A Non-Interventional Study to Generate Real-World Evidence on the Cardiovascular Safety of CONTRAVE® in the United States (U.S.)
Conditions: Obesity
Sponsor: Currax Pharmaceuticals

QAID 2102634.001 - 3547 
 
 
 
 
 
 
 
Final Protocol 
 
A Non-Interventional Study to Generate Real-World Evidence on the 
Cardiovascular Safety of CONTRAVE® in the United States (U.S.)  
 
 
 
 
Prepared for 
 
Michael Kyle, M.D. 
Currax Pharmaceuticals LLC 
+1 800 793 2145 
mkyle@curraxpharma.com 
 
 
Exponent contact 
 
David Dore, Pharm.D., Ph.D. 
Exponent Inc. 
+1 508 654 5104 
ddore@exponent.com 
 
 
January 26, 2023 

 
Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 2 of 29 
TABLE OF CONTENTS 
1  RESPONSIBLE PARTIES 
4 
1.1 
Sponsor and Primary Sponsor Contact 
4 
1.2 
Principal Investigator and Author of Record 
4 
2  DRUG DESCRIPTION 
5 
3  ABSTRACT 
6 
4  RATIONALE AND BACKGROUND 
8 
5  RESEARCH QUESTIONS AND OBJECTIVES 
9 
6  RESEARCH METHODS 
10 
6.1 
Study Design 
10 
6.2 
Settings 
10 
6.3 
Inclusion Criteria 
10 
6.4 
Exclusion Criteria 
11 
6.5 
Variables 
14 
6.5.1 
Exposure 
14 
6.5.2 
Outcomes and follow-up 
15 
6.5.3 
Covariates 
17 
7  DATA SOURCES 
19 
7.1 
Arcadia Data Research 
19 
7.2 
Datavant Death Data 
19 
8  STUDY SIZE AND STATISTICAL POWER 
20 
8.1 
Study Size 
20 
8.2 
Ranges of Statistical Power for MACE 
20 
9  DATA MANAGEMENT 
21 
9.1 
Descriptive Statistics 
21 
9.2 
Missing Data 
22 
9.3 
Crude Incidence Rate Difference (IRD) and Incidence Rate Ratio (IRR) Estimates
 
22 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 3 of 29 
9.4 
PS Matching Weights 
23 
9.5 
Estimation of Adjusted IRD and IRR Estimates 
23 
9.5.1 
Intention-to-Treat Analysis 
23 
9.5.2 
As-Treated Analysis 
24 
9.5.3 
Statistical Model for Cohort Analysis 
24 
9.6 
Quality Control 
25 
10  LIMITATIONS OF THE DATA AND RESEARCH METHODS 
26 
10.1 
Electronic Health Data 
26 
10.2 
Unmeasured Patient Risk Factors 
26 
11  PROTECTION OF HUMAN SUBJECTS 
26 
12  MANAGEMENT AND REPORTING OF ADVERSE EVENTS 
26 
13  PLANS FOR DISSEMINATION AND COMMUNICATING STUDY 
RESULTS 
27 
14  REFERENCES 
28 
 
 
 
 
 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 4 of 29 
1 RESPONSIBLE PARTIES 
1.1 Sponsor and Primary Sponsor Contact 
Currax Pharmaceuticals LLC 
155 Franklin Rd, Suite 450 
Brentwood, TN  37027 
Contact: Michael Kyle, M.D. 
+1 215 704 0475 
mkyle@curraxpharma.com 
 
1.2 Principal Investigator and Author of Record 
David Dore, Pharm.D., Ph.D. 
Principal Scientist 
Exponent Inc. 
1075 Worcester Street, Natick, MA 01760 U.S.A. 
+1 508 654 5104 
ddore@exponent.com 
 
 
 
 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 5 of 29 
2 DRUG DESCRIPTION 
The product of interest is a fixed-dose combination of naltrexone hydrochloride (HCl), 8mg, and 
bupropion HCl, 90mg, for oral use via extended-release oral tablet. The product is marketed 
under the trade name CONTRAVE® in the United States (U.S.). It is a combination of an 
opioid antagonist (naltrexone) and an aminoketone antidepressant (bupropion). Each constituent 
active ingredient is available separately in various doses and formulations.  
Following conventions within previous documents, hereafter we refer to the product 
CONTRAVE® as the branded product, under regulation. Use of CONTRAVE® or concomitant 
initiation of its constituent active ingredients, naltrexone and bupropion, will be referred to as 
NB within this protocol. 
CONTRAVE® is indicated 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) or 
 27 kg/m2 or greater (overweight) in the presence of at least one weight-related 
comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).1  
 
CONTRAVE® is recommended to be initiated according to a dose-escalation schedule 
beginning with one tablet each morning in week one and increasing to up to two tablets twice 
daily beginning in week four.  
 
The labeled contraindications include known allergy to any ingredient within CONTRAVE®; 
uncontrolled hypertension; seizure disorders; anorexia nervosa or bulimia; undergoing abrupt 
discontinuation of alcohol; use of benzodiazepines, barbiturates, or antiepileptic drugs; chronic 
opioid use; and taking currently, or within the past 14 days, a monoamine oxidase inhibitor.  
 
As specified in the product labeling under Warnings and Precautions and Limitations of Use, the 
effect of CONTRAVE® on cardiovascular morbidity and mortality has not been established. 
Additionally, the safety and effectiveness of CONTRAVE® in combination with other products 
intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal 
preparations, have not been established. In this protocol, we propose to evaluate the potential 
effects of NB on cardiovascular endpoints. 
 
