Clinical trial NCT03007394
Conditions: Cocaine-Related Disorders
Keywords: Cocaine Use Disorder
Sponsor: National Institute on Drug Abuse (NIDA)
Start date: 2017-12-19; Completion date: 2019-12-01
Enrollment: 272 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to evaluate the efficacy and safety of lorcaserin in the treatment of cocaine use disorder.

Detailed description:
This is a 19-week, multi-center, randomized, Phase 2 clinical study comparing the efficacy of lorcaserin (10mg, b.i.d) to matched placebo in the treatment of cocaine use disorder. Up to 3 weeks will be allowed for the Screening Period and a 13-week treatment phase, with a 3-week follow-up period, with scheduled visits during Study weeks 14 and 16.

Arms: arm 1: 10 mg capsule by mouth, twice a day, for 13 weeks arm 2: 10 mg placebo capsule, twice a day, for 13 weeks
Interventions: intervention 1: Lorcaserin intervention 2: Placebo Oral Capsule
Intervention descriptions: intervention 1: Lorcaserin Capsule intervention 2: sugar pill to mimic lorcaserin 10mg capsule

Protocol documents:
Prot_SAP_000.pdf: 
NIDA/VA CS #1033: Lorcaserin - Cocaine Treatment Study  
CONFIDENTIAL 
Protocol Version 3, Date: 04.17.2017 
 
 
 
 
 
 
NIDA/VA 
 
Cooperative Study #1033 
 
IND Number: 124,980 
 
 
PHASE 2, MULTI-CENTER TRIAL OF 
LORCASERIN IN THE TREATMENT OF 
COCAINE USE DISORDER 
 
 
PROTOCOL 
 
Version 3 
 
April 17, 2017 
 
 
 
 
 
 
 
 
 
Privileged & Confidential 
 
This document is a confidential communication of NIDA, the National Institute on Drug Abuse. 
Acceptance of this document constitutes agreement by the recipient that no unpublished 
information contained herein will be published or disclosed without NIDA’s prior written 
approval, except that this document may be disclosed to appropriate Institutional Review Boards 
under the condition that they are requested to keep it confidential. 


NIDA/VA CS #1033: Lorcaserin - Cocaine Treatment Study  
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Protocol Version 3, Date: 04.17.2017 
1 
STUDY #: NIDA/VA CSP-1033 
 
PHASE 2, MULTI-CENTER TRIAL OF LORCASERIN IN THE TREATMENT OF 
COCAINE USE DISORDER 
 
Investigational New Drug Application (IND) Number:  124,980 
 
NIDA Protocol Chairman: 
David McCann, Ph.D., Tel: 301-827-5934 
VA Protocol Chairperson: 
TBD 
NIDA Principal Investigator: 
Shwe Gyaw, M.D., Tel: 301-827-5924 
NIDA Medical Monitor: 
Tanya Ramey, M.D., Ph.D., Tel: 301-827-5944 
NIDA Project Manager: 
Liza Zeinert, M.A., Tel: 301-443-1138 
Funding Agency: 
Division of Therapeutics and Medical Consequences 
(DTMC)  
National Institute on Drug Abuse (NIDA), NIH  
6001 Executive Boulevard 
Bethesda, MD 20892 
VA Data Coordinating Center: 
VA Cooperative Studies Program Coordinating Center 
VA CSPCC – 151E 
P.O. Box 1010 
Perry Point, MD 21902 
VA Biostatistician: 
Joe Collins, Sc.D., Tel: 410-642-2411, ex. 5308 
VA Research Pharmacy: 
VA Cooperative Studies Program Clinical Research 
Pharmacy Coordinating Center 
VA CSPCRPCC 
2401 Centre Avenue, SE 
Albuquerque, NM 87106-4180 
VA Research Pharmacist: 
Kathy Boardman, R.Ph., M.S. Tel: 505-248-3203 
 
 
 
 
This document is a confidential communication of NIDA. Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein will be 
published or disclosed without NIDA’s prior written approval, except that this document may be 
disclosed to appropriate Institutional Review Boards under the condition that they are requested 
to keep it confidential.


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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ............................................................................................................. 2 
LIST OF ABBREVIATIONS ...................................................................................................... 6 
1 
STUDY SCHEMA ................................................................................................................ 8 
2 
SYNOPSIS ............................................................................................................................. 9 
3 
INTRODUCTION AND RATIONALE ............................................................................ 12 
3.1 
THERAPEUTIC STRATEGIES FOR TREATING COCAINE ABUSE ......................................... 12 
3.2 
USE OF SEROTONERGIC AGENTS TO TREAT COCAINE DEPENDENCY ............................. 12 
3.3 
RATIONALE FOR USE OF PREDICTIVE ENRICHMENT STRATEGIES ................................... 13 
3.4 
LORCASERIN .................................................................................................................. 14 
3.4.1 
FDA Label Indication .............................................................................................. 14 
3.4.2 
Receptor Pharmacology ........................................................................................... 14 
3.4.3 
Pre-Clinical Experience with Lorcaserin Relevant to Substance Abuse Treatment 14 
3.4.4 
Clinical Experience with Lorcaserin Relevant to Substance Abuse Treatment ...... 15 
3.4.5 
Pharmacokinetics ..................................................................................................... 16 
3.4.6 
Dose Justification ..................................................................................................... 17 
3.4.7 
Lorcaserin Safety ..................................................................................................... 17 
3.5 
ACETAZOLAMIDE SAFETY/DOSE JUSTIFICATION ........................................................... 19 
4 
STUDY OBJECTIVE ......................................................................................................... 19 
5 
IND HOLDER ..................................................................................................................... 19 
6 
STUDY SITES ..................................................................................................................... 19 
7 
STUDY DESIGN ................................................................................................................. 19 
8 
SUBJECT SELECTION .................................................................................................... 20 
8.1 
ELIGIBLE SUBJECTS ....................................................................................................... 20 
8.2 
INCLUSION CRITERIA ..................................................................................................... 21 
8.3 
EXCLUSION CRITERIA .................................................................................................... 21 
9 
INVESTIGATIONAL PRODUCTS ................................................................................. 23 
9.1 
LORCASERIN .................................................................................................................. 23 
9.2 
LORCASERIN PLACEBO .................................................................................................. 23 
9.3 
ACETAZOLAMIDE (ACZM) ............................................................................................ 23 
9.4 
PACKAGING AND LABELING ........................................................................................... 24 
9.5 
DRUG STORAGE ............................................................................................................. 24 
9.6 
DISPENSING RECORD ..................................................................................................... 24 
9.7 
USED/UNUSED INVESTIGATIONAL PRODUCTS ................................................................ 24 
10 INTERVENTIONS ............................................................................................................. 24 
10.1 
STUDY DRUG ................................................................................................................. 24 
10.2 
COUNSELOR GUIDED BEHAVIORAL THERAPY (COCAINE).............................................. 25 


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10.3 
COMPUTER-BASED THERAPY (ALCOHOL) ..................................................................... 25 
11 STUDY PROCEDURES .................................................................................................... 25 
11.1 
SUBJECT RECRUITMENT ................................................................................................. 28 
11.2 
SCREENING (STUDY DAYS -21 TO -1)............................................................................. 28 
11.3 
SCHEDULING OF STUDY DAY 1 VISIT ............................................................................. 28 
11.4 
STUDY DAY 1 (WEEK 1) – ENROLLMENT ....................................................................... 28 
11.5 
STUDY DAY 8 (WEEK 2) – RANDOMIZATION ................................................................. 29 
11.6 
STUDY VISITS (WEEKS 2 TO 13) .................................................................................... 29 
11.7 
FOLLOW-UP VISITS (WEEKS 14 AND 16) ....................................................................... 29 
11.8 
EARLY TERMINATION VISIT – PRIOR TO DOSING COMPLETION ..................................... 29 
11.9 
SITUATIONS REQUIRING STUDY DRUG DISCONTINUATION ............................................ 30 
11.10 EARLY STUDY TERMINATION ........................................................................................ 31 
11.11 PREVENTING STUDY DROP-OUTS .................................................................................. 31 
11.12 SUBJECT COMPENSATION............................................................................................... 31 
11.13 MAINTAINING AND BREAKING STUDY BLIND ................................................................ 34 
12 ASSESSMENT METHODS ............................................................................................... 34 
12.1 
SUBJECT LOCATOR FORM .............................................................................................. 34 
12.2 
MEDICAL HISTORY ........................................................................................................ 34 
12.3 
SMOKING AND ALCOHOL HISTORY ................................................................................ 35 
12.4 
PSYCHIATRIC HISTORY .................................................................................................. 35 
12.5 
DEMOGRAPHICS ............................................................................................................. 35 
12.6 
ADDICTION SEVERITY INDEX-LITE (ASI-LITE) .............................................................. 35 
12.7 
PHYSICAL EXAM ............................................................................................................ 35 
12.8 
VITAL SIGNS AND WEIGHT ............................................................................................ 35 
12.9 
PREGNANCY TEST .......................................................................................................... 35 
12.10 12-LEAD ECG ................................................................................................................ 36 
12.11 BECK DEPRESSION INVENTORY-SECOND EDITION (BDI-II) .......................................... 36 
12.12 COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) ............................................. 36 
12.13 BLOOD CHEMISTRIES ..................................................................................................... 37 
12.14 HEMATOLOGY ................................................................................................................ 37 
12.15 URINALYSIS ................................................................................................................... 37 
12.16 URINE DRUG SCREEN .................................................................................................... 37 
12.17 URINE FENTANYL .......................................................................................................... 37 
12.18 URINE COTININE ............................................................................................................ 37 
12.19 ETG URINE ALCOHOL TEST ........................................................................................... 37 
12.20 URINE BE TESTING ........................................................................................................ 38 
12.21 BLOOD COLLECTIONS FOR MEDICATION ADHERENCE ................................................... 38 
12.22 COGNITIVE BEHAVIORAL THERAPY (CBT) .................................................................... 38 
12.23 ALCOHOL INTERVENTION: QUIT TO QUIT ...................................................................... 38 
12.24 AIVIEW ADHERENCE MONITORING ............................................................................... 38 
12.25 CONCOMITANT MEDICATIONS ....................................................................................... 38 
12.25.1 Concomitant Medications Always Excluded ........................................................... 39 
12.25.2 Allowable Concomitant Medications with Limitations ........................................... 39 
12.26 SUBSTANCE USE REPORT (SUR) ................................................................................... 40 
12.27 BRIEF SUBSTANCE CRAVING SCALE (BSCS) ................................................................. 40 


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12.28 ADVERSE EVENTS .......................................................................................................... 40 
13 REGULATORY AND REPORTING REQUIREMENTS ............................................. 40 
13.1 
GOOD CLINICAL PRACTICES .......................................................................................... 40 
13.2 
FDA FORM 1572 ........................................................................................................... 40 
13.3 
IRB APPROVAL .............................................................................................................. 41 
13.4 
INFORMED CONSENT ...................................................................................................... 41 
13.5 
USE OF PROTECTED HEALTH INFORMATION .................................................................. 41 
13.6 
DRUG ACCOUNTABILITY ................................................................................................ 42 
13.7 
MONITORING ................................................................................................................. 42 
13.7.1 Data and Safety Monitoring Board .......................................................................... 42 
13.7.2 Medical Monitor ...................................................................................................... 42 
13.7.3 Clinical Monitors ..................................................................................................... 42 
13.8 
STUDY OR SITE DISCONTINUATION ................................................................................ 43 
13.9 
RETENTION OF RECORDS ............................................................................................... 43 
13.10 ADVERSE EVENTS REPORTING ....................................................................................... 43 
13.10.1 Pregnancy ................................................................................................................. 44 
13.11 SERIOUS ADVERSE EVENTS ........................................................................................... 44 
13.12 SUBJECT CONFIDENTIALITY ........................................................................................... 45 
14 STATISTICAL ANALYSIS .............................................................................................. 45 
14.1 
PREDICTIVE ENRICHMENT STRATEGY AND SAMPLE SIZE .............................................. 46 
14.2 
DEFINITIONS OF STUDY POPULATIONS ........................................................................... 48 
14.3 
OUTCOME MEASURES .................................................................................................... 49 
14.3.1 Primary Efficacy Outcome Measures ...................................................................... 49 
14.3.2 Secondary Efficacy Outcome Measures .................................................................. 50 
14.3.3 Exploratory Outcome Measures .............................................................................. 50 
14.4 
SAFETY EVALUATIONS .................................................................................................. 54 
15 DATA MANAGEMENT AND ELECTRONIC CASE REPORT FORMS 
(ECRFS) ....................................................................................................................................... 55 
15.1 
DATA COLLECTION ........................................................................................................ 55 
15.2 
DATA EDITING AND CONTROL ....................................................................................... 55 
15.3 
DATA ENTRY, PROCESSING AND ANALYSES .................................................................. 56 
16 PUBLICATION OF THE STUDY RESULTS................................................................. 56 
17 SIGNATURES..................................................................................................................... 57 
18 REFERENCES .................................................................................................................... 58 
 
 
 


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LIST OF TABLES 
Table 1. Lorcaserin Receptor Affinity .......................................................................................... 14 
Table 2. Adverse Reactions Reported by ≥2% of Lorcaserin-Treated Patients and More 
Commonly than with Placebo in Patients without Diabetes Mellitus........................................... 17 
Table 3.  Schedule of Events......................................................................................................... 26 
Table 4. Subject Compensation .................................................................................................... 33 
 
LIST OF FIGURES 
Figure 1. Study Schema .................................................................................................................. 8 
Figure 2. Effects of Lorcaserin on Responding for Cocaine or Food in Rhesus Monkeys .......... 15 
Figure 3. Enrichment Strategy Study Design ............................................................................... 48 
 
LIST OF APPENDICES 
APPENDIX I:  
Instructions for Evaluating and Reporting Adverse Events and Serious 
Adverse Events 
APPENDIX II: Procedure for Applying for Certificate of Confidentiality 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
5-HT 
serotonin (5-hydroxytryptamine) 
AA 
Alcoholics Anonymous 
AAA 
attempting alcohol abstinence 
ACZM 
Acetazolamide 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT/SGPT 
alanine aminotransferase/serum glutamate-pyruvate transaminase 
ANCOVA 
analysis of covariance 
ASI 
Addiction Severity Index 
AST/SGOT 
Aspartate aminotransferase/serum glutamic oxaloacetic 
transaminase 
AUC 
area under the concentration-time curve 
AUD 
alcohol use disorder 
BDI 
Beck Depression Inventory 
BE  
Benzoylecgonine 
BID 
twice daily 
BP 
blood pressure 
BSCS 
Brief Substance Craving Scale 
BUN 
blood urea nitrogen 
CA 
Cocaine Anonymous 
CBC 
complete blood cell count 
CBT 
cognitive behavioral therapy 
CI 
confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments of 1988 
Cmax 
maximum plasma concentration 
CRF 
case report form 
CSF 
cerebrospinal fluid 
CSP 
Cooperative Studies Program 
CSPCC 
Cooperative Studies Program Coordinating Center 
CSPCRPCC 
Cooperative Studies Program Clinical Research Pharmacy 
Coordinating Center 
CYP 
cytochrome P450 
DA 
Dopamine 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
DSMB 
Data and Safety Monitoring Board 
DTMC 
Division of Therapeutics and Medical Consequences 
EC50 
median effective dose 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
eDC 
electronic data capture 
EtG 
ethyl glucuronide 
FDA 
Food and Drug Administration 
FMO 
flavin containing monooxygenase 
GCP  
Good Clinical Practice 


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Abbreviation 
Definition 
GAD 
generalized anxiety disorder 
GGT 
gamma-glutamyltranspeptidase 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
Interactive Web Response System 
i.v. 
Intravenous 
LD50 
median lethal dose 
MAOI 
monoamine oxidase inhibitor 
MDD 
major depressive disorder 
NA 
Narcotics Anonymous 
NE 
Norepinephrine 
NDA 
New Drug Application 
NF 
National Formulary 
NIAAA 
National Institute on Alcohol Abuse and Alcoholism 
NIDA 
National Institute on Drug Abuse 
NMS 
neuroleptic malignant syndrome 
PK 
pharmacokinetic(s) 
PPEE 
prequalified for primary efficacy endpoint 
SAE 
serious adverse event 
SCID-5-RV 
Structured Clinical Interview for DSM-5 – Research Version 
SD 
standard deviation 
SI 
site investigator 
SNRI 
selective serotonin-norepinephrine reuptake inhibitor 
SSRI 
selective serotonin reuptake inhibitor 
SUR 
substance use report 
TCA 
tricyclic antidepressant 
TLFB 
timeline followback 
Tmax 
time to maximum concentration 
UDS 
urine drug screen 
USP 
United States Pharmacopeia 
VA 
Department of Veterans Affairs 
VTA 
ventral tegmental area 
 
 
 


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1 
STUDY SCHEMA 
 
Figure 1. Study Schema 
 
  
 
 


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2 
SYNOPSIS 
 
OBJECTIVE: The objective of this study is to evaluate the efficacy and safety of lorcaserin in 
the treatment of cocaine use disorder. 
STUDY DESIGN: This is a 19-week, multi-center, parallel group study that includes: 1) up to 3 
weeks for screening; 2) a 13-week Treatment Phase consisting of a 1­week, single-blind run-in 
period, when all subjects receive twice daily 15 mg acetazolamide capsules (a medication 
adherence marker), followed by randomization to either twice daily 10 mg lorcaserin or placebo 
capsules for the remaining 12 weeks; and 3) a 3-week follow-up period, with scheduled visits 
during Study Weeks 14 and 16. 
Beginning on Study Day 1, subjects will visit the clinic on a weekly basis throughout the 13-
week Treatment Phase.  At weekly clinic visits, subjects will receive study drug, provide urine 
samples and will participate in other protocol-specified assessments.  Subjects will also take part 
in a weekly one-hour, manualized individual cognitive behavioral therapy session (CBT) to 
facilitate avoidance of cocaine use.  
On Study Day 1, all subjects will view the first module of a computer-based alcohol intervention 
that describes the potential benefits of abstaining from alcohol during the trial. Though the 
module encourages abstinence from alcohol, each subject will determine for him/herself whether 
this will also be one of their goals during this trial. On Study Day 8, prior to randomization, 
subjects will be given the option of viewing the second module of the alcohol intervention. Each 
subject’s decision (yes or no) to continue viewing the alcohol intervention modules will be 
recorded prior to randomization, and will serve as one of the stratification factors for 
randomization.  
Beginning on Study Day 8, subjects will participate in a medication adherence monitoring 
procedure.  The procedure utilizes a handheld device (smartphone) to record the administration 
of each dose of study drug and reporting of cocaine and alcohol use.  Devices are issued by the 
site and are pre-programmed with the AiView application, a HIPAA-compliant medication 
monitoring software program. Use of the device carries associated opportunities to earn rewards 
contingent upon appropriate performance of tasks.  
A randomized block design within each site will be utilized with the following stratification 
factors: 
a. Number of subject-reported cocaine use days during the 30 days immediately prior to 
screening (<8 days versus 8 or more days); 
b. Continued viewing of the computer-based alcohol intervention on Study Day 8 (yes/no); 
c. Presence of alcohol and/or benzodiazepine dependence (yes/no). 
 
