Conditions: Blood Pressure
Keywords: Obesity Overweight Qsymia ABPM
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 565
Healthy volunteers: no

Brief summary:
The study is being conducted to evaluate the effect of VI-0521 (Qsymia®) on blood pressure as measured by 24-hour ambulatory blood pressure monitoring, compared to both placebo and an active control (phentermine 30 mg).

Detailed description:

Arms:
arm 1: Week 1: VI-0521 (Phentermine 3.75 mg + Topiramate 23 mg) oral capsule, once daily; Week 2: VI-0521 (Phentermine 7.5 mg + Topiramate 46 mg) oral capsule, once daily; Week 3: VI-0521 (Phentermine 11.25 mg + Topiramate 69 mg) oral capsule, once daily; Weeks 4-8: VI-0521 (Phentermine 15 mg + Topiramate 92 mg) oral capsule, once daily arm 2: Weeks 1-8: Phentermine 30mg oral capsule, once daily arm 3: Weeks 1-8: Placebo oral capsule, once daily

Interventions: intervention 1: VI-0521 intervention 2: Phentermine intervention 3: Placebo
Intervention descriptions: intervention 1: Phentermine/Topiramate Top Dose 15 mg/92 mg capsule intervention 2: Phentermine 30 mg capsule intervention 3: Inactive oral capsule

Protocol document:
Prot_000.pdf: 
Protocol Title:  Study OB-409: A Multicenter, Randomized, Double-Blind Study to 
Compare the Effects of VI-0521, Phentermine, and Placebo on Ambulatory Blood Pressure 
in Overweight or Obese Subjects 
NCT#: NCT05215418 
Document (protocol version) date: 15 October 2021 
 
 
 
 
 
 


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VIVUS LLC
CONFIDENTIAL
CLINICAL PROTOCOL
Protocol No.
OB-409
Title:
A Multicenter, Randomized, Double-Blind Study to Compare the Effects 
of VI-0521, Phentermine, and Placebo on Ambulatory Blood Pressure in 
Overweight or Obese Subjects
Study Phase:
4
US IND No.:
68,651
Version: 
Original, 9 March 2021
Amendment #1, 15 October 2021
Sponsor:
VIVUS LLC
900 East Hamilton Avenue, Suite 550
Campbell, CA 95008
Tel: (650) 934-5200
Approval Signatures:
CONFIDENTIAL
This document contains proprietary and confidential information of VIVUS LLC Acceptance of 
this document constitutes agreement by the recipient that no previously unpublished information 
contained herein will be published or disclosed without the prior written approval of VIVUS, Inc. 
with the exception that this document may be disclosed to study personnel under your supervision 
who need to know the contents for conducting the study and appropriate Institutional Review 
Boards (IRBs)/Independent Ethics Committees (IEC) under the condition that the personnel have 
agreed to keep this information confidential. The foregoing shall not apply to disclosure required 
by governmental regulations or laws, however, VIVUS LLC shall be promptly notified of any 
such disclosure.


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CONFIDENTIAL 
INVESTIGATOR AGREEMENT PAGE 
VIVUS LLC 
OB-409 
Protocol Title: A Multicenter, Randomized, Double-Blind Study to Compare the Effects of 
VI-0521, Phentermine, and Placebo on Ambulatory Blood Pressure in Overweight or 
Obese Subjects 
 
Version: Amendment #1, 15 October 2021 
 
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 to in writing. I also agree to conduct this clinical trial in compliance with all applicable 
federal, state and local regulations, International Conference on Harmonization Guidelines for 
Good Clinical Practice, and the Declaration of Helsinki, as well as with the requirements of the 
appropriate Institutional Review Board/Independent Ethics Committee and any other 
institutional requirements. 
 
Principal Investigator 
Signature: 
 
Date: 
 
Printed Name: 
 
Institution: 
 
Address: 
 
 


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CONFIDENTIAL 
1.0 
TABLE OF CONTENTS 
CLINICAL PROTOCOL ..............................................................................................................1 
INVESTIGATOR AGREEMENT PAGE ...................................................................................2 
1.0 
TABLE OF CONTENTS ..................................................................................................3 
LIST OF TABLES .........................................................................................................................5 
2.0 
PROTOCOL SYNOPSIS ..................................................................................................6 
3.0 
LIST OF ABBREVIATIONS .........................................................................................11 
4.0 
BACKGROUND ..............................................................................................................13 
4.1 
VI-0521 ..................................................................................................................13 
4.2 
Cardiovascular Risk and Blood Pressure Changes ................................................13 
5.0 
TRIAL OBJECTIVES.....................................................................................................14 
6.0 
TRIAL DESIGN...............................................................................................................14 
7.0 
STUDY ENDPOINTS ......................................................................................................15 
7.1 
Primary Endpoint ...................................................................................................15 
7.2 
Secondary Endpoints .............................................................................................15 
7.3 
Exploratory Endpoints ...........................................................................................15 
7.4 
Safety Evaluation ...................................................................................................16 
8.0 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................16 
8.1 
Inclusion Criteria ...................................................................................................16 
8.2 
Exclusion Criteria ..................................................................................................16 
8.3 
Discontinuation of Study Drug and Subject Withdrawal ......................................18 
9.0 
TREATMENT OF SUBJECTS ......................................................................................19 
9.1 
Study Treatment .....................................................................................................19 
9.2 
Allocation to Treatment .........................................................................................19 
9.3 
Breaking the Blind .................................................................................................19 
9.4 
Drug Supply ...........................................................................................................19 
9.4.1 
Formulation and Packaging ..................................................................20 
9.4.2 
Preparation and Dispensing ..................................................................20 
9.4.3 
Administration ......................................................................................20 
9.4.4 
Compliance ...........................................................................................21 
9.4.5 
Drug Storage and Drug Accountability.................................................21 
9.5 
Lifestyle Counseling Guidelines ............................................................................21 
9.6 
Concomitant Medications ......................................................................................21 
9.6.1 
Excluded Medications ...........................................................................21 
9.6.2 
Management of Blood Pressure ............................................................22 
9.6.3 
Management of Diabetes Medication ...................................................22 


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9.6.4 
Documentation of Concomitant Medication Use ..................................22 
10.0 
STUDY PROCEDURES .................................................................................................22 
10.1 
Screening (Visit 1) .................................................................................................22 
10.2 
Baseline/Randomization (Visit 2, Week 0/Beginning of Titration) ......................23 
10.3 
Week 4 (Visit 3, End of Titration) .........................................................................24 
10.4 
Week 8/End of Study or Early Termination (Visit 4) ............................................24 
11.0 
ASSESSMENTS ...............................................................................................................25 
11.1 
Weight Measurement .............................................................................................25 
11.2 
Height and BMI .....................................................................................................25 
11.3 
Vital Signs ..............................................................................................................26 
11.4 
24-hr Ambulatory Blood Pressure Monitoring (24-hr ABPM) .............................26 
11.5 
Laboratory Tests ....................................................................................................27 
11.6 
Physical Examination.............................................................................................28 
11.7 
Electrocardiograms ................................................................................................28 
12.0 
ADVERSE EVENT REPORTING ................................................................................29 
12.1 
Adverse Events ......................................................................................................29 
12.1.1 
Severity Assessment .............................................................................29 
12.1.2 
Causality Assessment ............................................................................29 
12.1.3 
Abnormal Test Findings ........................................................................30 
12.1.4 
Serious Adverse Events or Serious Suspected Adverse Reactions .......30 
12.1.5 
Definition of Hospitalization ................................................................31 
12.2 
Eliciting Adverse Event Information .....................................................................31 
12.3 
Reporting Period ....................................................................................................31 
12.4 
Reporting Requirements ........................................................................................31 
12.4.1 
Serious Adverse Event Reporting Requirements ..................................32 
12.4.2 
Non-Serious Adverse Event Reporting Requirements ..........................32 
12.4.3 
Pregnancy ..............................................................................................32 
13.0 
STATISTICAL CONSIDERATIONS ...........................................................................33 
13.1 
Statistical Analysis and Methods ...........................................................................33 
13.1.1 
Analysis of Primary Endpoint ...............................................................33 
13.1.2 
Method for Prevention and Treatment of Missing Values ....................34 
13.1.3 
Analysis of Secondary Endpoints .........................................................34 
13.1.4 
Multiplicity Adjustment to Control Family-wise Type 1 Error Rate ....34 
13.1.5 
Analysis of Exploratory Endpoints .......................................................34 
13.1.6 
Safety Analyses .....................................................................................35 
13.2 
Sample Size Determination ....................................................................................35 


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14.0 
TRIAL TERMINATION CRITERIA ...........................................................................36 
15.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION ................................36 
16.0 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................36 
17.0 
ETHICAL CONSIDERATIONS ....................................................................................37 
17.1 
Institutional Review Board /Independent Ethics Committee .................................37 
17.2 
Ethical Conduct of the Clinical Trial .....................................................................37 
17.3 
Subject Information and Consent...........................................................................37 
18.0 
DATA HANDLING AND RECORD KEEPING ..........................................................37 
18.1 
Case Report Forms/Electronic Data Record ..........................................................37 
18.2 
Record Retention ...................................................................................................38 
19.0 
PUBLICATION PLAN ...................................................................................................38 
20.0 
REFERENCES .................................................................................................................39 
APPENDIX 1: SCHEDULE OF EVENTS ................................................................................40 
APPENDIX 2: BMI CONVERSION CHART ..........................................................................41 
APPENDIX 3: SUMMARY OF CHANGES IN AMENDMENT #1 ......................................42 
 
LIST OF TABLES 
Table 1 
Dose Strengths by Titration Week .........................................................................20 
Table 2 
Clinical Laboratory Tests .......................................................................................28 
 


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2.0 
PROTOCOL SYNOPSIS 
Title of Clinical 
Trial: 
A Multicenter, Randomized, Double-Blind Study to Compare the 
Effects of VI-0521, Phentermine, and Placebo on Ambulatory Blood 
Pressure in Overweight or Obese Subjects 
Sponsor: 
VIVUS LLC (VIVUS) 
Phase of 
Development: 
4 
Trial Rationale: 
Qsymia® (known as VI-0521 in investigational studies) has been 
approved in the US since 2012 as an adjunct to a reduced-calorie diet 
and increased physical activity for chronic weight management in 
adults with an initial body mass index (BMI) of 30 kg/m2 or greater 
(obese) and 27 kg/m2 or greater (overweight) in the presence of at least 
one weight-related comorbidity such as hypertension, type 2 diabetes 
mellitus (T2DM), or dyslipidemia. 
Clinical data from the VI-0521 phase 2 and 3 studies indicate that 
VI-0521 is associated with a clinically meaningful decrease in blood 
pressure in normotensive and hypertensive subjects. Blood pressure 
changes reached their respective peaks within 4-8 weeks of treatment 
initiation and remained stable for up to one year. 
A large body of evidence indicates that blood pressure measured in an 
ambulatory blood pressure monitoring (ABPM) setting throughout the 
day has predictive value for major adverse cardiovascular events 
(MACE) over and above measurements obtained in-clinic. Although 
blood pressure measurements obtained in-clinic have been utilized in 
clinical trials demonstrating improved blood pressure control as well as 
improved outcomes, ABPM can offer a broader assessment of blood 
pressure responses. Given that blood pressure data collected to date for 
VI-0521 has been obtained only at clinic visits, assessment of changes 
in ambulatory blood pressure over a 24-hr period could provide 
additional insight into the potential implications of this treatment on 
the risk for MACE. Such blood pressure issues are particularly relevant 
given the common association of hypertension and borderline blood 
pressures in overweight and obese patients as well as the 
improvements seen in blood pressure with weight loss. The effects of 
VI-0521 would be best placed in the context of comparison to placebo, 
and to phentermine, which in addition to being a component of VI-
0521, is also commonly used alone for the short-term treatment of 
obesity. 
Trial Objectives: 
The objective of this study is to evaluate the effect of VI-0521 on 
blood pressure as measured by 24-hr ABPM, compared to both placebo 
and an active control (phentermine 30 mg). 
Trial Design: 
This randomized, double-blind, placebo and active comparator-
controlled study will be conducted at about 35 sites in the US. 


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Approximately 555 subjects will be randomized, stratified by gender, 
age, and hypertensive status, to daily treatment with top-dose VI-0521 
(phentermine and topiramate extended-release capsules 15 mg/92 mg), 
phentermine 30 mg, or placebo (185 subjects per group). Subjects will 
undergo a four-week titration period with dose increases until the 
randomized dose is reached. 
Following randomization, subjects will receive diet and exercise 
counseling on maintaining an appropriate healthy diet with a 
recommended initial caloric deficit of approximately 500 kcal per day 
and at least 30 minutes of regular physical activity on most days of the 
week. The total duration of study treatment will be 8 weeks (4 weeks 
of dose titration and 4 weeks of treatment at the assigned dose) with 
24-hr ABPM recordings performed at baseline/randomization and 
again at Week 8/end of study or early termination. Clinic visits will 
occur at Screening, Baseline (2-day outpatient visit), Week 4, and 
Week 8/end of study (2-day outpatient visit). The 24-hr ABPM data 
will be read and analyzed in a blinded manner by a central reader, 
using validated software. 
Study Population: 
Key Inclusion Criteria (see Section 8.1 for a complete list): 
• Overweight or obese adult males and females 18-75 years of 
age with a BMI ≥ 27 kg/m2; 
• 
Medical diagnosis of at least 1 weight-related comorbidity (i.e., 
hypertension, dyslipidemia, type 2 diabetes mellitus or 
prediabetes, or obstructive sleep apnea). 
Study Population: 
Key exclusions include (see Section 8.2 for a complete list): 
• Screening blood pressure of > 140/90 mmHg; 
• Type 1 diabetes; type 2 diabetes mellitus treated with insulin, 
sulfonylureas (SFUs), GLP-1 receptor agonists, SGLT 
inhibitors; or not on stable diabetic medications for at least 3 
months prior to randomization; 
• Clinically significant cardiac, hepatic, renal, pulmonary, or 
thyroid disease; 
• History of bipolar disorder, psychosis, greater than one lifetime 
episode of major depressive disorder, or presence or history of 
suicidal behavior or suicidal ideation with intent to act; 
• History of glaucoma; 
• Night shift workers; 
• Obesity of known genetic or endocrine origin; recent history of 
weight instability, or recent participation in a formal weight 
loss program within 3 months prior to screening; and 
• 
Smoking cessation within 3 months prior to screening. 


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Primary Endpoint 
Evaluation: 
The primary endpoint of the study is the change from baseline to Week 
8 in mean systolic blood pressure (SBP) as measured by 24-hr ABPM. 
Secondary Efficacy 
Endpoints: 
The secondary endpoints of the study are: 
• Change from baseline to Week 8 in mean diastolic blood pressure 
(DBP) as measured by 24-hr ABPM; 
• 
Mean change in SBP and DBP from baseline to Week 8 as 
measured in clinic. 
Exploratory 
Endpoints: 
The exploratory endpoints of the study are: 
• Mean hourly change in SBP and DBP from baseline to Week 8; 
• Change in mean daytime and nighttime SBP as measured by 24-hr 
ABPM from baseline to Week 8; 
• Change from baseline to Week 8 in nighttime “dipping” of SBP, 
and the percentage of subjects with a normal SBP “dipping” pattern 
at Week 8. A normal “dipping” pattern of SBP will be defined as a 
reduction of mean nighttime SBP of ≥ 10% relative to mean 
daytime SBP during the same 24-hr recording; 
o SBP dipping is calculated as: 100 x [(mean daytime SBP – 
mean nighttime SBP)/ mean daytime SBP] 
• Change from baseline to Week 8 in nighttime “dipping” of DBP, 
and the percentage of subjects with a normal DBP “dipping” 
pattern at Week 8. A normal “dipping” pattern of DBP will be 
defined as a reduction of mean nighttime DBP of ≥ 10% relative to 
mean daytime DBP during the same 24-hr recording. 
o DBP dipping is calculated as: 100 x [(mean daytime DBP – 
mean nighttime DBP)/ mean daytime DBP] 
For assessment of daytime and nighttime blood pressure, “night” 
will be defined as the mean of all systolic and diastolic blood 
pressure values recorded between 24:00 and 05:00 (inclusive) and 
“day” will be defined as the mean of all systolic and diastolic blood 
pressure values recorded between 07:30 and 21:30 (inclusive);  
• Change from baseline to Week 8 in mean 24-hr heart rate, mean 
daytime heart rate, mean nighttime heart rate, and mean hourly 
heart rate; 
• 
Mean percent change in body weight from baseline to Week 8. 
Safety Evaluation: 
Safety will be evaluated by analyses of adverse events, changes in 
laboratory parameters, changes in ECG, physical exam findings, vital 
signs, and requirement for rescue therapy for blood pressure and 
T2DM. 