 
 
 
 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 6 of 29 
3 ABSTRACT 
Title: 
A Non-Interventional Study to Generate Real-World Evidence 
on the Cardiovascular Safety of CONTRAVE® in the United 
States (U.S.)  
Background and Rationale: 
The fixed-dose combination of naltrexone 8mg and bupropion 
90mg extended-release oral tablet is marketed under the trade 
name CONTRAVE® in the U.S. In this protocol, we propose 
to generate real-world evidence (RWE) from electronic health 
records (EHR) and linked claims data to assess the 
cardiovascular safety of CONTRAVE® and all NB in usual 
clinical practice. 
Research Question and 
Objectives: 
The main objective of this study is to compare the incidence of 
the primary endpoint (major adverse cardiovascular events 
[MACE]) between initiators of NB and initiators of an active 
comparator, lorcaserin (1.0).  
The study will also compare the incidence of the secondary 
endpoint (each component of MACE) between initiators of NB 
and initiators of lorcaserin, overall and across subgroups of 
interest (1.1) 
This study includes three additional objectives to support the 
assessment of the robustness of the results for the primary and 
secondary endpoints: 
 To assess the comparability of the results from the 
same EHR data to the results of the 2018 randomized 
clinical trial assessing cardiovascular endpoints among 
lorcaserin users, in a manner consistent with the 
Randomized Controlled Trials Duplicated Using 
Prospective Longitudinal Insurance Claims: Applying 
Techniques of Epidemiology Initiative (RCT 
DUPLICATE) (2.0); 
 To quantify differences in cardiovascular safety 
endpoints between the 2018 trial and the results of this 
EHR study (2.1); 
 To conduct other sensitivity analyses, including a self-
controlled, case-crossover analysis to quantify the 
potential effect of NB on MACE (2.2). 
Study Design: 
Retrospective, new-user cohort study. 
Population: 
The primary study population includes initiators of NB or the 
active comparator, lorcaserin.  

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 7 of 29 
Inclusion and exclusion criteria for the main objective will 
ensure that only new users are included, and that the NB and 
comparison groups are comparable on risk factors for MACE 
after application of propensity score (PS) matching weights. 
Inclusion and exclusion criteria for the additional objectives 
will align with those used in the 2018 trial assessing 
cardiovascular endpoints among lorcaserin users, insofar as the 
data support a comparable replication.  
Variables: 
The key variables are initiation of NB, initiation of lorcaserin 
(active comparator), time on treatment, and the endpoint of 
MACE. The individual components of MACE will also be 
quantified. Covariates will be derived from clinical 
measurements, past medical history, diagnoses, observations, 
and prescription records. Multiple imputation will be applied 
to address missing data, coupled with PS analyses to address 
confounding. 
Data Sources: 
EHR and linked claims data from Arcadia Data Research. The 
data currently cover approximately 75 million people in the 
U.S. 
Study Size: 
There are approximately 37,000 apparent NB initiators in the 
Arcadia data.  
There are approximately 16,000 apparent lorcaserin initiators. 
Data Analysis: 
Descriptive statistics of the study cohorts, multiple imputation 
of missing covariates, estimation of crude incidence rates of 
MACE among initiators of NB, and adjusted incidence rates of 
MACE after applying PS matching weights will be calculated 
(1.0 and 1.1). Analogs to intention-to-treat and per-protocol 
cohort analyses will be conducted. The analysis will also 
follow the principles of the RCT DUPLICATE Initiative (2.0 
and 2.1) to assess the concordance between findings in an EHR 
study to those in the lorcaserin cardiovascular safety endpoints 
trial. In addition, we will conduct a case-crossover study to 
assess the effects of NB on MACE (2.2) and other sensitivity 
analyses.  
Milestones: 
Start of Data Collection  
 
September 2014 
End of Data Collection 
 
February 2020 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 8 of 29 
4 RATIONALE AND BACKGROUND 
The U.S. Food and Drug Administration (FDA) approved  CONTRAVE® on September 10, 
2014, for chronic weight management in obese adults (body mass index [BMI] ≥30 kg/m2) and 
in those who are overweight (BMI ≥27 kg/m2) with at least one weight-related comorbidity 
(e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). CONTRAVE® is used as an 
adjunct to a reduced-calorie diet and increased physical activity. The labeling indication 
includes two Limitations of Use, one of which states that the effect of  CONTRAVE® on 
cardiovascular morbidity and mortality has not been established. Since 2014, real-world data 
(RWD) on NB have accumulated through use in clinical practice and afford an opportunity to 
generate RWE on the drug’s safety profile. This protocol proposes the generation of RWE from 
EHRs and linked claims data to assess the cardiovascular safety of NB in usual clinical practice.  
 
We also include several additional objectives; prime among them is assessing the comparability 
of findings using RWD to those generated from a clinical trial. RWD studies are often more 
cost-effective and feasible compared to their RCT counterparts. When sufficiently calibrated, 
RWD studies can reach similar conclusions to RCTs and can contribute meaningfully to 
evidence generation for therapeutics in real-world clinical practice2,3. The RCT DUPLICATE 
Initiative supports this goal and was created to quantify differences between RCT findings and 
corresponding RWD replications, to understand the types of research questions suitable for 
RWD, and to understand the methods that should be used for such studies. Comparisons to 
trial results can help to assess and quantify the presence of (potential) biases in RWD studies.  
This protocol was developed in accordance with regulatory guidance, draft and international 
society guidelines, and frameworks for observational database studies involving RWE4-6. 
 
 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 9 of 29 
5 RESEARCH QUESTIONS AND OBJECTIVES 
The study will assess whether patients who initiate treatment with NB are at an elevated risk of 
MACE compared with patients who initiated treatment with lorcaserin, an active comparator 
chosen to reduce potential confounding7,8. Lorcaserin was approved in the U.S. under the brand 
names BELVIQ® and BELVIQ XR® for the same indication as NB, and withdrawn from the 
market due to cancer safety concerns in 20209-11. Lorcaserin is not believed to have adverse 
effects on cardiovascular outcomes. The CAMELLIA-TIMI 61 trial was a comparison of 
lorcaserin relative to placebo in overweight and obese patients with cardiovascular disease and 
cardiovascular disease risk factors. The trial found no difference in the rate of cardiovascular 
events12. 
 