SAMPLE SIZE: Approximately 272 total subjects will be enrolled across 10 or more clinical 
sites. Enrolled subjects who do not progress to randomization on Study Day 8 will not be 
replaced. 


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DURATION: The enrollment period is anticipated to be approximately 12 months and the total 
study duration will be approximately 18 months. 
STUDY POPULATION: Two hundred seventy-two treatment-seeking males and females who 
meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for 
cocaine use disorder will be recruited from 10 or more clinical sites. Entry into the study will be 
open to men and women between 18 to 65 years of age, from all racial and ethnic groups. Only 
those subjects who authorize their enrollment in the Verified Clinical Trials registry and who 
provide written informed consent; who report cocaine use during the 30 days prior to screening; 
who provide at least one urine specimen positive for benzoylecgonine (BE) during screening; 
and who meet all other eligibility criteria and will be enrolled to receive study drug. 
INTERVENTIONS: Beginning on the day of enrollment (Study Day 1), subjects will take 
acetazolamide (ACZM) 15 mg twice a day (BID) for seven days. Starting on the day of 
randomization (Study Day 8), subjects will take either lorcaserin 10 mg BID or matched placebo 
BID for the remaining 12 weeks of the Treatment Phase (Weeks 2-13). 
All subjects will participate in weekly, one-hour, individual cognitive behavioral therapy session 
during the Treatment Phase (Weeks 1-13) which will be conducted as described in the NIDA 
therapy manual entitled “A Cognitive-Behavioral Approach: Treating Cocaine Addiction” 
(Carroll et al., 1998). A computer-based alcohol intervention, “Quit to Quit”, will be viewed by 
all subjects on Study Day 1 and will be continued on an optional basis at the discretion of each 
subject (for a total of 4 modules).  “Quit to Quit” is a modified version of “Take Control,” an 
interactive set of modules developed by the National Institute on Alcohol Abuse and Alcoholism 
(NIAAA) for use in medication trials (Devine et al., 2016). 
SAFETY ASSESSMENTS: During Screening, all subjects who provided informed consent will 
undergo the following assessments to determine their suitability for enrollment: physical 
examination, body weight, vital signs (blood pressure [BP], pulse, and respiratory rate), 12-lead 
electrocardiogram (ECG), clinical laboratory tests (blood chemistry, hematology, and urinalysis), 
on-site urine drug screen for cocaine and other substances of abuse (methamphetamine, 
amphetamine, methadone, buprenorphine, oxycodone and other opiates), prior/concomitant 
medication use and suicidality (using the Columbia Suicide Severity Rating Scale [C-SSRS]). 
Adverse events will be documented beginning on the day the subject provides Informed Consent. 
A pregnancy test will be performed during Screening on all female subjects.  
Beginning on the day of enrollment (Study Day 1), subjects will attend the clinic once per week 
during the Treatment Phase (Weeks 1-13) for assessments of vital signs, body weight, 
concomitant medication use, suicidality (using the C-SSRS), treatment-emergent adverse events 
(AEs), and a pregnancy test (if female). At the clinic visit during week 7, clinical laboratory tests 
and an ECG will be performed.  
Subjects who completed treatment through Week 13 will return for a follow-up visit during 
Week 14.  Assessments at the Week 14 Follow-Up Visit include:  AEs, vital signs, body weight, 
concomitant medication use, suicidality (using the C-SSRS), and a pregnancy test (if female).  A 
final Follow-Up Visit will occur at the end of the study (Week 16).  Subjects will be evaluated 
for AEs, suicidality , vital signs, physical exam, body weight, clinical laboratory tests, ECG, and 


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pregnancy (if female).  Subjects who terminated earlier than Week 13 will complete these 
assessments at the time of early termination. 
EFFICACY ASSESSMENTS: An enrichment strategy based on pre-randomization data from 
the run-in phase will be used to define a subpopulation of study participants who are likely to be 
medication adherent during the Treatment Phase and who are likely to exhibit a low placebo 
response rate. Data from only this subpopulation, termed the “prequalified for primary efficacy 
endpoint” (PPEE) population, will be utilized for the primary endpoint success/failure analysis. 
The PPEE population consists of subjects who have demonstrated adherence to the 
acetazolamide run-in regimen (based on the plasma sample collected on Study Day 8) and who, 
on the first day of Screening, reported 8 or more days of cocaine use in the previous 30 days. The 
primary endpoint is the percentage of subjects successfully achieving abstinence from cocaine 
during the last three weeks of treatment (Study Weeks 11-13) in the PPEE population. 
At the beginning of Study Day 1, at each weekly clinic visit from Week 1 though Week 14, and 
at the Week 16 Follow-Up Visit, data for the efficacy endpoints will be collected (including 
urine BE, cotinine and alcohol).  
A subject will be regarded as a treatment success (abstinent from cocaine during the last three 
weeks of treatment) if: 
a. There are self-report data indicating no cocaine use on each day of the 3-week period; 
b. There is at least one benzoylecgonine (BE) assay result for a urine sample collected 
within the 3-week period; and 
c. BE assay results are negative (BE <150 ng/mL) for all urine samples collected during the 
3-week period. 
Subjects not meeting these three criteria (including dropouts) will be regarded as treatment 
failures. 
The secondary endpoint is the proportion of subjects who successfully achieve abstinence from 
cocaine during the last three weeks of treatment (Study Weeks 11-13) in the subset of the PPEE 
population who are either Non-Drinkers or who are attempting alcohol abstinence, as evidenced 
by their decision to continue viewing the alcohol intervention modules on Study Day 8. 
Comparison of this proportion in subjects receiving lorcaserin vs. placebo will constitute the 
secondary endpoint analysis. In the analysis, abstinence will be defined as described for the 
primary endpoint.  
An important exploratory endpoint will focus on the efficacy of lorcaserin in facilitation of 
abstinence from alcohol based on self-reported drinking and urine ethyl glucuronide (EtG) 
assays.


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3 
INTRODUCTION AND RATIONALE 
3.1 
Therapeutic Strategies for Treating Cocaine Abuse 
Cocaine dependence is a significant public health problem which is associated with serious medical, 
psychiatric, social, and economic consequences. The treatment of cocaine dependence can decrease 
addiction-related health care utilization and costs as well as improve the health and quality of life for those 
who are addicted to cocaine. In particular, homelessness and unemployment are common in those who are 
addicted to cocaine. Typically, addiction-related behaviors present significant barriers to securing stable 
housing and employment. 
A variety of neuropharmacological strategies are being pursued in the search for an effective treatment for 
cocaine abuse. These include: 1) preventing or attenuating cocaine’s effects, 2) restoration of central nervous 
system homeostasis, 3) reducing craving or enhancing the addict’s ability to manage his/her response to 
craving, 4) treating underlying comorbid conditions that may predispose targeted subpopulations toward 
dependence, and 5) stress reduction to prevent relapse. Although many compounds have been evaluated for 
the treatment of cocaine dependence, none have been approved by the Food and Drug Administration (FDA) 
for this indication. Psychosocial and behavioral therapy are currently the treatments of choice for cocaine 
dependence. 
3.2 
Use of Serotonergic Agents to Treat Cocaine Dependency  
Cocaine has three primary mechanisms of action in the brain. It binds to and inhibits the activity of the 
dopamine (DA) transporter, the norepinephrine (NE) transporter, and the serotonin (5-HT) transporter. These 
actions prevent reuptake of the three neurotransmitters after release from neurons, which increases their 
extracellular concentrations after acute exposure to cocaine. In contrast, the effect of chronic cocaine use is 
to decrease dopaminergic, noradrenergic, and serotonergic tone (as the brain adapts to the presence of 
cocaine). Thus, a theoretical rationale can be developed for potential efficacy in the treatment of cocaine use 
disorder for almost any compound that interacts with one or more of the three neurotransmitter systems. 
Unfortunately, many clinical trials focusing on the treatment of cocaine use disorder have failed to show 
robust efficacy for compounds that act to inhibit the activity of the transporters, for compounds that act to 
stimulate the release of DA and NE, and for compounds that act directly at DA receptors (Castells et al., 
2010; Amato et al., 2011). 
Preclinical and clinical studies indicate that agents stimulating 5-HT release might be effective in treating 
cocaine use disorder. For example, the 5-HT releaser fenfluramine has been shown to decrease responding to 
intravenous cocaine in rhesus monkeys (Negus et al., 2007) and to reduce reported levels of cocaine craving 
in a human laboratory study of experienced cocaine users (Buydens-Branchey et al., 1998). Unfortunately, 
fenfluramine (an anorectic agent originally approved by the FDA in 1973) causes valvular abnormalities in 
the heart (Connolly et al., 1997) and it had to be withdrawn from the United States (U.S.) market. It is likely 
that all 5­HT releasers would demonstrate this same toxicity, which appears to be medicated by the 
stimulation of 5-HT (2b) receptors (Roth, 2007). The 5-HT (2b) receptor is 1 of 14 known types of 5-HT 
receptors, all of which are stimulated by 5-HT releasers, such as fenfluramine. Thus, direct 5-HT receptor 
agonists that do not stimulate 5-HT (2b) receptors (but stimulate other types of 5-HT receptors) could 
produce the desirable effects of fenfluramine without the associated cardiac toxicity.  
Fletcher et al. (2004) summarize early rodent data suggesting a potential role for 5-HT (2c) receptor agonists 
in the treatment of cocaine use disorder. The 5-HT (2c) receptor has a widespread distribution in mammalian 
brain tissue, and is especially abundant in dopaminergic cell body regions of the substantia nigra and ventral 


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tegmental area (VTA) as well as in terminal projection areas of the nucleus accumbens, striatum, and 
prefrontal cortex. The moderately selective 5-HT (2c) receptor agonist Ro60-0175 reduces the firing rate of 
mesolimbic DA neurons originating in the VTA, leading to a reduction in DA release in terminal regions of 
the nucleus accumbens and frontal cortex. Additionally, the selective 5-HT (2c) antagonist SB242,084, by 
itself, increases the burst-firing of dopaminergic neurons in the VTA, leading to increased release of DA in 
the nucleus accumbens (Di Matteo et al., 1999). Thus, it appears that 5-HT (2c) receptors may exert a tonic 
inhibitory influence over the activity of ascending DA neurons. Ro60-0175 reduces cocaine self-
administration in rats (Fletcher et al., 2004). It also attenuates the ability of stress or conditioned cues to 
stimulate cocaine-seeking behavior in rats with a prior history of cocaine self-administration (Fletcher et al., 
2008). These promising findings led to the preclinical lorcaserin/cocaine studies described below.  
3.3 
Rationale for Use of Predictive Enrichment Strategies 
Evaluation and selection of safe and effective medications for drug abuse and addiction through clinical trials 
is an important public health objective. Unfortunately, deception to gain enrollment has been well 
documented in repeat clinical trial participants (Devine et al., 2013; Shiovitz et al., 2013), which can lead to 
low medication compliance as the subjects may not be truly seeking treatment. In one recent placebo-
controlled study, oral vigabatrin was examined as a treatment for cocaine dependence with a primary 
outcome measure of 2-week cocaine abstinence (Somoza et al., 2013). No significant difference was found 
between the placebo and vigabatrin groups; however, post hoc measures of urine vigabatrin levels suggested 
that only 40-60% of patients were fully adherent to the protocol-specified vigabatrin regimen. In a National 
Institute on Drug Abuse (NIDA) trial evaluating modafinil for the treatment of methamphetamine 
dependence (Anderson et al., 2012), 10% of subjects in the active treatment groups never had any detectable 
modafinil in their urine samples from Week 1 through the end of the 12-week trial. One concern is the 
existence of “professional subjects,” who may participate in clinical trials due to the financial incentives but 
are not truly treatment-seeking and have no intention of ingesting study medications (McCann et al., 2015). 
These subjects can alter clinical outcomes, masking any genuine therapeutic effect. This can result in the 
failure to develop potentially effective medicines, or result in additional cost and delay in the drug 
development cycle. 
One difficulty with “professional subjects” is the possibility that, if they are made aware (via informed 
consent) of a monitored run-in phase with the possibility of study termination for non-compliant subjects, 
they will change their normal behavior and comply to avoid detection. For this reason, in part, study drug 
non-adherence during the run-in phase of the current study will not result in early termination. Instead, a 
predictive enrichment strategy based on pre-randomization data will be used to define a subpopulation of 
study participants who are likely to be medication adherent during the treatment phase of the trial and likely 
to exhibit a low placebo response rate. Data from only this subpopulation, termed the “prequalified for 
primary efficacy endpoint” (PPEE) population, will be utilized for the primary efficacy endpoint. Predictive 
enrichment strategies have been endorsed by the FDA (Food and Drug Administration, Guidance for 
Industry: Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological 
Products, December, 2012), and their use has been suggested as a means to address the overlapping issues of 
medication nonadherence, “professional subjects,” and increasing placebo response rates (McCann et al., 
2015). 
Specific details of the enrichment strategy used in this study are described in Section 14.1 


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3.4 
Lorcaserin 
3.4.1 FDA Label Indication 
Lorcaserin (trade name Belviq®) is indicated as an adjunct to a reduced-calorie diet and increased physical 
activity for chronic weight management in adult patients who are obese or who are overweight with at least 
one related co-morbid condition (Belviq® Product Label, 2012). 
3.4.2 Receptor Pharmacology 
Lorcaserin binds more tightly to and is much more potent an agonist for 5-HT (2c) receptors than for 5-HT 
(2a) or 5-HT (2b) receptors, whether human or rat (Thomsen et al., 2008) (Table 1).  
Table 1. Lorcaserin Receptor Affinity 
Receptor 
Affinity K1 (nM) 
Human 5-HT (2c) 
15 ± 1 
Human 5-HT (2a) 
112 ± 7 
Human 5-HT (2b) 
174 ± 32 
Rat 5-HT (2c) 
29 ± 7 
Rat 5-HT (2a) 
159 ± 27 
Rat 5-HT (2b) 
190 ± 5 
 
3.4.3 Pre-Clinical Experience with Lorcaserin Relevant to Substance Abuse Treatment 
Lorcaserin has shown activity in animal models that are relevant to the treatment of multiple substance use 
disorders. For example, lorcaserin reduces nicotine self-administration and blunts the subjective effects of 
nicotine in rats (Levin et al., 2011; Higgins et al., 2012). It also reduces the self-administration of alcohol 
(Rezvani et al., 2014) and cocaine (Harvey-Lewis et al., 2016) in rats. In a recently published study in rhesus 
monkeys, lorcaserin was shown to both reduce cocaine self-administration and blunt the subjective effects of 
cocaine (Collins et al., 2016). In addition, unpublished studies of lorcaserin in rhesus monkeys have 
generated similar findings in a second laboratory (Bergman et al.; presented at the 78th Annual Scientific 
Meeting of the College on Problems of Drug Dependence, 2016). From these unpublished studies, Figure 2 
shows the effect of chronic lorcaserin treatment on responding for intravenous cocaine (left panel) or food 
pellets (right panel). The monkeys received constant intravenous infusions of saline or lorcaserin through one 
lumen of a double-lumen catheter (the total daily dose of lorcaserin is indicated above each panel), and the 
dose of lorcaserin was escalated every 5 days. Once daily, in 100 minute sessions, the monkeys had an 
opportunity to press a key to receive injections of cocaine through the other lumen of their catheters (30 key 
presses were required and 0.01 mg/kg cocaine was delivered per injection). Immediately prior to and 
immediately after each cocaine session, the monkeys had an opportunity to press a different key to obtain 
food pellets. Chronic treatment with lorcaserin produced a persistent reduction in cocaine self-administration 
with limited effects on food-maintained behavior. The selectivity of this effect rules out sedation or 
impairment of responding as an explanation for the reductions in cocaine self-administration. Different 
conditions (e.g., unlimited availability of highly palatable food) would have been required to observe the 
well-established ability of lorcaserin to decrease food consumption. 


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Figure 2. Effects of Lorcaserin on Responding for Cocaine or Food in Rhesus Monkeys 
 
Related to safety, NIDA conducted a lorcaserin/cocaine interaction study in rats (Smithers Avanza Study No. 
1812-12132). In this study, Sprague Dawley rats were given oral doses of lorcaserin at 5 mg/kg (a dosage 
yielding peak plasma levels in rats that are similar to peak plasma levels in humans taking 10 mg twice daily) 
and 25 mg/kg (a 5-fold safety margin). Cocaine was administered at doses of 3.2, 5.6, 10.0, and 17.5 mg/kg. 
Lorcaserin was administered 30 min ± 5 min prior to intravenous (i.v.) cocaine (this pretreatment time 
corresponded to the time to maximum plasma concentration [Tmax] of oral lorcaserin in rats). There was a 
dose-dependent mortality due to cocaine, and all deaths occurred by 9 min after cocaine administration. The 
cocaine median lethal dose (LD50) was 8.58 mg/kg (95% confidence interval [CI] 6.50-11.31 mg/kg), 12.47 
mg/kg (CI 9.30-16.71 mg/kg), and 10.54 mg/kg (CI 7.43-14.94 mg/kg) after lorcaserin dose levels of 0, 5 
mg/kg, and 25 mg/kg, respectively. Cocaine treatment also increased convulsions in a dose-related manner. 
The cocaine median effective dose (ED50) values as a convulsant were 6.58 mg/kg (CI 5.12-8.47 mg/kg), 
7.25 mg/kg (CI 2.43-21.62 mg/kg), and 5.38 mg/kg (CI 3.71-7.79 mg/kg) at lorcaserin dose levels of 0, 5 
mg/kg, and 25 mg/kg, respectively. The mortality, convulsions, and clinical observations noted in Sprague 
Dawley rats challenged with i.v. cocaine after oral administration of lorcaserin were consistent with the 
known effects of cocaine, and the data did not reveal a substantive increase in cocaine toxicity following 
lorcaserin treatment. 
3.4.4 Clinical Experience with Lorcaserin Relevant to Substance Abuse Treatment 
In 2014, Arena Pharmaceuticals, with study design guidance from NIDA, conducted an outpatient trial to 
evaluate the efficacy of lorcaserin in smoking cessation (Shanahan, Rose, Glicklich, Stubbe & Sanchez-Kam, 
2016). In this study, 603 smokers were randomized (1:1:1) to receive 10 mg lorcaserin once daily, 10 mg 
lorcaserin twice daily (BID), or placebo for 12 weeks. The primary endpoint was the proportion of subjects 
in each group achieving abstinence from smoking during the last 4 weeks of treatment (Study Weeks 9-12). 
The primary endpoint of smoking abstinence was achieved by 5.6% of subjects in the placebo group, 8.7% 
of subjects in the lorcaserin 10 mg once daily group, and 15.3% of subjects in the lorcaserin 10 mg BID 
group (p=0.003 and odds ratio=3.02 for BID lorcaserin vs. placebo). It was reported that the adverse event 
profile appeared “…similar to the profile in previous trials of lorcaserin, with the most common adverse 
events being headache, nausea, constipation, dizziness and dry mouth.”  To date, the efficacy of lorcaserin 
vs. other substance abuse disorders has not been evaluated in clinical trials, and it is anticipated that the 
current study will be the first evaluation of lorcaserin in the treatment of cocaine use disorder.  