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Statistical 
Considerations 
All analyses will be performed on the intent-to-treat (ITT) population. 
For the primary endpoint, and all other endpoints evaluating 
continuous variables, an analysis of covariance (ANCOVA) model will 
be used to evaluate between group differences in changes from 
baseline (top-dose VI-0521 vs. placebo, top-dose VI-0521 vs. 
phentermine 30 mg, and phentermine 30 mg vs. placebo) in mean 24-
hr SBP. Factors included in the model are treatment (VI-0521, 
phentermine, and placebo), gender (male; female), age (< 50; ≥ 50 
years), and hypertensive status (no medical diagnosis of or treatment 
for hypertension; medical diagnosis of hypertension treated with 0-2 
antihypertensive agents; or medical diagnosis of hypertension treated 
with 3 or more antihypertensive agents). Baseline values of the 
dependent variable will be adjusted in the model as a covariate. 
Multiple imputation method will be applied to impute missing Week 8 
measurements. Adjusted means (LS Mean ± standard error) with 
associated two-sided 95% confidence intervals for the between-
treatment comparisons and for the changes from baseline will be 
reported. 
To claim success for a non-inferiority test, the upper bound of the two-
sided 95% confidence interval for the between-treatment group 
difference (VI-0521 minus placebo or phentermine) in mean change 
from baseline in 24-hr SBP should be less than 3 mmHg. If the upper 
bound of the two-sided 95% confidence interval is less than 0 mmHg 
(i.e., p-value less than 0.05 significance level), superiority will be 
claimed. 
A hierarchical gatekeeping approach will be used to control the family-
wise type 1 error of the primary and secondary endpoints. The order of 
the hypothesis testing will be: (1) the comparison between top-dose 
VI-0521 and placebo for non-inferiority, (2) the comparison between 
top-dose VI-0521 and placebo for superiority, (3) the comparison 
between top-dose VI-0521 and phentermine for non-inferiority, and (4) 
the comparison between top-dose VI-0521 and phentermine for 
superiority. The comparison between phentermine and placebo will be 
for assay sensitivity and will not be included in the hierarchical testing 
procedure. 
If the superiority of top-dose VI-0521 versus phentermine is achieved 
for the primary endpoint, the same testing order will be applied in the 
same manner to the secondary endpoints: change from baseline to 
Week 8 in mean DBP as measured by 24-hr ABPM, and then mean 
change in SBP and DBP from baseline to Week 8 as measured in 
clinic, respectively. In this hierarchical testing procedure, only when 
testing of a given hypothesis is successful will the subsequent 
hypothesis tests will be evaluated; otherwise, the subsequent 
hypothesis tests will be considered exploratory. 


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Subgroup ABPM analyses will be performed on subjects within each 
baseline stratum for hypertensive status. All analyses will be described 
in further detail in the statistical analysis plan (SAP). 
Sample Size 
Determination: 
Approximately 555 subjects (185 per group) will be randomized to 
top-dose VI-0521, phentermine 30 mg, or placebo. Assuming a 
standard deviation of 10 mmHg for change in mean 24-hr SBP as 
measured by ABPM, the intended sample size of 185 subjects per 
treatment group will provide 80% power to detect superiority of VI-
0521 to comparator treatments (placebo or phentermine) if the 
comparator subtracted change in mean SBP has a value of less than -
3.0 mmHg, and will provide 80% power to demonstrate non-inferiority 
based on a non-inferiority margin of 3 mmHg if the comparator 
subtracted change in mean SBP is less than 0.0 mmHg. The above-
mentioned calculations were based on two-sample equal variance t-test 
at 2-sided alpha=0.05 for demonstrating superiority and at 1-sided 
alpha=0.025 for demonstrating non-inferiority. This sample size 
estimate also accounts for a 5% drop-out rate over the course of the 
study. 


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3.0 
LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition/Explanation 
ABPM 
Ambulatory blood pressure monitoring 
AE 
Adverse event 
ALT 
Alanine transaminase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate transaminase 
BMI 
Body mass index 
BP 
Blood pressure  
bpm 
Beats per minute  
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
COPD 
Chronic obstructive pulmonary disease 
CPAP 
Continuous positive airway pressure  
CRF 
Case report form 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase 
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 
hr 
Hour 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LDL-C 
Low-density lipoprotein cholesterol 


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Abbreviation or Term 
Definition/Explanation 
MACE 
Major adverse cardiovascular events 
MDRD 
Modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeters of mercury 
NYHA 
New York Heart Association 
OTC 
Over-the-counter 
PHEN 
Phentermine 
PK 
Pharmacokinetics 
QD 
Once per day 
RTSM 
Randomization and Trial Supply Management 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SGLT 
Sodium-glucose cotransporter 
SFU 
Sulfonylurea  
TPM 
Topiramate 
TSH 
Thyroid-stimulating hormone 
T2DM 
Type 2 diabetes mellitus 
ULN 
Upper limit of normal 
USA 
United States of America 
WOCBP 
Women of Childbearing Potential 
 


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4.0 
BACKGROUND 
4.1 
VI-0521 
Qsymia® (known as VI-0521 in investigational studies) has been approved in the US since 2012 
as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight 
management in adults with an initial body mass index (BMI) of 30 kg/m2 or greater (obese) and 
27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbidity such 
as hypertension, type 2 diabetes mellitus, or dyslipidemia. 
VI-0521 is a combination product for oral administration that contains VIVUS’ proprietary 
formulations of immediate-release phentermine hydrochloride beads and extended-release 
topiramate beads in a hard gelatin capsule. 
The clinical development program of VI-0521 for the treatment of obesity enrolled more than 
5,000 subjects in multiple studies, including two large pivotal studies in which over 3,500 
subjects were treated for 1 year, and an extension study in which more than 600 subjects were 
treated for up to 2 years.1 Data from these pivotal studies demonstrated that Qsymia® produces 
significant weight loss averaging approximately 10% at one year in conjunction with 
improvements in obesity-related co-morbidities such as hypertension, diabetes, and 
dyslipidemia.2,3 
Several of the most commonly observed adverse events, notably paresthesia, dry mouth, 
dysgeusia, and insomnia, are well known and characterized side effects of one or the other 
individual components and do not represent the new onset of side effects arising from the 
combined pharmacology of the two component drugs. There was no evidence of any new or 
unexpected safety issues with Qsymia® relative to phentermine or topiramate monotherapy. 
Phentermine, as a sympathomimetic agent, has been a subject of concern for possible 
cardiovascular adverse reactions such as tachycardia or elevation of blood pressure. Although 
mechanistically, these effects could be caused by an imbalance of cardiovascular autonomic 
function due to increased sympathetic nerve tone, it is likely that the selective release of 
norepinephrine within the hypothalamus with little or no dopamine or 5-hydroxytryptamine 
activity provides a rational basis for it having minimal cardiovascular effects at therapeutic 
doses.4 In a clinical trial evaluating multiple dose levels of phentermine, topiramate, and 
combinations of these agents, phentermine given at daily doses of 7.5 mg and 15 mg for 6 
months produced modest increases in heart rate compared to placebo, but no increases in systolic 
or diastolic blood pressure.5 When phentermine was given in combination with topiramate, 
increases in heart rate were still observed at the top dose level, but clinically meaningful 
decreases in both systolic and diastolic blood pressure (BP) compared to placebo were 
achieved.2,3,5,6 
4.2 
Cardiovascular Risk and Blood Pressure Changes 
The association between blood pressure and Major Adverse Cardiovascular Events (MACE) has 
been extensively evaluated, and it is now recognized that in adults of middle age or older, 
increased blood pressure is associated with an increased risk for MACE.7,8 This association, 
along with the benefits of blood pressure-lowering agents for reducing the risk of these events 
has been acknowledged in FDA guidance documents.9 Additionally, evidence indicating that 
blood pressure measured in an ambulatory setting throughout the day has predictive value for 


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MACE over and above spot measurements obtained in clinic has also been assembled.10 Given 
that blood pressure data collected to date for VI-0521 has been obtained only at clinic visits, 
typically in the morning, assessment of changes in ambulatory blood pressure over a 24-hr 
period could provide a useful insight to better understand potential implications of this treatment 
on the risk for MACE. 
5.0 
TRIAL OBJECTIVES 
The objective of this study is to evaluate the effect of VI-0521 on blood pressure as measured by 
24-hr ABPM, compared to both placebo and an active control (phentermine 30 mg). 
6.0 
TRIAL DESIGN 
This randomized, double-blind, placebo and active comparator-controlled study will be 
conducted at about 35 sites in the US. Approximately 555 eligible subjects will be randomly 
assigned with equal probability, to daily treatment with top-dose VI-0521 (phentermine and 
topiramate extended-release capsules 15 mg/92 mg), phentermine 30 mg, or placebo 
(1:1:1 ratio;185 subjects per group). Stratification factors include gender (male; female), age 
(< 50; ≥ 50 years), and hypertensive status (no medical diagnosis of or treatment for 
hypertension; medical diagnosis of hypertension treated with 0-2 antihypertensive agents; or 
medical diagnosis of hypertension treated with 3 or more antihypertensive agents). 
Subjects will undergo a four-week titration period with weekly dose increases until the 
randomized dose is reached (Section 9.4.1). 
Following randomization, subjects will receive diet and exercise counseling on maintaining an 
appropriate healthy diet with a recommended initial caloric deficit of approximately 500 kcal per 
day and at least 30 minutes of regular physical activity on most days of the week. The total 
duration of study treatment will be 8 weeks (4 weeks of dose titration and 4 weeks of treatment 
at the assigned dose) with 24-hr ABPM recordings performed at baseline/randomization and 
again at Week 8/end of study or early termination. Clinic visits will occur at Screening, Baseline 
(2-day outpatient visit), Week 4, and Week 8/end of study (2-day outpatient visit). The 24-hr 
ABPM data will be read and analyzed in a blinded manner by a central reader, using validated 
software. 
In order to minimize the potential confounding of study results by changes in other medications, 
all concomitant medications, particularly those for management of blood pressure or other 
weight-related comorbidities, will be fixed in number, dose, and frequency for the duration of the 
study unless specific “rescue” criteria are met for blood pressure (≥ 160/100 mmHg, or ≤ 100/60 
mmHg and symptoms of hypotension). Any changes in concomitant medication will be fully 
documented. 


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7.0 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
The primary endpoint of the study is the change from baseline to Week 8 in mean systolic blood 
pressure (SBP) as measured by 24-hr ABPM. 
7.2 
Secondary Endpoints 
The secondary endpoints of the study are: 
• Change from baseline to Week 8 in mean DBP as measured by 24-hr ABPM; 
• Mean change in SBP and DBP from baseline to Week 8 as measured in clinic. 
7.3 
Exploratory Endpoints 
The exploratory endpoints of the study are: 
• Mean hourly changes in SBP and DBP from baseline to Week 8, defined as the mean change 
from baseline at each hour; 
• Change in mean daytime and nighttime SBP as measured by 24-hr ABPM from baseline to 
Week 8; 
• Change from baseline to Week 8 in nighttime “dipping” of SBP, and the percentage of 
subjects with a normal SBP “dipping” pattern at Week 8. A normal “dipping” pattern of SBP 
will be defined as a reduction of mean nighttime SBP of ≥ 10% relative to mean daytime 
SBP during the same 24-hr recording; 
o SBP dipping is calculated as: 100 x [(mean daytime SBP – mean nighttime SBP)/ 
mean daytime SBP] 
• Change from baseline to Week 8 in nighttime “dipping” of DBP, and the percentage of 
subjects with a normal DBP “dipping” pattern at Week 8. A normal “dipping” pattern of 
DBP will be defined as a reduction of mean nighttime DBP of ≥ 10% relative to mean 
daytime SBP during the same 24-hr recording; 
o DBP dipping is calculated as: 100 x [(mean daytime DBP – mean nighttime DBP)/ 
mean daytime DBP] 
• Change from baseline to Week 8 in mean 24-hr heart rate, mean daytime heart rate, mean 
nighttime heart rate, and mean hourly heart rate; 
• Mean percent change in body weight from baseline to Week 8. 
For assessment of daytime and nighttime blood pressure, “night” will be defined as the mean of 
all systolic and diastolic blood pressure values recorded between 24:00 and 05:00 (inclusive) and 
“day” will be defined as the mean of all systolic and diastolic blood pressure values recorded 
between 07:30 and 21:30 (inclusive). 


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7.4 
Safety Evaluation 
Safety will be evaluated by analysis of adverse events, changes in laboratory parameters, 
changes in ECG, physical exam findings, vital signs, and requirement for rescue therapy for 
blood pressure and T2DM. 
8.0 
SELECTION AND WITHDRAWAL OF SUBJECTS 
The following eligibility criteria are intended to select subjects for whom protocol treatment is 
considered appropriate and does not subject participants to undue medical risk. All relevant 
medical and non-medical conditions should be taken into consideration when deciding whether 
this protocol is suitable for a particular subject. 
8.1 
Inclusion Criteria 
To be eligible for enrollment into this study, subjects must meet all of the following criteria at 
Screening (unless otherwise specified): 
1. 
Overweight or obese adult males and females 18-75 years of age with a BMI ≥ 27 kg/m2; 
2. 
Medical diagnosis of at least 1 weight-related comorbidity (i.e., hypertension, 
dyslipidemia, type 2 diabetes mellitus or prediabetes, or obstructive sleep apnea); 
3. 
Must be ambulatory, willing, and able to wear ABPM monitor apparatus for 24 hours 
during two study measuring visits, at Baseline and Week 8/end of study or early 
termination; 
4. 
Screening laboratory values that are within the ranges specified below: 
a. Bicarbonate 
≥ LLN 
b. AST and ALT 
< 3 x ULN 
c. HbA1c 
≤ 7.5% 
d. TSH 
≤ 1.5 x ULN 
e. Triglyceride 
≤ 400 mg/dL 
f. Creatinine clearance 
≥ 60 mL/minute (MDRD) 
5. 
Females of childbearing potential must be using adequate contraception, defined as 
double barrier methods, stable hormonal contraception plus single barrier method, or 
previously documented bilateral tubal ligation. Women are considered of childbearing 
potential unless they are ≥ 50 years of age with spontaneous amenorrhea for at least 12 
months or have had a hysterectomy and/or bilateral oophorectomy; 
6. 
Provide written informed consent; and 
7. 
Willing and able to comply with scheduled study visits, treatment plan, laboratory tests, 
and other study procedures. 
8.2 
Exclusion Criteria 
To be eligible for enrollment into this study, subjects must not meet any of the following criteria 
at screening (unless otherwise specified): 
1. 
Screening blood pressure of > 140/90 mmHg; 


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2. 
Known allergy or hypersensitivity to phentermine or topiramate, any prior use of a 
combination of phentermine and topiramate for weight loss or use of phentermine or 
topiramate for any indication within the past 3 months; 
3. 
Weight gain or loss of greater than 5 kg, use of a very low-calorie diet, or participation in 
a formal weight loss program (investigational or otherwise) within the past 3 months (this 
includes: Weight Watchers and related dietary/lifestyle intervention programs; prepared 
food programs; prescribed or over-the-counter weight loss medications; dietary 
supplement or herbal preparations, teas, or tinctures intended for weight loss; or any 
medically-supervised fast or very low calorie diet); 
4. 
Obesity of a known genetic or endocrine origin; 
5. 
Previous bariatric surgery or other non-surgical weight loss procedure; 
6. 
History of any eating disorders (e.g., bulimia, binge eating disorder) within the past year; 
7. 
History or presence of a seizure disorder; 
8. 
History of drug or alcohol abuse within the past year or positive drug test; 
9. 
Smoking cessation within the past 3 months or intent to quit during the study; 
10. Use of antihypertensive medications, antidiabetic medications, statins or other lipid 
lowering agents, or CPAP therapy that has not been stable for at least 3 months prior to 
randomization; 
11. Chronic conditions/diseases associated with a reduced ability to maintain autonomic 
regulation such as multiple sclerosis or any known autonomic neuropathy; 
12. History of glaucoma, increased intraocular pressure, or any past or present use of 
medications to treat increased intraocular pressure; 
13. Clinical evidence of hyperthyroidism, or use of thyroid hormone treatment that has not 
been stable for at least 3 months prior to randomization; 
14. Use of chronic systemic glucocorticoid therapy, or any other steroid hormone therapy 
that has not been stable for at least 3 months at the time of randomization; 
15. Any history of bipolar disorder or psychosis, greater than one lifetime episode of major 
depressive disorder, or presence or any history of suicidal behavior or suicidal ideation 
with some intent to act; any use of tricyclic antidepressants, monoamine oxidase 
inhibitors (MAOIs), lithium, levodopa, or dopamine receptor agonists; or allowed 
antidepressant use that has not been stable for at least 3 months; 
16. Need to perform strenuous manual labor or exercise while wearing the ABPM monitor 
during the 24-hr periods when those measurements are being recorded; 
17. Night shift workers who routinely sleep during the daytime and whose work hours 
include midnight to 4:00 am, or workers who are subject to assignment to different shifts 
during the study; 
18. Diagnosis of type 1 diabetes; type 2 diabetes mellitus with ongoing insulin, sulfonylureas 
(SFUs), GLP-1 receptor agonist, or SGLT inhibitor therapy; 
19. Stroke, myocardial infarction, or coronary revascularization within the past 6 months; 