The study’s main objective is to compare the incidence of the primary endpoint (MACE) 
between initiators of NB and initiators of lorcaserin (1.0). The study will also compare the 
incidence of the secondary endpoint, consisting of each component of MACE, between initiators 
of NB and initiators of lorcaserin, across the following subgroups (1.1): 
 Patients with obesity (i.e., most recent BMI measurement ≥30 kg/m2); 
 Patients with a diagnosis of hypertension, regardless of BMI; 
 Patients with a diagnosis of type 2 diabetes mellitus, regardless of BMI; 
 Patients with a diagnosis of dyslipidemia, regardless of BMI. 
 
The study’s additional objectives aimed at testing the robustness of the methods are: 
 To assess the comparability of findings from an EHR study to those of a 2018 clinical 
trial, aligning with the RCT DUPLICATE Initiative (2.0); 
 To quantify differences in cardiovascular safety endpoints between the clinical trial and 
the results of this EHR study (2.1); 
 To conduct other sensitivity analyses, including a self-controlled, case-crossover 
analysis to quantify the potential effect of NB on MACE (2.2). 
 
 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 10 of 29 
6 RESEARCH METHODS 
6.1 Study Design 
A retrospective cohort study design will be used for the main objective and endpoints. Initiators 
of NB will be identified between September 2014 and February 2020. Contemporaneously, we 
will identify all lorcaserin users between 2012 and 2020. A self-controlled, case-crossover 
design will be used for the sensitivity analysis (2.2). 
 
6.2 Settings 
The cohorts for all study objectives will be drawn from a large EHR data source, representing a 
geographically diverse patient population. The data will include diagnoses, procedures, 
medications (prescribed and administered), clinical measures (biometric and laboratory values), 
and observations derived from clinical notes. A subset of the population will have linked, 
adjudicated claims data available to support sensitivity analyses.  
EHR data, generated from routine clinical care offer timely clinical information not typically 
available in claims databases, including information on patient attributes, observations from 
physicians’ notes, patient symptoms and history, diagnostic information, and planned and actual 
treatments, and prescription medicines not covered by health plans (e.g., CONTRAVE®). 
Notably, EHR data include measures of BMI for descriptive analysis and evaluation as a 
potential confounder and effect modifier. These EHR data will be linked to proprietary 
information from First Databank to identify medications of interest accurately, including NB. 
 
6.3 Inclusion Criteria 
For the main objective (1.0, 1.1), patients are eligible if they meet the following inclusion 
criteria: 
 Have at least one prescription for NB between September 2014 and February 2020, 
including concurrent prescriptions (within 15 days) for naltrexone and bupropion; or 
have at least one prescription for lorcaserin;  
 Have at least 180 days of data available prior to cohort entry with no evidence of 
prescriptions or dispensings of NB or lorcaserin; 
 Have at least one BMI value available in the 180 days prior to cohort entry, inclusive of 
the index date; 
 Have documentation of at least one outpatient medical visit 180 or more days prior to 
cohort entry, and at least one healthcare interaction in the 180 days prior to cohort entry; 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 11 of 29 
 Are at least 18 years of age on the cohort entry date. 
 
Of note, having at least one BMI value is the only inclusion criterion that is potentially missing 
within the EHR. Documentation of at least one outpatient medical visit more than 180 days 
prior to cohort entry, and at least one healthcare interaction in the 180 days prior to cohort entry 
is required. This criteria will facilitate the inclusion of individuals who appear to have sufficient 
engagement with an Arcadia-contributing health system and would have enough clinical data to 
meet the study objectives.  
 
For the comparability study (2.0 and 2.1), inclusion criteria will be based on the CAMELLIA-
TIMI 61 trial, insofar as the information is available in the data. Examples include: 
 BMI ≥27 kg/m2; 
 Age ≥40 years with history of documented myocardial infarction (MI) or ischemic 
stroke >1 month prior to baseline, peripheral artery disease, revascularization or 
significant unrevascularized coronary arterial stenosis;   
 Women age ≥55 years or men age ≥50 years who have type 2 diabetes mellitus without 
established cardiovascular disease but at least one cardiovascular risk factor 
(hypertension, dyslipidemia, calculated creatinine clearance ≥30 to ≤60 mL/min, or 
urinary albumin-to-creatinine ratio ≥30 µg/mg)13. 
 
The full list of inclusion criteria are included in the CAMELLIA-TIMI 61 publication and 
protocol12. 
Where variables are not available in the EHR or claims data, we will search for suitable proxies 
based on the literature and the recommendations of a U.S.-licensed physician consultant.  
For the case-crossover study (2.2), patients are eligible if they meet the following inclusion 
criteria: 
 Experience a MACE event (“index event”) after September 2014; 
 Have at least one prescription or dispensing of NB prior to the index event; 
 Are at least 18 years of age at the time of the first prescription/dispensing of interest. 
 
6.4 Exclusion Criteria 
For the main objective, patients are not eligible if they have a diagnosis of any of the following 
conditions in the 180 days before the cohort entry date: 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 12 of 29 
 Epilepsy; 
 Bulimia; 
 Anorexia nervosa; 
 Surgical procedure for weight loss.  
 