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In 2015, in anticipation of the current study, NIDA conducted a human laboratory study under a contract 
with Vince & Associates Clinical Research (Overland Park, KS) with a primary focus on the safety of the 
lorcaserin/cocaine combination (ClinicalTrials.Gov/National Library of Medicine Identifier: NCT02393599). 
This unpublished, double-blind, parallel-group study in non-treatment seeking cocaine users assessed the 
safety and potential pharmacokinetic (PK) interactions of lorcaserin (10 mg BID) vs. placebo when 
combined with intravenous infusions of saline or cocaine doses of 20 or 40 mg. Of the 26 subjects exposed 
to either lorcaserin or placebo, 20 subjects (11 receiving lorcaserin, 9 receiving placebo) completed the 7-
day, 13-dose treatment regimen and all PK assessments. Steady-state lorcaserin plasma concentrations were 
attained starting on the fifth day of study drug administration (Study Day 8), with plasma concentrations of 
approximately 35 ng/mL. The administered dose of 10 mg BID lorcaserin was safe and tolerable. All 26 
participants in the study experienced at least one AE. All but one AE was mild in severity. There were no 
severe AEs and only one moderate AE, a case of euphoria subsequent to cocaine infusion that was judged to 
be cocaine-related/lorcaserin-unrelated in a participant receiving lorcaserin. Of the subjects receiving 
lorcaserin (n=11), the only lorcaserin-related AEs were mild headaches in 2 subjects (13%). The frequency 
and severity of cocaine-related AEs reported in all 20 study completers coincided with the scheduled cocaine 
infusions and were consistent with the risk-profile of cocaine administration. These events included euphoric 
mood (96%), abnormal feelings (42%), hyperhidrosis (38%), feeling hot (38%), tachycardia (23%), and 
paresthesia (19%). As compared to placebo, vital signs recorded before, during, and after cocaine infusion 
were not affected in a statistically significant manner in subjects receiving lorcaserin. One subject in each 
treatment group experienced an electrocardiogram (ECG) abnormality; both spontaneously resolved, and the 
abnormality experienced by the subject in the lorcaserin group occurred prior to lorcaserin dosing (during a 
baseline cocaine infusion). Lorcaserin did not appear to affect cocaine’s subjective effects, as measured by a 
visual analog scale assessment, but there was a nonsignificant trend towards a reduction in the cocaine 
craving increase from baseline (pre-infusion) to 125 min after 40 mg cocaine infusion, as measured by the 
Brief Substance Craving Scale (p=0.0952, difference between lorcaserin and placebo craving score change = 
-0.8 or -80%). A between-group analysis of covariance (ANCOVA) comparing baseline (Day 2) to post-
treatment (final dose taken approximately 2 hours prior to cocaine infusion) showed that lorcaserin had no 
statistically significant effect on the plasma PK of cocaine or its primary metabolite, BE. 
3.4.5 Pharmacokinetics 
Lorcaserin is absorbed from the gastrointestinal tract with peak plasma concentration occurring 1.5 to 2 
hours after oral dosing and can be administered with or without food (Belviq® Product Label, 2012). 
Lorcaserin has a plasma half-life of approximately 11 hours; steady state is reached within 3 days after BID 
dosing, and accumulation is estimated to be approximately 70%. 
Lorcaserin hydrochloride is moderately bound (~70%) to human plasma proteins and distributes to the 
cerebrospinal fluid (CSF) and central nervous system in humans. Although in rats the ratio of brain-to-
plasma exposure (exposure expressed as the area under the concentration-time curve [AUC]) was 13.3 
(Thomson et al., 2008), in humans the ratio of CSF-to-plasma exposure (AUC) was 0.017. After 10 mg BID 
for 7 days, the mean human CSF and plasma AUC values were 8.6 ng·hr/mL vs. 520 ng·hr/mL, respectively 
(Lorcaserin Clinical Pharmacology Review, 2012). Although the CSF levels are low compared to plasma 
levels in humans, human CSF levels nevertheless approximate the ED50 against the 5-HT (2c) receptor. 
Lorcaserin is extensively metabolized in the liver by multiple enzymatic pathways (Belviq® Product Label, 
2012). The primary oxidative metabolites are N-hydroxylorcaserin, 7-hydroxylorcaserin, 5-
hydroxylorcaserin, and 1-hydroxylorcaserin (Usmani et al., 2012). Human CYP1A2, CYP2A6, CYP2B6, 


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CYP2C19, CYP2D6, CYP3A4, and FMO1 are involved in N-hydroxylorcaserin formation; CYP2D6 and 
CYP3A4 are involved in 7-hydroxylorcaserin formation; CYP1A1, CYP1A2, CYP2D6, and CYP3A4 are 
involved in 5-hydroxylorcaserin formation; and CYP3A4 is involved in 1-hydroxylorcaserin formation.  
The major circulating metabolite is lorcaserin sulfamate, with a maximum plasma concentration (Cmax) that 
exceeds lorcaserin Cmax by 1- to 5-fold. N-carbamoyl glucuronide lorcaserin is the major metabolite in urine; 
lorcaserin sulfamate is a minor metabolite in urine, representing approximately 3% of dose. Unchanged 
lorcaserin in urine accounted for only 2.5% of an oral dose in normal subjects. Other minor metabolites 
excreted in urine were identified as glucuronide or sulfate conjugates of oxidative metabolites. The principal 
circulating metabolites exert no pharmacological activity at 5-HT receptors. In a human mass balance study 
in which healthy subjects ingested radiolabeled lorcaserin, 94.5% of radiolabeled material was recovered, 
with 92.3% and 2.2% recovered from urine and feces, respectively. 
Lorcaserin is not recommended for patients with severe renal impairment (creatinine clearance <30 mL/min) 
or patients with end stage renal disease. Dose adjustment is not required for patients with mild to moderate 
hepatic impairment. The effect of severe hepatic impairment on lorcaserin was not evaluated. 
No dosage adjustment is required based on age, gender, or race. 
3.4.6 Dose Justification 
This study will use the approved lorcaserin dose for weight loss, 10 mg BID, during Weeks 2-13 of the 
Treatment Phase. As mentioned above, this same 10 mg BID dose of lorcaserin demonstrated significant 
efficacy in a smoking cessation trial, whereas 10 mg once daily lorcaserin did not yield a significant effect. 
Moreover, as summarized above, a previous human laboratory study demonstrated that the 10 mg BID 
lorcaserin dose was safe and tolerable when administered for 1 week to non-treatment seeking cocaine users, 
and there was no evidence of an adverse interaction with intravenous cocaine infusions. 
3.4.7 Lorcaserin Safety 
3.4.7.1 Common Adverse Reactions 
The most common adverse reactions for non-diabetic patients treated with lorcaserin compared to placebo 
were headache, dizziness, fatigue, nausea, dry mouth, and constipation. The incidence of these side effects is 
shown in Table 2. 
Table 2. Adverse Reactions Reported by ≥2% of Lorcaserin-Treated Patients and More Commonly 
than with Placebo in Patients without Diabetes Mellitus 
Adverse Reactions 
Lorcaserin 10 mg BID 
N=3195 
Placebo 
N=3185 
Gastrointestinal Disorders 
 
 
 Nausea 
264 (8.3) 
170 (5.3) 
 Diarrhea 
207 (6.5) 
179 (5.6) 
 Constipation 
186 (5.8) 
125 (3.9) 
 Dry Mouth 
169 (5.3) 
74 (2.3) 
 Vomiting 
122 (3.8) 
83 (2.6) 
General Disorders and Administration Site Conditions 
 
 
 Fatigue 
229 (7.2) 
114 (3.6) 
Infections and Infestations 
 
 


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Adverse Reactions 
Lorcaserin 10 mg BID 
N=3195 
Placebo 
N=3185 
 Upper respiratory tract infections 
439 (13.7) 
391 (12.3) 
 Nasopharyngitis 
414 (13.0) 
381 (12.0) 
 Urinary tract infection 
207 (6.5) 
171 (5.4) 
Musculoskeletal and Connective Tissue Disorders 
 
 
 Back pain 
201 (6.3) 
178 (5.6) 
 Musculoskeletal pain 
65 (2.0) 
43 (1.4) 
Nervous System Disorders 
 
 
 Headache 
537 (16.8) 
321 (10.1) 
 Dizziness 
270 (8.5) 
122 (3.8) 
 Respiratory, Thoracic and Mediastinal Disorders 
 
 
 Cough 
136 (4.3) 
109 (3.4) 
 Oropharyngeal pain 
111 (3.5) 
80 (2.5) 
 Sinus congestion 
93 (2.9) 
78 (2.4) 
Skin and Subcutaneous Tissue Disorders 
 
 
 Rash 
67 (2.1) 
58 (1.8) 
 
The most common adverse reactions leading to discontinuation more often among lorcaserin-treated patients 
than placebo were headache (1.3% vs. 0.8%), depression (0.9% vs. 0.5%) and dizziness (0.7% vs. 0.2%). 
3.4.7.2 Potential for Serotonin or Neuroleptic Malignant Syndrome (NMS)-like Reactions 
In the prescribing information for lorcaserin (Belviq® Product Label, 2012), under “WARNINGS AND 
PRECAUTIONS,” it is noted that: 1) lorcaserin is a serotonergic drug and 2) “development of a potentially 
life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been 
reported during use of serotonergic drugs, including, but not limited to, selective serotonin-norepinephrine 
reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants 
(TCAs), bupropion, triptans, dietary supplements such as St. John’s Wort and tryptophan, drugs that impair 
metabolism of serotonin (including monoamine oxidase inhibitors [MAOIs]), dextromethorphan, lithium, 
tramadol, antipsychotics or other dopamine antagonists, particularly when used in combination.”  The use of 
serotonergic drugs is not contraindicated in patients receiving lorcaserin (in fact, no medications are 
contraindicated); however, in the “DRUG INTERACTIONS” section of the prescribing information 
(Belviq® Product Label, 2012), it is stated that “based on the mechanism of action of Belviq and the 
theoretical potential for serotonin syndrome” lorcaserin should be “used with extreme caution in combination 
with other drugs that may affect the serotonergic neurotransmitter systems.”  This legitimate concern is 
entirely theoretical. During three phase 3 trials, in which a total of 4,347 patients received lorcaserin, no 
subjects met the clinical criteria for diagnosis of serotonin syndrome (Nguyen et al., 2016), and from the 
time of FDA approval (February, 2012) to the time of this writing (August, 2016), there have been no 
published case reports suggesting serotonin syndrome in patients receiving lorcaserin. In addition, during the 
course of the phase 3 studies, 814 patients receiving lorcaserin and 624 patients receiving placebo were 
found to be taking a wide range of serotonergic agents (some that were protocol-allowed, such as 
dextromethorphan, and some that were protocol-prohibited, such as antidepressants), and an evaluation of 
adverse events in these subpopulations revealed no signal of serotonin toxicity with the concurrent use of 
lorcaserin and the serotonergic agents (Nguyen et al., 2016). The number of co-exposures to lorcaserin and 
other serotonergic agents during the phase 3 studies (814) was much greater than the total number of subjects 
who will receive lorcaserin in the current study (up to 136). Thus, even though depression is a common 
comorbidity in patients with cocaine use disorder, and a subset of subjects in the current study will almost 
certainly be taking antidepressants, it appears unlikely that any subjects will experience serotonin syndrome. 


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Due to the serious nature of serotonin syndrome and the theoretical possibility of its occurrence, subjects will 
be closely monitored for signs of serotonin toxicity when adverse events are assessed during each weekly 
visit. 
3.5 
Acetazolamide Safety/Dose Justification 
Because of its long half-life and other desirable properties, a very low dose of acetazolamide (15 mg, which 
is just 6% of the recommended starting therapeutic dose) can serve as a useful marker of study drug 
adherence during clinical trials (Hampson et al., 2016). In the current study, subjects will receive 15 mg 
capsules of acetazolamide BID during the one-week run-in period (from the evening of Study Day 1 through 
the morning of Study Day 8) only. This dose is much lower than the therapeutic doses of 250 to 1000 mg 
daily. Data from a NIDA PK study conducted under a contract with Vince & Associates Clinical Research 
(Overland Park, KS) indicate that plasma acetazolamide concentrations can be expected to stay above 15 
ng/mL for 48 hours after a single 15 mg oral dose in approximately 99.9% of subjects. In the current study, 
plasma samples will be drawn on Study Day 8 (following 7 days of BID dosing with 15 mg acetazolamide) 
and the samples will be assayed for acetazolamide. Subjects with plasma levels below 15 ng/mL will be 
regarded as study-drug non-adherent (they would have to skip at least their last 4 doses of study drug before 
the Study Day 8 visit to fall below 15 ng/mL) and they will not qualify for the PPEE population. 
There are very limited data on adverse events for this low (15 mg) dose of acetazolamide, but it is anticipated 
that this dose will present minimal risk to subjects. In the NIDA PK study mentioned above, 24 healthy 
subjects were administered a single 15 mg oral dose of acetazolamide, no moderate or severe AEs were 
observed, and 3 out of 24 subjects (13%) experienced mild AEs (1 alopecia, 2 headache; unpublished data). 
In the only relevant published study (Hampson et al., 2016), 10 subjects received 15 mg oral acetazolamide 
for four consecutive days, and one subject reported a metallic taste in the mouth on one of the four dosing 
days. That is the only acetazolamide-specific adverse event mentioned in the publication. 
4 
STUDY OBJECTIVE 
The objective of this study is to evaluate the efficacy and safety of lorcaserin in the treatment of cocaine use 
disorder. 
5 
IND HOLDER 
This study will be conducted under an Investigational New Drug Application (IND) held by the National 
Institute on Drug Abuse (NIDA). 
6 
STUDY SITES 
This clinical trial will be conducted as a multi-center study at 10 or more clinical sites throughout the United 
States . 
7 
STUDY DESIGN 
This is a 19-week, multi-center, parallel group study that includes: 1) up to 3 weeks for screening; 2) a 13-
week Treatment Phase consisting of a 1­week, single-blind run-in period, when all subjects receive twice 
daily 15 mg acetazolamide capsules (a medication adherence marker), followed by randomization to either 
twice daily 10 mg lorcaserin or placebo capsules for the remaining 12 weeks; and 3) a 3-week follow-up 
period, with scheduled visits during Study Weeks 14 and 16. 


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Upon providing informed consent, subjects will be screened over a period of up to 21 days and will complete 
baseline evaluations. Subjects who complete all screening and baseline evaluations and meet the specified 
inclusion/exclusion criteria will be eligible to enter the treatment phase.  Eligible subjects will receive 15 mg 
BID acetazolamide during the 1-week run-in period, which will be used to define the PPEE population (on 
the basis of plasma acetazolamide concentrations ≥15 ng/mL and self-report of cocaine use on at least 8 days 
during the 30 days immediately prior to screening). Following the 1-week run-in period, all subjects will be 
randomly assigned to receive either placebo or 10 mg BID lorcaserin for 12 weeks, with weekly clinic visits 
during those 12 weeks, and with follow-up assessments 1 and 3 weeks after treatment completion. 
A randomized block design within each site will be utilized with the following stratification factors: 
a. Number of subject-reported cocaine use days during the 30 days immediately prior to screening (<8 
days versus 8 or more days); 
b. Continued viewing of the computer-based alcohol intervention on Study Day 8 (yes/no); 
c. Diagnosis of Alcohol Use Disorder and/or Sedative, Hypnotic, or Anxiolytic use disorder (yes/no). 
Beginning on Study Day 1, subjects will visit the clinic on a weekly basis throughout the 13-week Treatment 
Phase. At each weekly clinic visit, subjects will receive study drug, provide urine samples and will 
participate in other protocol-specified assessments.  Subjects will also take part in a weekly one-hour, 
manualized individual cognitive behavioral therapy session (CBT) to facilitate avoidance of cocaine use. On 
Study Day 1, all subjects will view the first module of a computer-based alcohol intervention that describes 
the potential benefits of abstaining from alcohol during the trial. Though the module encourages abstinence 
from alcohol, each subject will determine for him/herself whether this will also be one of their goals during 
this trial. On Study Day 8, prior to randomization, subjects will be given the option of viewing the second 
module of the alcohol intervention.  Each subject’s decision (yes or no) to continue viewing the alcohol 
intervention modules will be recorded prior to randomization and will serve as one of the stratification 
factors for randomization. 
Beginning on Study Day 8, subjects will participate in a medication adherence monitoring procedure.  
Following randomization, subjects will be instructed on the use of a handheld device to log daily use of 
cocaine and alcohol and to record the daily administration of study drug.  The devices are smartphones 
furnished by the sites and come pre-loaded with the medication monitoring AiView software.  These devices 
are password protected and are programmed with limited functionality so that their use is restricted to study-
specific tasks and activities.  Use of the device grants subjects associated opportunities to earn rewards 
contingent upon appropriate performance of tasks.  
Two Follow-Up Visits will occur at Week 14 and at Week 16.  Subjects will be asked to return to the clinic 
at these visits to provide self-report data on cocaine use, perform vitals, and provide a urine sample. 
Additional safety evaluations (physical exam, blood chemistry, hematology, and urinalysis) will occur at the 
final Follow-up Visit (Week 16), more than two weeks after the last dose of study drug. 
8 
SUBJECT SELECTION 
8.1 
Eligible Subjects 
Approximately two hundred seventy-two (272) treatment-seeking males and females who meet DSM-5 
criteria for cocaine use disorder will be recruited from 10 or more clinical sites. Entry into the study will be 


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open to men and women, between 18 to 65 years of age, from all racial and ethnic groups. Subjects who are 
enrolled, but who do not proceed to randomization on Study Day 8 will not be replaced. 
8.2 
Inclusion Criteria 
A subject must meet all of the following criteria in order to be included in the study: 
1. Is between 18 to 65 years of age. 
2. Has DSM-5 diagnosis of current cocaine use disorder as verified by the Structured Clinical Interview for 
DSM-5 – Research Version (SCID-5-RV).  
3. Is seeking treatment for cocaine use disorder. 
4. Is able to understand and provide written informed consent. 
5. Has used cocaine on at least 1 day in the last 30 days prior to screening (based on SUR at first screening 
visit). 
6. Has completed all psychological assessments and procedures during the screening period (up to 3 
weeks). 
7. Female subjects: 
a. Cannot be pregnant 
b. Cannot be lactating 
c. Must be unable to conceive (i.e., surgically sterilized, sterile, or post-menopausal defined as 
1 year without bleeding or spotting) OR must agree to use an acceptable method of birth control 
(e.g., birth control pills, intrauterine device [IUD], or a double barrier method of birth control 
(condoms and spermicide together; or diaphragm, condom and spermicide together) 
8. Has a total body weight of >50 kg (110 pounds) and a body mass index (BMI) of > 20 at screening. 
9. Is, in the opinion of the study physician, in stable health as determined by pre-study physical 
examination, medical history, ECG, and laboratory evaluations and is likely to complete the study. 
8.3 
Exclusion Criteria 
A subject who meets any of the following criteria may not be included in the study: 
1. Use of lorcaserin HCl for any indication, including prior participation in this or any study of lorcaserin 
HCl, within the last 30 days prior to screening.  
2. Has DSM-5 diagnosis of current substance use disorder, as verified by the SCID-5-RV, for any 
psychoactive substance other than cocaine, benzodiazepine, alcohol, nicotine, caffeine, or marijuana.  
3. Has received methadone or buprenorphine maintenance treatment during the year prior to screening. 