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20. Presence of cardiac pacemaker or implantable defibrillator; 
21. Presence or history of clinically significant atrial fibrillation or atrial flutter, AV block > 
1st degree, ventricular ectopy, or sustained ventricular tachycardia; 
22. Unstable angina, congestive heart failure (NYHA Class III or IV), or known or suspected 
cardiac valvulopathy; 
23. Presence of asthma or COPD (chronic obstructive pulmonary disease) requiring routine 
or rescue treatment with an adrenergic bronchodilator; 
24. Any history of malignancy within the past 5 years other than surgically excised basal or 
squamous cell carcinoma of the skin or cervical cancer; 
25. Cholelithiasis within the past 6 months; 
26. Any history of nephrolithiasis; 
27. Use of any investigational medication or device for any indication within a month prior to 
randomization; 
28. COVID-19 vaccination or treatment for severe COVID-19 infection within a month prior 
to randomization; or 
29. Clinically significant renal, pulmonary, hepatic, psychiatric or other condition by history, 
physical examination or laboratory studies that, in the opinion of the investigator, would 
contraindicate the administration of study drugs, affect compliance, interfere with study 
evaluations or confound the interpretation of study results. 
8.3 
Discontinuation of Study Drug and Subject Withdrawal 
The Sponsor reserves the right to discontinue this trial at any time. The investigator must 
discontinue subjects from the study should any of the following occur: 
• 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 in which, in the 
judgment of the investigator, continued participation in the study is not in the best interest 
of the subject; 
• Pregnancy; 
• Subject elects to withdraw; 
• Requirement for other medical treatment that is excluded by the protocol; 
• Subject is unblinded by the investigator; 
• Failure of the subject to comply with protocol requirements or study related procedures; 
or 
• Termination of the clinical trial by the Sponsor or by FDA. 


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Reason(s) for subject withdrawals as well as details relevant to the subject withdrawal will be 
documented. If a subject is withdrawn from the clinical trial prior to trial completion, the subject 
will undergo all end of study procedures. 
9.0 
TREATMENT OF SUBJECTS 
9.1 
Study Treatment 
Eligible subjects will receive either top-dose VI-0521 (phentermine and topiramate extended-
release capsules 15 mg/92 mg), phentermine 30 mg capsules, or placebo capsules for daily use. 
The duration of treatment will be 8 weeks, and the total duration of participation will be a total of 
approximately 12 weeks. 
9.2 
Allocation to Treatment 
Subjects will be assigned to study treatment via an electronic data capture (EDC)/Randomization 
and Trial Supply Management (RTSM) System. Eligible subjects will be randomly assigned with 
equal probability, to daily treatment with top-dose VI-0521, phentermine 30 mg, or placebo 
(1:1:1 ratio). Randomization will be stratified by gender (male; female), age (< 50; ≥ 50 years), 
and hypertensive status (no medical diagnosis of or treatment for hypertension; medical 
diagnosis of hypertension treated with 0-2 antihypertensive agents; or medical diagnosis of 
hypertension treated with 3 or more antihypertensive agents). For hypertensive patients who are 
being treated with fixed-dose combinations, these should be counted as 2 antihypertensive 
agents. 
Sites will be pre-stocked with study drug corresponding to each treatment group. When study 
subjects qualify for randomization, site personnel will contact the EDC/RTSM through a 
designated website and provide the requested information about the study subject. The 
randomization assignment will be made, and site personnel will be instructed to dispense a 
specific titration blister card or treatment bottle corresponding to the treatment assignment to the 
study subject. Additional study drug will be shipped to sites to replace those dispensed. 
9.3 
Breaking the Blind 
Study drug must not be unblinded during the study unless it is considered necessary by the 
investigator for the management of an adverse event or other medical emergency. In the event of 
such medical emergency, the site should contact the study designated medical monitor. The 
identity of the study treatment will be obtained through the EDC/RTSM and VIVUS or designee 
will be notified of the unblinding. Any subject whose treatment assignment has been unblinded 
must be discontinued from the study. 
Investigators are also required to ensure that any potential serious adverse events (SAEs) are 
reported according to the requirements outlined in Section 12.4.1 and provide a written report to 
VIVUS or designee within 7 days to document the reason for unblinding. 
9.4 
Drug Supply 
Clinical supplies will be manufactured for VIVUS by 
 in 
accordance with current Good Manufacturing Practices. All clinical supplies will be labeled with 
information required by national regulations. 


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9.4.1 
Formulation and Packaging 
Study drug will consist of #0 elongated capsules filled with beads containing phentermine and 
topiramate extended-release, phentermine, or placebo. Doses specified for each treatment group 
will be achieved by varying the amounts of phentermine beads, topiramate beads, or placebo 
beads added to each capsule. All study treatments will be administered as a single capsule of 
medication to be taken in the morning. 
Study drug will be packaged into titration blister cards (first 4 weeks) and treatment bottles (last 
4 weeks). Each titration blister card will contain 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. Each treatment bottle 
will contain 35 capsules of study drug at the treatment dosages (top dose VI-0521, phentermine 
30 mg, or placebo). Each blister card or bottle will be labeled with the study number, a unique kit 
number, storage instructions, and spaces for the subject number and initials. 
Subjects will undergo a four-week titration period with dose increases as described below until 
the randomized dose is reached. 
Table 1 
Dose Strengths by Titration Week 
Assigned Doses of 
PHEN/TPM (mg/mg) 
N 
Titration Doses (mg/mg) of PHEN/TPM QD 
Week 1 
Week 2 
Week 3 
Week 4 
Placebo  
185 
0/0 
0/0 
0/0 
0/0 
Phentermine 30  
185 
30/0 
30/0 
30/0 
30/0 
VI-0521 Top-Dose 15/92 
185 
3.75/23 
7.5/46 
11.25/69 
15/92 
PHEN: phentermine; TPM: topiramate; QD = once per day 
9.4.2 
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. Assignment of study drug to study subjects will require the use of 
the EDC/RTSM. No other preparation of clinical supplies is required of the site staff. 
9.4.3 
Administration 
Investigators will instruct subjects to take 1 capsule of study drug every morning with or without 
food. Capsules must be taken whole, and should not be broken or split apart in any manner. 
When dispensing titration blister cards, investigators should ensure that subjects understand that 
each blister card contains a 4-week supply of study drug, 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 each bottle contains extra capsules 
that should only be taken for special circumstances (e.g. capsule is accidently dropped and 
cannot be retrieved or subject cannot return to the end of study visit within window). Study drug 
will not be dispensed until the morning of Day 2 after the ABPM device is removed following 
the baseline 24-hr recording and data has been confirmed to be compliant. 
Subjects will be instructed to withhold dosing of study drug on study visit days until after certain 
procedures are completed. 


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9.4.4 
Compliance 
Subject compliance with dosing of study drug will be assessed by counting capsules that are 
returned by subjects at each study visit. Subjects whose actual medication consumption differs 
from their expected capsule consumption should be queried by site personnel about reasons for 
not using study drug as directed, and site personnel should implement any corrective action as 
necessary. Trough blood samples will also be collected at study completion, and may be used to 
identify subjects with compliance levels that are unacceptable for inclusion in per-protocol 
analyses. 
Study drug must be dispensed and administered according to the procedures described herein. In 
accordance with applicable regulatory requirements, only subjects who are enrolled in the study 
may receive study drug, and only authorized members of the site staff may supply or administer 
the study drug. 
9.4.5 
Drug Storage and Drug Accountability 
All unused study drug must be stored in its packaging at room temperature, 15 to 25°C (59 to 
77°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 and VI-0521 are Schedule IV controlled substances. 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 
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 study drug (blister cards and the bottle, even if empty) in its 
original packaging at each study visit and sites must make an accounting of drug use by each 
subject. No study drug or packaging, used or unused, may be discarded. All packaging and used 
and unused study drug must be returned to the sponsor upon completion of the study. 
9.5 
Lifestyle Counseling Guidelines 
All randomized subjects will receive diet and exercise counseling at the baseline visit with 
support and reinforcement provided at follow-up visits. Guidelines should include advice on 
maintaining an appropriate healthy diet with a recommended initial caloric deficit of 
approximately 500 kcal per day, and at least 30 minutes of regular physical activity on most days 
of the week. On days when ABPM is attached, subjects should refrain from heavy exercise. 
9.6 
Concomitant Medications 
9.6.1 
Excluded Medications 
Use of any of the following medications during participation in this study is prohibited: 
• Tricyclic antidepressants, MAOIs, lithium, levodopa, and dopamine receptor agonists;  
• Insulin, sulfonylureas (SFUs), GLP-1 receptor agonists, SGLT inhibitors for subjects 
with type 2 diabetes mellitus; or 


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• OTC, prescription medications, herbal agents and dietary supplements used to lose body 
weight. 
9.6.2 
Management of Blood Pressure 
Concomitant medications used for management of blood pressure, must be fixed in number, 
dose, and frequency for the duration of the study unless specific “rescue” criteria are met for 
blood pressure. 
Rescue criteria are defined as: 
• Blood pressure ≥ 160/100 mmHg, or; 
• Blood pressure ≤ 100/60 mmHg, and subjects exhibiting symptoms associated with low 
blood pressure, concomitant antihypertensive medications should be withdrawn or doses 
should be reduced. 
As this study has a short (8-week) duration, and as the first post-randomization evaluation occurs 
after 4 weeks of treatment (half way through the study), if rescue criteria for blood pressure are 
met at the Week 4 visit, sites should make all reasonable efforts to keep the subject on the study, 
to continue taking study drug, and to have them return within 1-2 weeks for re-evaluation of their 
blood pressure. If rescue criteria are still met at the repeat visit, then sites should complete the 
final ABPM evaluation and end of study procedures. Once the final ABPM evaluation and end of 
study procedures have been completed, rescue therapy should be initiated, and the subject 
discontinued from the study. 
Adverse events that require initiation or modification of antihypertensive therapy are considered 
events of special interest and should be clearly documented and explained to enable narratives. 
9.6.3 
Management of Diabetes Medication 
If subjects require addition of therapy with insulin, SFUs, GLP-1 receptor agonists, or SGLT 
inhibitors during the study, investigators should discontinue these subjects from the study, 
making all reasonable attempts to collect ABPM and assessments that are scheduled to occur at 
study completion prior to stopping study drug and changing these concurrent therapies. 
9.6.4 
Documentation of Concomitant Medication Use 
All concomitant medications, including OTC products and nutritional/herbal supplements, must 
be listed on the appropriate case report form (CRF) at study entry. Any changes in concomitant 
medication use during the course of the study must also be noted on the appropriate CRF. 
10.0 
STUDY PROCEDURES 
A schedule of study activities by visit are presented in Appendix 1. For baseline and end of study 
ABPM visits, when possible, subjects should come in on the same day of the week to minimize 
within-subject variability. A detailed list of these activities is provided below. 
10.1 
Screening (Visit 1) 
A schedule of study activities by visit is presented in Appendix 1. A detailed list of these 
activities is provided below. 


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The following activities will take place at Screening (within 4 weeks of Baseline): 
• Obtain written informed consent; 
• Obtain demographics (including age, gender, race, and ethnicity) and medical history; 
• Assess inclusion/exclusion criteria; 
• Obtain body weight and 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; 
• Perform a physical examination; 
• Obtain vital signs (blood pressure, heart rate, respiration rate and temperature); 
• Record prior and concomitant medications; 
• Obtain blood sample for chemistry (full panel), hematology, lipids, HbA1c, TSH, HIV, 
HIV, and HBsAg; and urine sample for cotinine, urinalysis, and onsite urine drug screen. 
Refer to Appendix 1 and Table 2 for a listing of specific tests; 
• Perform urine pregnancy test (women of childbearing potential [WOCBP] only) and 
remind subject about contraception. If the subject is pregnant, no further screening 
procedures should be performed; 
• Perform 12-lead electrocardiogram (ECG); 
• Enter screened subject into EDC/RTSM; and 
• Schedule the Randomization visit within 4 weeks (+3 days). 
10.2 
Baseline/Randomization (Visit 2, Week 0/Beginning of Titration) 
The following activities will take place at Visit 2A (first day of 2-day visit): 
• Assess inclusion/exclusion criteria (applicable criteria referencing the baseline visit); 
• Obtain body weight; 
• Obtain vital signs (blood pressure, heart rate, respiration rate and temperature); 
• Record any adverse events reported or observed; 
• Record any changes in concomitant medications; 
• Perform a urine pregnancy test (WOCBP only) and remind subject about contraception. 
If the subject is pregnant, she will not qualify for the study; 
• Set up 24-hr ABPM monitoring equipment, and initiate monitoring; 
• Provide subject with instructions for proper handling of ABPM device and remind the 
subject to return to the clinic in 24 hours to complete evaluation. 
The following activities will take place at Visit 2B (second day of 2-day visit): 
• Record any adverse events reported or observed; 
• Record any changes in concomitant medications; 


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• End 24-hr ABPM monitoring, disconnect devices, and upload data; 
• Contact EDC/RTSM to obtain randomization assignment for subject upon verifying 
successful ABPM; if verification of successful ABPM cannot be made, repeat 24-hr 
ABPM setup as described for Visit 2A and bring subject back in 24 hours to complete 
evaluation; 
• Dispense study drug and instruct the subject to take one capsule every morning (with or 
without food) in the order indicated on the blister card (Section 9.4.3) and advise on 
lifestyle counseling. Subject should also be instructed to withhold dosing on the morning 
of the next scheduled study visit; and 
• Schedule the next study visit in 4 weeks (28 ± 3 days). 
10.3 
Week 4 (Visit 3, End of Titration) 
The following activities will take place at Week 4: 
• Obtain body weight; 
• Obtain vital signs (blood pressure, heart rate, respiration rate and temperature); 
• Record any adverse events reported or observed; 
• Record any changes in concomitant medications; 
• Collect blood sample for limited chemistry panel; 
• Perform a urine pregnancy test (WOCBP only) and remind subject about contraception. 
If the subject is pregnant, she will be withdrawn from study; 
• Administer the final dose of study drug from the previous visit, collect previously 
dispensed drug, assess treatment compliance, and perform drug accountability (do not 
administer study drug if subject has taken a dose prior to coming in for this visit, and 
instruct the subject that for the next visit, they must not take their study drug until they 
arrive at the clinic); 
• Contact EDC/RTSM to dispense study drug and instruct the subject on the proper use of 
the study drug (including withholding dosing on the morning of the next scheduled visit), 
and advise on lifestyle counseling; 
• Schedule the next study visit in 4 weeks (28 ± 3 days). 
10.4 
Week 8/End of Study or Early Termination (Visit 4) 
The following activities will take place at Visit 4A (first day of 2-day visit): 
• Obtain body weight; 
• Obtain vital signs (blood pressure, heart rate, respiration rate and temperature); 
• Collect PK blood sample for assessment of phentermine and topiramate levels (prior to 
dosing); 
• Record any adverse events reported or observed; 


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• Record any changes in concomitant medications; 
• Perform a urine pregnancy test (WOCBP only) and remind subject about contraception; 
• Set up 24-hr ABPM monitoring equipment;  
• Collect study drug from previous visit, assess treatment compliance, and perform drug 
accountability;  
• Administer last daily dose of study drug, record time of dosing, then initiate ABPM 
monitoring; and 
• Provide subject with instructions for proper handling of ABPM device and remind the 
subject to return to the clinic in 24 hours to complete study. 
The following activities will take place at Visit 4B (second day of 2-day visit): 
• Record any adverse events reported or observed (note that as described in Section 12.3 
adverse events known to the investigator and occurring within 28 days after the last dose 
of study drug must be reported); 
• Record any changes in concomitant medications; 
• Perform a physical examination; 
• End 24-hr ABPM monitoring, disconnect devices, and upload data upon verifying 
successful ABPM; if verification of successful ABPM cannot be made, repeat 24-hr 
ABPM setup as described for Visit 4A and bring subject back in 24 hours to complete 
evaluation; 
• Perform 12-lead electrocardiogram (ECG); 
• Obtain full blood chemistry, hematology, and urinalysis for laboratory testing; 
• Obtain vital signs (blood pressure, heart rate, respiration rate and temperature); and  
• Discontinue subject’s study participation.  
11.0 
ASSESSMENTS 
11.1 
Weight Measurement 
Subject’s weight will be obtained at each 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. 
11.2 
Height and BMI 
Height measurements (cm) and BMI will be determined by the site at Screening only (see BMI 
chart in Appendix 2). Height measurements should be made without shoes and should be 
recorded to the nearest centimeter. 