Patients also must not have been prescribed opioids or monoamine oxidase inhibitors in the 180 
days before entry into the cohort.  
Patients with prescriptions for both NB and lorcaserin will be randomly assigned to a baseline 
treatment group to preserve sample size and mitigate selection bias.  
Patients are not eligible for inclusion in the comparability study if they have any of the 
following, as feasibly measured in the Arcadia data, including: 
 Congestive cardiac failure; 
 Known left ventricular ejection fraction <20%; 
 Moderate or higher pulmonary hypertension ; 
 Known severe valvular disease;  
 Moderate renal impairment, severe renal impairment, or end-stage renal disease; 
 Severe hepatic impairment; 
 Use of other products intended for weight loss;  
 Use of, within 1 month prior to baseline, more than one other serotonergic drug 
including, but not limited to: 
o Selective serotonin reuptake inhibitors;  
o Serotonin norepinephrine reuptake inhibitors;  
o Tricyclic antidepressants; 
o Bupropion; 
o Triptans; 
o St. Johnʼs Wort and tryptophan; 
o Monoamine oxidase inhibitors, linezolid, dextromethorphan, lithium; 
o Tramadol, antipsychotics or other dopamine antagonists; 
 Use of drugs known to increase the risk for cardiac valvulopathy within 6 months prior 
to baseline including, but not limited to:  
o Cyproheptadine; 
o Amoxapine; 
o TCAs; 
o Mirtazapine; 
o Pergolide; 
o Ergotamine; 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 13 of 29 
o Methysergide; 
o Cabergoline; 
 History or evidence of clinically significant disease (e.g., malignancy, cardiac, 
respiratory, gastrointestinal, renal or psychiatric disease);  
 Use of lorcaserin HCl within 6 months prior to screening;  
 Hypersensitivity to lorcaserin HCl or any of the excipients. 
 
The full list of exclusion criteria are included in the CAMELLIA-TIMI 61 publication and 
protocol12. 
Similar to the exclusion criteria for the primary objective, patients with any of the diagnoses or 
prescriptions for opioids and/or monoamine oxidase inhibitors in the 180 days prior to the index 
event date will be excluded from the case-crossover analysis. 
 
 
 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 14 of 29 
6.5 Variables 
6.5.1 Exposure 
Initiation of NB and lorcaserin will be identified using Hierarchical Ingredient Code Lists 
(HICLs) from First Databank. If necessary, individual searches of National Drug Codes (NDCs) 
and free-text strings will also be used. See Figure 1 for visual depiction of the study design.  
 
Figure 1. NB safety study design 
 
 
 
 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 15 of 29 
For the cohort, among the subset of patients with EHR data whose records can be linked to 
health insurance claims, we will assess the concordance between receiving a prescription for NB 
and lorcaserin (in the EHR) and filling the prescription (in the claims).  
 
The time of entry into the NB cohort will be the date of first prescription for those taking  
CONTRAVE®, the date of the second overlapping prescription of naltrexone or bupropion in 
the case of concomitant use of naltrexone and bupropion, or the date of first prescription for 
lorcaserin from date of approval in the U.S. to withdrawal from the market, as applicable. 
 
In the case-crossover study, a 90-day hazard window will immediately precede the index event 
date within which the occurrence of a prescription or dispensing will define exposure status. 
Similarly, a 90-day referent window will precede the hazard window, with exposure status 
designated comparably. A 30-day washout window between the hazard and referent windows 
will be used to mitigate any carryover effects from the prior exposure. Please see Figure 2 for a 
visual depiction of the case-crossover study design. 
 
Figure 2. Case-crossover study design 
 
 
6.5.2 Outcomes and follow-up 
  
The primary study endpoint is MACE, defined as the composite of:  
 
 Medically attended non-fatal acute myocardial infarction; 
 Medically attended non-fatal stroke;  
 Cardiovascular-related death. 
 
The secondary endpoints are: 
 
 Individual components of MACE, analyzed separately, as (1) medically attended non-
fatal acute myocardial infarction; (2) medically attended non-fatal stroke; and (3) 
cardiovascular-related death. 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 16 of 29 
In accordance with the CAMELLIA-TIMI 61 trial, the comprability study will examine safety 
endpoints for the secondary objectives (2.0 and 2.1).  
 
The safety endpoint was defined as a composite of: 
 
 Cardiovascular death; 
 Myocardial infarction; 
 Stroke12.  
 
For all study objectives, information on myocardial infarction and stroke will be obtained from 
the EHR data, while information on death will be obtained from Datavant. Datavant compiles 
mortality data from government sources, obituaries, newspapers, and claims data for more than 
90% of the U.S. population. Cause of death will be ascertained from the subset of individuals 
whose records can be linked to death certificates; otherwise, diagnoses adjacent to death will be 
identified, as feasible, using information from the EHR (e.g., cardiovascular-related 
hospitalizations or emergency department visits immediately preceding date of death).  
 
A U.S.-licensed physician consultant, blinded to exposure, will review the detailed 
chronological listing of individual-level EHR data (and claims, where relevant) of a randomly 
selected subset of apparent MACE cases to determine whether MACE occurred. The 
adjudication process will compare the operational definition of MACE in the EHR to the 
physician’s professional judgement and the occurrence of MACE in the EHR and claims data. If 
the initial EHR-based definition of MACE does not meet a pre-specified threshold for 
concordance, then adjustments to the initial list of diagnoses and procedure codes will be made 
to improve the accuracy of the operational definition of MACE14,15.  
 
Follow-up time will be calculated separately for each study endpoint. Patients will be followed 
starting the day after initial exposure until the first of the following censoring events: (1) the 
study endpoint of interest, (2) death (for those who do not have the endpoint of interest), or (3) 
end of available data for those who do not have the event of interest (i.e., censoring due to end 
of available EHR data). Person-time will be calculated by summing the days from cohort entry 
(day 0) to the date of the first relevant censoring event. 
 
To test the robustness of assumptions about the date of censoring, analyses with differing 
censoring definitions will be performed, and estimates compared:  
 
 To assess whether the censoring date needs to be adjusted, the physician consultant will 
review a random sample of patient health profiles to determine whether there is a clear 
indicator of censoring. Insofar as there appears to be a clear indicator of censoring, the 
physician will record this date (blinded to exposure), and this information will be used to 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 17 of 29 
adjust the censoring date. Indeed, this information may be treated as an annotation for a 
machine learning model. 
 To account for a patient still being on the insurance plan but not accessing the healthcare 
system, adjust the end of follow-up to be 6 months, 1 and 2 years following their last 
healthcare encounter in the EHR.   
 To assess the reliability of our method for computing time until censoring in the EHR, 
compare follow-up times in the EHR to those observed in the claims enrollment files 
using a subset of those with EHR and claims data.   
 To test robustness of the method for computing follow-up time in the EHR, compute the 
distribution of follow-up times based on enrollment spans within the subset of 
individuals with claims and EHR data and apply the median follow-up time within 
populations with particular health profiles.  
 To implement a more specific definition of follow-up time, assume that a last healthcare 
encounter with a primary care provider, endocrinologist, or geriatric care provider in 
combination with no death information is the end of enrollment.  
6.5.3 Covariates 
A range of demographics will be assessed for each patient at cohort entry, including the 
following: 
 
 Age; 
 Sex; 
 Race/ethnicity. 
 