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4. Has current alcohol use disorder that is judged to require medically supervised detoxification. 
5. Fails to provide at least one urine sample that is benzoylecgonine (BE)-positive (>150 ng/mL) during the 
screening period. 
6. Meets the DSM-5 criteria for schizophrenia, bipolar I and II disorder or any other psychotic disorder as 
verified by the SCID-5-RV. NOTE: Participants with other psychiatric conditions, such as MDD, GAD, 
Dysthymia, social phobia or specific phobia may be enrolled in the study if they are clinically stable, and 
if taking medications, dosages must be stable (no adjustment) in the past 3 months prior to screening. 
7. Acute suicidality, as evidenced by answering “yes” for Question 4 or Question 5 on the Columbia-
Suicide Severity Rating Scale (C-SSRS), indicating active suicidal ideation with any intent to act, during 
the screening period. NOTE: these subjects will be referred to the appropriate medical provider. 
8. History of suicidal behavior such that a determination of “yes” is made on the Suicidal Behavior section 
of the C-SSRS for “Actual Attempt”, “Interrupted Attempt”, or “Aborted Attempt.” 
9. Undergoing separate drug testing as a condition of probation or as mandated by a government agency 
(e.g., social services) or a court. 
10. Has one or more positive on-site urine drug screen (UDS) test results for methamphetamine, 
amphetamine, methadone, buprenorphine, oxycodone, or other opiates during the screening period. 
11. Is currently participating in or screening for potential participation in another clinical trial of an 
investigational (un-marketed) medication or has participated in any clinical trial of an investigational 
medication within 6 months prior to providing Informed Consent. 
12. Has, in the opinion of the site study physician, any of the following: 
a. Clinically significant hepatic, renal, or gastrointestinal disorders that could alter absorption, 
metabolism, or excretion of the study drug.  
b. Significant heart disease (including report or documentation of myocardial infarction within one 
year prior to randomization), valvular heart disease, or symptomatic orthostatic hypotension. 
c. Any clinically significant ECG abnormality at screening, as determined by the study physician.  
d. History of cerebrovascular disease or stroke. 
e. A diagnosis of severe chronic obstructive pulmonary disease (COPD) and/or pulmonary 
hypertension. 
f. Uncontrolled and/or unstable metabolic and/or endocrine disorder.  
g. Any other medical or neurological disorder that would place the subject at greater risk or 
prejudice evaluation of the safety and efficacy of the study drug. 
h. Clinically significant laboratory values outside the normal range as determined by the study 
physician. 
i. History of serotonin syndrome or neuroleptic malignant syndrome.  
j. Impaired renal function as determined by estimated creatinine clearance (CrCl) <30 ml/min, 
calculated from the Cockcroft-Gault equation at screening. o Cockcroft-Gault equation: CrCl = 
(140-age) x body weight in kg/ serum creatinine (mg/dl) x 72 (x 0.85 for females)  
k. Impaired liver function as evidence by LFT (AST, ALT or total bilirubin) > 3 times of upper 
normal limit at screening.  


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l. Systolic Blood Pressure > 160 mmHg and/or Diastolic Blood Pressure  >100 mmHg (confirmed 
after repeated measurement) at screening.  
 
13. Has a serious or unstable medical or psychiatric condition or clinically significant new illness within the 
last 6 months prior to screening. 
14. Has a known allergy to lorcaserin or sulfonamides. 
15. Has a Beck Depression Inventory-II (BDI-II) score > 20 at screening 
16. Has Diabetes (all types). 
17. Refuses to sign Verified Clinical Trials Authorization. 
18. Is not, in the judgment of the site investigator (SI), expected to attend regular study visits or to complete 
the study protocol assessments as directed.  
NOTE: If any medical conditions requiring treatment are uncovered during screening, the individual 
will be notified of the results and referred to appropriate treatment. 
9 
INVESTIGATIONAL PRODUCTS 
9.1 
Lorcaserin 
The three drug products described below will match each other in color, shape and size of the hard gelatin 
capsules that will be used in this study. 
The chemical name for lorcaserin hydrochloride (trade name Belviq®) is (R)-8-chloro-1-methyl-2,3,4,5-
tetrahydro-1H-3-benzazepine hydrochloride hemihydrate (Belviq® Product Label, 2012). Each Belviq® tablet 
contains 10.4 mg of crystalline lorcaserin hydrochloride hemihydrate, equivalent to 10.0 mg anhydrous 
lorcaserin hydrochloride, and the following inactive ingredients: silicified microcrystalline cellulose; 
hydroxypropyl cellulose National Formulary (NF); croscarmellose sodium NF; colloidal silicon dioxide NF, 
polyvinyl alcohol United States Pharmacopeia (USP), polyethylene glycol NF, titanium dioxide USP, talc 
USP, FD&C Blue #2 aluminum lake, and magnesium stearate NF. Lorcaserin will be obtained by the 
research pharmacy from a commercial site. Each 10 mg lorcaserin tablet will be over-encapsulated in a size 0 
light blue opaque hard gelatin capsule with a mixture of microcrystalline cellulose and magnesium stearate 
as filler by Murty Pharmaceuticals Inc. (Lexington, KY) under a contract with the National Institute on Drug 
Abuse. 
9.2 
Lorcaserin Placebo 
Placebo capsules will be an identical match to the over-encapsulated lorcaserin capsule prepared by Murty 
Pharmaceuticals. Each placebo capsule will contain a filler that is a mixture of microcrystalline cellulose and 
magnesium stearate. 
9.3 
Acetazolamide (ACZM) 
The 15 mg capsules will be manufactured using size 0 light blue opaque hard gelatin capsules by Murty 
Pharmaceuticals Inc. (Lexington, KY) under a contract with the National Institute on Drug Abuse. The 
acetazolamide (USP-NF) was procured from Spectrum Chemical (Catalog # A1266). Each acetazolamide 


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capsule will contain 15 mg acetazolamide and the following inactive ingredients: lactose monohydrate USP-
NF (NF 310 Regular), sodium starch glycolate USP-NF (Type A), corn starch USP-NF, povidone USP 
(Kollidon 30), and magnesium stearate USP-NF. 
9.4 
Packaging and Labeling 
The VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center (CSPCRPCC) in 
Albuquerque, NM will serve as the research pharmacy for the current study.  
Medication for week one (acetazolamide) will be provided to study sites in boxes containing 10 bottles. Each 
bottle will contain 14 capsules of 15 mg acetazolamide, sufficient study drug for one week. Each bottle will 
be labeled with the study number week, a bottle number, and dosing instructions. 
Subject-specific treatment kits will contain 12 bottles with 20 capsules per bottle of 10 mg lorcaserin or 
matching placebo and two (2) emergency-dose bottles with 20 capsules per bottle of 10 mg lorcaserin or 
matching placebo, respectively. The emergency-dose bottles will be available in case a subject misplaces a 
bottle. Each bottle will contain sufficient study drug for one week plus extra doses to cover possible missed 
clinic visits. Each bottle within the treatment kit will be labeled with the study number, week number, 
treatment kit number, bottle number, and dosing instructions.  
9.5 
Drug Storage 
Lorcaserin and ACZM will be stored at controlled room temperature (20°C – 25°C; 68°F – 77°F) with 
excursions permitted to 15C°- 30C°; 59F°- 86F° and protected from light in a secure location at each SI’s 
facility. For further information, SI should refer to the product label.  
9.6 
Dispensing Record 
A Receipt, Dispensing and Disposition/Returns to PCC log will be completed for each subject weekly. 
Accurate recording of all study drug dispensing will be made in the appropriate section of the log. On each 
weekly clinic visit starting with Study Day 8 (Week 2), subjects will be asked to return the bottle dispensed 
in the previous week with all unused drugs. Unused investigational product will be inventoried for 
discrepancies. Subjects who have not been taking their capsules regularly will be encouraged to do so in the 
future. At each and all clinic visits, self-reports of investigational product use since the last clinic visit will 
also be recorded. 
9.7 
Used/Unused Investigational Products 
During the study, all investigational products not used by the subject must be returned to the clinic for 
assessment of subject compliance. At the end of the study, all unused drugs must be inventoried. If any 
investigational product is lost or damaged, its disposition should be documented on the dispensing log 
provided by the CSPCRPCC. Unused investigational products, including empty medication bottles, will be 
returned to the CSPCRPCC at the end of the study. 
10 INTERVENTIONS 
10.1 Study Drug 
On Study Day 1, subjects will be given a child-proof, take-home bottle containing 14 “compliance marker 
capsules” containing a very low dose (15 mg) of acetazolamide. Subjects will be instructed to take one 


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capsule on the evening of Study Day 1 and two capsules per day, approximately 12 hours apart on Study 
Days 2-7.  
On Study Day 8, subjects who progress to randomization will be assigned a subject-specific treatment kit, 
via the Interactive Web Response System (IWRS).  Each subject’s treatment kit is tied to one of two 
treatment groups, 10 mg lorcaserin or matching placebo, and contains enough study drug for the remaining 
12 weeks of the Treatment Phase.  At each weekly clinic visit during Study Weeks 2 to 13, subjects will be 
given a take-home bottle from their treatment kit containing 20 capsules and will be instructed to take one 
capsule two times a day, approximately 12 hours apart.  
10.2 Counselor Guided Behavioral Therapy (Cocaine) 
All subjects will be offered and encouraged to attend individual CBT in one-hour weekly sessions beginning 
at Week 1 and continuing until Week 13. The date and length of time for each CBT session will be recorded 
within the subject’s CRFs. If a subject declines to participate in CBT, it will be recorded on the CRF and will 
not be considered to be a protocol violation. 
The NIDA-published CBT treatment manual for cocaine dependence, “Cognitive Behavioral Therapy 
Approach: Treating Cocaine Addiction” will be implemented across all sites (Carroll, 1998). CBT regards 
coping skills training as the key component for avoiding drug use and preventing relapse. Skills training 
techniques include: (1) self-monitoring and functional analysis of situational factors associated with craving 
or drug use; (2) learning alternative non-drug responses for handling high risk situations; and (3) general 
lifestyle modifications (e.g., increasing pleasant drug-free events, anger management, interpersonal skills, 
and general problem solving).  
10.3 
Computer-Based Therapy (Alcohol) 
A computer-based alcohol intervention will be viewed by all subjects on Study Day 1 and will be continued 
on an optional basis at the discretion of each subject. The alcohol intervention, “Quit to Quit”,  is an 
interactive set of modules based on an intervention developed by the National Institute on Alcohol Abuse 
and Alcoholism (NIAAA) for use in medication trials (Devine et al., 2016). 
11 STUDY PROCEDURES 
Table 3, Schedule of Events, provides a detailed time table of study activities. 


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Table 3.  Schedule of Events 
Study Phase 
Screen 
Treatment Phasea 
Early 
Term 
Follow-Up 
Study Week 
-3 to -
1a 
1 
(Study 
Day 1)b 
2 
(Study 
Day 8) 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
 
 
14 
16 
  Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  DSM-5 / (SCID-5-RV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
  Vital Signs/Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  12-lead ECG 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
  C-SSRS (initial & since last visit) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  BDI - II 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
  Prior/Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Brief Subs. Craving Scale (BSCS) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
  Drug Dispensing/Reconciliation 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  Adverse Events 
X 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood/Plasma 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Plasma (lorcaserin) 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
  Plasma (acetazolamide) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Blood Chemistries c 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
  Hematology d 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Urine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Urine Pregnancy Test 
X 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Medical Urinalysis e 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
  Urine Toxicology Screen f 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Urine Fentanyl 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Urine Cotinine 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Urine BE  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Urine Alcohol Test (EtG) 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Substance Use 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Smoking & Alcohol History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  ASI –Lite 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 


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Study Phase 
Screen 
Treatment Phasea 
Early 
Term 
Follow-Up 
Study Week 
-3 to -
1a 
1 
(Study 
Day 1)b 
2 
(Study 
Day 8) 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
 
 
14 
16 
  SUR (initial & since last visit) 
X 
 Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  AiView Data Collection (device) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Behavioral Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  CBT (cocaine) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
  Quit to Quit (alcohol 
intervention) 
 
X 
 Xg 
Xg 
 
 
  
 
Xg 
 
 
 
 
 
 
 
 
 
* Procedure that will be completed just prior to enrollment. 
a  Screening may take place during one or multiple visits within 21 days of providing Informed Consent. 
b Treatment visits are scheduled to occur the same day of the week as much as possible. 
c Blood chemistries include sodium, potassium, chloride, carbon dioxide, glucose, creatinine, calcium, alanine aminotransferase (ALT/SGPT), aspartate 
aminotransferase (AST/SGOT), gamma-glutamyltranspeptidase (GGT), total bilirubin, alkaline phosphatase (ALP), blood urea nitrogen (BUN). 
d Hematology includes complete blood count (CBC) with differentials and platelets. 
e Urinalysis: Urine will be collected and analyzed for specific gravity, pH, blood, protein, glucose, ketones, leukocytes, and nitrite. 
f The urine toxicology screen includes BE, marijuana, methamphetamines, amphetamines, ecstasy, phencyclidine, propoxyphene, benzodiazepines, barbiturates, 
tricyclic antidepressants, methadone, buprenorphine, oxycodone, and opiates. 
g Subjects will be given the choice of viewing these optional modules of the alcohol intervention prior to randomization on Study Day 8 (Week 2). NOTE: Study 
Day 1 (Week 1) module is mandatory. 
h Update at every clinic visit 
i Repeat test at every screening visit (when applicable) 
 
 


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11.1 Subject Recruitment 
Subjects will be recruited from a variety of sources which include but are not limited to: 
advertisements in local media, through local treatment providers, and by word of mouth. This 
study is also registered online at www.clinicaltrials.gov (NCT03007394). Recruitment 
advertisements must be approved by the site’s Institutional Review Board (IRB) and by NIDA. 
11.2 Screening (Study Days -21 to -1) 
The purpose of screening is to establish the candidate’s eligibility for study participation. The 
screening assessments required to determine eligibility are summarized in the Table 3, Schedule 
of E. At no time during the screening process will subjects be given information regarding 
exclusion criteria. When subjects are evaluated, questions should be asked in a way that the 
criteria are not discernable. If a subject meets inclusion/exclusion criteria for enrollment, s/he 
will be scheduled for the Study Day 1 visit.  
The screening phase commences the day informed consent is signed and terminates when any of 
the following conditions have been met: 
 
• The subject is determined to be ineligible for the study.  
• The subject is enrolled in the single-blind run-in period (Study Day 1).  
• 21 days have passed since the informed consent form (ICF) was signed and the subject 
has not been enrolled. No extensions beyond the prescribed 21 days for screening will be 
considered. 
An electronic case report form (eCRF) indicating the primary reason each subject was deemed 
ineligible will be submitted for all screen failures. 
Results from all screening assessments must be available and reviewed for verification of entry 
criteria prior to the enrollment visit (Day 1). Subjects who are found ineligible for the study will 
not be rescreened. 
NOTE: The last day of screening cannot be the first day of enrollment 
11.3 Scheduling of Study Day 1 Visit 
As soon as possible after a subject has passed all screening assessments, s/he should be contacted 
to schedule both the Study Day 1 visit and the Study Day 8 visit. Subjects must be available on 
the same day of the week for two consecutive weeks to accommodate this scheduling because 
missing the Study Day 8 visit results in early termination from the study,. The Study Day 1 visit 
should be scheduled as soon as possible and no later than 21 days after signing the consent form. 
11.4 Study Day 1 (Week 1) – Enrollment 
At the time of arrival to the clinic on Study Day 1, a pregnancy test will be performed on every 
female subject. If the pregnancy test is positive, the subject’s participation in the study will end 
and no other assessments will be done. 


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On Study Day 1, following enrollment, all other required assessments for Study Day 1(listed in 
Table 3) will be completed, including the subjects’ participation in both the individual CBT 
session for cocaine dependence and the computer-based alcohol intervention, detailed in Sections 
10.2 and 10.3, respectively.    
11.5 Study Day 8 (Week 2) – Randomization  
On Study Day 8, eligible subjects will be randomized using the Interactive Web Response 
System (IWRS). Although randomization occurs on Study Day 8, study staff must bear in mind 
that subjects are blinded to the change in study drug (from ACZM to lorcaserin or matched 
placebo) and should exercise appropriate caution in maintaining this blind.  Subjects who fail to 
show up for their Study Day 8 visit or who are unable or unwilling to continue taking study drug 
for other reasons (e.g., adverse events) will not be randomized. 
Beginning on Study Day 8, all subjects will begin participating in a medication adherence 
monitoring procedure.  Following randomization, subjects will be instructed on the use of a 
handheld device to log daily use of cocaine and alcohol and to record the daily administration of 
study drug.  The devices are smartphones furnished by the sites and come pre-loaded with the 
medication monitoring AiView software.  These devices are password protected and are 
programmed with limited functionality so that their use is restricted to study-specific tasks and 
activities completed by the subject.  Use of the device grants subjects associated opportunities to 
earn rewards contingent upon appropriate performance of tasks. Rewards are described in Table 
4, Subject Compensation. Other assessments are listed in Table 3, for Study Day 8 and are to be 
completed before the subject leaves the clinic.  
11.6 Study Visits (Weeks 2 to 13) 
Assessments to be performed at Study Visits during Weeks 2-13 are summarized in Table 3 and 
are further described in Section 12. 
11.7 Follow-Up Visits (Weeks 14 and 16) 
Subjects will attend two separate Follow-Up Visits in the clinic at Study Week 14 and Study 
Week 16.  All assessments to be completed during the Initial and the Final Follow-Up Visits are 
detailed in Table 3, Schedule of Events.  In addition to required assessments at the Week 14 
Follow-Up Visit, a final record of medication adherence data will be collected along with 
medication bottles and the handheld devices used for medication monitoring . 
11.8 Early Termination Visit – Prior to Dosing Completion 
A subject’s participation in the study will be terminated early if: 
- 
The subject is unable to comply with the study protocol requirements 
- 
The subject is incarcerated 
- 
In the opinion of the SI, the continued participation would compromise the subjects’ 
safety, the safety of others, or study integrity. 
NOTE: Subjects terminated from the protocol secondary to a medical or psychiatric concern will 
be referred for appropriate treatment. 