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If a subject does not meet the BMI criterion for inclusion into the study, no further screening 
procedures should be undertaken. 
11.3 
Vital Signs 
Vital signs (systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, 
temperature) will be assessed at Screening, Randomization, Week 4, and Week 8/end of study or 
early termination. 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 blood pressure monitor should be employed for blood 
pressure measurements. 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. 
Clinic blood pressure for determining hypertension should be the average of three successive BP 
readings, collected at least 2 minutes apart. The mean of the three values will be recorded as the 
subject’s blood pressure. 
11.4 
24-hr Ambulatory Blood Pressure Monitoring (24-hr ABPM) 
At Baseline and at Week 8/end of study or early termination, 24-hr ABPM will be performed 
non-invasively using a validated oscillometric monitor provided by a central vendor. Blood 
pressure and heart rate will be measured every 20 minutes from 6:00 to 22:00 hours, and every 
30 minutes from 22:01 to 5:59 hours for 24 consecutive hours, while subjects continue normal 
routine activities. The monitor will be attached in the morning and removed after at least 24 
hours. Data will be uploaded to a computer at the end of the recording session and prior to 
discharging the subject from the study visit, site staff will review the data to assure that: (1) at 
least 80% of the readings are valid, (2) there are at least 24 hours of data, and (3) there are no 
more than two consecutive hours of missing data. If any of these criteria are not satisfied, 
subjects will be asked to repeat the assessment for an additional 24 hours. ABPM hook up will 
be done by qualified staff. 
The accuracy of ABPM reading is highly dependent upon proper use of the equipment. Using a 
correct cuff is vital to the accuracy of monitoring data. Site staff must ensure at the Screening 
visit that the ABPM cuff size used is appropriate for the patient’s upper arm circumference, and 
the same size cuff must be used for both the screening, and end of study visits. The cuff will be 
placed on the subject’s non-dominant upper arm. Fresh batteries should be installed prior to 
hooking up the ABPM monitor. 
With reference to the ABPM operating manuals, clinical site personnel will ensure appropriate 
hook-up and safe use of the monitor by explaining the following instructions to the subjects, 
including but not limited to: 
• The importance of proper cuff fitting and data quality; 
• Wear loose fitting clothes on days when ABPM is performed; 
• Keep their arm steady during measurement; 
• Keep the cuff at heart level during measurement; 


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• Maintain normal activities between measurements; 
• Avoid swimming, showering, or bathing during monitoring; 
• The frequency of inflation and deflation as per protocol; 
• Avoid strenuous activities, or operating heavy equipment or power tools, as 
vibrations may functionally disrupt the monitor; 
• Keep the monitor attached at night; and 
• Place the monitor under a pillow or on the bed at night, making sure the hose 
connecting the cuff to the monitor is not kinked. 
Diurnal and nocturnal blood pressure variation will be assessed during the study; therefore 
subjects should be reminded to go to bed and rise about the same time during the study. 
A central 24-hr ABPM reading laboratory will perform data collection, reading, quality 
evaluation and data analyses. Software for the ABPM device will use default settings for 
exclusion of outliers (including failed inflations) from the overall averaged statistics on the final 
ABPM report for each recording. Additionally, readings that are not acceptable will contain error 
codes associated with failed inflations specifying what happened (i.e., too much movement, 
kinked hose, etc.). Data transfers will include all data, including data excluded from analyses for 
errors. Excluded data will be labeled with error codes. 
All readers will be blinded to treatment. Quality control will be monitored by the central reader. 
11.5 
Laboratory Tests 
Safety laboratory tests will be performed at a licensed, certified central testing laboratory 
approved by the Sponsor. Testing will be conducted according to the schedule of study activities 
(Appendix 1). Clinical 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. 
For WOCBP, a urine pregnancy test will be performed locally at in-clinic study visit per 
Appendix 1. 
A blood sample for trough pharmacokinetic evaluations will be collected at the end of study to 
assess treatment compliance. 
Table 2 summarizes the clinical laboratory testing for the study. 


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Table 2 
Clinical Laboratory Tests 
Hematology 
Blood Chemistry (Full) 
Urine Pregnancy Test (WOCBP; 
Done Onsite) 
• hemoglobin 
• hematocrit 
• red blood cell count 
• total white blood cell count 
• white blood cell differential 
(neutrophils, lymphocytes, 
monocytes, eosinophils, and 
basophils) 
• platelet count 
• albumin 
• alkaline phosphatase 
• ALT 
• AST 
• GGT 
• blood urea nitrogen 
• serum calcium 
• serum chloride 
• serum sodium 
• bicarbonate 
• creatinine (and estimated 
creatinine clearance) 
• glucose 
• lactate dehydrogenase 
• serum phosphorus 
• serum potassium 
• total and direct bilirubin 
• total protein 
• uric acid 
Urinalysis 
• midstream urinalysis with reflex 
microscopic evaluation 
Urine Drug Screen (Screening 
Only; Done Onsite)  
• cannabinoids 
• amphetamines 
• cocaine 
• barbiturates 
• benzodiazepine 
• opiates 
Blood Chemistry (Limited) 
• blood urea nitrogen 
• serum chloride 
• serum sodium 
• bicarbonate 
• creatinine (and estimated 
creatinine clearance) 
• glucose 
• serum potassium 
Serology (Screening only)  
• HBsAg 
• HCV 
• HIV 
Other (Screening Only) 
Lipid Panel 
• thyroid stimulating hormone 
• total cholesterol 
• triglycerides 
• LDL-C 
• HDL-C 
Glycemic Testing 
Urine Cotinine (Screening Only) 
• HbA1c 
PK Sample (End of Study Only) 
• Phentermine 
• Topiramate 
11.6 
Physical Examination 
A complete physical examination will be performed at screening, 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. 
11.7 
Electrocardiograms 
Twelve-lead ECG assessments will be performed at screening, 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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12.0 
ADVERSE EVENT REPORTING 
12.1 
Adverse Events 
Adverse events are defined as any untoward medical occurrences in subjects administered 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. 
Investigators must pursue and obtain information adequate to describe adverse events, their 
severity, 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 any adverse events meet the criteria for classification as 
an SAE (see Section 12.1.4), which requires immediate notification to VIVUS or its designated 
representative. 
12.1.1 
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 (see Section 12.1.4). 
12.1.2 
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 
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. 


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12.1.3 
Abnormal Test Findings 
Merely repeating an abnormal test, in the absence of any of the conditions described below, 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; and/or 
• Test result is considered by the investigator or Sponsor to represent a clinically 
significant finding. 
12.1.4 
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 
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. 
For this study, blood pressure values that exceed 180 mmHg (systolic) or 110 mmHg (diastolic) 
should be reported as serious adverse events. 
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. 


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12.1.5 
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 this definition. 
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, 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); and 
• 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. 
12.2 
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 scheduled in-clinic and scheduled telephone study 
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. 
12.3 
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 dose of the investigational product is 
administered. All adverse events that occur during this period and are known to the investigator 
must be reported according to the requirements outlined in Section 12.4. 
12.4 
Reporting Requirements 
All adverse events will be reported on the adverse event page of the CRF. In addition, serious 
adverse events information must also be reported on a designated section of the AE 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 


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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. 
12.4.1 
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 
SAEs. 
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 designee. 
12.4.2 
Non-Serious Adverse Event Reporting Requirements 
Non-serious adverse events meeting the reporting requirements described above (Section 12.4) 
are to be reported on the Adverse Event CRFs, which are to be submitted to VIVUS or designee. 
12.4.3 
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. 


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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. 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Statistical Analysis and Methods 
All analyses will be performed on the intent-to-treat (ITT) population (all randomized subjects 
who received at least one dose of study drug). Analyses of a per-protocol population may also be 
utilized to confirm the presence or absence of a pressor signal. Subject demographic data and 
baseline characteristics will be summarized for all subjects enrolled in the study. 
Detailed methodology for summary and statistical analyses of the data collected in this clinical 
trial will be documented in a prospectively developed Statistical Analysis Plan (SAP). This 
document may modify the plans outlined in the protocol; however, any major modifications of 
the primary endpoint 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. 
13.1.1 
Analysis of Primary Endpoint 
The primary endpoint of the study is change from baseline to Week 8 (or imputed Week 8 values 
for early termination subjects) in mean SBP obtained from 24-hr ABPM. The primary hypothesis 
is that VI-0521 does not have deleterious effects on SBP as measured by mean 24-hr ABPM in 
overweight or obese subjects. A deleterious effect of study treatment may be ruled out if the 
upper bound of the two-sided 95% confidence interval for the between-treatment comparison 
with placebo is less than 3 mmHg. This study will also attempt to demonstrate differences 
between the top-dose of VI-0521 and phentermine 30 mg with respect to changes from baseline 
to Week 8 in mean 24-hr SBP. 
The analysis of the primary endpoint will be based on the intent-to-treat (ITT) population. An 
analysis of covariance (ANCOVA) model will be used to evaluate between-group differences in 
changes from baseline (top-dose VI-0521 vs. placebo, top-dose VI-0521 vs. phentermine, and 
phentermine vs. placebo) in mean 24-hr SBP. Factors included in the model are treatment (VI 
0521, phentermine, and placebo), gender (male and female), age (< 50; ≥ 50 years), and 
hypertensive status (no medical diagnosis of or treatment for hypertension; medical diagnosis of 
hypertension treated with 0-2 antihypertensive agents; or medical diagnosis of hypertension 
treated with 3 or more antihypertensive agents). Baseline values of the dependent variable will 
be adjusted in the model as a covariate. Multiple imputation method will be applied to impute 
missing Week 8 measurements. Adjusted means (LS Mean ± standard error) with associated 
two-sided 95% confidence intervals for the between-treatment comparisons and for the changes 
from baseline will be reported. 
To claim success for a non-inferiority test, the upper bound of the two-sided 95% confidence 
interval for the between-treatment group difference (VI-0521 minus placebo or phentermine) in 
mean change from baseline in 24-hr SBP should be less than 3 mmHg. If the upper bound of the 
two-sided 95% confidence interval is less than 0 mmHg (i.e., p-value less than 0.05 significance 
level), superiority will be claimed. 


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Subgroup ABPM analyses will be performed on subjects within each baseline stratum for 
hypertensive status. Details will be described in the SAP. 
13.1.2 
Method for Prevention and Treatment of Missing Values 
For subjects who discontinue treatment prior to study completion, every attempt will be made to 
obtain end of study ABPM assessments prior to their discontinuation of treatment or initiation of 
changes to concomitant antihypertensive medications. 
Several sensitivity analyses will be considered to explore any deviations from statistical 
assumptions and the impact of missing data on the conclusion of the primary analysis. The 
details of the sensitivity analyses will be included in the SAP. 
13.1.3 
Analysis of Secondary Endpoints 
Secondary endpoints will be analyzed using the same methods as described above for the 
primary endpoints. 
The secondary endpoints will be: 
• Change from baseline to Week 8 in mean DBP as measured by 24-hr ABPM; 
• Mean change in SBP and DBP from baseline to Week 8 as measured in clinic. 
13.1.4 
Multiplicity Adjustment to Control Family-wise Type 1 Error Rate 
A hierarchical gatekeeping approach will be used to control the family-wise type 1 error of the 
primary and secondary endpoints. The order of the hypothesis testing will be: (1) the comparison 
between top-dose VI-0521 and placebo for non-inferiority, (2) the comparison between top-dose 
VI-0521 and placebo for superiority, (3) the comparison between top-dose VI-0521 and 
phentermine for non-inferiority, and (4) the comparison between top-dose VI-0521 and 
phentermine for superiority. The comparison between phentermine and placebo will be for assay 
sensitivity and will not be included in the hierarchical testing procedure. 
If the superiority of top-dose VI-0521 versus phentermine is achieved for the primary endpoint, 
the same testing order will be applied in the same manner to the secondary endpoints: change 
from baseline to Week 8 in mean DBP as measured by 24-hr ABPM, and then mean change in 
SBP and DBP from baseline to Week 8 as measured in clinic, respectively. 
In this hierarchical testing procedure, only when testing of a given hypothesis is successful will 
the subsequent hypothesis tests will be evaluated; otherwise, the subsequent hypothesis tests will 
be considered exploratory. 
13.1.5 
Analysis of Exploratory Endpoints 
Exploratory endpoints that are continuous measurements will be analyzed using the same 
methods as described above for the primary endpoint. For categorical outcomes, differences 
between treatments will be evaluated using a non-parametric method. Details will be provided in 
the SAP. 
The exploratory endpoints will be the difference between treatment groups (top-dose VI-0521 vs. 
placebo, top-dose VI-0521 vs. phentermine, and phentermine vs. placebo) in the change from 
baseline in: 


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• Mean hourly changes in SBP and DBP from baseline to Week 8, defined as the mean change 
from baseline at each hour. 
• Change in mean daytime and nighttime SBP as measured by 24-hr ABPM from baseline to 
Week 8; 
• Change from baseline to Week 8 in nighttime “dipping” of SBP, and the percentage of 
subjects with a normal SBP “dipping” pattern at Week 8. A normal “dipping” pattern of SBP 
will be defined as a nighttime reduction of mean nighttime SBP of ≥ 10% relative to mean 
daytime SBP during the same 24-hr recording. 
o SBP dipping is calculated as: 100 x [(mean daytime SBP – mean nighttime SBP)/ 
mean daytime SBP]. 
• Change from baseline to Week 8 in nighttime “dipping” of DBP, and the percentage of 
subjects with a normal DBP “dipping” pattern at Week 8. A normal “dipping” pattern of 
DBP will be defined as a nighttime reduction of mean nighttime DBP of ≥ 10% relative to 
mean daytime SBP during the same 24-hr recording. 
o DBP dipping is calculated as: 100 x [(mean daytime DBP – mean nighttime DBP)/ 
mean daytime DBP]. 
• Change from baseline to Week 8 in mean 24-hr heart rate, mean daytime heart rate, mean 
nighttime heart rate, and mean hourly heart rate; 
• Mean percent change in body weight from baseline to Week 8. 
For assessment of daytime and nighttime blood pressure, “night” will be defined as the mean of 
all systolic and diastolic blood pressure values recorded between 24:00 and 05:00 (inclusive) and 
“day” will be defined as the mean of all systolic and diastolic blood pressure values recorded 
between 07:30 and 21:30 (inclusive). 
13.1.6 
Safety Analyses 
Safety analyses will be performed on the ITT population (all randomized subjects who received 
at least one dose of study drug). 
The incidence of adverse events will be summarized. The summary will be repeated for events 
considered related to study drug and for any serious adverse events. Laboratory results and vital 
signs will be summarized by timepoint and change from baseline. Changes to physical exam and 
ECG and requirement for rescue therapy for blood pressure and T2DM will be compared across 
treatment groups. The number of subjects taking concomitant medications will be summarized 
by medication. The primary reason for any early discontinuation will be summarized. The results 
of laboratory tests will be included in the safety analysis. 
Adverse events will be coded according to MedDRA and summarized for each treatment group. 
The number and percentage of subjects experiencing adverse events in each treatment group will 
be tabulated by MedDRA system organ class and preferred term. 
13.2 
Sample Size Determination 
Approximately 555 subjects (185 per group) will be randomized to top-dose VI-0521, 
phentermine 30 mg, or placebo. Assuming a standard deviation of 10 mmHg for change in mean 


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24-hr SBP as measured by ABPM, the intended sample size of 185 subjects per treatment group 
will provide 80% power to detect superiority of VI-0521 to comparator treatments (placebo or 
phentermine) if the comparator subtracted change in mean SBP has a value of less than -3.0 
mmHg, and will provide 80% power to demonstrate non-inferiority based on a non-inferiority 
margin of 3 mmHg if the comparator subtracted change in mean SBP is less than 0.0 mmHg. The 
above-mentioned calculations were based on two-sample equal variance t-test at 2-sided 
alpha=0.05 for demonstrating superiority and at 1-sided alpha=0.025 for demonstrating non-
inferiority. This sample size estimate also accounts for a 5% drop-out rate over the course of the 
study. 
14.0 
TRIAL TERMINATION CRITERIA 
Premature termination of this clinical trial may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, or drug safety problems. In addition, VIVUS retains the right 
to discontinue this trial at any time. 
If a clinical trial is prematurely terminated or discontinued, VIVUS will promptly notify the 
investigators. After notification, the investigator must contact all participating subjects within 
2 - 3 days. As directed by VIVUS or designee, all study materials must be collected and all CRFs 
completed to the greatest extent possible. 
15.0 
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. 
16.0 
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) guidelines 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 trial-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. 