A set of comorbidities will be assessed in the 180 days before cohort entry, including the 
following: 
 
 Acute myocardial infarction; 
 Stroke; 
 Dyslipidemia; 
 Type 2 diabetes mellitus; 
 Transient ischemic attack; 
 Hypertension; 
 Heart failure; 
 Unstable angina; 
 Peripheral vascular disease; 
 Coronary heart disease; 
 Cerebrovascular disease; 
 Chronic kidney disease; 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 18 of 29 
 Sleep apnea; 
 Mood disorders. 
 
A set of concomitant medications will be assessed in the 180 days before cohort entry, including 
the following: 
 
 Medications that affect cardiovascular outcomes, including: 
o Antihypertensives; 
o Statins; 
o Anticoagulants; 
o Antiplatelets; 
o Antihyperglycemics. 
 
 Other medications listed in the  CONTRAVE® Prescribing Information Drug 
Interactions, including: 
o Selective serotonin reuptake inhibitors; 
o Tricyclic antidepressants; 
o Antipsychotics; 
o Beta-blockers; 
o Type 1C antiarrhythmics (e.g., propafenone and flecainide); 
o Digoxin; 
o Antiplatelets. 
 
A set of relevant laboratory test results and biometric values will be assessed during the 180 
days before cohort entry, including the following:  
 
 BMI; 
 Blood glucose or HbA1c; 
 Liver function; 
 Dyslipidemias; 
 Resting heart rate; 
 Respiratory rate; 
 Systolic blood pressure; 
 Diastolic blood pressure; 
 Glomerular filtration rate/serum creatinine. 
 
Where multiple values are available, the most recent will be selected. Where no value is present, 
multiple imputation procedures will be used to generate a value under the assumption that the 
values are missing at random. 
 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 19 of 29 
7 DATA SOURCES 
7.1 Arcadia Data Research 
The study will use EHR data and linked claims data from Arcadia, which has assembled one of 
the largest EHR datasets available to life science organizations, currently covering 
approximately 75 million individuals in the U.S. Arcadia partners with health systems and 
payers to create a centralized, physically integrated EHR system that has nationwide coverage 
and integrates clinical data from multiple electronic medical records within and across health 
systems via their Master Patient Index, a proprietary person-matching technology that identifies 
distinct patients across disparate data sources16. The typical research extract includes patient 
demographics, encounters, appointments, provider data, charges, assessments, immunizations, 
health maintenance and medical history, orders/results, vitals, insurance, prescriptions and 
active medications, problem lists, and allergy information. 
Arcadia’s EHR data are sourced from large integrated delivery networks, academic medical 
centers, ambulatory, primary care, core hospitals, and other providers. Arcadia’s de-identified 
dataset for research includes a mix of populations representing individuals with commercial 
insurance, along with Medicare and Medicaid coverage. Adjudicated claims data from multiple 
payers are available for approximately 46% of the EHR patients. 
 
7.2 Datavant Death Data 
We will link data from Arcadia to death data from Datavant, a private U.S. data curator, 
specializing in organizing health data17. Datavant’s mortality database contains information on 
deceased individuals in the U.S. and Canada18. Datavant’s Death Index contains information on 
individual deaths including year and month of death, gender, and cause of death, where 
available. Information is obtained from the Social Security Administration’s Death Master File 
in addition to private obituaries, newspapers and claims data, and is updated on a weekly 
basis18,19. In 2018, information was present for just over 2.4 million deaths18.  
In order to de-identify records, names, addresses, and social security numbers are removed in 
addition to modifications such as changing a person’s date of birth to year of birth alone19. 
Datavant’s proprietary technology adds encrypted tokens to each record, constructed from the 
underlying personally identifiable information. Since these tokens correspond to unique 
individuals, they can be used to link death information to other health-related datasets. 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 20 of 29 
8 STUDY SIZE AND STATISTICAL POWER 
8.1 Study Size 
According to the most recent available data from Arcadia (delivered to Exponent November 
2022), ~37,000 patients had an apparent initiation of NB. Of those patients ~64% had linked, 
adjudicated claims data at some point in time. Seventy percent of apparent initiators were 
women. 
 
8.2 Ranges of Statistical Power for MACE 
In a similar population of overweight/obese individuals, Ritchey et al.20 found that the incidence 
rate of MACE was estimated at 2/1,000 person-years among individuals unexposed to weight 
loss drugs (95% confidence interval [CI], 1.85–2.17). Guided by this estimated incidence rate of 
MACE, Figure 3 describes a range of plausible estimates for the statistical power of the NB 
safety study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 21 of 29 
Figure 3. Range of power estimates for the endpoint of MACE in the NB safety 
study  
 
This Figure was generated using a general cohort power calculation methodology.  
Abbreviation: NB, Naltrexone and Buproprion; PY, person-years; RR, relative risk 
 
Assuming an incidence rate of MACE of 2 per 1,000 years of follow-up within this study, and 
that there are ~37,000 initiators of NB, it appears that we have greater than 80% power to detect 
a relative risk of 2.0.  
 
9 DATA MANAGEMENT 
9.1 Descriptive Statistics 
Descriptive statistics will be used to summarize each covariate by treatment group for all study 
objectives. For dichotomous variables, we will report the number and proportion of patients 
with each covariate. For categorical variables, we will report the number and proportion of 
patients in each level of the covariate. For continuous variables, the mean and standard 
deviation will be estimated. Standardized differences in means and proportions will be used to 
assess covariate balance between weighted treatment groups.  