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Terminated subjects will not be replaced. 
If a subject discontinues prematurely, prior to dosing completion, regardless of the reason, the  SI 
should be notified and the subject should return for the Early Termination Visit within 7 to 14 
days of his/her last dose of study drug. All assessments required at the Early Termination Visit 
are outlined in Table 3, Schedule of Events. An Early Termination form documenting the 
reason for discontinuation is required for all subjects who discontinue prematurely. Once 
terminated, subjects may not re-enter the study.  
 
Whenever a study subject stops coming to the clinic without notification, study staff will make a 
concerted effort to contact the subject (or the designated contact person if subject cannot be 
reached) to assure that s/he has no untoward effects from study participation. After three 
documented attempts, the research staff will cease to try to make further contact.  
11.9 Situations Requiring Study Drug Discontinuation 
A subject should no longer receive study drug if: 
- 
The subject wishes to stop taking study drug or no longer wishes to participate in the 
study. 
- 
The subject develops a medical illness, complication or side effects from study drug, 
and/or has an adverse experience which, in the opinion of the SI or physician, precludes 
safe continuation of the study drug. 
- 
The subject fails to take study drug (for any reason) for 14 consecutive days. 
- 
The female subject becomes pregnant (as evidenced by a positive pregnancy test) at any 
time during study. 
- 
The subject has a BDI-II score of > 28 or scores > 0 on question # 9 (suicidal thoughts 
and wishes) will be referred to a mental health practitioner or primary care physician for 
further evaluation and follow-up.  
- 
The subject has clinically significant abnormal laboratory findings and vital signs (after 
confirmatory repeat measurements) as deemed by the SI or physician, including but not 
limited to; 
o CrCl < 30 ml/min  
o LFT > 5 times UNL 
o Uncontrolled hypertension; SBP ≥ 180 mmHg and/or DBP ≥ 110 mmHg 
 
If a subject loses substantial weight during the treatment period and, in the opinion of the site 
physician, he/she is approaching the lower limit of acceptable weight, the subject will be 
counselled for appropriate eating and nutrient intake, and the subject’s weight will be followed 
closely during each subsequent visit.  If the subject continues to lose weight so that, in the 
opinion of the site physician, it is unsafe to continue treatment, study medication will be 
discontinued. 
 


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If a subject expresses suicidal thoughts or exhibits acute psychosis or suicidal/homicidal 
behavior, the subject will be referred to a local treatment center, emergency department or be 
hospitalized as appropriate and study drug will be discontinued. 
 
Subjects who are no longer receiving study drug will continue to be followed and will complete 
regularly scheduled assessments to provide as much data as possible. These subjects will be paid 
for each clinic visit but will not be rewarded for any additional bonus payments (including 
device-related rewards).  
 
NOTE: Subjects who become pregnant during study participation will be immediately 
discontinued from the study drug. Subjects will be asked to sign a release of information form 
for study personnel to access medical records and information regarding the outcome of the 
pregnancy. 
NOTE: In the event of uncontrolled hypertension, study drug should be withheld and the subject 
should be referred to a primary care physician for proper evaluation and treatment. The subject 
may resume his/her study drug (within 14 days) only after evaluation and reassessment by the 
site SI or physician for safe continuation. Study drug will be discontinued if an evaluation is not 
done, or not completed, within 14 days or if uncontrolled hypertension persists. 
11.10 Early Study Termination 
NIDA has the right to terminate this study at any time. Reasons for terminating the study may 
include, but shall not be limited to, the following: 
  
• The incidence or severity of AEs indicates a potential health hazard to subjects. 
• Subject enrollment is unsatisfactory. 
• Data recording is inaccurate or incomplete. 
 
NIDA will continue those subjects currently in treatment to completion if there is no compelling 
safety concern. 
11.11 Preventing Study Drop-Outs 
Subjects will be encouraged to come for treatment and evaluation sessions as described in this 
protocol. It will be emphasized to subjects during screening and throughout the study that even if 
they continue to use cocaine and/or have a relapse they should come to all scheduled 
appointments. Subjects will be discouraged from using cocaine, but there will be no penalty for 
using cocaine. 
11.12  Subject Compensation 
For the screening visit(s) and for up to 15 clinic visits during the treatment and follow-up 
periods, all subjects will receive $15 per visit as compensation for their time and inconvenience 
(up to $270 total). In addition, subjects will have the opportunity to earn additional compensation 
(totaling up to $635) as rewards for following specific protocol requirements. To promote regular 
clinic attendance and decrease the probability of missing data, subjects will receive a $20 reward 
in Week 6 if they have attended all of their scheduled visits for Weeks 3-6, they will receive a 
$30 reward in Week 10 if they have attended all of their scheduled visits for Weeks 7-10, and 


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they will receive a $40 reward in Week 14 if they have attended all of their scheduled visits on 
Weeks 11-14. They will receive a $5 reward on each visit from Week 1-14 if they provide 
complete self-report data on cocaine, alcohol, and cigarette use since their previous visit (data 
provided for each day), and they will receive a $5 reward on each visit from Weeks 2-14 if they 
bring their medication bottle with them.  
Subjects are also eligible to earn rewards for remote documentation of medication adherence and 
for reporting of cocaine and alcohol use via the electronic handheld device (using AiView 
software). This is to promote appropriate use and return of the devices. Specifically, on each 
weekly visit during Weeks 3-14, subjects may receive up to two $15 rewards (up to $30 per visit) 
as follows: They will receive $15 if the number of capsules returned is within three capsules 
(over or under) of the number expected to be returned based on data transmitted by the device 
since their last visit and they will receive $15 if they have answered the device’s questions about 
their cocaine and alcohol use each day since their last visit. Also, subjects will receive a $50 
reward during the Week 16 (or Early Termination) visit if they have returned their device. 
In summary, all subjects have the opportunity to receive up to $905 in compensation, as shown 
in Table 4 below.


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Table 4. Subject Compensation 
SUBJECT COMPENSATION 
Scheduled Visit 
Time and 
inconvenience 
(attended visit) 
Bonus for 
attending four 
consecutive 
weekly visits 
(specified below) 
Provide 
Complete Self-
Report Data on 
Cocaine, 
Cigarette and 
Alcohol Use 
Since Last Visit 
Bottle 
Returned 
# Capsules 
Returned 
= # Expected ±3 
(requires bottle 
return) 
Provide Daily 
Report of 
Cocaine and 
Alcohol Use 
Since Last Visit 
via Device 
Device 
Returned 
TOTAL 
Screening (1) 
$15 
$15 
Screening (2) 
$15 
$15 
Screening (3) 
$15 
$15 
Week 1 
$15 
$5 
$20 
Week 2 
$15 
$5 
$5 
 
 
 
$25 
Week 3 
$15 
$5 
$5 
$15 
$15 
 
$55 
Week 4 
$15 
$5 
$5 
$15 
$15 
 
$55 
Week 5 
$15 
 
$5 
$5 
$15 
$15 
 
$55 
Week 6 
$15 
$20 (wks 3-6) 
$5 
$5 
$15 
$15 
 
$75 
Week 7 
$15 
 
$5 
$5 
$15 
$15 
 
$55 
Week 8 
$15 
 
$5 
$5 
$15 
$15 
 
$55 
Week 9 
$15 
 
$5 
$5 
$15 
$15 
 
$55 
Week 10 
$15 
$30 (wks 7-10) 
$5 
$5 
$15 
$15 
 
$85 
Week 11 
$15 
 
$5 
$5 
$15 
$15 
 
$55 
Week 12 
$15 
 
$5 
$5 
$15 
$15 
 
$55 
Week 13 
$15 
 
$5 
$5 
$15 
$15 
 
$55 
Week 14 
$15 
$40 (wks 11-14) 
$5 
$5 
$15 
$15 
 
$95 
Week 16 
$15 
$50 
$65 
TOTAL 
$270 
$90 
$70 
$65 
$180 
$180 
$50 
$905 
 
 


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11.13   Maintaining and Breaking Study Blind 
Participating subjects, NIDA staff, the VA Protocol Chairperson, study personnel at each site, 
and individuals serving as adjudicators for inclusion criteria and study endpoints will be blinded 
to treatment assignment from the day of randomization (Study Day 8) forward.  Subjects will be 
blinded to the change in study drug (from ACZM to lorcaserin or matched placebo) on Study 
Day 8, and appropriate caution will be exercised by site staff in conversations with subjects to 
maintain this blind.  
 
Every study subject will be encouraged to carry a wallet card that identifies him or her as a 
subject in a clinical research study. The card will provide the emergency contact information for 
the SI, study physician and the study’s research pharmacist. The card will also instruct the non-
study physician rendering emergency care to provide information to the study site physician with 
regards to that care.  
 
The study blind should not be broken except in a medical emergency, where knowledge of the 
study drug received is necessary for the medical management of the subject, or for a regulatory 
requirement. The SI should contact the CSPCRPCC Study Pharmacist and NIDA Medical 
Monitor to request an unblinding authorization. 
 
If the blind is broken for an individual subject due to a medical emergency, the following 
information must be recorded in the subject’s source documents: Date and time of unblinding 
together with the reason for the unblinding, and all associated AE information. The source 
documents should note that the subject’s treatment assignment was unblinded and include the 
date of the unblinding to enable censoring of any data as appropriate. 
 
Treatment assignment for all subjects within the study will remain blinded except as noted above 
and will not be revealed until all final clinical data have been entered into the database and all 
data queries have been resolved for all subjects, i.e., after the database is locked. 
12 ASSESSMENT METHODS 
Clinical assessments will be conducted according to the Schedule of Events (Table 3) and are 
briefly described as follows: 
12.1 Subject Locator Form 
A Subject Locator Form will be completed and will be kept securely at the clinical site, separate 
from the subject’s study data. Data collected on the Subject Locator Form will be used to 
facilitate contact with the subject during the research and follow-up. Subjects will be asked to 
provide locator information including their residential street address and a working telephone 
number, and the contact information for a relative or friend who can reach the subject in 
emergencies. 
12.2 Medical History 
During screening, a medical history will be collected and reviewed by a clinical staff member 
with medical training to determine subject eligibility before enrollment. 


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12.3 Smoking and Alcohol History  
The Smoking History Survey is a modified version of the Mayo Nicotine Dependence Center 
Patient Questionnaire (1991) and will be administered by a research assistant. The Smoking 
History Survey asks subjects the following: how many cigarettes per day they smoke and how 
many times they have attempted to quit (including methods). Information on other non-cigarette 
tobacco products is also noted. Subjects will also be asked about their alcohol consumption 
during the last 30 days: how many days did they have at least one drink; how many drinks did 
they usually have on the days they drank; and the largest number of drinks consumed on any one 
day during the 30-day period. 
12.4 Psychiatric History 
Structured Clinical Interview for DSM-5 – Research Version (SCID-5-RV) will be conducted by 
appropriately trained clinical staff. The SCID-5-RV will evaluate the subject’s history or current 
diagnosis of the following categories of neuropsychiatric disorders: psychosis, bipolar illness, 
major depression, anorexia nervosa or bulimia, or presence of current anxiety disorder. 
12.5 Demographics 
Age, gender, race, ethnicity, years of education, usual employment pattern in the last 30 days, 
and marital status data will be collected on all consented subjects, whether or not they are 
randomized. 
12.6 Addiction Severity Index-Lite (ASI-Lite) 
The ASI-Lite is a multidimensional, semi-structured, clinician-administered interview. It is 
widely used in the substance abuse field and has good reliability and validity. It is designed to 
provide a comprehensive assessment of functioning in seven areas – medical, employment, 
alcohol use, drug use, legal, family/social relationships, and psychiatric symptoms. For each of 
the seven functional areas, the instrument produces composite scores, which are based on the 
respondent’s answers to particular items.  
12.7 Physical Exam 
A physical exam of the head, eyes, ears, nose and throat, cardiovascular system, lungs, abdomen 
(liver/spleen), extremities, skin, brief neurological exam, musculoskeletal system and general 
appearance will be performed by a licensed study staff member with medical training. Subject’s 
height will also be recorded on this form. 
12.8 Vital Signs and Weight 
Vital signs to be assessed include temperature, blood pressure (sitting after 3 minutes), pulse 
rate, and respiratory rate. Weight (in pounds) will also be measured.  Body Mass Index (BMI) 
will be calculated at screening to verify inclusion criteria #8. 
12.9 Pregnancy Test 
An FDA-approved urine pregnancy test designed to measure β-human chorionic gonadotropin 
will be used. All female subjects will be tested regardless of their child-bearing capacity. 


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12.10   12-lead ECG 
A 12-lead ECG will be performed on all subjects according to standard procedures. A licensed 
physician or a non-physician who is certified/accredited by the participating institution to read 
ECGs must read all ECGs. A board-certified cardiologist can be consulted, if needed. 
12.11 Beck Depression Inventory-Second Edition (BDI-II) 
The Beck Depression Inventory Second Edition (BDI-II) is a 21-item self-report instrument 
intended to assess the existence and severity of symptoms of depression. This assessment 
includes items intending to index symptoms of severe depression, which would require 
hospitalization. When presented with the BDI-II, the subject will be asked to consider each 
statement as it relates to the way they have felt for the past two weeks. Subsequent assessments 
of BDI-II during treatment will be compared to the subject’s previous assessment in order to 
evaluate change (i.e. worsening.)  
The subject will be asked to consider each statement as it relates to the way he/she has felt during 
the assessment period as described above. Each of the 21 items corresponding to a symptom of 
depression is summed to give a single score for the BDI-II. There is a four-point scale for each 
item ranging from 0 to 3. A total score of 0-13 is considered minimal depression range, 14-19 is 
mild, 20-28 is moderate, and 29-63 is severe. 
During the treatment phase, the following action will be taken by the site investigator/team in 
response to BDI-II score: 
- 
Score < 20: 
no action 
- 
Score 20-28: consider further evaluation of possible clinical depression 
Score > 28: 
discontinue study drug and refer to mental health practitioner or to 
primary care physician for evaluation of clinical depression 
12.12   Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a 2-page form asking questions about suicidal ideation, intensity of ideation, and 
suicidal behavior developed by Posner and collaborators at the New York State Psychiatric 
Institute (Oquendo et al., 2003). The “baseline/screening” version of the C-SSRS will be used to 
assess lifetime suicidality. The “since last visit” C-SSRS will be used to assess current 
suicidality. This scale is intended for use by trained administrators. The questions contained in 
the C-SSRS are suggested probes. Ultimately, the determination of the presence of suicidality 
depends on clinical judgment. Training is required before administering the C-SSRS through a 
30-minute interactive slide presentation followed by a question-answer session through the 
Columbia University Medical Center. Those completing the training are certified to administer 
the C-SSRS, and must provide a valid training certificate for the study’s regulatory files. 
NOTE: If a subject expresses suicidal thoughts or exhibits acute psychosis or suicidal/homicidal 
behavior, the subject will be referred to a local treatment center, emergency department or be 
hospitalized as appropriate and study drug will be discontinued. 
 


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12.13   Blood Chemistries 
Blood will be collected by the sites in serum separation evacuated venous blood collection tubes 
(e.g., Vacutainer®) and will be separated according to standard procedures and sent to a central 
clinical laboratory for testing (Q2 Solutions, Valencia, CA). Quantitative analysis will be 
performed for the following analytes: sodium, potassium, chloride, carbon dioxide, glucose, 
creatinine, calcium, alanine aminotransferase (ALT/SGPT), aspartate aminotransferase 
(AST/SGOT), gamma-glutamyltranspeptidase (GGT), total bilirubin, alkaline phosphatase 
(ALP), and blood urea nitrogen (BUN). Results will be made available to the clinical site staff 
upon completion of testing. 
12.14   Hematology 
Blood will be collected by the sites in evacuated venous blood collection tubes containing 
anticoagulant (e.g., Vacutainer®) for hematologic assessments and sent to a central clinical 
laboratory for testing (Q2 Solutions, Valencia, CA). Complete blood counts (CBC) with 
differentials and platelet count will be performed. Quantitative analyses for hemoglobin, 
hematocrit, red blood cells, platelets, total white blood cells, neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils will be performed. Results will be made available to the 
clinical site staff upon completion of testing. 
12.15   Urinalysis 
Urine will be collected using the collection kit provided by the central clinical laboratory (Q2 
Solutions, Valencia, CA) and analyzed for: specific gravity, pH, blood, protein, glucose, ketones, 
leukocytes, and nitrite. Results will be made available to the clinical site staff upon completion 
of testing. 
12.16   Urine Drug Screen 
Urine samples will be tested for cocaine and other drugs of abuse (as noted in Table 3, Schedule 
of Events) using a multi-panel on-site test device (Branan ToxCup® DT14) to identify 
individuals potentially using illicit drugs. 
12.17   Urine Fentanyl 
Urine samples will be collected and tested using an on-site one-step rapid fentanyl test stick to 
determine qualitative detection of fentanyl metabolite at 50 ng/mL cut-off concentration. 
12.18   Urine Cotinine 
Urine samples will be collected and tested using an on-site one-step rapid nicotine test stick to 
determine qualitative detection of cotinine levels at 200 ng/mL cut-off concentration. 
12.19   EtG Urine Alcohol Test 
Urine samples will be collected and tested using an on-site one-step rapid ethyl glucuronide 
(EtG) test stick to determine qualitative detection of alcohol levels at 500 ng/mL cut-off 
concentration and be used to evaluate the abstinence from the consumption of alcohol. 