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17.0 
ETHICAL CONSIDERATIONS 
17.1 
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 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 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 or designee 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. 
17.2 
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. 
17.3 
Subject Information and Consent 
The informed consent form and any changes to the informed consent form during the course of 
the trial must be agreed to by VIVUS or designee, 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 trial 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 or designee 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. 
18.0 
DATA HANDLING AND RECORD KEEPING 
18.1 
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. 


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A CRF is required and should be completed for each 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 
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. 
18.2 
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 written 
VIVUS’ written permission before disposing of any records prior to completion of the 
required/stipulated retention period. 
19.0 
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. 


VI-0521 
 
 
15 October 2021 
Clinical Trial Protocol OB-409 
 
Page 39 of 43 
VIVUS LLC 
 
CONFIDENTIAL 
20.0 
REFERENCES 
1. Qsymia® (VI-0521) Investigator Brochure. 13 (8 Oct 2021) ed. Campbell, CA: VIVUS LLC; 
2021. 
2. Allison DB, Gadde KM, Garvey WT, et al. Controlled-Release Phentermine/Topiramate in 
Severely Obese Adults: A Randomized Controlled Trial (EQUIP). Obesity (Silver Spring) 
2011;20:330-42. 
3. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, 
phentermine plus topiramate combination on weight and associated comorbidities in 
overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. 
Lancet 2011;377:1341-52. 
4. Jordan J, Astrup A, Engeli S, Narkiewicz K, Day WW, Finer N. Cardiovascular effects of 
phentermine and topiramate: a new drug combination for the treatment of obesity. J 
Hypertens 2014. 
5. Aronne LJ, Wadden TA, Peterson C, Winslow D, Odeh S, Gadde KM. Evaluation of 
phentermine and topiramate versus phentermine/topiramate extended-release in obese adults. 
Obesity (Silver Spring) 2013;21:2163-71. 
6. Winslow DH, Bowden CH, Didonato KP, McCullough PA. A randomized, double-blind, 
placebo-controlled study of an oral, extended-release formulation of phentermine/topiramate 
for the treatment of obstructive sleep apnea in obese adults. Sleep 2012;35:1529-39. 
7. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual 
blood pressure to vascular mortality: a meta-analysis of individual data for one million adults 
in 61 prospective studies. Lancet 2002;360:1903-13. 
8. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of 
cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations 
from prospective epidemiological studies. BMJ 2009;338:b1665. 
9. Guidance for Industry Hypertension Indication: Drug Labeling for Cardiovascular Outcome 
Claims. 2011. 
10. Verdecchia P, Angeli F, Cavallini C. Ambulatory blood pressure for cardiovascular risk 
stratification. Circulation 2007;115:2091-3. 


VI-0521 
 
 
15 October 2021 
Clinical Trial Protocol OB-409 
 
Page 40 of 43 
VIVUS LLC 
 
CONFIDENTIAL 
APPENDIX 1: SCHEDULE OF EVENTS 
 
Screening 
Baseline/ 
Randomization1 
End of 
Titration 
End of Study or 
Early Termination 
Study Week  
Week -4 
Week 0 
Week 4 
Week 8 
Visit # (Window in Days) 
1 
2A2(+3) 
2B2 
3(± 3) 
4A2(± 3) 
4B2 
Informed Consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
Weight 
X 
X 
 
X 
X 
 
Height, BMI 
X 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
X 
Vital Signs 
X 
X3 
 
X 
X3 
X 
Prior/Concomitant 
Medications4 
X 
X 
X 
X 
X 
X 
Adverse Events5 
 
X 
X 
X 
X 
X 
Chemistry (Full Panel) 
X 
 
 
 
 
X 
Chemistry (Limited Panel) 
 
 
 
X 
 
 
Hematology/Lipids/HbA1c 
X 
 
 
 
 
X 
TSH 
X 
 
 
 
 
 
HIV, HCV, HBsAg 
X 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
X 
Urine Cotinine and Urine 
Drug Screen6 
X 
 
 
 
 
 
PK Trough Sample (Prior to 
Dosing) 
 
 
 
 
X 
 
Urine Pregnancy Test 
(WOCBP)6 / Contraception 
Reminder 
X 
X 
 
X 
X 
 
24-hr ABPM Recording – 
Begin 
 
X 
 
 
X 
 
24-hr ABPM Recording – 
End & Removal 
 
 
X 
 
 
X 
ABPM Device Instruction 
 
X 
 
 
X 
 
12-Lead ECG 
X 
 
 
 
 
X 
Lifestyle Counseling 
 
 
X 
X 
 
 
Contact EDC/RTSM 
X 
 
X 
X 
 
 
Randomization 
 
 
X 
 
 
 
Dispense Study Drug 
 
 
X 
X 
 
 
Study Drug Accountability 
 
 
 
X 
X 
X 
Schedule Next Visit 
X 
X 
X 
X 
X 
 
1. Baseline can occur up to 4 weeks from Screening 
2. Outpatient visits 
3. Done prior to ABPM hook up. Blood pressure should be the average of three successive BP readings, collected 
at least 2 minutes apart. The mean of the three values will be recorded as the subject’s blood pressure. 
4. Prior medications will be recorded only at Screening 
5. Through 28 days post last day of study drug 
6. Urine drug screen and urine pregnancy test will be done onsite. 


VI-0521 
 
 
15 October 2021 
Clinical Trial Protocol OB-409 
 
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VIVUS LLC 
 
CONFIDENTIAL 
APPENDIX 2: BMI CONVERSION CHART 
Weight 
(lb) 
125 
130 
135 
140 
145 
150 
155 
160 
165 
170 
175 
180 
185 
190 
195 
200 
205 
210 
215 
220 
225 
(kg) 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 
97.7 100.0 102.3 
Height 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(in) 
(cm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
58 
147.3 
26 
27 
28 
29 
30 
31 
32 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
59 
149.9 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
43 
44 
45 
46 
60 
152.4 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
61 
154.9 
24 
25 
26 
27 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
62 
157.5 
23 
24 
25 
26 
27 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
38 
39 
40 
41 
63 
160.0 
22 
23 
24 
25 
26 
27 
28 
28 
29 
30 
31 
32 
33 
34 
35 
36 
36 
37 
38 
39 
40 
64 
162.6 
22 
22 
23 
24 
25 
26 
27 
28 
28 
29 
30 
31 
32 
33 
34 
34 
35 
36 
37 
38 
39 
65 
165.1 
21 
22 
23 
23 
24 
25 
26 
27 
28 
28 
29 
30 
31 
32 
33 
33 
34 
35 
36 
37 
38 
66 
167.6 
20 
21 
22 
23 
23 
24 
25 
26 
27 
27 
28 
29 
30 
31 
32 
32 
33 
34 
35 
36 
36 
67 
170.2 
20 
20 
21 
22 
23 
24 
24 
25 
26 
27 
27 
28 
29 
30 
31 
31 
32 
33 
34 
35 
35 
68 
172.7 
19 
20 
21 
21 
22 
23 
24 
24 
25 
26 
27 
27 
28 
29 
30 
30 
31 
32 
33 
34 
34 
69 
175.3 
18 
19 
20 
21 
21 
22 
23 
24 
24 
25 
26 
27 
27 
28 
29 
30 
30 
31 
32 
33 
33 
70 
177.8 
18 
19 
19 
20 
21 
22 
22 
23 
24 
24 
25 
26 
27 
27 
28 
29 
29 
30 
31 
32 
32 
71 
180.3 
17 
18 
19 
20 
20 
21 
22 
22 
23 
24 
24 
25 
26 
27 
27 
28 
29 
29 
30 
31 
31 
72 
182.9 
17 
18 
18 
19 
20 
20 
21 
22 
22 
23 
24 
24 
25 
26 
27 
27 
28 
29 
29 
30 
31 
73 
185.4 
17 
17 
18 
19 
19 
20 
20 
21 
22 
22 
23 
24 
24 
25 
26 
26 
27 
28 
28 
29 
30 
74 
188.0 
16 
17 
17 
18 
19 
19 
20 
21 
21 
22 
23 
23 
24 
24 
25 
26 
26 
27 
28 
28 
29 
75 
190.5 
16 
16 
17 
18 
18 
19 
19 
20 
21 
21 
22 
23 
23 
24 
24 
25 
26 
26 
27 
28 
28 
76 
193.0 
15 
16 
16 
17 
18 
18 
19 
20 
20 
21 
21 
22 
23 
23 
24 
24 
25 
26 
26 
27 
27 


VI-0521 
 
 
15 October 2021 
Clinical Trial Protocol OB-409 
 
Page 42 of 43 
VIVUS LLC 
 
CONFIDENTIAL 
APPENDIX 3: SUMMARY OF CHANGES IN AMENDMENT #1 
Amendment #1 (15 October 2021) 
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 
Throughout  
Revised: VIVUS Inc. to VIVUS LLC and other administrative wording edits 
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. 
Table of Contents 
Updated Table of Contents 
Protocol Synopsis 
(Study Population Key 
Exclusions) 
Text revised: “Screening blood pressure of ≥ > 140/90 mmHg” 
Section 8.2, Exclusion 
#8 
Text added: “History of drug or alcohol abuse within the past year or positive drug 
test;” 
Section 8.2, Exclusion 
#9 
Text added: “Smoking cessation within the past 3 months or intent to quit during the 
study;” 
Section 8.2, Exclusion 
#15 
Text added: “Any history of bipolar disorder or psychosis, greater than one lifetime 
episode of major depressive disorder, or presence or any history of suicidal behavior 
or suicidal ideation with some intent to act; any use of tricyclic antidepressants, 
monoamine oxidase inhibitors (MAOIs), lithium, levodopa, or dopamine receptor 
agonists; or allowed antidepressant use that has not been stable for at least 3 
months;” 
Section 8.2, Exclusion 
#23 
Text removed: “Left ventricular ejection fraction (LVEF) ≤ 40% based on available 
medical records;” 
Section 9.6.1 Excluded 
Medications  
Text added: “Tricyclic antidepressants, MAOIs, lithium, levodopa, and dopamine 
receptor agonists;” 
Section 9.6.2 
Management of Blood 
Pressure  
Text added: “As this study has a short (8-week) duration, and as the first post-
randomization evaluation …. subject on the study, to continue taking study drug, and 
to have …. the subject discontinued from the study. 
Section 10.1 Screening 
(Visit 1) 
Text revised: “Obtain blood and urine samples for chemistry (full panel), hematology, 
lipids, HbA1c, TSH, HIV, HIV, and HBsAg; and urine sample for cotinine, 
urinalysis, and onsite urine drug screen. Refer to Appendix 1 and Table 2 for a listing 
of specific tests; 


VI-0521 
 
 
15 October 2021 
Clinical Trial Protocol OB-409 
 
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VIVUS LLC 
 
CONFIDENTIAL 
Section and/ 
or Item 
Changes Effected 
Section 10.2 
Baseline/Randomization 
Section 10.4 
Week 8/End of Study  
Text added: “Contact EDC/RTSM to obtain randomization assignment for subject 
upon verifying successful ABPM; if verification of successful ABPM cannot be made, 
repeat 24-hr ABPM setup as described for Visit 2A and bring subject back in 24 hours 
to complete evaluation; 
Section 11.5 Laboratory 
Tests, Table 2 
Text revised: “Urine Pregnancy Testing Urine pregnancy test (WOCBP; Done 
Onsite)” 
Text added: “Urine Drug Screen (Screening Only; Done Onsite)” 
Section 20.0  
Reference #1  
Text revised: “Qsymia® (VI-0521) Investigator Brochure. 132 (85 Oct 202118) ed. 
Mountain View Campbell, CA: VIVUS LLC, Inc.; 202118. 
Appendix 1: Schedule 
of Events 
Added Footnote #6 and additional texts for clarification 
 

SAP_001.pdf: 
Protocol Title:  Study OB-409: A Multicenter, Randomized, Double-Blind Study to 
Compare the Effects of VI-0521, Phentermine, and Placebo on Ambulatory Blood Pressure 
in Overweight or Obese Subjects 
NCT#: NCT05215418 
Document date: Statistical Analysis Plan dated 27 April 2023 
 
 
 
 
 
 


VIVUS LLC  
OB-409 Statistical Analysis Plan (Final, 27 April 2023) 
 
Page 1 of 31 
 
Statistical Analysis Plan 
 
Protocol OB-409 
VIVUS LLC 
 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND STUDY TO COMPARE THE 
EFFECTS OF VI-0521, PHENTERMINE, AND PLACEBO ON AMBULATORY 
BLOOD PRESSURE IN OVERWEIGHT OR OBESE SUBJECTS 
 
Phase 4 
 
Original Protocol: March 9, 2021 
Amendment 1 Protocol: October 15, 2021 
Prepared by
 
 
 
 
 
 
 
 
 
 
Version: 
Final 
Date: 
Draft 1: August 2, 2021 
 
Draft 2: June 1, 2022 
 
 
Final: April 27, 2023 


VIVUS LLC  
OB-409 Statistical Analysis Plan (Final, 27 April 2023) 
 
Page 2 of 31 
 
Statistical Analysis Plan 
 
Protocol OB-409 
VIVUS LLC 
 
 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND STUDY TO COMPARE THE 
EFFECTS OF VI-0521, PHENTERMINE, AND PLACEBO ON AMBULATORY 
BLOOD PRESSURE IN OVERWEIGHT OR OBESE SUBJECTS 
 
Phase 4 
 
 
Original Protocol: March 9, 2021 
Amendment 1 Protocol: October 15, 2021 
 
 
This Statistical Analysis Plan has been reviewed and approved by: 
 
 
 
Date 
Vivus LLC 
 
 
 



VIVUS LLC  
OB-409 Statistical Analysis Plan (Final, 27 April 2023) 
 
Page 3 of 31 
 
TABLE OF CONTENTS 
1 
INTRODUCTION ........................................................................................................................................... 7 
2 
STUDY OBJECTIVES ................................................................................................................................... 7 
3 
STUDY OVERVIEW ..................................................................................................................................... 7 
3.1 
Study Design ........................................................................................................................................ 7 
3.2 
Study Procedures .................................................................................................................................. 8 
3.3 
Randomization Schedule and Blinding Procedures ............................................................................ 11 
4 
STUDY ENDPOINTS .................................................................................................................................. 11 
4.1 
Primary Endpoint ................................................................................................................................ 11 
4.2 
Secondary Endpoints .......................................................................................................................... 11 
4.3 
Exploratory Endpoints ........................................................................................................................ 11 
4.4 
Safety Endpoints ................................................................................................................................. 13 
5 
ANALYSIS POPULATIONS ....................................................................................................................... 13 
5.1 
Enrolled Population ............................................................................................................................ 13 
5.2 
Intent-to-Treat (ITT) Population ......................................................................................................... 13 
5.3 
Safety Population ................................................................................................................................ 13 
5.4 
Per Protocol (PP) Population .............................................................................................................. 13 
6 
STUDY SUBJECTS ..................................................................................................................................... 14 
6.1 
Subject Disposition ............................................................................................................................. 14 
6.2 
Demographic and Baseline Characteristics ........................................................................................ 14 
6.3 
Medical History .................................................................................................................................. 15 
6.4 
Inclusion/Exclusion Criteria and Subject Eligibility .......................................................................... 15 
6.5 
Study Drug Exposure and Treatment Compliance ............................................................................. 15 
6.6 
Concomitant Medications ................................................................................................................... 15 
6.7 
Protocol Deviations ............................................................................................................................ 16 
7 
STATISTICAL METHODS OF ANALYSIS ............................................................................................... 16 
7.1 
General Considerations ....................................................................................................................... 16 
7.1.1 
Statistical Notation and Presentation .................................................................................... 17 
7.1.2 
Hypothesis Testing ............................................................................................................... 17 
7.1.2.1 
Multiplicity Adjustment ..................................................................................... 18 
7.1.3 
Baseline and Change from Baseline ..................................................................................... 18 
7.1.4 
Handling of Ambulatory Blood Pressure Monitoring Data .................................................. 18 
7.1.5 
Handling of Multiple Observations or Out of Window Observations .................................. 19 
7.1.6 
Handling of Missing or Partial Dates ................................................................................... 20 
7.1.7 
Handling of Missing Efficacy Data ...................................................................................... 21 
7.2 
Efficacy Analyses ............................................................................................................................... 21 
7.2.1 
Primary Efficacy Analysis .................................................................................................... 21 
7.2.1.1 
Sensitivity Analyses of Primary Endpoint .......................................................... 23 
7.2.1.2 
Supportive Analysis of Primary Endpoint .......................................................... 26 
7.2.1.3 
Subgroup Analyses of Primary Endpoint ........................................................... 26 
7.2.2 
Analyses of Secondary Endpoints ........................................................................................ 26 
7.2.3 
Analysis of Exploratory Endpoints ....................................................................................... 27 
7.2.4 
Pharmacokinetic Analyses .................................................................................................... 28 
7.3 
Safety Analyses .................................................................................................................................. 28 
7.3.1 
Adverse Events ..................................................................................................................... 28 
7.3.2 
Clinical Laboratory Evaluations ........................................................................................... 28 
7.3.3 
Vital Signs ............................................................................................................................ 30 
7.3.4 
Physical Examination ........................................................................................................... 30 
7.3.5 
Electrocardiogram Findings ................................................................................................. 30 
7.3.6 
Blood pressure and T2DM ................................................................................................... 30 
8 
POWER AND SAMPLE SIZE ..................................................................................................................... 30 
9 
STATISTICAL SOFTWARE ....................................................................................................................... 31 