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 22 of 29 
9.2 Missing Data 
Some biometric variables within the EHR (e.g., laboratory values, such as HbA1c) are expected 
to be missing in a non-random way. We will employ multiple imputation methods to address 
missing covariate data at baseline by creating standard intervals (e.g., within periods of one, 
three or six months) for ascertainment of important missing values. If multiple results are 
available in an interval, we will select the valid observation that is most proximal to the cohort 
entry date. 
 
Consistent with our previous research on missing data within EHRs21,22, we will then use 
multiple imputation methods to impute missing values within intervals with no observed values 
for a given patient. To account for the uncertainty of imputed values, we will produce 10 
complete datasets to quantify within- and between-dataset variance and to correct standard 
errors. That is, the full analysis will be conducted within each of the 10 complete datasets, the 
results will be averaged across the datasets, and the measures of statistical uncertainty (e.g., CIs) 
corrected for the imputation. Because of the number of possible covariates requiring imputation, 
we will use a fully conditional specification of the multiple imputation procedure (i.e., chained 
equations), which does not require the stringent assumption that some models make about the 
joint distribution of missing covariates23. 
 
The multiple imputation procedure reduces the potential for missing data bias at the population 
level and relaxes the assumptions necessary to interpret results as unbiased estimates. Dr. Dore 
designed and successfully conducted a cohort study with a large EHR using these techniques, 
and the results of that study were similar to trial results of the same comparisons21.  
 
 
9.3 Crude Incidence Rate Difference (IRD) and Incidence Rate Ratio 
(IRR) Estimates 
The incidence rate for each group is the cumulative number of observed endpoint events, 
divided by the total person-years of follow-up. The crude IRD is the absolute difference in the 
observed incidence rate between initiators of NB and initiators of lorcaserin, with no adjustment 
for differences in patient characteristics between groups. The crude IRR is the relative 
difference (i.e., ratio) in the observed incidence rate of initiators of NB, divided by the observed 
incidence rate for initiators of lorcaserin, with no adjustment for differences in patient 
characteristics between groups. 
 
 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 23 of 29 
9.4 PS Matching Weights 
PS matching weights will be used to control for confounding between treatment groups24,25. A 
logistic regression model will be used to estimate the predicted probability of treatment with NB 
versus treatment with lorcaserin, conditional on pre-specified covariates. Each patient’s PS, or 
predicted probability from the model, will be the probability that the patient received NB. The 
complement of each patient’s PS (i.e., 1-PS) will be the probability that the patient received 
lorcaserin. Each patient will be assigned a matching weight, which is a function of their PS and 
the treatment received. The numerator of the matching weight is the smaller of the PS or the 
complement of the PS (1-PS). The denominator is the PS if the patient received NB, and it is 1-
PS if the patient received lorcaserin. For example, a patient with a PS value of 0.6 (1-PS = 0.4) 
who received NB would have a matching weight of 0.4/0.6 or 0.667. These weights will be used 
in regression models to account for confounding.  
 
Similar methods will be used to generate propensity score weights within the CAMELLIA-
TIMI 61 comparability cohort. Covariates will include demographics, calendar time of treatment 
initiation, comorbidities, medications, cardiovascular procedures, and indicators of health care 
utilization as proxy for overall disease state, care intensity, and surveillance.  
 
Matching weights are the weighting analog of 1:1 PS matching, but include the entire eligible 
patient population, are more statistically efficient than matching, and produce better balance on 
covariates. Thus, matching weights standardize the distribution of patient characteristics to the 
area of common support (or empirical equipoise26) in which patients could have reasonably 
received either treatment. 
 
9.5 Estimation of Adjusted IRD and IRR Estimates 
This study will include analogs of intention-to-treat (ITT) and per-protocol analyses, in 
accordance with clinical trial conventions. Both analyses estimate the effect of NB on the 
incidence of MACE relative to comparators, but differ in the handling of person-time, as 
described below. We adopt the term ITT and refer to the per-protocol analogue as the as-treated 
analysis.  
 
9.5.1 Intention-to-Treat Analysis 
The ITT defines each day of follow-up for everyone according to their exposure status at the 
time of cohort entry (e.g., initiation of NB). Classification of person-time in the ITT analysis is 
subject to exposure misclassification as individuals discontinue treatment or switch to the other 
study drug before their end of follow-up. In contrast, the ITT estimate preserves the balance in 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 24 of 29 
baseline covariates that will be achieved through PS matching weights because individuals 
remain in the cohort to which they were assigned at baseline, when the PS weights are applied. 
The results from this approach are best interpreted as providing an estimate of the effect of 
starting treatment – or intending to start treatment – on the rate of the outcomes.  
 
9.5.2 As-Treated Analysis 
The ITT analysis will be juxtaposed with analyses of person-time classified by actual exposure 
to NB and lorcaserin, grouped into categories of current, recent, and past use. These person-time 
classifications estimate the effect of being on (or off) the treatment on the rate of the outcomes. 
Such estimates are often desirable for drug safety questions because they avoid misclassification 
of exposure that arises in ITT analysis; however, the balance introduced at baseline by PS 
matching weights may deteriorate as patients switch non-randomly among different study drugs. 
Therefore, the ITT and as-treated analyses are best interpreted together. 
 
To obtain the hazard ratios necessary to compare trial results to those obtained through use of 
RWD, we will use an ITT analysis for the primary analyses, and as-treated for sensitivity 
analyses, as was done in the CAMELLIA-TIMI 61 trial. 
 
9.5.3 Statistical Model for Cohort Analysis 
 
For all primary study objectives, weighted Poisson models will be used to estimate IRDs and 
IRRs (and 95% CIs), adjusted for all covariates included in the PS model. Robust variance 
estimators will be used to account for the weighting. Analyses will be conducted amongst the 
overall NB cohort and also stratified by initiators of CONTRAVE® and those with overlapping, 
concomitant use of Naltrexone and Bupropion.  
 