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12.20   Urine BE Testing 
Urine samples will be collected and sent to a central laboratory (Laboratory Corporation of 
America, Research Triangle Park, NC) to be analyzed for BE and creatinine using validated 
liquid chromatography-tandem mass spectrometry methods for analysis. The details of sample 
collection, labeling, storage, and shipment will be provided in a Study Operations Manual.  
12.21   Blood Collections for Medication Adherence 
As specified in Table 3, Schedule of Events, blood samples will be collected to determine the 
plasma concentrations of both acetazolamide (Study Day 8) and lorcaserin (Study Weeks 3 and 
7) as a medication adherence marker. Each blood sample will be collected into a sodium heparin-
containing Vacutainer® tube, and plasma will be separated according to standard procedures. 
Plasma concentrations of ACZM and lorcaserin will be determined at a central bioanalytical lab 
(XenoBiotic Laboratories, Inc., Plainsboro, NJ) using a validated liquid chromatography-tandem 
mass spectrometry method. The details of sample collection, labeling, storage, and shipment will 
be provided in a Study Operations Manual.  
12.22   Cognitive Behavioral Therapy (CBT) 
Attendance at the clinic for assessments and the behavioral counseling session will be recorded 
on an eCRF including the length of the session. The Behavioral Counseling eCRF will also 
record any additional behavioral methods the subject may have used on their own, e.g., NA, AA, 
hypnosis, etc. 
12.23   Alcohol Intervention: Quit to Quit 
A computer-based alcohol intervention will be viewed by all subjects on Study Day 1 and will be 
continued on an optional basis at the discretion of each subject. The alcohol intervention, “Quit 
to Quit”, will encourage abstinence from alcohol but it will be up to each subject to decide 
whether or not this will be one of their goals during the trial. Each subject’s decision (yes or no) 
to continue viewing the alcohol intervention modules will serve as one of the stratification 
factors for randomization.  The subject’s case report forms will contain a record of all alcohol 
intervention modules viewed. 
12.24   AiView Adherence Monitoring 
Beginning on Study Day 8, subjects will participate in a medication adherence monitoring 
procedure, with associated opportunities to earn rewards that are contingent upon appropriate 
performance of tasks using a site-provided cell phone loaded with Health Insurance Portability 
and Accountability Act (HIPAA)-compliant AiView software (AiCure Technologies, New York, 
NY). AiView uses facial recognition and motion-sensing technology to confirm the ingestion of 
a study medication and transfers the resulting data (encrypted and blurred) to a secure central 
server in real time. The software will also be configured to remind patients of upcoming 
scheduled doses and record the previous day’s cocaine and alcohol use.  
12.25   Concomitant Medications 
All medications taken by the subject within the 30 days prior to screening and during the 
screening period, up to and including the day of randomization, will be recorded. The reported 
medications will be reviewed and approved by the SI/study physician for possible interactions 


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with study drugs or an indication of a serious chronic or acute medical condition that would 
exclude the candidate from participation. 
All medications taken by the subject during the Treatment Phase of the study through the Week 
16 Follow-Up Visit will be recorded. Any medications taken during this time must be pre-
approved by the SI/study physician whenever possible to avoid interactions with study drug. 
NOTE: In general, participants who require any concomitant medications at the time of 
screening must have a stable medical condition and stable dosages for the 3 months prior to 
enrollment in the study. Subjects will be cautioned not to take concomitant medications, whether 
prescription, over-the-counter, herbal supplements, or health store products without first 
consulting with the SI or his/her designee. The NIDA Medical Monitor should be contacted if 
there are any questions. 
12.25.1 Concomitant Medications Always Excluded 
In general, concomitant medications that have been associated with serotonin syndrome and 
durgs that are metabolized by CYP 2D6 are not permitted under this protocol.  The list below 
contains medications that are specifically not allowed at any time during the course of study 
participation. In addition, section 12.23.2 delineates a list of concomitant medications with 
limitations of use. Again, if in doubt, consult a physician assigned to the study or the NIDA 
Medical monitor. 
Including but not limited to: 
• Antispychotic Medications: haloperidol, thioridazine, aripiprazole, etc. 
• All opioids: tramadol, oxycodone, hydrocodone, codeine, morphine, methadone, 
buprenorphine, etc. 
• All beta-blockers: propranolol, metoprolol, etc. 
• All Class I antiarrhythmic drug: flecainide, propafenone, mexiletine, etc. 
• All  monoamine oxidase inhibitors (MAOIs) 
• Dexamphetamine, Lisdexamfetamine or Methamphetamine 
• All tryptans, lithium, ondansetron, dolasetron, donepezil, metoclopramide, palanosetron, 
promethazine, safinamide, St. John’s wort, tryptophan and any other dopaminergic or 
serotonergic drug that is not specifically listed as allowable in this protocol. 
• Medications to treat erectile dysfunction (e.g. Viagra, Cialis, etc) 
12.25.2 Allowable Concomitant Medications with Limitations 
Subjects will be allowed to receive no more than one medication, included in the list below, 
at any given time during the course of study participation. 
• Non-MAOI antidepressants: amitriptyline, atomoxetine, bupropion, clomipramine, 
desipramine, desvenlafaxine, duloxetine, fluoxetine, fluvoxamine, imipramine, 
levomilnacipran, minanserin, mirtazapine, paraoxetine, venlafaxine, vilazodone, and 
vortioxetine 


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• Dextromethorphan 
12.26   Substance Use Report (SUR) 
The SUR measures the subject’s self-report of days of recent drug use. The use of cocaine, 
alcohol, nicotine, marijuana, methamphetamines, amphetamines, opiates, and benzodiazepines 
will be recorded on the SUR form. NOTE: Timeline Followback (TLFB) of cocaine and alcohol 
use will be obtained only for missing data beginning at Study Day 8 (data not captured by the 
AiView device). 
12.27   Brief Substance Craving Scale (BSCS) 
The BSCS is a self-administered assessment that asks the subject to rate his/her craving for 
cocaine. The BSCS used for this study is a modification of the State of Feelings and Cravings 
Questionnaire (Mezinskis et al., 2001). The composite BSCS severity score is a sum of three 
items: intensity, frequency, and length (each item ranges from 0 for no use to 4 for extreme use), 
ranging from 1 to 12. The higher the score, the more severe the cocaine craving is. However, 
members of study staff are not to offer interpretations of the questions.  
12.28   Adverse Events 
Adverse events will be assessed by medically trained study staff. If an adverse event requires 
medical attention, it will be reported to a study physician immediately. Adverse events will be 
assessed by asking the subject, "How have you been feeling since I saw you last?" After current 
adverse events are assessed, the study physician must review with the subject and assess 
any adverse events unresolved from the previous visit. After the adverse event assessment at 
each clinic visit, the type of adverse event, severity of each adverse event, and the relationship to 
the study drugs will be recorded on the Adverse Events eCRF, according to the procedures 
described in Appendix I. These categories are asking for the clinician's best judgment of the 
severity and relatedness of each adverse event. 
As a precaution, all subjects will be closely monitored for treatment reports or signs of serotonin 
toxicity such as spontaneous clonus, inducible clonus with agitation or diaphoresis, ocular clonus 
with agitation or diaphoresis, tremor and hyperreflexia, hypertonia and hyperpyrexia with ocular 
or inducible clonus when adverse events are assessed during each weekly visit. The Hunter 
Serotonin Syndrome diagnostic criteria are noted in Appendix I. 
NOTE: All follow-up Week 16 AEs will be recorded and followed to resolution, only if they 
are serious, or if the study physician assesses them to be clinically significant. 
13 REGULATORY AND REPORTING REQUIREMENTS  
13.1 Good Clinical Practices 
This study will be conducted in accordance with the most current version of the International 
Conference on Harmonisation Guide for Good Clinical Practices (GCP).  
13.2 FDA Form 1572 
The SI agrees to sign and submit a Statement of Investigator (FDA Form 1572) to the sponsor 
prior to initiating this study. 


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13.3 IRB Approval 
Prior to initiating the study, the SI will obtain written IRB approval to conduct the study. Should 
changes to the study protocol become necessary, the SI will submit protocol amendments in 
writing to the IRB for IRB approval prior to implementation. In addition, IRBs will approve all 
advertising materials used for subject recruitment and any educational materials given to the 
subject. Annual reports and progress reports will be submitted to the IRB annually or at a 
frequency requested by the IRB.  
The SI will ensure that a duly constituted IRB at the study site that conforms to FDA regulations 
(21 CFR Part 56) will review the protocol and the volunteer informed consent form. The SI will 
follow IRB and FDA guidance regarding reporting of AEs. The SI will promptly report to the 
IRB all changes in research activity and all unanticipated problems involving risks to human 
subjects or others and will not make any changes in the protocol without IRB approval, except 
where necessary to eliminate immediate hazards to human subjects. 
13.4 Informed Consent 
The investigator, sub-investigators, study physician, or designated staff at each site will explain 
all aspects of the study in lay language and answer all of the candidate’s questions regarding the 
study. If the candidate desires to participate in the study, s/he will be asked to sign and Informed 
Consent. No study procedure will be performed prior to signing Informed Consent. Candidates 
who refuse to participate or participants who withdraw from the study will be regarded without 
prejudice. All study subjects will be given a copy of the signed Informed Consent(s). 
13.5 Use of Protected Health Information 
At the time of informed consent, all potential candidates will be asked to sign a waiver 
authorizing the release and use of protected health information in this study. Clinical sites will 
employ a Protected Health Information Disclosure that details the health information that will be 
collected as part of this research and the agencies that may access that information during the 
study and after the study has been completed.  
Health information gathered during this research study may be reviewed by representatives of 
NIDA, the Food & Drug Administration (FDA) and designated appointees for monitoring 
purposes. All data collected for this study will be sent to the VA CSP Coordinating Center 
(CSPCC) in Perry Point, MD for processing and analyses. Case report form data will be 
transmitted electronically to a secure server owned and operated by Medidata Solutions, Inc.  
The Medidata server is compliant with the Federal Information Security Management Act of 
2002 (FISMA).  Retrieval of data stored on the server is restricted to data management personnel 
at the VA CSPCC. De-identified data from third parties, such as clinical laboratory values or 
toxicology results, will be provided to the VA CSPCC electronically through NIDA’s LiveLink 
server.   Following retrieval of data, a database will be constructed and maintained locally at the 
VA CSPCC and all data contained within will be stored according to the HIPAA Privacy Rule.  


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13.6 Drug Accountability 
Upon receipt, the SI/pharmacist is responsible for taking inventory of the study drug. A record of 
this inventory must be kept and usage must be documented. Any unused or expired study drug 
shall be returned to the VA CSPCRPCC by the sites, unless otherwise instructed. 
13.7 Monitoring 
13.7.1 Data and Safety Monitoring Board 
Blinded safety data will be reviewed by the NIDA Data and Safety Monitoring Board that will 
convene on a quarterly basis during the conduct of this study, or earlier, if deemed necessary.  
The DSMB will make a recommendation to the sponsor regarding whether to stop or continue 
the study. If the DSMB determines that the study should be stopped, all subjects will be 
immediately discontinued from receiving any investigational products and no new subjects will 
be consented or randomized. 
In addition, NIDA has the right to discontinue the investigation at any time. 
13.7.2 Medical Monitor 
The NIDA medical monitor, Dr. Tanya Ramey, will be available for making recommendations to 
the SI on the severity of any SAEs, the relatedness to the study drug, and for determining if the 
SAE should be reported to the FDA in a 7- or 15-day expedited report or an annual report 
(Appendix I). The medical monitor will also be responsible for tracking and assessing trends in 
the adverse events reported. 
13.7.3 Clinical Monitors 
All SIs will allow representatives of the Sponsor to periodically review, at mutually convenient 
times during and after the study, all eCRFs and corresponding source documents for each 
subject. These monitoring visits provide the Sponsor with the opportunity to evaluate the 
progress of the study and to inform the Sponsor of potential problems at the study sites. The 
monitors will: ensure that submitted data are accurate and are in agreement with source 
documentation; verify that study drugs are properly stored and accounted for, verify that 
subjects’ consent for study participation has been properly obtained and documented, confirm 
that subjects entered into the study meet inclusion and exclusion criteria, and assure that all 
essential documentation required by GCP guidelines are appropriately filed. 
Clinical monitors will conduct a site initiation visit prior to the start of the study. At this visit, 
they will assure that proper study-related documentation exists, assist in training SIs and other 
site personnel in study procedures and GCP guidelines, confirm receipt of study supplies, and 
assure that acceptable facilities are available to conduct the study. 
Routine monitoring visits by the Sponsor’s representatives will be scheduled at appropriate 
intervals. At these visits, the monitors will verify that study procedures are being conducted 
according to the protocol guidelines. At the end of the study, they will advise on storage of study 
records and return of unused study drugs. All sites should anticipate visits by NIDA, the 
Sponsor, and the FDA. 


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13.8 Study or Site Discontinuation  
The Sponsor has the right to terminate this study at any time. Reasons for terminating the study 
may include, but are not limited to, the following: 
• The incidence or severity of AEs in this or other studies indicates a potential health hazard to 
subjects. 
• Subject enrollment is unsatisfactory. 
• Data recording is inaccurate or incomplete. 
The Sponsor will continue those subjects currently in treatment to completion, if there is no 
significant safety issue. 
13.9 Retention of Records 
Study documentation includes all eCRFs, workbooks, source documents, monitoring logs, 
appointment schedules, sponsor and SI correspondence, and regulatory documents (e.g., signed 
protocol and amendments, IRB correspondence, approved consent form and signed informed 
consent forms, Statement of Investigator form, and clinical supplies receipt and distribution 
records). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
Accordingly, source documents include, but are not limited to, laboratory reports, ECG tracings, 
X-rays, radiologist reports, subject diaries, biopsy reports, ultrasound photographs, subject 
progress notes, hospital charts or pharmacy records and any other similar reports or records of 
any procedure performed in accordance with the protocol. Whenever possible, the original 
recording of an observation should be retained as the source document; however, a photocopy is 
acceptable provided that it is a clear, legible, and exact duplication of the original document. 
Clinical records for all subjects studied including history and physical findings, laboratory data, 
and results of consultations are to be maintained by the SI in a secure storage facility. 
Government agency regulations and directives require that the SI must retain all study 
documentation pertaining to the conduct of a clinical trial. These documents must be kept for a 
minimum of two years after discontinuation of the IND or two years after the approval of a new 
drug application (NDA) and finalization of all marketing strategies. In all instances you must get 
permission from NIDA prior to disposition of any study documentation and materials. 
13.10 Adverse Events Reporting 
In accordance with FDA reporting requirements, all AEs occurring during the course of the 
clinical trial will be collected, documented, and reported by the SI or sub-investigator according 
to the specific instructions detailed in this section of the protocol and Appendix I. The 
occurrence of AEs will be assessed at each study visit beginning on the day the Informed 
Consent is signed through the Follow-up Visit at Week 16. 
An AE is defined as any reaction, side effect, or untoward event that occurs during the course of 
the clinical trial, whether or not the event is considered investigational product-related or 
clinically significant. For this study, AEs will include events reported by the subject, as well as 


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clinically significant abnormal findings on physical examination or laboratory evaluation. A new 
illness, symptom, sign or clinically significant clinical laboratory abnormality or worsening of a 
pre-existing condition or abnormality is considered an AE. Stable chronic conditions, such as 
arthritis, which are present prior to clinical trial entry and do not worsen are not considered AEs. 
All AEs must be recorded on the AE CRF. The AE CRF is also used to record follow-up 
information for unresolved events reported on previous visits. 
Each week, a study physician must review all new AEs reported the previous week and any 
events that were reported as continuing. All AEs, including clinically significant abnormal 
findings on laboratory evaluations, regardless of severity, will be followed by SIs until 
satisfactory resolution. 
13.10.1 Pregnancy  
A subject’s reported pregnancy at any time during study participation starting after the first dose 
of study drug through the final study visit is considered an AE and must be reported to NIDA in 
accordance with the reporting requirements described in Appendix I. Subjects who become 
pregnant will be discontinued from the study drug and will be referred for appropriate treatment 
as necessary. Subjects will be asked to sign a release of information form for study personnel to 
access medical records to obtain information regarding the outcome of the pregnancy.
13.11 Serious Adverse Events 
Each AE or reaction will be classified by the SI as serious or non-serious. Based on the 
seriousness of the adverse event or reaction, appropriate reporting procedures will be followed. 
The “International Conference on Harmonisation (ICH) Guideline for Industry: Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting, ICH-E2A March 1995,” 
as implemented by the U.S. Food and Drug Administration defines serious adverse event (SAE) 
or reaction as any untoward medical occurrence that at any dose: 
• results in death; 
• is life-threatening; (NOTE: The term "life-threatening" in the definition of "serious" 
refers to an event in which the patient was at risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused death if it were more 
severe.) 
• requires inpatient hospitalization or prolongation of existing hospitalization; 
• results in persistent or significant disability/incapacity; or 
• is a congenital anomaly/birth defect. 
 
In addition, important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug reaction, when based on appropriate 
medical judgment that may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the above definition. An unexpected event is 
one that is not described with respect to nature, severity, or frequency in the current 
Investigator’s Brochure or product package insert. 


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Reporting of AEs and SAEs is described in Appendix I. There can be serious consequences 
including criminal and/or civil penalties for Sponsors who fail to comply with FDA regulations 
governing the reporting of SAEs to FDA. The SIs in this study have the responsibility of 
promptly reporting all SAEs to NIDA in order that NIDA, as the IND Sponsor, can comply with 
these regulations. 
If a study subject withdraws from the study or if a SI decides to discontinue the subject from the 
study because of a SAE, the subject must have appropriate follow-up medical monitoring. If the 
subject is hospitalized, medical monitoring will consist of not less than daily evaluation by 
physical examination, vital signs, laboratory evaluations, and if applicable, ECG monitoring for 
significant treatment-emergent abnormalities. Monitoring will continue until the problem 
prompting hospitalization has resolved or stabilized with no further change expected or is 
discovered to be clearly unrelated to use of investigational products or progresses to death. 
13.12 Subject Confidentiality 
To maintain subject confidentiality, all laboratory specimens, eCRFs, and reports will be 
identified by an alpha-numeric code. Clinical records will be stored separately from research 
records in a secure location. Subject information will not be released without the subject’s 
written permission, except as necessary for monitoring by the FDA, the VA CSP, and Sponsor 
authorized monitors. Release of personal health information will be in accordance with current 
Standards for Privacy of Individually Identifiable Health Information (45 CFR parts 160 and 
164) of the Health Insurance Portability and Accountability Act (HIPAA). 
Particular attention is drawn to the regulations promulgated by the FDA under the Freedom of 
Information Act providing, in part, that proprietary information furnished to SIs and IRBs will be 
kept confidential by the FDA only if maintained in confidence by the SI and IRB. 
By participating in this protocol the SI affirms to NIDA that information furnished to the SI by 
NIDA will be maintained in confidence and such information will be divulged to the IRB, 
Ethical Review Committee or similar expert committee; affiliated institution; and employees 
only under an appropriate understanding of confidentiality with such board or committee, 
affiliated institution and employees. 
By participating in this protocol the SI agrees that within local regulatory restrictions and ethical 
considerations, NIDA or any regulatory agency may consult and/or copy study documents in 
order to verify eCRF data. 
The procedure for applying for a certificate of confidentiality is provided in Appendix II. 
14 STATISTICAL ANALYSIS  
Descriptive statistics will be used to present study data. Continuous variables will be presented 
as number of observations (n), mean, standard deviation (SD), median, minimum and maximum 
values. Categorical variables will be presented as counts and percentages. All data will be 
presented separately by treatment group. Summaries of the safety data will be presented for the 
Safety Population and the Evaluable Population. All data will be presented in listings. 