VIVUS LLC  
OB-409 Statistical Analysis Plan (Final, 27 April 2023) 
 
Page 4 of 31 
 
10 REFERENCE ................................................................................................................................................ 31 
 
LIST OF TABLES 
Table 1 Dose Strengths by Titration Week ............................................................................................................. 7 
Table 2 Schedule of Events .................................................................................................................................... 9 
Table 7-1 Analysis Visit Window ........................................................................................................................ 19 
Table 7-2 Rules for Missing or Partial Dates ....................................................................................................... 20 
 
 
 
 


VIVUS LLC  
OB-409 Statistical Analysis Plan (Final, 27 April 2023) 
 
Page 5 of 31 
 
LIST OF ABBREVIATION 
 
ABPM 
Ambulatory blood pressure monitoring 
AE 
Adverse Events 
ALT 
Alanine transaminase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate transaminase 
ATC 
Anatomic therapeutic chemistry 
BMI 
Body mass index 
BP 
Blood pressure  
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CSR 
Clinical study report 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
EOS 
End of Study 
GGT 
Gamma-glutamyl transpeptidase 
HbA1c 
Hemoglobin A1c 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
Human immunodeficiency virus 
ICH 
International Conference on Harmonization 
ITT 
Intent-to-treat 
LDL-C 
Low-density lipoprotein cholesterol 
LSM 
Least square mean 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI  
Multiple imputation 
MNAR 
Missing not at random 
PHEN 
Phentermine 
PP 
Per protocol 
PR 
Pulse rate 
PT 
Preferred term 
QD 
Once per day 


VIVUS LLC  
OB-409 Statistical Analysis Plan (Final, 27 April 2023) 
 
Page 6 of 31 
 
RR 
Respiration rate 
RTSM 
Randomization and Trial Management System 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SBP 
Systolic blood pressure 
SD 
Standard Deviation 
SE 
Standard Error  
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TPM 
Topiramate 
TSH 
Thyroid-stimulating hormone 
T2DM 
Type 2 diabetes mellitus 
USA 
United States of America 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
Women of Childbearing Potential 
 
 
 


VIVUS LLC  
OB-409 Statistical Analysis Plan (Final, 27 April 2023) 
 
Page 7 of 31 
 
1 
INTRODUCTION 
This document provides a detailed description of the statistical methods and procedures to be 
implemented during the analysis of protocol OB-409. The proposed methods and approaches 
to the data analysis should be viewed as flexible. If the data suggest and warrant it, deviations 
from this plan will be considered. However, any deviations from this statistical analysis plan 
(SAP) must be substantiated by sound statistical rationale and documented in the final 
clinical study report. 
2 
STUDY OBJECTIVES 
The objective of this study is to evaluate the effect of VI-0521 on blood pressure as measured 
by 24-hr Ambulatory Blood Pressure Monitoring (ABPM), compared to both placebo and an 
active control (phentermine 30 mg). 
3 
STUDY OVERVIEW 
3.1 
Study Design 
This randomized, double-blind, placebo and active comparator-controlled study will be 
conducted at about 35 sites in the US. Approximately 555 eligible subjects will be randomly 
assigned with equal probability, to daily treatment with top-dose VI-0521 (phentermine and 
topiramate extended-release capsules 15 mg/92 mg), phentermine 30 mg, or placebo (1:1:1 
ratio; 185 subjects per group). Stratification factors include sex (male; female), age (< 50; ≥ 
50 years), and hypertensive status (no medical diagnosis of or treatment for hypertension; 
medical diagnosis of hypertension treated with 0-2 antihypertensive agents; or medical 
diagnosis of hypertension treated with 3 or more antihypertensive agents). The duration of 
treatment will be 8 weeks, and the total duration of participation will be a total of 
approximately 12 weeks. Subjects will undergo a 4-week titration period using blister cards 
with dose increases as described in Table 1 until the randomized dose is reached.  
Table 1 Dose Strengths by Titration Week 
Assigned Doses of PHEN/TPM 
(mg/mg) 
N 
Titration Doses (mg/mg) of PHEN/TPM QD 
Week 1 
Week 2 
Week 3 
Week 4 
Placebo  
185 
0/0 
0/0 
0/0 
0/0 
Phentermine 30  
185 
30/0 
30/0 
30/0 
30/0 
VI-0521 Top-Dose 15/92 
185 
3.75/23 
7.5/46 
11.25/69 
15/92 
PHEN = phentermine; TPM = topiramate; QD = daily 
 


VIVUS LLC  
OB-409 Statistical Analysis Plan (Final, 27 April 2023) 
 
Page 8 of 31 
 
3.2 
Study Procedures  
A schedule of study activities is presented in Table 2. Following randomization, subjects will 
receive diet and exercise counseling on maintaining an appropriate healthy diet with a 
recommended initial caloric deficit of approximately 500 kcal per day and at least 30 minutes 
of regular physical activity on most days of the week. The total duration of study treatment 
will be 8 weeks (4 weeks of dose titration and 4 weeks of treatment at the assigned dose) 
with 24-hr ABPM recordings performed at Baseline/Randomization and again at Week 
8/End of Study or Early Termination. Clinic visits will occur at Screening, 
Baseline/Randomization (2-day outpatient visit), Week 4, and Week 8/End of Study or Early 
Termination (2-day outpatient visit). The 24-hr ABPM data will be collected and transferred 
to the data management/biostatics vendor for analysis in a blinded manner prior to study 
unblinding, using validated software. 
In order to minimize the potential confounding of study results by changes in other 
medications, all concomitant medications, particularly those for management of blood 
pressure or other weight-related comorbidities, will be fixed in number, dose, and frequency 
for the duration of the study unless specific “rescue” criteria are met for blood pressure (≥ 
160/100 mmHg, or ≤ 100/60 mmHg and symptoms of hypotension). Any changes in 
concomitant medication will be fully documented. 
 
 


VIVUS LLC  
OB-409 Statistical Analysis Plan (Final, 27 April 2023) 
 
Page 9 of 31 
 
Table 2 Schedule of Events 
 
Screening  
Baseline/ 
Randomization1 
End of 
Titration  
End of Study or  
Early Termination  
Study Week 
Week -4 
Week 0 
Week 4 
Week 8 
Visit # (window in days) 
1 
2A2 (+3) 
2B2 
3(± 3) 
4A2(± 3) 
4B2 
Informed Consent 
X 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
Weight 
X 
X 
 
X 
X 
 
Height, BMI 
X 
 
 
 
 
 
Physical Exam  
X 
 
 
 
 
X 
Vital Signs 
X 
X3 
 
X 
X3 
X 
Prior/Concomitant 
Medications4 
X 
X 
X 
X 
X 
X 
Adverse Events5 
 
X 
X 
X 
X 
X 
Chemistry (Full Panel) 
X 
 
 
 
 
X 
Chemistry (Limited Panel) 
 
 
 
X 
 
 
Hematology/Lipids/HbA1c 
X 
 
 
 
 
X 
TSH 
X 
 
 
 
 
 
HIV, HCV, HBsAg 
X 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
X 
Urine Cotinine and Urine Drug 
Screen 
X 
 
 
 
 
 
PK trough sample (prior to 
dosing) 
 
 
 
 
X 
 
Urine pregnancy (WOCBP) / 
Contraception Reminder 
X 
X 
 
X 
X 
 


VIVUS LLC  
OB-409 Statistical Analysis Plan (Final, 27 April 2023) 
 
Page 10 of 31 
 
24-hr ABPM Recording - 
Begin  
 
X 
 
 
X 
 
24-hr ABPM Recording – End 
& Removal 
 
 
X 
 
 
X 
ABPM Device Instruction 
 
X 
 
 
X 
 
12-Lead ECG 
X 
 
 
 
 
X 
Lifestyle counseling  
 
 
X 
X 
 
 
Contact RTSM 
X 
 
X 
X 
 
 
Randomization 
 
 
X 
 
 
 
Dispense Study Drug 
 
 
X 
X 
 
 
Study Drug Accountability  
 
 
 
X 
X 
X 
Schedule Next Visit  
X 
X 
X 
X 
X 
 
1. Baseline can occur up to 4 weeks from Screening  
2. Outpatient visits  
3. Done prior to ABPM hook up. Blood pressure should be the average of three successive BP readings, collected at least 2 minutes apart. The 
mean of the three values will be recorded as the subject’s blood pressure.  
4. Prior medications will be recorded only at Screening  
5. Through 28 days post last day of study drug 
 


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3.3 
Randomization Schedule and Blinding Procedures 
Eligible subjects will be randomly assigned with equal probability, to daily treatment with 
top-dose VI-0521, phentermine 30 mg, or placebo (1:1:1 ratio). Subjects will be assigned to 
study treatment via a Randomization and Trial Supply Management (RTSM) system. 
Randomization will be stratified by sex (male; female), age (< 50; ≥ 50 years), and 
hypertensive status (no medical diagnosis of or treatment for hypertension; medical diagnosis 
of hypertension treated with 0-2 antihypertensive agents; or medical diagnosis of 
hypertension treated with 3 or more antihypertensive agents). For hypertensive patients who 
are being treated with fixed-dose combinations, these will be counted as 2 antihypertensive 
agents. Both the subject and the study site will be blinded as to subject randomization. 
Study drug will not be unblinded during the study unless it is considered necessary by the 
investigator for the management of an adverse event or other medical emergency. In the 
event of such medical emergency, the site will contact the study designated medical monitor. 
The identity of the study treatment will be obtained through the RTSM and VIVUS or 
designee will be notified of the unblinding. Any subject whose treatment assignment has 
been unblinded must be discontinued from the study. 
4 
STUDY ENDPOINTS 
4.1 
Primary Endpoint 
The primary endpoint of the study is the change from baseline to Week 8 in mean systolic 
blood pressure (SBP) as measured by 24-hr ABPM. 
4.2 
Secondary Endpoints 
The secondary endpoints of the study are: 
• 
Change from baseline to Week 8 in mean diastolic blood pressure (DBP) as measured 
by 24-hr ABPM; 
• 
Mean change in SBP and DBP from baseline to Week 8 as measured in clinic. 
4.3 
Exploratory Endpoints 
The exploratory endpoints of the study are: 
x Mean hourly changes in SBP and DBP from baseline to Week 8, defined as the mean 
change from baseline at each hour; 
x Change in mean daytime and nighttime SBP as measured by 24-hr ABPM from 
baseline to Week 8; 


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x Change from baseline to Week 8 in nighttime “dipping” of SBP, and the percentage 
of subjects with a normal SBP “dipping” pattern at Week 8. A normal “dipping” 
pattern of SBP will be defined as a reduction of mean nighttime SBP of ≥ 10% 
relative to mean daytime SBP during the same 24-hr recording; 
o SBP dipping is calculated as: 100 x [(mean daytime SBP – mean nighttime 
SBP)/ mean daytime SBP] 
x Change from baseline to Week 8 in nighttime “dipping” of DBP, and the percentage 
of subjects with a normal DBP “dipping” pattern at Week 8. A normal “dipping” 
pattern of DBP will be defined as a reduction of mean nighttime DBP of ≥ 10% 
relative to mean daytime SBP during the same 24-hr recording; 
o DBP dipping is calculated as: 100 x [(mean daytime DBP – mean nighttime 
DBP)/ mean daytime DBP] 
x Percentage of subjects meeting the following BP thresholds at baseline and Week 8 as 
measured by 24-hr ABPM; 
o SBP: ≥ 160 mmHg for 2 consecutive readings; ≥ 180 mmHg for 2 consecutive 
readings;  
o DBP: ≥ 100 mmHg for 2 consecutive readings; ≥ 110 mmHg for 2 
consecutive readings; 
x Percentage of subjects with the average of three successive BP meeting the following 
thresholds at baseline and each post-baseline visit as measured in clinic; 
o SBP: ≥ 160 mmHg; ≥ 180 mmHg; ≥ 20 mmHg increase from baseline; 
o DBP: ≥ 100 mmHg; ≥ 110 mmHg; ≥ 15 mmHg increase from baseline; 
x Change from baseline to Week 8 in mean 24-hr heart rate, mean daytime heart rate, 
mean nighttime heart rate, and mean hourly heart rate; 
x Percentage of subjects meeting the following heart rate thresholds at baseline and 
Week 8 as measured by 24-hr ABPM; 
o > 100 bpm for 2 consecutive readings; > 100 bpm for at least 1 hour; > 100 
bpm for at least 2 hours; > 100 bpm for at least 3 hours; > 100 bpm for at least 
4 hours; mean daytime heart rate > 100 bpm; 
x Percentage of subjects meeting the following heart rate thresholds at baseline and 
each post-baseline visit as measured in clinic; 
o > 100 bpm; 
o ≥ 10 bpm increase from baseline; ≥ 20 bpm increase from baseline 
o ≥ 80 bpm at baseline and ≥ 10 bpm increase from baseline; ≥ 90 bpm at 
baseline and ≥ 10 bpm increase from baseline; ≥ 100 bpm at baseline and ≥ 10 
bpm increase from baseline; 
x Mean percent change in body weight from baseline to Week 8. 