For the secondary objective of assessing the comparability of findings in a RWD cohort with the 
lorcaserin clinical trial, we will conduct a time-to event analysis in the propensity-score matched 
cohort. We will produce hazard ratios (HR) and 95% confidence intervals using a weighted Cox 
proportional-hazards model with the stratification factor as a covariate. 
 
Additionally, informed by previous work in the RCT DUPLICATE Initiative, we will examine 
the following metrics in concert to assess the comparability in findings between the 
CAMELLIA-TIMI 61 trial and findings in the data:  
 
 Regulatory agreement, which is the ability of the study using RWD to replicate the 
direction and magnitude of the RCT; 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 25 of 29 
 Estimate agreement, defined as a HR from the replication study that was within the 95% 
CI for the RCT estimate; 
 Standardized difference between the RCT and replication effect estimate, with a p-value 
< 0.05 considered statistically significant. 
 
 
Conditional logistic regression models will be used to compare the odds of exposure to NB in 
the hazard window to the odds of exposure in the referent window (i.e., odds ratio) for the case 
cross-over design.  
 
9.6 Quality Control 
The study will be carried out according to Exponent’s Quality Management System (QMS), 
with specific procedures being consistent with the International Society for 
Pharmacoepidemiology’s Guidelines for Good Pharmacoepidemiology Practices 
(http://www.pharmacoepi.org), as well as the FDA Best Practice Guidance document 
(http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/)4-6,27. In 
particular, the QMS at Exponent ensures that processes and deliverables are documented, 
reviewed, and validated in sufficient detail to allow for subsequent re-examination or 
replication. Exponent’s quality management system is independently assessed against the most 
recognized and comprehensive international standard for quality management systems, ISO 
9001. Exponent complies with the ISO 9001:2015 standard; the ISO 17025:2017 standard; U.S. 
Code of Federal Regulations, Title 10, Part 50, Appendix B; U.S. Code of Federal Regulations, 
Title 10, Part 21; and the respective advertising policy for each registration, accreditation, and 
approval. 
 
The core project team will consist of at least one Principal Scientist who will provide scientific 
oversight of the study, a senior epidemiologist who will manage day-to-day aspects of the 
scientific conduct of the study, research analyst(s), and a project manager. Project management 
is integrated into the project team and supports the development of the project plan, monitoring 
timelines and budgets, securing appropriate study resources, and facilitating completion of 
contracted deliverables. In addition, Exponent staff members will support the project team by 
providing review and quality assurance of documents and programs associated with the conduct 
of the study, including assurance of appropriate data confidentiality, storage, and management.  
 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 26 of 29 
10 LIMITATIONS OF THE DATA AND RESEARCH METHODS 
10.1 Electronic Health Data 
All EHR databases and healthcare registries have certain inherent limitations because the data 
are collected for clinical patient management, administration, and other non-research purposes. 
EHR data represent the intent of the prescriber through the written prescription for a medication; 
they do not indicate that a medication was filled, consumed, or taken as prescribed.  
The EHR data will not include healthcare encounters or prescriptions from providers that do not 
contribute to the EHR aggregating entity (Arcadia). This can result in under-capture of some 
medication exposure. In addition, patients prescribed medications may not have them dispensed 
and may not consume them as prescribed even when they are dispensed. This can overestimate 
some patients’ actual medication exposure.  
 
10.2 Unmeasured Patient Risk Factors 
In this study, robust PS adjustment relies on accurate measurement of risk factors for MACE. 
As such, the lack of important risk factors can introduce unmeasured confounding, where these 
risk factors remain imbalanced between groups after PS adjustment. The use of an active 
comparator will mitigate some unmeasured confounding, because it shares the same indication 
as NB28. Self-controlled designs are not subject to measured or unmeasured confounding by 
factors that do not vary over the observation window. Therefore, the case-crossover study will 
help inform the extent to which residual confounding may affect the cohort analysis. 
11 PROTECTION OF HUMAN SUBJECTS 
Confidentiality of patient records will be maintained at all times. All analyses will be performed 
in accordance with applicable laws and regulations. All study reports will only contain 
aggregated results and will not identify individual patients or physicians. At no time during the 
study will Currax, Exponent, or any consultants on the study receive patient-identifying 
information. 
12 MANAGEMENT AND REPORTING OF ADVERSE EVENTS 
For this study using previously collected and deidentified electronic healthcare data, the 
research team does not anticipate any new adverse events to be identified. If, however, new 
adverse events are found during the course of the study, they will be vetted through the 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 27 of 29 
pharmacovigilance processes at Currax Pharmaceuticals LLC and reported to regulatory 
authorities, as appropriate. 
 