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14.1 Predictive Enrichment Strategy and Sample Size 
A predictive enrichment strategy based on pre-randomization data (collected during screening 
and the one-week, single-blind run-in period) will be used to define a subpopulation of study 
participants who are likely to be medication adherent after randomization and likely to exhibit a 
low placebo response rate. Data from only this subpopulation, termed the “prequalified for 
primary efficacy endpoint” (PPEE) population, will be utilized for the primary efficacy endpoint. 
Predictive enrichment strategies have been endorsed by the FDA (US Department of Health and 
Human Services Food and Drug Administration. Guidance for industry enrichment strategies for 
clinical trials to support approval of human drugs and biological products, December, 2012) and 
their use has been suggested as a means to address the overlapping issues of medication 
nonadherence, “professional subjects” and increasing placebo response rates (McCann et al., 
2015). 
While 272 subjects will be enrolled in the current study, it is estimated that 180 subjects 
(approximately 90 subjects per group) will meet criteria for inclusion in the PPEE population. 
Assuming 6% and 20% success rates (for achieving abstinence from cocaine) during placebo and 
lorcaserin treatment, respectively, 90 subjects per group in the PPEE population would yield 
80% power (Pearson’s Chi-square test for two proportions; two-sided comparison, alpha = 0.05). 
The assumption of 6% success in the placebo group is based on results from similar cocaine 
medication trials conducted by NIDA in the past, using the same definition of “success” (placebo 
group success rates have ranged from 0 to 9%). The goal of 20% success in the lorcaserin group 
would constitute slightly more than a three-fold increase in success compared to the expected 
placebo success rate. Such efficacy would be clinically meaningful. No medications are currently 
approved for the treatment of cocaine use disorder, but a 3-fold increase in quit rate (vs. placebo) 
would constitute greater efficacy than has been observed for FDA-approved smoking cessation 
medications. A recent meta-analysis of randomized, placebo-controlled smoking cessation trials 
(Eisenberg et al., 2008) revealed that placebo and bupropion quit rates were 11% and 20%, 
respectively (16 trials), placebo and nicotine gum quit rates were 14% and 19%, respectively (22 
trials), placebo and nicotine patch quit rates were 7.5% and 13%, respectively (30 trials), and 
placebo and varenicline quit rates were 15% and 26%, respectively (13 trials). For the current 
study, multiple factors were considered in estimating that 180 of the 272 enrolled subjects will 
qualify for inclusion in the PPEE population. Further explanation requires an understanding of 
enrichment strategy details. 
For a subject to be included in the PPEE population, two criteria must be met. First, the plasma 
sample collected prior to randomization on Study Day 8 must yield an acetazolamide 
concentration of at least 15 ng/mL. Based on a prior NIDA PK study (unpublished), plasma 
acetazolamide concentrations can be expected to stay above 15 ng/mL for 48 hours after a single 
15 mg oral dose in approximately 99.9% of subjects (the lower boundary of the 99.9% CI for 
plasma samples collected 48 hours post-dose was 15.2 ng/mL). As subjects are supposed to take 
15 mg acetazolamide capsules twice daily during the single-blind run-in period (with the last 
dose on the morning of Study Day 8), they would have to miss at least three or more consecutive 
doses at the end of the run-in period for their plasma concentrations to fall below 15 ng/mL 
during the clinic visit on Study Day 8. When such extreme nonadherence occurs during the first 
week of a trial, it brings into question the motivation of the subject. Such a subject may not be 
interested in receiving treatment and may have falsely claimed to be “treatment seeking” to gain 


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study enrollment. Unfortunately, deception to gain enrollment has been well-documented in 
repeat clinical trial participants (Devine et al., 2013; Shiovitz et al., 2013). In a prior NIDA trial 
that evaluated modafinil in the treatment of methamphetamine dependence (Anderson et al., 
2012), 10% of subjects in the active treatment groups never had any detectable modafinil in their 
urine samples from week 1 through the end of the 12-week trial. Based on this experience, it is 
estimated that that approximately 10% of subjects who enroll in the current study will fail to 
meet the 15 ng/mL acetazolamide cutoff level and will therefore not qualify for the PPEE 
population. 
The second criterion for inclusion in the PPEE population is focused on cocaine use self-report 
data collected during the first day of screening. To be included in the PPEE population, subjects 
must report using cocaine on at least 8 days during the 30 days immediately prior to screening. 
Subjects reporting 1 to 7 days of cocaine use will still be enrolled, and their data will be 
evaluated for exploratory efficacy endpoints, but they will not qualify for the PPEE population. 
In an unpublished evaluation of recent NIDA-sponsored cocaine medication trials, higher 
placebo success rates were observed for subjects reporting <8/30 days of cocaine use 
immediately prior to screening. For example, in a trial evaluating nepicastat vs. cocaine 
dependence (manuscript in preparation), 18% of placebo subjects reporting <8/30 days of 
cocaine use prior to screening were successful in achieving 3 weeks of abstinence at the end of 
the study, whereas only 6% of placebo subjects reporting >7/30 days of cocaine use prior to 
screening were able to achieve this same duration of abstinence. In the nepicastat trial, 22% of 
enrolled subjects reported <8/30 days of cocaine use. Based on this experience, we estimate that 
approximately 22% of subjects who enroll in the current trial will report <8/30 days of cocaine 
use prior to screening and, therefore, will not qualify for the PPEE population. 
In addition to subjects failing to meet the two criteria mentioned above, it is anticipated on the 
basis of past experience that approximately 5% of subjects who are enrolled in the current study 
will drop out prior to randomization on Study Day 8 (a 5% dropout rate was seen during the first 
week of the NIDA nepicastat trial).  
With the above factors in mind, the estimated size of the PPEE population can be addressed. If 
272 subjects are enrolled and 22% (60) report <8/30 days cocaine use (excluding them from the 
PPEE population), 212 subjects remain eligible. If approximately 10% (22) of the remaining 212 
subjects fail to qualify for the PPEE population based on nonadherence during the run-in period 
(Study Day 8 plasma acetazolamide <15 ng/mL), 190 subjects remain eligible. If approximately 
5% (10) of the remaining 190 subjects drop out prior to Study Day 8, 180 subjects will qualify 
for the PPEE population. 
While the enrichment strategy adds complexity to the process of data analysis, it does not 
substantively complicate clinical site procedures. Subjects will be classified as “PPEE” or “Non-
PPEE” during data analysis, and clinical site staff will not be aware of key data (acetazolamide 
plasma concentrations) required for the classification. 
Figure 3 schematically depicts this predictive enrichment strategy for the purposes of endpoint 
analysis. 
 
 


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Figure 3. Enrichment Strategy Study Design 
 
 
14.2 Definitions of Study Populations 
1) The “Intent-to-Treat (ITT) Population” – All subjects who may have taken at least one dose of 
lorcaserin or placebo after randomization on Study Day 8. This includes all subjects who receive 
at least one bottle of study drug (lorcaserin or placebo) after randomization on Study Day 8, with 
the exception of any subjects who return the full bottle before leaving the clinic on Study Day 8 
(this may occur, for example, if a subject changes his/her mind about continuing in the study). 
2) The “PPEE Population” – The subset of the ITT Population who prequalify for the primary 
efficacy endpoint by meeting the specified PPEE criteria prior to randomization. 
3) The “Non-PPEE Population” – The subset of the ITT Population who fail to meet the 
specified PPEE criteria and, therefore, do not prequalify for the primary efficacy endpoint. 


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4) The “Non-Drinker Population” – The subset of the ITT Population who are non-drinkers, as 
evidenced by 100% negative results for the presence of EtG in urine from the beginning of 
screening through the urine test on Study Day 8, prior to randomization and 2) consistent self-
report of no alcohol use throughout this same period of time, as well as the 30 days prior to 
screening. 
5) The “Attempting Alcohol Abstinence (AAA) Population” – The subset of the ITT Population 
who: 1) fail to meet criteria for the “Non-Drinker Population” and 2) commit to quitting drinking 
during the study, as evidenced by viewing the optional Quit to Quit module on Study Day 8 prior 
to randomization.  
6) The “Baseline Low Use/Adherent Population” – The subset of the non-PPEE Population who 
failed to qualify for the primary efficacy endpoint only because they reported <8 days of cocaine 
use during the 30 days prior to screening (plasma acetazolamide level on Study Day 8 was ≥15 
ng/mL). 
7) The “Baseline Adherent Population” – The combination of the PPEE Population and the 
Baseline Low Use/Adherent Population (all subjects with Study Day 8 plasma acetazolamide 
levels ≥15 ng/mL). 
8) The Baseline Non-Adherent Population – The subset of the ITT Population who are not part 
of the Baseline Adherent Population (all subjects with Study Day 8 plasma acetazolamide levels 
<15 ng/mL). 
9) The “Acetazolamide Safety Population” – All subjects who participate in the 1-week, single-
blind run-in period. Note: Treatment-emergent AEs recorded during this period will be assessed 
in relationship to acetazolamide. 
10) The “Lorcaserin/Placebo Safety Population” – The same group of subjects defined above for 
the ITT Population. Note: Treatment-emergent AEs recorded in this group after randomization 
will be assessed in relationship to lorcaserin/placebo. 
14.3 Outcome Measures 
14.3.1 Primary Efficacy Outcome Measures 
The primary endpoint is the proportion of subjects successfully achieving abstinence from 
cocaine during the last three weeks of treatment (Study Weeks 11-13) in the PPEE population. 
Comparison of this proportion in subjects receiving lorcaserin vs. placebo will constitute the 
primary endpoint analysis. 
 
A subject will be regarded as a treatment success (abstinent from cocaine during the last three 
weeks of treatment) if:  
 
• There are self-report data indicating no cocaine use on each day of the 3-week period; 
 
• There is at least one benzoylecgonine (BE) assay result for a urine sample collected 
within the 3-week period; and 
 


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• BE assay results are negative (BE <150 ng/mL) for all urine samples collected during 
the 3-week period. 
 
Subjects not meeting these three criteria (including dropouts) will be regarded as treatment 
failures.  
14.3.2 Secondary Efficacy Outcome Measures 
The secondary endpoint is the proportion of subjects successfully achieving abstinence from 
cocaine during the last three weeks of treatment (Study Weeks 11-13) in the subset of the PPEE 
population who are also part of the Non-Drinker Population or the AAA Population. Comparison 
of this proportion in subjects receiving lorcaserin vs. placebo will constitute the secondary 
endpoint analysis. Abstinence will be defined as described for the primary endpoint. 
14.3.3 Exploratory Outcome Measures 
a) The proportion of subjects successfully achieving abstinence from cocaine during the last 
three weeks of treatment (Study Weeks 11-13) in the ITT population. Comparison of this 
proportion in subjects receiving lorcaserin vs. placebo will constitute the analysis. Abstinence 
will be defined as described for the primary endpoint. (Note: what the primary endpoint would 
have been if there were no enrichment strategy) 
b) The proportion of subjects successfully achieving abstinence from cocaine during the last 
three weeks of treatment (Study Weeks 11-13) in the subset of the ITT population who are also 
part of the Non-Drinker population or the AAA Population. Comparison of this proportion in 
subjects receiving lorcaserin vs. placebo will constitute the analysis. Abstinence will be defined 
as described for the primary endpoint. (Note: what the secondary endpoint would have been if 
there were no enrichment strategy) 
c) The proportion of subjects successfully achieving abstinence from cocaine during the last 
three weeks of treatment (Study Weeks 11-13) in the non-PPEE population. Comparison of this 
proportion in subjects receiving lorcaserin vs. placebo will constitute the analysis. Abstinence 
will be defined as described for the primary endpoint.  
d) The proportion of subjects successfully achieving abstinence from cocaine during the last 
three weeks of treatment (Study Weeks 11-13) in the subset of the non-PPEE population who are 
also part of the Non-Drinker population or the AAA Population. Comparison of this proportion 
in subjects receiving lorcaserin vs. placebo will constitute the analysis. Abstinence will be 
defined as described for the primary endpoint. 
e) The proportion of subjects successfully achieving abstinence from cocaine during the last 
three weeks of treatment (Study Weeks 11-13) in the Baseline Low Use/Adherent Population. 
Comparison of this proportion in subjects receiving lorcaserin vs. placebo will constitute the 
analysis. Abstinence will be defined as described for the primary endpoint. (Note: similar to 
primary endpoint but in subjects excluded from the PPEE population only because of low 
baseline cocaine use) 
f) The proportion of subjects successfully achieving abstinence from cocaine during the last three 
weeks of treatment (Study Weeks 11-13) in the subset of the Baseline Low Use/Adherent 
Population who are also part of the Non-Drinker population or the AAA Population. Comparison 


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of this proportion in subjects receiving lorcaserin vs. placebo will constitute the analysis. 
Abstinence will be defined as described for the primary endpoint. (Note: similar to secondary 
endpoint but in subjects excluded from the PPEE population only because of low baseline 
cocaine use) 
g) The proportion of subjects successfully achieving abstinence from cocaine during the last 
three weeks of treatment (Study Weeks 11-13) in the Baseline Adherent Population. Comparison 
of this proportion in subjects receiving lorcaserin vs. placebo will constitute the analysis. 
Abstinence will be defined as described for the primary endpoint. (Note: what the primary 
endpoint would have been if low baseline cocaine use had not excluded subjects from the PPEE 
Population) 
h) The proportion of subjects successfully achieving abstinence from cocaine during the last 
three weeks of treatment (Study Weeks 11-13) in the subset of the Baseline Adherent Population 
who are also part of the Non-Drinker population or the AAA Population. Comparison of this 
proportion in subjects receiving lorcaserin vs. placebo will constitute the analysis. Abstinence 
will be defined as described for the primary endpoint. (Note: what the secondary endpoint would 
have been if low baseline cocaine use had not excluded subjects from the PPEE Population) 
i) The proportion of subjects successfully achieving abstinence from cocaine during the last three 
weeks of treatment (Study Weeks 11-13) in the subset of the AiView Users Population who are 
also part of the PPEE Population. Comparison of this proportion in subjects receiving lorcaserin 
vs. placebo will constitute the analysis. Abstinence will be defined as described for the primary 
endpoint. 
j) The proportion of subjects successfully achieving abstinence from cocaine during the last three 
weeks of treatment (Study Weeks 11-13) in the subset of the AiView Non-Users Population who 
are also part of the PPEE Population. Comparison of this proportion in subjects receiving 
lorcaserin vs. placebo will constitute the analysis. Abstinence will be defined as described for the 
primary endpoint. 
k) The proportion of subjects successfully achieving abstinence from alcohol during the last 
three weeks of treatment (Study Weeks 11-13) in the subset of the AAA Population who are also 
in the Baseline Adherent Population and who received a diagnosis of Alcohol Use Disorder 
(AUD) during screening. Comparison of this proportion in subjects receiving lorcaserin vs. 
placebo will constitute the analysis. A subject will be regarded as abstinent from alcohol during 
the last three weeks of treatment if:  
 
• There are self-report data indicating no alcohol use on each day of the 3-week period; 
 
• There is at least one ethyl glucuronide (EtG) assay result for a urine sample collected 
within the 3-week period; and 
 
• EtG assay results are negative (EtG < 500 ng/mL) for all urine samples collected 
during the 3-week period. 
 
Subjects not meeting these three criteria (including dropouts) will be regarded as having failed to 
achieve abstinence from alcohol. 


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l) The proportion of subjects successfully achieving abstinence from alcohol during the last three 
weeks of treatment (Study Weeks 11-13) in the subset of the AAA Population who are also in 
the Baseline Adherent Population. Comparison of this proportion in subjects receiving lorcaserin 
vs. placebo will constitute the analysis. Abstinence from alcohol will be defined as described 
above. (Note: attempting alcohol abstinence and good baseline adherence +/- AUD) 
m) The proportion of subjects successfully achieving abstinence from alcohol during the last 
three weeks of treatment (Study Weeks 11-13) in the subset of the AAA Population who 
received a diagnosis of AUD during screening. Comparison of this proportion in subjects 
receiving lorcaserin vs. placebo will constitute the analysis. Abstinence from alcohol will be 
defined as described above. (Note: attempting alcohol abstinence with AUD +/- good baseline 
adherence) 
n) The proportion of subjects successfully achieving abstinence from alcohol during the last 
three weeks of treatment (Study Weeks 11-13) in the subset of the ITT Population who received 
a diagnosis of AUD during screening. Comparison of this proportion in subjects receiving 
lorcaserin vs. placebo will constitute the analysis. Abstinence from alcohol will be defined as 
described above. (Note: includes all subjects with AUD whether or not trying to abstain from 
alcohol)  
o) The proportion of subjects successfully achieving abstinence from alcohol during the last 
three weeks of treatment (Study Weeks 11-13) in the ITT Population. Comparison of this 
proportion in subjects receiving lorcaserin vs. placebo will constitute the analysis. Abstinence 
from alcohol will be defined as described above.  
p) The proportion of subjects in the ITT Population reporting no alcohol use for each day of the 
last three weeks of treatment (Study Weeks 11-13). Comparison of this proportion in subjects 
receiving lorcaserin vs. placebo will constitute the analysis. (Note: comparison with results for 
the endpoint described immediately above will provide an indication of the extent to which 
subjects under-reported their alcohol use and falsely claimed alcohol abstinence at the end of the 
study)  
q) The proportion of subjects successfully achieving abstinence from cocaine during the last 
three weeks of treatment (Study Weeks 11-13) in the subset of the PPEE Population who 
completed the Treatment Phase (remaining through the end of Study Week 13) and were 
abstinent from alcohol during the last three weeks of treatment. Comparison of this proportion in 
subjects receiving lorcaserin vs. placebo will constitute the analysis. Abstinence from cocaine 
will be defined as described for the primary endpoint, and abstinence from alcohol will be 
defined as described above.  
r) The proportion of subjects successfully achieving abstinence from cocaine during the last three 
weeks of treatment (Study Weeks 11-13) in the ) in the subset of the PPEE Population who 
completed the Treatment Phase (remaining through the end of Study Week 13) and were NOT 
abstinent from alcohol during the last three weeks of treatment. Comparison of this proportion in 
subjects receiving lorcaserin vs. placebo will constitute the analysis. Abstinence from cocaine 
will be defined as described for the primary endpoint, and abstinence from alcohol will be 
defined as described above. 


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s) The proportion of subjects successfully achieving abstinence from cocaine during the last six 
weeks of treatment (Study Weeks 8-13) in the PPEE population. Comparison of this proportion 
in subjects receiving lorcaserin vs. placebo will constitute the primary endpoint analysis. 
 
A subject will be regarded as a treatment success (abstinent from cocaine during the last six 
weeks of treatment) if:  
 
• There are self-report data indicating no cocaine use on each day of the 6-week period; 
 
• There is at least one benzoylecgonine (BE) assay result for a urine sample collected 
within the 6-week period; and 
 
• BE assay results are negative (BE < 150 ng/mL) for all urine samples collected during 
the 6-week period. 
 
Subjects not meeting these three criteria (including dropouts) will be regarded as treatment 
failures.  
 
t) The proportion of subjects successfully achieving abstinence from alcohol during the last six 
weeks of treatment (Study Weeks 8-13) in the subset of the AAA Population who are also in the 
Baseline Adherent Population and who received a diagnosis of Alcohol Use Disorder (AUD) 
during screening. Comparison of this proportion in subjects receiving lorcaserin vs. placebo will 
constitute the analysis. A subject will be regarded as abstinent from alcohol during the last six 
weeks of treatment if:  
 
• There are self-report data indicating no alcohol use on each day of the 6-week period; 
 
• There is at least one ethyl glucuronide (EtG) assay result for a urine sample collected 
within the 6-week period; and 
 
• EtG assay results are negative (EtG < 500 ng/mL) for all urine samples collected 
during the 6-week period. 
 
