• 
TEAEs related to treatment by maximum severity by SOC and PT 
• 
TEAEs causing discontinuation from treatment by SOC and PT 
• 
TEAEs related to treatment causing discontinuation from treatment by SOC and 
PT 
• 
SAEs by SOC and PT 
In the above summaries, subjects with more than one AE within a particular SOC are 
counted only once for that SOC.  Similarly, subjects with more than one AE within a 
particular PT are counted only once for that PT. For summaries by maximum severity, 
subjects with multiple AEs within a particular SOC or PT will be counted under the 
category of their most severe AE within that SOC or PT.    
No statistical comparisons of AEs between treatment groups will be performed. 
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6.7.7 Laboratory Evaluations 
A summary of observed values and change from baseline will be presented for all 
laboratory parameters with numerical measures using descriptive statistics. Shift 
tables displaying low-normal-high at baseline versus low-normal-high at end of study 
in a 3-by-3 contingency table will be provided. For selected laboratory parameters, 
scatter plots of baseline versus Week 56 results, will be produced by treatment group.  
A laboratory value that is above or below normal range will be considered an 
abnormal value. For selected laboratory parameters, threshold limits of clinical 
concern will be defined as multiplicative factors of the normal ranges. The list of 
multiplicative factors for each laboratory parameter will be included in the Statistical 
Analysis Plan. The frequency and percentage of subjects with laboratory results above 
or below the normal range and threshold limits at each scheduled assessment or any 
time during the treatment will be summarized by treatment group. 
Table 3: Clinical Laboratory Tests 
 
Fasting blood chemistry 
Hematology 
Other 
• albumin 
• alkaline phosphatase 
• ALT 
• AST 
• GGT 
• bicarbonate 
• blood urea nitrogen 
• serum calcium 
• serum chloride 
• serum sodium 
• creatinine (and estimated 
creatinine clearance) 
• glucose 
• lactate dehydrogenase 
• serum phosphorus 
• serum potassium 
• total and direct bilirubin 
• total protein 
• uric acid 
• hemoglobin 
• hematocrit 
• red blood cell count 
• red blood cell indices 
• total white blood cell count 
• white blood cell differential 
(neutrophils, lymphocytes, 
monocytes, eosinophils, 
and basophils) 
• platelet count 
• thyroid stimulating hormone 
Urinalysis 
• midstream urinalysis with 
reflex microscopic evaluation 
• pregnancy test (all female 
subjects) 
Urine Drug Screen 
• cannabinoids 
• amphetamines 
• cocaine 
• barbiturates 
• benzodiazepine 
• opiates 
Lipid panel 
• total cholesterol 
• LDL-C 
• HDL-C 
• triglycerides 
Glycemic testing 
Serology 
• HbA1c 
• insulin 
• glucose 
• HBsAg 
• HCV 
• HIV 
 