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4.4 
Safety Endpoints 
The safety endpoints include evaluation of the following: 
x Adverse events (AEs) 
x Changes in laboratory parameters 
x Changes in Electrocardiograms (ECG) 
x Physical exam findings 
x Vital signs 
x Requirement for rescue therapy for blood pressure and type 2 diabetes mellitus 
(T2DM) 
5 
ANALYSIS POPULATIONS 
The following analysis populations will be defined for study summaries and analyses.   
5.1 
Enrolled Population 
Enrolled Population will be comprised of all enrolled subjects (non-screen failures), 
regardless of randomization. The Enrolled Population will be used for by-subject listings 
when appropriate.  
5.2 
Intent-to-Treat (ITT) Population 
ITT Population will be comprised of all randomized subjects who received at least one dose of 
study drug. Subjects will be analyzed according to the treatment group they are allocated to 
by randomization, regardless of early dropout or being exposed to wrong study medication. 
The ITT population will be used for summaries of subject disposition, demographic and 
baseline subject characteristics, medical history, concomitant medication, protocol deviations 
and efficacy evaluations. 
5.3 
Safety Population 
Safety Population will be comprised of all randomized subjects who received at least one 
dose of study drug. Subjects will be analyzed according to the treatment received. The Safety 
Population will be used for safety evaluations. 
5.4 
Per Protocol (PP) Population 
PP Population will be comprised of ITT subjects who met all of the following criteria:  


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x Compliant to study treatment (defined as ≥ 80% treatment compliance as specified in 
Section 6.5); 
x Last daily dose of study drug administered on the same date that ABPM was initiated 
at Visit 4A (first day of Week 8/End of Study or Early Termination); 
x Had at least 23.5 hours of ABPM data (i.e. blood pressure and heart rate data) at 
baseline and at Week 8/End of Study or Early Termination, and at least 75% of 24-hr 
ABPM readings (or equivalently 48 readings during the 24-hr period) are not missing; 
x Subjects with any major protocol deviation that had impact on ABPM readings will 
be excluded from the PP Population.  
The PP population will be used to assess the primary and secondary endpoints as primary 
analyses. Subject inclusion in the PP population will be determined and documented prior to 
database lock and treatment unblinding. 
6 
STUDY SUBJECTS 
6.1 
Subject Disposition 
Counts and percentages of subjects who were screened, enrolled, randomized, randomized 
and not treated, completed or were discontinued from the study, as well as the reason for 
discontinuation, will be summarized by treatment group.  
6.2 
Demographic and Baseline Characteristics 
Demographic and baseline characteristic data, including but not limited to, age, sex, race, 
ethnicity, hypertensive status, SBP, DBP, diabetic status (Yes/No for T2DM), height, weight, 
and body mass index (BMI) will be summarized by treatment group for subjects in the ITT 
population. 
If a subject meets one of the following criteria, the subject will be counted as “Yes” for 
T2DM: 
x Has a medical history of T2DM 
x Uses concomitant antidiabetic medications (see Section 6.6 for concomitant 
medications) 
x Has baseline lab fasting glucose ≥126 mg/dL (see Section 7.1.3 for the definition of 
baseline) 


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6.3 
Medical History  
Medical history will be listed and summarized descriptively with count and percentage by 
coded term and treatment group for the ITT population. Coded terms will be defined using a 
current version of the Medical Dictionary for Regulatory Activities (MedDRA).  
6.4 
Inclusion/Exclusion Criteria and Subject Eligibility 
Subject eligibility, e.g., inclusion and exclusion criteria failures will be listed for all screened 
subjects. 
6.5 
Study Drug Exposure and Treatment Compliance 
The extent of exposure to study drug will be presented by duration of treatment and will be 
summarized with descriptive statistics by treatment group. Duration of exposure (in days) 
will be defined as (last dose date – first dose date + 1).  
Treatment compliance, e.g., based on difference between actual capsule consumption and the 
expected capsule consumption of subjects, will be summarized by treatment group for the 
ITT population. Percent study drug compliance for the overall treatment period is calculated 
as: 100 × [(total number of capsules consumed)/(planned number of capsules the subject 
should have consumed while still actively enrolled)]. The total number of capsules consumed 
will be calculated from the total capsules dispensed minus unused capsules returned for each 
subject.  
Study drug exposure and accountability will be presented in listings. 
6.6 
Concomitant Medications 
The latest World Health Organization Drug Dictionary (WHO-DD) will be used to categorize 
verbatim descriptions of non-study medications into the Anatomic Therapeutic Chemistry 
(ATC) classification system. Each verbatim name will be classified by anatomical main 
group (ATC level 1), therapeutic subgroup (ATC level 2), pharmacological subgroup (ATC 
level 3), chemical subgroup (ATC level 4), preferred term, and trade name (if appropriate). 
Concomitant medications are referred to non-study medications that have been used on or 
after receiving the first randomized study medication. Medications will be categorized into 3 
types: 
Pre-treatment medications: any non-study medications that started and stopped prior to 
receiving the first randomized study dose. 
Prior concomitant medications: any non-study medications taken before the first randomized 
study dose date and continued beyond the first randomized study dose date. 


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New concomitant medications: any new non-study medications that started on or after 
receiving the first randomized study medication. 
Counts and percentages of subjects receiving concomitant medications, prior concomitant 
medications, and new concomitant medications will be summarized by treatment group and 
ATC classification level 4 and preferred term for the ITT population. Additionally, 
concomitant medications used for management of blood pressure or diabetes, if any, will be 
summarized separately. 
Pre-treatment medications will be provided in a listing.  
6.7 
Protocol Deviations 
Protocol deviations may include deviations from informed consent, study procedure, study 
medication administration, study restrictions, etc. All protocol deviations will be reviewed by 
clinical and statistical personnel to identify major deviations (those anticipated to have an 
impact on efficacy or safety findings) prior to database lock and unblinding. The ICH 
guideline on protocol deviation classification will be followed. The major protocol deviations 
will be used as one of the criteria to determine the subject’s eligibility for inclusion in the PP 
population. Major protocol deviations will be summarized by treatment group and deviation 
category for the ITT population. All protocol deviations will be presented in a listing.   
7 
STATISTICAL METHODS OF ANALYSIS 
7.1 
General Considerations 
Efficacy data will be summarized “as-randomized,” meaning the subjects will be summarized 
under the treatment they were randomized to, regardless of what treatment was actually 
received. The PP population will be the primary analysis population for all efficacy analyses 
while the ITT population will be used to support efficacy analyses, if appropriate. The Safety 
Population will be the primary analysis population for all safety analyses.  
Estimand and its estimator(s) and estimate(s) for primary and secondary efficacy endpoints 
will be defined, where inferential statistical comparison and hypothesis testing related to a 
treatment effect are of interest. When analyzing the efficacy endpoints, effort will be made to 
distinguish intercurrent events from non-informative withdrawals, as well as applying 
various sensitivity analyses to assess the robustness of the estimate(s) for the pre-specified 
estimands. Details on estimands, estimators, estimates, and intercurrent events are discussed 
in individual endpoint analysis section. 


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7.1.1 
Statistical Notation and Presentation 
For descriptive statistical summaries, the sample size (n), mean, standard deviation (SD), 
standard error (SE), median, minimum and maximum will be calculated for continuous 
variables. For categorical variables, frequency and percentage in each category will be 
provided. Inferential statistical analyses will be performed using either parametric method 
(e.g., assessing continuous variables) or non-parametric method (e.g., assessing categorical 
variables). All tabulations of analysis results will include summaries for the three treatment 
groups: VI-0521 PHEN 15 mg/TPM 92 mg, Phentermine 30mg and Placebo. 
Minimum and maximum values will be rounded to the precision of the original value. Means 
and medians will be rounded to one decimal place greater than the precision of the original 
value. SDs, SEs, and 95% confidence intervals (CIs) will be rounded to two decimal places 
greater than the precision of the original value. Percentages for summarizing categorical data 
will be rounded to one decimal place. P-values, if needed, will be presented with 4 decimal 
places and values less than 0.0001 will be presented as <0.0001. 
The by-subject listings, including data at scheduled and unscheduled visits, will be sorted by 
treatment group, subject number, and then by date/time of the records. 
7.1.2 
Hypothesis Testing  
All hypothesis testing will be based on two-sided test at a significance level of 0.05. The 
primary hypothesis is that VI-0521 does not have deleterious effect on SBP as measured by 
mean 24-hr ABPM in overweight or obese subjects compared to placebo.  
For non-inferiority tests, the null hypothesis (H0) to be tested is that the upper bound of the 
two-sided 95% confidence interval for the between-treatment group difference (VI-0521 
minus placebo or phentermine) in change from baseline in 24-hr mean SBP is equal to or 
more than 3 mmHg. The alternative hypothesis (Ha) is that the upper bound of the two-sided 
95% confidence interval for the between-treatment comparison with placebo (or 
phentermine) is less than 3 mmHg. Thus: 
H0: ∆U ≥ 3 mmHg  
Ha: ∆U < 3 mmHg 
For superiority tests, the null hypothesis (H0) to be tested is that the upper bound of the two-
sided 95% confidence interval for the between-treatment group difference (VI-0521 minus 
placebo or phentermine) in change from baseline in 24-hr mean SBP is equal to or more than 
0 mmHg. The alternative hypothesis (Ha) is that the upper bound of the two-sided 95% 
confidence interval for the between-treatment comparison with placebo (or phentermine) is 
less than 0 mmHg. Thus: 
H0: ∆U ≥ 0 mmHg  
Ha: ∆U < 0 mmHg 


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7.1.2.1 
Multiplicity Adjustment 
This study is designed to maintain an overall study-wise type I error rate of α=0.05. A 
hierarchical gatekeeping approach will be used to control the family-wise type 1 error of the 
primary and secondary endpoints. The order of the hypothesis testing will be:  
(1) The comparison between VI-0521 and placebo for non-inferiority,  
(2) The comparison between VI-0521 and phentermine for non-inferiority,  
(3) The comparison between VI-0521 and placebo for superiority, and  
(4) The comparison between VI-0521 and phentermine for superiority. 
If the superiority of top-dose VI-0521 versus phentermine is achieved for the primary 
endpoint, the same testing order and hypothesis tests will be applied to the secondary 
endpoints: change from baseline to Week 8 in mean DBP as measured by 24-hr ABPM, and 
then mean change in SBP and DBP from baseline to Week 8 as measured in clinic, 
respectively. 
In this hierarchical testing procedure, only when testing of a given hypothesis is successful, 
the subsequent hypothesis tests will be evaluated; otherwise, the subsequent hypothesis tests 
will be considered exploratory. 
7.1.3 
Baseline and Change from Baseline 
In general, the baseline value for each variable is defined as the last non-missing observation 
obtained prior to the dispense of the first study drug. The actual first randomized dose 
date/time will be compared to the date/time of data collection to define the baseline for each 
parameter. In the case where the last non-missing measurement (except AE and concomitant 
medications) and the first dose coincide at the same time, or the same date if time of the 
measurement is not collected, that measurement will be considered as baseline value. The 
change from baseline value is defined as post-baseline value minus baseline value.  The 
percent change from baseline value is defined as (post-baseline value minus baseline value) / 
baseline value × 100. 
7.1.4 
Handling of Ambulatory Blood Pressure Monitoring Data  
For the 24-hr ABPM, blood pressure and heart rate will be measured every 20 minutes from 
6:00 to 22:00 hours, and every 30 minutes from 22:01 to 5:59 hours for 24 consecutive hours. 
The baseline and post-baseline values for mean ABPM (SBP and DBP) will be calculated by 
taking the average of ABPM measurements over the given 24-hr time period. 
For assessment of daytime and nighttime blood pressure, “night” will be defined as the mean 
of all systolic or diastolic blood pressure values recorded between 24:00 and 05:00 
(inclusive) and “day” will be defined as the mean of all systolic or diastolic blood pressure 
values recorded between 07:30 and 21:30 (inclusive).  


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Mean hourly changes in blood pressure and heart rate will be calculated by taking the 
average of ABPM measurements available at each hour and calculating the change from 
baseline of the average. The measurements taken in the 60 minute duration prior to each hour 
will be used to get the average value. For example, the average of blood pressure 
measurements taken at 6:05, 6:25 and 6:45 will be defined as the mean blood pressure at 
7:00.  
7.1.5 
Handling of Multiple Observations or Out of Window Observations 
For efficacy data, if multiple assessments were recorded for the same protocol defined visit 
(e.g., same nominal visit but different time points or re-assayed), the later one or the re-
assayed data will be used for data summary and analysis.  
If a subject has a scheduled visit, the assessment obtained at the scheduled visit will be used 
for data summary and analysis. Otherwise, if no scheduled visit assessment exists but 
unscheduled visit assessments are available within the visit window, the data from the latest 
unscheduled visit will be used for statistical analysis.  
Regarding the visit windows that will be applied to handle multiple observations and 
unscheduled visits, Table 7-1 shows the protocol-defined visit windows and the data analysis 
visit windows. Protocol-defined visit windows are usually more stringent to ensure study 
better adherence to study schedule; however, it could be too narrow for inclusion of 
unscheduled visits for data analysis. In order to include study data collected from any 
unscheduled visits, the analysis time windows will be widened for visit attribution. Note that 
data collected from an unscheduled visit that is out of the time window will not be included 
in data analysis, but will be provided in listings. 
Table 7-1 Analysis Visit Window 
Visit 
Number 
Visit Name 
Study 
Week 
Target 
Study 
Day[1] 
Protocol-
Defined Time 
Window 
Time Window to 
Attribute 
Unscheduled 
Visit to Analysis 
Visit 
1 
Screening 
Week -4 
-28 
-- 
-- 
2A 
Baseline/Randomization 
Week 0 
-1 
+3 days 
The last 
measurement 
prior to receiving 
the 1st randomized 
dose 


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Visit 
Number 
Visit Name 
Study 
Week 
Target 
Study 
Day[1] 
Protocol-
Defined Time 
Window 
Time Window to 
Attribute 
Unscheduled 
Visit to Analysis 
Visit 
2B 
Baseline/Randomization 
Week 0 
1 
-- 
-- 
3 
End of Titration  
Week 4 
28 
±3 days 
-3 and +6 
4A 
End of Study or Early Termination 
Week 8 
56 
±3 days 
Week 7 to all 
visits before or on 
the last study dose 
date 
4B 
End of Study or Early Termination 
Week 8 
57 
-- 
All visits after the 
last study dose 
date 
[1] Study day 1 is defined as the date of the first dose for each subject.  
7.1.6 
Handling of Missing or Partial Dates 
In cases of incomplete dates for AEs or non-study medications, the missing component(s) 
will be assumed as the most conservative value(s) possible. For example, the imputation rule 
is to conservatively capture AEs with missing start dates as treatment-emergent AEs 
(TEAEs). Actual data values, as they appear in the clinical database, will be shown in the 
data listings. Rules for partial dates are described in Table 7-2. 
Table 7-2 Rules for Missing or Partial Dates 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date for AEs 
D only 
M and Y same as M and Y of first 
dose of study drug 
Date of first dose of study drug 
M and/or Y not same as M and Y 
of first dose of study drug 
First day of non-missing month 
D and M 
Y same as Y of first dose of study 
drug 
Date of first dose of study drug 
Y not same as Y of first dose of 
study drug 
Use Jan 1 of non-missing year 
M, D and Y 
None – date completely missing 
Date of first dose of study drug 
Stop date for AEs 
D only 
 
Last day of non-missing month      
D and M 
 
Use Dec 31 of non-missing year 
M, D and Y 
Deceased  
Date of death 
Not deceased 
Date of the end of trial 
participation 


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Parameter 
Missing 
Additional Conditions 
Imputation 
Start date for non-
study medications 
D only 
M and Y same as M and Y of first 
dose of study drug 
Date of first dose of study drug 
M and/or Y not same as M and Y 
of first dose of study drug 
First day of non-missing month 
D and M 
Y same as Y of first dose of study 
drug 
Date of first dose of study drug 
Y not same as Y of first dose of 
study drug 
Use Jan 1 of non-missing year 
M, D and Y 
None – date completely missing 
Date prior to date of first dose of 
study drug 
Stop date for non-
study medications  
D only 
M and Y same as M and Y of first 
dose of study drug 
Last day of non-missing month      
M and/or Y not same as M and Y 
of first dose of study drug 
Last day of non-missing month      
D and M 
Y same as Y of first dose of study 
drug 
Use Dec 31 of non-missing year 
Y not same as Y of first dose of 
study drug 
Use Dec 31 of non-missing year 
M, D and Y 
None – date completely missing 
Date will not be imputed 
Notes: D=Day, M=Month, Y=Year 
7.1.7 
Handling of Missing Efficacy Data 
Every effort will be made to obtain the protocol-required data for all subjects according to 
the study schedule. However, subjects may withdraw from the study prior to completion, or 
discontinue study medication for any reasons. For subjects who discontinue treatment prior 
to study completion, every attempt will be made to obtain end of study ABPM assessments 
prior to their discontinuation of treatment or initiation of changes to concomitant 
antihypertensive medications or prohibited treatments for diabetes or weight loss. Missing 
data imputation methods and sensitivity analyses are discussed in each of the endpoint 
analysis section.  
To retain as much observed data as possible, the imputation of missing data will proceed 
after unscheduled visits have been mapped to analysis visits, if applicable. Refer to Section 
7.1.5 for handling multiple observations and unscheduled visits. 
7.2 
Efficacy Analyses 
7.2.1 
Primary Efficacy Analysis 
The primary efficacy endpoint of change in mean SBP obtained from 24-hr ABPM from 
baseline to Week 8 (or imputed Week 8 values for early termination subjects) will be 
evaluated on the PP population. An analysis of covariance (ANCOVA) model will be used to 
evaluate between-group differences in changes from baseline (top-dose VI-0521 vs. placebo 
and top-dose VI-0521 vs. phentermine) in 24-hr mean SBP. Factors included in the model are 


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treatment (VI 0521, phentermine, and placebo), sex (male and female), age (< 50; ≥ 50 
years), and hypertensive status (no medical diagnosis of or treatment for hypertension; 
medical diagnosis of hypertension treated with 0-2 antihypertensive agents; or medical 
diagnosis of hypertension treated with 3 or more antihypertensive agents). Baseline values of 
24-hr mean SBP will be adjusted in the model as a covariate. Adjusted means (LS Mean ± 
standard error) with associated two-sided 95% confidence intervals for the between-treatment 
comparisons and for the changes from baseline will be reported.  
If the upper bound of the two-sided 95% confidence interval for the between-treatment group 
difference (VI-0521 minus placebo or phentermine) in change from baseline in 24-hr mean 
SBP is less than 3 mmHg, success for a non-inferiority test will be claimed and the null 
hypothesis will be rejected. If the upper bound of the two-sided 95% confidence interval is 
less than 0 mmHg, i.e., with a p-value less than 0.05 significance level, superiority will be 
claimed. 
The estimand, estimator, and estimate of this primary endpoint are defined as follows:  
Estimand 
Population 
Per Protocol 
 
Endpoint 
Changes from Baseline in mean SBP obtained from 24-hr ABPM at Week 8  
 
How to account 
for intercurrent 
events 
The treatment policy strategy will be followed, whereby the observed value (if 
not missing) for the endpoint of interest will be used for analysis. 
 