13 PLANS FOR DISSEMINATION AND COMMUNICATING 
STUDY RESULTS 
A report of the findings of this study will be presented to FDA upon finalization of study output. 
Additionally, Currax Pharmaceuticals LLC intends for the research team to publish the results in 
a peer reviewed journal expeditiously and in keeping with ISPE GPP (2015) and authorship 
guidelines presented by the International Committee of Medical Journal Editors (ICMJE) 
recommendations (2019). 
 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 28 of 29 
14 REFERENCES 
1. 
Contrave Prescribing Information. (https://contrave.com/contrave-pi/). 
2. 
Franklin JM, Patorno E, Desai RJ, et al. Emulating randomized clinical trials with 
nonrandomized real-world evidence studies: first results from the RCT DUPLICATE 
initiative. Circulation 2021;143(10):1002-1013. 
3. 
Merola D, Young J, Schrag D, Lin KJ, Robert N, Schneeweiss S. Oncology Drug 
Effectiveness from Electronic Health Record Data Calibrated Against RCT Evidence: 
The PARSIFAL Trial Emulation. Clinical Epidemiology 2022;14:1135-1144. 
4. 
Administration FaD. Framework for FDA’s Real-World Evidence Program. 
(https://www.fda.gov/media/120060/download). 
5. 
Administration FaD. Real-World Data: Assessing Electronic Health Records and 
Medical Claims Data To Support Regulatory DecisionMaking for Drug and Biological 
Products Guidance for Industry. (https://www.fda.gov/media/152503/download). 
6. 
Administration FaD. Submitting Documents Using Real-World Data and Real-World 
Evidence to FDA for Drug and Biological Products 
Guidance for Industry. (https://www.fda.gov/media/124795/download). 
7. 
Schneeweiss S, Patrick AR, Stürmer T, et al. Increasing levels of restriction in 
pharmacoepidemiologic database studies of elderly and comparison with randomized 
trial results. Medical care 2007;45(10 SUPL):S131. 
8. 
Suissa K, Schneeweiss S, Kim DW, Patorno E. Prescribing trends and clinical 
characteristics of patients starting antiobesity drugs in the United States. Diabetes, 
Obesity and Metabolism 2021. 
9. 
BELVIQ Prescribing Information. Revised 4/2018. Available from: 
https://www.belviq.com/pdfs/Belviq_Prescribing_information-pdf.pdf. Accessed May 
30, 2021. 
10. 
BELVIQ Prescribing Information. 
(https://www.belviq.com/pdfs/Belviq_Prescribing_information-pdf.pdf). 
11. 
FDA requests the withdrawal of the weight-loss drug Belviq, Belviq XR (lorcaserin) 
from the market: Potential risk of cancer outweighs the benefits. 
https://www.fda.gov/media/135189/download: U.S. Food and Drug Administration; 
2020. 
12. 
Bohula EA, Wiviott SD, McGuire DK, et al. Cardiovascular safety of lorcaserin in 
overweight or obese patients. New England Journal of Medicine 2018;379(12):1107-
1117. 
13. 
Valente MA, Hillege HL, Navis G, et al. The Chronic Kidney Disease Epidemiology 
Collaboration equation outperforms the Modification of Diet in Renal Disease equation 
for estimating glomerular filtration rate in chronic systolic heart failure. European 
journal of heart failure 2014;16(1):86-94. 
14. 
Cutrona SL, Toh S, Iyer A, et al. Validation of acute myocardial infarction in the Food 
and Drug Administration's Mini-Sentinel program. Pharmacoepidemiol Drug Saf 
2013;22(1):40-54. (In eng). DOI: 10.1002/pds.3310. 
15. 
Davis LA, Mann A, Cannon GW, Mikuls TR, Reimold AM, Caplan L. Validation of 
diagnostic and procedural codes for identification of acute cardiovascular events in US 
veterans with rheumatoid arthritis. EGEMS 2013;1(3). 

Confidential Information 
CONTRAVE® Cardiovascular Safety Study, Final Protocol  
January 26, 2023 
Page 29 of 29 
16. 
Arcadia. Aggregate Pop. Health Data. 2021 (https://arcadia.io/products/aggregate-your-
data/). 
17. 
Datavant. Health and Data Analytics. (https://datavant.com/solutions/health-data-
analytics/). 
18. 
Du M, Hou J, Hsu B, et al. Incorporating Datavant’s Death Index in Mortality Analysis. 
(https://www.soa.org/globalassets/assets/files/resources/research-
report/2021/population-mortality-
comparisions.pdf#:~:text=Datavant%2C%20Inc.%2C%20a%20private%20U.S.%20com
pany%20specializing%20in,databases%2C%20can%20be%20aggregated%20and%20m
odeled%20for%20analysis.). 
19. 
Datavant. Mortality Data in Healthcare Analytics Sourcing Robust Data in a HIPAA-
Compliant Manner. (https://datavant.com/wp-
content/uploads/dlm_uploads/2018/09/White-Paper_-Mortality-Data-in-Healthcare.pdf). 
20. 
Ritchey ME, Harding A, Hunter S, et al. Cardiovascular safety during and after use of 
phentermine and topiramate. The Journal of Clinical Endocrinology & Metabolism 
2019;104(2):513-522. 
21. 
Loughlin AM, Qiao Q, Nunes AP, et al. Effectiveness and tolerability of therapy with 
exenatide once weekly vs basal insulin among injectable-drug-naïve elderly or renal 
impaired patients with type 2 diabetes in the United States. Diabetes, Obesity and 
Metabolism 2018;20(4):898-909. DOI: 10.1111/dom.13175. 
22. 
Nunes AP, Loughlin AM, Qiao Q, et al. Tolerability and effectiveness of exenatide once 
weekly relative to basal insulin among type 2 diabetes patients of different races in 
routine care. Diabetes Therapy 2017;8(6):1349-1364. 
23. 
Lee KJ, Carlin JB. Multiple imputation for missing data: fully conditional specification 
versus multivariate normal imputation. American journal of epidemiology 
2010;171(5):624-632. 
24. 
Harder VS, Stuart EA, Anthony JC. Propensity score techniques and the assessment of 
measured covariate balance to test causal associations in psychological research. 
Psychological methods 2010;15(3):234. 
25. 
Brookhart MA, Schneeweiss S, Rothman KJ, Glynn RJ, Avorn J, Stürmer T. Variable 
selection for propensity score models. American journal of epidemiology 
2006;163(12):1149-1156. 
26. 
Lee BK, Lessler J, Stuart EA. Weight trimming and propensity score weighting. PloS 
one 2011;6(3):e18174. 
27. 
(ISPE) ISfP. Guidelines for Good Pharmacoepidemiology Practices (GPP). 
(https://www.pharmacoepi.org/resources/policies/guidelines-08027/). 
28. 
Seeger JD, Nunes A, Loughlin AM. Using RWE research to extend clinical trials in 
diabetes: an example with implications for the future. Diabetes, Obesity and Metabolism 
2020;22:35-44.