All laboratory data will be reported in International System of Units (SI) and 
Conventional units.  Out-of-reference-range values will be flagged as high (H) or low 
(L) in the listings.  
For analysis purposes, values preceded by a “<” or a “>” sign (i.e. those below or 
above the limits of quantification) will be considered equal to the lower or upper limit 
of quantification, respectively. 
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For analysis by visit, analysis windowing as described in Section 5.1 will be utilized 
for each scheduled visit such that unscheduled visits will also be considered. For each 
laboratory analyte, the baseline value will be defined as last scheduled or 
unscheduled value collected prior to the first dose of treatment.   
6.7.8 Vital Signs 
The following vital signs will be listed and summarized by treatment group and visit. 
• 
Systolic and diastolic blood pressure (mmHg) 
• 
Heart rate (breaths/min) 
• 
Weight (kg) 
• 
respiration rate (breaths/min) 
• 
body temperature (°C or °F) 
Vital signs data and changes from baseline in vital signs will be summarized by visit 
using standard descriptive statistics for the Safety population.  The baseline value 
will be defined as last scheduled or unscheduled value collected prior to the first dose 
of study treatment.  For post-baseline, only data from scheduled visits will be included 
in the summary tables.  
6.7.9 Electrocardiograms 
The following quantitative ECG measurements will be listed and summarized by 
treatment group and visit for the Safety population: 
• 
heart rate (bpm) 
• 
RR interval (msec) 
• 
PR interval (msec) 
• 
QRS interval (msec) 
• 
QT interval (msec) 
An overall clinically significant Investigator assessment of ECG will be provided 
(categories “Yes”, “No”). 
6.7.10 
Physical Examination 
Abnormalities identified from physical examination are recorded in the eCRF will be 
listed. 
For each physical examination body system, the number and percentage of subjects 
with abnormalities at baseline and post-baseline will be summarized by treatment 
group for the Safety population. 
6.8 Interim Analysis 
No interim analysis is planned. 
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6.9 Data Monitoring Committee 
An 
independent 
Data 
Monitoring 
Committee 
(DMC) 
with 
multidisciplinary 
representation will be established to evaluate accumulating study data on a periodic 
basis and to assess the ongoing safety of the study for the subjects enrolled and to 
be enrolled. As a result, following each data review, the DMC will make a 
recommendation to the sponsor regarding continuation, revision, or termination of 
the study. Details related to DMC responsibilities, authorities, and procedures will be 
documented in the DMC charter, which will be finalized by the DMC prior to the first 
DMC data review meeting. 
7. Changes in Planned Analysis 
None 
8. Data Issues 
None 
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9. References 
1 
ICH. Statistical Principles for Clinical Trials, Guideline E9, 1998. Available at 
http://www.emea.eu.int/pdfs/human/ich/036396en.pdf 
2 
CPMP. Points to Consider on Missing Data. EMEA: London, 2001. Available at 
http://www.emea.eu.int/pdfs/human/ewp/177699EN.pdf 
3 
Phillips A and Haudiquet V. ICH E9 guideline “Statistical principles for clinical 
trials”: a case study. Statistics in Medicine 2003; 22:1-11 
4 
Brown D J. ICH E9 guideline “Statistical principles for clinical trials”: a case 
study. Response to A. Phillips and V. Haudiquet. Statistics in Medicine 2003; 
22:13-17 
5 
Phillips A, Ebbutt A, France L, Morgan D, Ireson M, Struthers L and Heimann 
G. Issues in applying recent CPMP “Points to Consider” and FDA guidance 
documents with biostatistical implications. Pharmaceutical Statistics 2003; 
2:241-251 
6 
Senn S. Statistical Issues in Drug Development. John Wiley & sons 
(Chichester), 1997. 
7 
Chow S-C and Liu J-P. Design and Analysis of Clinical Trials: Concepts and 
Methodologies. John Wiley & sons (New York), 1998. 
8 
Brown H and Prescott R. Applied Mixed Models in Medicine. John Wiley & sons 
(Chichester), 1999. 
9 
Fairclough D L. Design and Analysis of Quality of Life Studies in Clinical Trials. 
Chapman & Hall/CRC, 2002. 
10 
Green S, Benedetti J and Crowley J. Clinical Trials in Oncology (2nd edition). 
Chapman & Hall/CRC, 2002. 
11 
McEntegart D. Forced randomization when using interactive voice response 
systems. Applied Clinical Trials October 2003; 50-58. 
12 
CPMP. Points to Consider on Adjustment for Baseline Covaraites. EMEA: 
London, 2003 
13 
ICH. ICH E3 Guideline: Structure and Content of Clinical Study Reports 
Questions & Answers, 2012. Available at 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Eff
icacy/E3/E3_QAs_R1_Step4.pdf 
14 
Modified z-scores in the CDC growth charts 
http://www.cdc.gov/nccdphp/dnpa/growthcharts/resources/BIV-cutoffs.pdf 
15 
The PHQ Validity of a Brief Depression Severity Measure  
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1495268/pdf/jgi_01114.pdf 
 
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