Population-level 
summary 
The between-treatment difference in changes from baseline to Week 8 in mean 
SBP from 24-hr ABPM. 
 
Estimator 
Analysis 
ANCOVA with treatment, stratification factors (sex, age and hypertensive status) 
and baseline value of 24-hr mean SBP as a covariate. 
Estimates 
Primary to support 
the estimand 
Between-group comparison (effect in VI-0521 minus effect in placebo [or 
phentermine]): 
9 LSM for the between-group difference 
9 95% CI of the LSM 
9 p-value 
Tributary 
Within-treatment group comparison (effect at Week 8 minus the value at 
baseline): 
9 LSM for the within-group difference 
9 95% CI of the LSM 
9 p-value 
 
The following SAS programming codes will be applied: 
PROC MIXED DATA=DATAIN; 
CLASS TREATMENT(REF=’Placebo’ [or ‘Phentermine’]) SEX AGE HYPSTATUS; 
MODEL CHG_SBP=TREATMENT SEX AGE HYPSTATUS BASE_SBP/SOLUTION DDFM=KR; 
LSMEANS TREATMENT/ALPHA=0.05 PDIFF CL; 


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RUN; 
For subjects who discontinue from the study but complete Early Termination ABPM 
assessments, such measurements will be mapped to Week 8/End of Study or Early 
Termination for analysis. For subjects who have missing 24-hr SBP measurements at 
baseline or at Week 8 after mapping unscheduled visits, missing data will be imputed using 
the approach below. If the percentage of missing readings at either visit is ≤ 25% (see 
Section 5.4), 24-hr mean SBP values will be calculated by taking the average of non-missing 
and imputed measurements over the 24-hr time period. Imputed measurements will be 
derived as follows: 
1. For any intermediate missing observations between two non-missing readings BP1 
and BP2, missing observations will be imputed using the formula: BP = (BP2 – 
BP1)/(t2 – t1) × (t – t1) + BP1; whereas t1, t, and t2 are the time of the measurements 
respectively; 
2. If missing observations are at the beginning or at the end, the beginning observations 
will be imputed as the average of non-missing and step 1 imputed data points from 
6:00 to 22:00 hours. The end observations will be imputed similarly using data points 
from 22:01 to 5:59 hours. 
7.2.1.1 
Sensitivity Analyses of Primary Endpoint 
The following sensitivity analyses will be conducted on the ITT Population to evaluate the 
robustness of the primary analysis results and the effect of missing data for the primary 
endpoint: 
Missing at Random (MAR) based Multiple Imputation (MI) 
Step 1: If the percentage of missing 24-hr SBP readings at baseline or at Week 8 is ≤ 25%, 
such missing subject data will be imputed using the approach specified in Section 7.2.1. The 
24-hr mean SBP value will be calculated by taking the average of non-missing and imputed 
measurements over the 24-hr time period. 
Step 2: If the percentage of missing 24-hr SBP readings at baseline or at Week 8 is > 25%, 
MAR-based MI approach with Fully Conditional Specification (FCS) Regression will be 
applied to impute the 24-hr mean SBP value using Step 1 calculated 24-hr mean SBP values.  
Example SAS programming codes are: 
The ANCOVA model will be examined for each set of data. The results from the 50 sets of 


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data will be combined via Rubin’s rule to produce estimated LSMs and 95% CIs that 
incorporate the uncertainty from missing data. PROC MIANALYZE will be used.  
Example SAS programming codes are: 
Two-way Tipping Point Analysis 
An additional sensitivity analysis using 2-way tipping point strategy1 will be conducted on 
Step 2 above to explore the influence of missing data for 1) VI-0521 versus placebo; 2) VI-
0521 versus phentermine on the overall conclusion of 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. The goal is to find 
a ‘tipping’ point from among these assumptions under which the study conclusions shift from 
being favorable to VI-0521 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 when the result is no longer statistically 
significant.    


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To conduct this analysis, the PROC MI procedure will be used with additional “shift” 
parameters to account for missing not at random (MNAR). The shift parameters will be 
added using MNAR ADJUST syntax.  
Example SAS codes for this MI procedure are: 
SHIFTPARAM1
 
SHIFTPARAM2), the MI procedure outlined above will be executed. ANCOVA analysis will be 
run on all imputed datasets. Confidence intervals of the between-treatment comparisons 
estimated from the PROC MIANALYZE will be reported. The following shift parameters 
will be identified: 
1. For non-inferiority: when the upper bound of the two-sided 95% confidence interval 
just crosses 3 mmHg; 
2. For superiority: when the upper bound of the two-sided 95% confidence interval just 
crosses 0 mmHg. 
Analysis of Missing Data Pattern 
Number and percentage of subjects with at least 75% of non-missing 24-hr ABPM readings 
at baseline and Week 8 will be summarized by the following variables on the ITT 
Population: 
x Baseline mean SBP as measured by 24-hr ABPM (< population median and ≥ 
population median); 
x Baseline mean DBP as measured by 24-hr ABPM (< population median and ≥ 
population median); 
x Sex (male and female); 
x Age (< 50 and ≥ 50 years);  
x Race (white and not white); 
x Hypertensive status (no medical diagnosis of or treatment for hypertension; medical 
diagnosis of hypertension treated with 0-2 antihypertensive agents; or medical 
diagnosis of hypertension treated with 3 or more antihypertensive agents). 


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Number and percentage of subjects with more than two consecutive hours of missing 24-hr 
ABPM readings will also be summarized by visit on the ITT Population.  
7.2.1.2 
Supportive Analysis of Primary Endpoint 
Observed Case  
The primary efficacy analysis will be repeated using only the observed case data for the PP 
population. The data will include any unscheduled visits that have been mapped to analysis 
visits using the rules outline in Table 7-1. Data will not be imputed after mapping 
unscheduled visits. 24-hr mean SBP values will be calculated using the non-imputed data.  
7.2.1.3 
Subgroup Analyses of Primary Endpoint 
The primary efficacy analysis will be performed for the following subgroups for the PP 
population: 
x Sex (male and female);  
x Age (< 50 and ≥ 50 years);  
x Race (white and not white); 
x Hypertensive status (no medical diagnosis of or treatment for hypertension; medical 
diagnosis of hypertension treated with 0-2 antihypertensive agents; or medical 
diagnosis of hypertension treated with 3 or more antihypertensive agents). 
The primary efficacy analysis for the subgroup medical diagnosis (T2DM and obstructive 
sleep apnea) may be performed if applicable.  
7.2.2 
Analyses of Secondary Endpoints 
Secondary endpoints including change from baseline to Week 8 in mean DBP as measured 
by 24-hr ABPM, mean change in SBP and DBP from baseline to Week 8 as measured in 
clinic will be analyzed for the PP population using a similar ANCOVA model structure as 
that of the primary analysis. The model will comprise of treatment, stratification factors (sex, 
age and hypertensive status) and baseline value of the dependent variable as a covariate. 
Adjusted means (LS Mean ± standard error) with associated two-sided 95% confidence 
intervals for the between-treatment comparisons and for the changes from baseline will be 
reported. 
The estimand, estimator, and estimate of these secondary endpoints are defined as follows:  
Estiman
d
Population 
Per Protocol 
 
Endpoint 
Changes from Baseline in Variable X at Week 8  
 


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How to account 
for intercurrent 
events 
The treatment policy strategy will be followed, whereby the observed value (if 
not missing) for the endpoint of interest will be used for analysis. 
 
Population-level 
summary 
The between-treatment difference in changes from baseline to Week 8 in Variable 
X. 
 
Estimator 
Analysis 
ANCOVA with treatment, stratification factors (sex, age and hypertensive status) 
and baseline value of variable X as a covariate. 
Estimates 
Primary to support 
the estimand 
Between-group comparison (effect in VI-0521 minus effect in placebo [or 
phentermine]): 
9 LSM for the between-group difference 
9 95% CI of the LSM 
9 p-value 
Tributary 
Within-treatment group comparison (effect at Week 8 minus the value at 
baseline): 
9 LSM for the within-group difference 
9 95% CI of the LSM 
9 p-value 
 
Similar imputation method as described in Section 7.2.1 will be carried out for missing DBP 
values from the 24-hr ABPM. For missing clinic SBP and DBP, data will not be imputed 
after mapping unscheduled visits. 
Additionally, supportive analysis of the 24-hr mean DBP endpoint will be carried out 
similarly as described in Section 7.2.1.2. Supportive analysis of the clinical SBP and DBP 
endpoint will be performed using the observed case data for the ITT population. Extra 
sensitivity analyses similar to the primary endpoint may be conducted on the secondary 
endpoints if applicable. 
7.2.3 
Analysis of Exploratory Endpoints 
Analysis of exploratory endpoints will be performed on the PP population using the observed 
case data.  
All change from baseline exploratory endpoints will be analyzed using ANCOVA models in 
a similar manner to the primary and secondary endpoints. For the endpoints on percentage of 
subjects with a normal SBP and DBP ‘dipping pattern’ at Week 8, a Cochran-Mantel-
Haenszel (CMH) χ2 test that is stratified by sex, age and hypertensive status will be used for 
analysis. Corresponding estimates of the common Mantel-Haenszel relative risk will be 
provided along with 95% confidence intervals (CIs). For the endpoints on percentage of 
subjects meeting the BP or heart rate thresholds, descriptive summary will be provided.  
Example SAS codes for CMH test are: 


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No sensitivity analysis is planned for the exploratory endpoints. 
In addition, all 24-hr ABPM measurements including blood pressure and heart rate that are 
summarized in the endpoints will be presented in a listing. 
7.2.4 
Pharmacokinetic Analyses 
PK blood samples will be collected at the end of the study and will be used to obtain the PK 
profile of phentermine and topiramate levels. The concentration data will be summarized 
descriptively by treatment group.  
7.3 
Safety Analyses 
All safety analyses will be performed on the Safety population. 
7.3.1 
Adverse Events 
Adverse events (AEs) 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 reported terms (investigator descriptions) for AEs will be coded using the most 
recent version of the MedDRA. TEAEs are defined as any AEs that occurred or worsened 
after the first randomized study medication; regardless of on-treatment or off-treatment 
periods. All TEAEs will be summarized with frequencies and percentages of subjects by 
treatment group, system organ class (SOC), and preferred term (PT). The frequencies and 
percentage of subjects with any AE across all SOCs will be summarized by treatment group. 
The AEs occurring prior to receiving the first randomized dose are defined as pre-treatment 
AEs and will be listed only.  
TEAEs leading to discontinuation of study drug, TEAEs related to study drug, serious 
TEAEs, and TEAEs by maximum severity will be summarized and listed. Deaths will be 
listed if any. An overall summary of the above categories by treatment group will also be 
provided. All AEs leading to discontinuation from study, serious AEs, and death will be 
provided in listings.  
TEAEs of special interest including AEs that require initiation or modification of 
antihypertensive therapy will be summarized separately, if applicable. 
7.3.2 
Clinical Laboratory Evaluations 
All hematology, fasting blood chemistry, lipid panel, urinalysis and other lab results will be 
listed, including scheduled and unscheduled/repeat measurements (if any). Laboratory 


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assessments that are outside of normal ranges and/or with potential clinical significance will 
be considered an abnormal value and flagged in the listings.  
Baseline values, values at post-baseline visits, and change from baseline values will be 
summarized descriptively for all laboratory parameters with numerical measures by 
treatment. Additionally, shift tables will be generated to summarize the normal and abnormal 
(abnormal high and abnormal low) status change from baseline to post-baseline visits. 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. All laboratory measurements that are collected from 
unscheduled visits will be mapped according to the visit window defined in Section 7.1.5.  
Data from any unscheduled visits that are not be able to mapped to a scheduled visit will not 
be summarized in the by-visit descriptive tables, but will be included in the assessment when 
summarizing the worst case scenario, e.g., abnormality status. 
Laboratory tests are shown in the table below. 
Hematology 
Fasting blood full chemistry Pregnancy Testing 
x hemoglobin 
x hematocrit 
x red blood cell count 
x total white blood cell 
count 
x white blood cell 
differential (neutrophils, 
lymphocytes, monocytes, 
eosinophils, and 
basophils) 
x platelet count 
x albumin 
x alkaline phosphatase 
x ALT 
x AST 
x blood urea nitrogen 
x serum calcium 
x serum chloride 
x serum sodium 
x bicarbonate 
x creatinine (and estimated 
creatinine clearance) 
x gamma-glutamyl 
transpeptidase (GGT) 
x glucose 
x lactate dehydrogenase 
x serum phosphorus 
x serum potassium 
x total and direct bilirubin 
x total protein 
x uric acid 
x total cholesterol 
x triglycerides 
x LDL-C 
x HDL-C 
x TSH (at screening only) 
x HbA1c  
x Urine pregnancy test (WOCBP) 
Urinalysis 
x midstream urinalysis with 
reflex microscopic evaluation 
Urine Drug Screen (Screening 
Only) 
x cannabinoids 
x amphetamines 
x cocaine 
x barbiturates 
x benzodiazepine 
x opiates 
Serology (Screening only)  
x HBsAg 
x HCV 
x HIV 
Urine Cotinine (Screening Only) 
PK sample (End of Study Only) 
x Phentermine  
x Topiramate 
Limited chemistry panel: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose. 


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7.3.3 
Vital Signs 
Baseline values, values at post-baseline visits, and change from baseline values will be 
summarized descriptively by treatment group and visit for the Safety Population. Vital signs 
parameters include systolic blood pressure, diastolic blood pressure, heart rate, respiration 
rate, temperature. For blood pressure, the average of three successive readings will be used 
for summary. All vital signs data will be presented in a listing.  
7.3.4 
Physical Examination 
Physical examination will be done at Screening and Week 8/End of Study or Early 
Termination visits. The results will be provided in a listing. Abnormal physical exam 
findings will be summarized descriptively by treatment group, if applicable. 
7.3.5 
Electrocardiogram Findings 
ECG will be performed at Screening and Week 8 or early termination visits. ECGs will be 
evaluated for arrhythmias, conduction disturbances, or other clinically relevant changes 
during the study period. Changes from baseline of the ECG will be summarized descriptively 
by treatment group at each visit for heart rate, RR interval, PR interval, QRS interval and QT 
interval. The number of subjects with clinically significant ECG abnormalities will also be 
summarized by treatment group and visit. All ECG data will be included in the listing. 
7.3.6 
Blood pressure and T2DM 
Requirement for rescue therapy for blood pressure and T2DM, if any, will be compared 
across treatment groups.  
8 
POWER AND SAMPLE SIZE 
Approximately 555 subjects (185 per group) will be randomized to top-dose VI-0521, 
phentermine 30 mg, or placebo. Assuming a standard deviation of 10 mmHg for change in 
24-hr mean SBP as measured by ABPM, the intended sample size of 185 subjects per 
treatment group will provide 80% power to detect superiority of VI-0521 to comparator 
treatments (placebo or phentermine) if the comparator subtracted change in mean SBP has a 
value of less than -3.0 mmHg, and will provide 80% power to demonstrate non-inferiority 
based on a non-inferiority margin of 3 mmHg if the comparator subtracted change in mean 
SBP is less than 0.0 mmHg. The above-mentioned calculations were based on two-sample 
equal variance t-test at 2-sided α=0.05 for demonstrating superiority and at 1-sided α=0.025 
for demonstrating non-inferiority. This sample size estimate also accounts for a 5% drop-out 
rate over the course of the study. 


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9 
STATISTICAL SOFTWARE 
All statistical analyses will be performed using SAS® version 9.4 (or later). 
10 REFERENCE  
1.  Yuan, Yang. "Sensitivity analysis in multiple imputation for missing data." Proceedings 
of the SAS Global Forum 2014 Conference:[http://support. sas. 
com/resources/papers/proceedings14/SAS270-2014. pdf]. 2014.