Subjects not meeting these three criteria (including dropouts) will be regarded as having failed to 
achieve abstinence from alcohol. 
u) The proportion of subjects in the [subset of the Baseline Adherent Population with at least one 
lorcaserin plasma assay result] whose lorcaserin plasma levels were in the expected range for all 
assay results (expected range to be specified in Statistical Analysis Plan). 
v) The proportion of subjects in the [subset of the Baseline Non-Adherent Population with at 
least one lorcaserin plasma assay result] whose lorcaserin plasma levels were in the expected 
range for all assay results (expected range to be specified in Statistical Analysis Plan). 


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w) The proportion of subjects in the [subset of the PPEE Population with at least one lorcaserin 
plasma assay result] whose lorcaserin plasma levels were in the expected range for all assay 
results (expected range to be specified in Statistical Analysis Plan). 
x) The proportion of subjects in the [subset of the Non-PPEE Population with at least one 
lorcaserin plasma assay result] whose lorcaserin plasma levels were in the expected range for all 
assay results (expected range to be specified in Statistical Analysis Plan). 
y) Self-reported cigarette consumption in the subset of the Baseline Adherent Population who 
report smoking during the screening period. The outcome will be compared in subjects receiving 
lorcaserin vs. placebo. Further details of the analysis will be included in the Statistical Analysis 
Plan. 
z) The relationship between Study Day 8 plasma acetazolamide levels and observed study drug 
adherence after randomization will be explored. Details of the analysis will be included in the 
Statistical Analysis Plan. 
aa) Descriptive breakdown of the PPEE and Non-PPEE populations by severity of cocaine use 
disorder (the proportion of subjects in each population with diagnosed severity of mild, moderate 
and severe). 
bb) Change in ASI-Lite score (placebo vs. lorcaserin) for the subgroup of the PPEE population 
who have values from both Day 1 and Week 13 visits. 
cc) Change in BSCS score (placebo vs. lorcaserin) from baseline through week 13 for the 
subgroup of the PPEE population who remain in treatment through at least the week 3 visit (first 
visit after lorcaserin dosing with BSCS assessment). For this analysis, baseline = average of 
BSCS results from Week 1 (Day 1) and Week 2 (Day 8) visits for each subject. 
14.4 Safety Evaluations 
During the course of the study, safety data will be collected for all subjects who have entered 
screening. For the Combined PPEE/Non-PPEE Population, data will be summarized by 
treatment group (and by visit, when applicable). 
The incidence and severity of treatment-emergent AEs will be summarized by treatment group. 
The results of clinical laboratory tests; 12-lead ECGs; physical examinations; suicidality 
evaluations (C-SSRS), body weight and vital sign measurements will be summarized with 
descriptive statistics, by treatment group, for all time-points at which these variables are 
collected. Individual patient data for vital signs, ECG results, and laboratory test results will be 
assessed for potentially clinically significant values according to predetermined criteria. Any 
potentially clinically significant values identified will be summarized by treatment group. 
For parameters measured during screening, the safety variables of interest are the changes from 
baseline. Data collected after subjects receive the first dose of acetazolamide but before 
randomization to lorcaserin will be summarized and compared with data collected during 
screening. Adverse events will also be summarized for subjects who do not progress beyond 
screening. 


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15 DATA MANAGEMENT AND ELECTRONIC CASE REPORT FORMS (ECRFS) 
Data management activities and statistical analytical support will be coordinated through the 
CSPCC at the VA in Perry Point, MD. 
15.1 Data Collection 
Site Investigators are responsible for maintaining accurate, complete and up-to-date records for 
each subject. This includes all source documentation related to the study, such as progress notes, 
films, ECG tracings, computer discs or tapes. After initial data entry onto source documents, site 
staff will make subsequent data entries onto electronic case report forms (eCRFs) within the 
study’s electronic data capture (eDC) system. The eDC system will contain a record for every 
subject who provides consent to participate in the study. Data entry will be guided through 
nested folders that are accessible sequentially, usually upon completion of required procedures. 
For example, site personnel may only access enrollment forms once screening data have been 
entered. 
The eDC system utilized for this study is furnished by Medidata Solutions, Inc. The eDC system 
will be accessible only by site personnel who have received the required training. Further, 
permissions to add, modify or view data will be customized based on individual site personnel’s 
roles within the study. Permissions will be set and maintained by the CSPCC, the data 
coordinating center for the study. The CSPCC will revoke permissions for any staff member who 
fails to maintain required training, including human subjects protection and good clinical 
practices (GCP) training. 
15.2 Data Editing and Control  
Data submitted via the eDC system will undergo a series of automated and manual quality 
checks and reviews. Incomplete, inconsistent or inaccurate data will generate requests for 
clarification that will require response(s) from site personnel. Details of the number of subjects 
entered into the system and the quality and quantity of the data submitted will be available by 
site to end users upon log in. These data will also be made available to representatives of the 
NIDA DTMC on a monthly basis, or as needed to chart the study’s progress or individual sites’ 
performance. 
Site investigators agree to routine data audits by the staff of the Department of Veterans Affairs 
Cooperative Studies Program (VA CSP) monitoring unit, as well as by NIDA. VA CSP monitors 
will routinely visit each site to assure that data submitted on the appropriate forms are in 
agreement with source documents at the sites. They will also verify that study drugs have been 
properly stored and accounted for, subject informed consent for study participation has been 
obtained and documented in the subject’s progress notes, all essential documents required by 
GCP regulations are on file, and sites are conducting the study according to the research 
protocol. Any inconsistencies will be resolved, and any changes to the data forms will be made 
using established CSPCC procedures. Further, monitors will be granted access to view and query 
data remotely within the eDC system in preparation for their routine visits. 


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15.3 Data Entry, Processing and Analyses  
Data from eCRFs will be transmitted into a database at the CSPCC. When the study is completed 
and all data have been entered into the clinical database, and the database has been checked by 
Quality Assurance and locked, statistical analysis of the data will be performed by the CSPCC 
statisticians in accordance with the Statistical Analysis Plan (SAP) of this protocol. Periodically, 
during the investigation, CSPCC will also prepare summary reports of the data so that progress 
of the study can be monitored by NIDA and the DSMB. De-identified datasets will also be 
submitted to the NIDA DTMC central data repository. 
16 PUBLICATION OF THE STUDY RESULTS 
NIDA and the investigative group agree that data will be made available to individual SIs to 
encourage other publications, either by a group or by an individual SI provided that: manuscripts 
based on the use of lorcaserin for cocaine use disorder may not be submitted for publication until 
the main findings of the study have been published. Review of manuscripts resulting from this 
study or from data generated during this study must occur according to the NIDA DTMC 
Publications Policy prior to submission for publication. Authorship shall be consistent with 
NIDA and DTMC policies. 
 


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17 SIGNATURES 
 
NIDA/VA REPRESENTATIVES 
 
Typed Name  
 
 
 
 
 
 
Signature  
 
 
 
 
 
 
Date 
 
Dave McCann, Ph.D.  
 
 
__________________________  
_________________ 
National Institute on Drug Abuse 
 
Shwe Gyaw, M.D. 
 
 
 
__________________________  
_________________ 
National Institute on Drug Abuse 
 
TBD  
 
 
 
 
 
 
__________________________  
_________________ 
VA Protocol Chairperson 
 
Kousick Biswas, Ph.D. 
 
 
__________________________  
_________________ 
VA Cooperative Studies Program 
 
SITE INVESTIGATOR(S) 
I agree to conduct this clinical study in accordance with the design and specific provisions of this 
protocol; deviations from the protocol are acceptable only with a mutually agreed upon protocol 
amendment with the IRB approval. I also agree to report all information or data in accordance 
with the protocol, and in particular I agree to report any serious adverse experiences as defined in 
Section 13.10 of this protocol. 
 
Typed Name 
Signature 
Date 
 
                                     
 
__________________________  
_________________ 
Principal Investigator 
 


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Available at http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=abeb13eb-66a5-4030-
9bc2-5981acd196b9  
Amato L, Minozzi S, Pani PP, Solimini R, Vecchi S, Zuccaro P, Davoli M. Dopamine agonists 
for the treatment of cocaine dependence (Review). The Cochrane Collaboration. 2011; 
Published by John Wiley & Sons, Ltd. 
 
Anderson AL, Li SH, Biswas K, McSherry F, Holmes T, et al. Modafinil for the treatment of 
methamphetamine dependence. Drug Alcohol Depend. 2012; 120:135-141. 
Belviq® (lorcaserin hydrochloride) tablets. Product Label. Eisai Inc.; June 2012. Available at 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022529lbl.pdf  
Buydens-Branchey L, Branchey M, Hudson J, Rothman M, Fergeson P, McKernin C. Effect of 
fenfluramine challenge on cocaine craving in addicted male users. Am J Addict. 1998; 7:142-155. 
Carroll KM. A Cognitive-Behavioral Approach: Treating Cocaine Addiction. Therapy Manuals 
for Drug Abuse: Manual 1. NIH Publication Number: 98-4308. Rockville, MD: National 
Institute on Drug Abuse; 1998. 
Castells X, Casas M, Pérez-Mañá C, Roncero C, Vidal X, Capellà D. Efficacy of 
psychostimulant drugs for cocaine dependence. Cochrane Database Syst Rev. 2010; CD007380. 
 
Collins GT, Gerak LR, Javors MA, France CP. Lorcaserin reduces the discriminative stimulus 
and reinforcing effects of cocaine in rhesus monkeys. J Pharmacol Exp Ther. 2016; 356:85-95. 
 
Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV. 
Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997; 337:581-
588. 
Devine EG, Ryan ML, Falk DE, Fertig JB, Litten, RZ. An exploratory evaluation of Take 
Control: A novel computer-delivered behavioral platform for placebo-controlled 
pharmacotherapy trials for alcohol use disorder. Contemp Clin Trials. 2016; 50:178-185. 
Devine EG, Waters ME, Putnam M, Surprise C, O'Malley K, et al. Concealment and fabrication 
by experienced research subjects. Clin Trials. 2013; 10:935-948. 
Di Matteo V, Di Giovanni G, Di Mascio M, Esposito E. SB 242084, a selective serotonin2C 
receptor antagonist, increases dopaminergic transmission in the mesolimbic system. 
Neuropharm. 1999; 38:1195-1205. 
 
Eisai Inc., and Arena Pharmaceuticals Inc. Press Release. Eisai and Arena Pharmaceuticals 
report results of an investigational phase 2 trial of lorcaserin HCl as an aid for smoking 
cessation. November 3, 2014. Available at 


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http://files.shareholder.com/downloads/ARNA/2641484823x0x790638/D8F6EDCD-1B75-
4DCD-A98F-FF410D84B7AB/ARNA_News_2014_11_3_General.pdf  
Eisenberg MJ, Filion KB, Yavin D, Bélisle P, Mottillo S, et al. Pharmacotherapies for smoking 
cessation: a meta-analysis of randomized controlled trials. CMAJ. 2008; 179: 135-144. 
FDA Guidance for Industry: Enrichment Strategies for Clinical Trials to Support Approval of 
Human Drugs and Biological Products. U.S. Department of Health and Human Services, Food 
and Drug Administration. Center for Drug Evaluation and Research (CDER), Center for 
Biologics Evaluation and Research (CBER), Center for Devices and Radiological Health 
(CDRH). December 2012. 
Fletcher PJ, Rizos Z, Sinyard J, Tampakeras M, Higgins GA. The 5-HT2C receptor agonist 
Ro60-0175 reduces cocaine self-administration and reinstatement induced by the stressor 
yohimbine, and contextual cues. Neuropsychopharmacology. 2008; 33:1402-1412. 
Fletcher PJ, Chintoh AF, Sinyard J, Higgins GA. Injection of the 5-HT2C receptor agonist Ro60-
0175 into the ventral tegmental area reduces cocaine-induced locomotor activity and cocaine 
self-administration. Neuropsychopharmacology. 2004; 29:308-318. 
Hampson AJ, Babalonis S, Lofwall MR, Nuzzo PA, Krieter P, Walsh SL. A pharmacokinetic 
study examining acetazolamide as a novel adherence marker for clinical trials. J Clin 
Psychopharmacol. 2016; 36:324-332. 
Harvey-Lewis C, Li X, Higging GA, Fletcher PJ. The 5-HT2C receptor agonist lorcaserin 
reduces cocaine self-administration, reinstatement of cocaine-seeking and cocaine induced 
locomotor activity. Neuropharmacology. 2016; 101:237-245. 
Higgins GA, Silenieks LB, Rossmann A, Rizos Z, Noble K, Soko AD, Fletcher PJ. The 5-HT2C 
receptor agonist lorcaserin reduces nicotine self-administration, discrimination, and 
reinstatement: relationship to feeding behavior and impulse control. Neuropsychopharmacology. 
2012; 37:1177-1191. 
Levin ED, Johnson JE, Slade S, Wells C, Cauley M, Petro A, Rose JE. Lorcaserin, a 5-HT2C 
agonist, decreases nicotine self-administration in female rats. J Pharmacol Exp Ther. 2011; 
338:890-896.  
Litten RZ, Ryan ML, Fertig JB, Falk DE, Johnson BA, et al. A double-blind, placebo-controlled 
trial assessing the efficacy of varenicline tartrate for alcohol dependence. J Addict Med. 2013; 
7:277-286. 
Lorcaserin Clinical Pharmacology and Biopharmaceutics Review(s). Arena Pharmaceuticals Inc. 
2012. Available at:  
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022529Orig1s000ClinPharmR.pdf  
McCann DJ, Petry NM, Bresell A, Isacsson E, Wilson E, Alexander RC. Medication 
nonadherence, “professional subjects,” and apparent placebo responders: Overlapping challenges 
for medications development. J Clin Psychopharmacol. 2015; 35:566-573. 


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Mezinskis JP, Honos-Webb L, Kropp F, Somoza E. The measurement of craving. J Addict Dis. 
2001; 20(3):67-85. 
Negus SS, Mello NK, Blough BE, Baumann MH, Rothman RB. Monoamine releasers with 
varying selectivity for dopamine/norepinephrine versus serotonin release as candidate "agonist" 
medications for cocaine dependence: studies in assays of cocaine discrimination and cocaine 
self-administration in rhesus monkeys. J Pharmacol Exp Ther. 2007; 320:627-36. 
Nguyen CT, Zhou S, Shanahan W, Fain R. Lorcaserin in Obese and Overweight Patients Taking 
Prohibited Serotonergic Agents: A Retrospective Analysis. Clinical Therapeutics. 2016; 
38:1498-1509. 
Oquendo MA, Halberstam B, Mann JJ. Risk factors for suicidal behavior: The utility and 
limitations of research instruments. In: First MB, ed. Standardized Evaluation in Clinical 
Practice. Washington, DC: American Psychiatric Publishing; 2003: 103-130. 
Rezvani AH, Cauley MC, Levin ED. Lorcaserin, a selective 5-HT2C receptor agonist, decreases 
alcohol intake in female alcohol preferring rats. Pharmacol Biochem Behav. 2014; 125:8-14. 
Roth BL. Drugs and valvular heart disease. New Engl J Med. 2007; 356:6-9. 
Shanahan, WR; Rose, JE; Glicklich, A; Stubbe S; Sanchez-Kam , M.  Lorcaserin for smoking 
cessation and associated weight gain: A randomized 12-week clinical trial.  Nicotine Tob Res. 
2016; ntw301. doi: 10.1093/ntr/ntw301  
Shiovitz TM, Wilcox CS, Gevorgyan L, Shawkat A. CNS sites cooperate to detect duplicate 
subjects with a clinical trial subject registry. Innov Clin Neurosci. 2013; 10:17-21 
Somoza EC, Winship D, Gorodetzky CW, Lewis D, Ciraulo DA, et al. A multisite, double-blind, 
placebo-controlled clinical trial to evaluate the safety and efficacy of vigabatrin for treating 
cocaine dependence. JAMA Psychiatry. 2013; 70:630-647. 
Thomsen WJ, Grottick AJ, Menzaghi F, Reyes-Saldana HH, Espitia S, Yuskin D, Whelan K, 
Martin M, Morgan M, Chen WW, Al-Shamma HH, Smith B, Chalmers D, Behan D. Lorcaserin, 
a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological 
characterization. J Pharmacol Exp Ther. 2008; 325:577-587.  
Usmani KA, Chen WG, Sadeque AJ. Identification of human cytochrome P450 and flavin-
containing monooxygenase enzymes involved in the metabolism of lorcaserin, a novel selective 
human 5-hydroxytryptamine 2C agonist. Drug Metab Dispos. 2012; 40:761-771. 
 
 
 


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APPENDIX I: Instructions for Evaluating and Reporting Adverse Events and Serious 
Adverse Events 
 
A. GENERAL INSTRUCTIONS 
 
1. 
Adverse Events (AEs) will be assessed and reviewed at each clinic visit by a medically 
trained study staff member. 
 
2. 
Record AEs beginning on the day of informed consent.  
 
3. 
Report the severity of the event following the guidance in Section B below. 
  
4. 
Report the relatedness of the event to the study drug administration according to the 
guidance in Section C. 
 
B. DEFINITIONS 
B-1. 
Adverse Event (AE) 
 
An adverse event is any undesirable experience associated with the use of a medical product in a 
patient.  
 
B-2. 
Serious Adverse Event (SAE) 
 
A 'serious' AE is defined as any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening - The patient was at substantial risk of dying at the time of the adverse 
event, or use or continued use of the device or other medical product might have resulted 
in the death of the patient 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Required intervention to prevent permanent impairment or damage (Devices) 
• 
Is an important medical event - The event may jeopardize the patient and may require 
medical or surgical intervention (treatment) to prevent one of the other outcomes.  
B-3. 
Severity of Events 
 
Mild:  
Awareness of symptom, but easily tolerated. 
 
Moderate: 
Discomfort enough to cause interference with usual activity. 
 
Severe: 
Incapacitating with inability to work or do usual activity. 
 
 
 
 


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B-4. Unexpected Adverse Event 
 
An adverse event is considered "unexpected" if it is not listed in the Investigator’s Brochure or is 
not listed at the specificity or severity that has been observed; or, if the Investigator’s Brochure is 
not required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as amended). 
 
C. DEFINITIONS – RELATEDNESS OF EVENTS 
 
 
The study physician is responsible for defining, in his/her best judgment, the relationship of the 
AE/SAE to the study drug. The degree of certainty for which the AE/SAE is attributed to the 
study drug or alternative causes (e.g., natural history of the underlying disease, concomitant 
therapies, etc.) should be determined by how well the experience can be understood in terms of 
one or more of the following: 
 
• Exposure:  Is there evidence that the subject was actually exposed to the drug/compliance 
marker?  
 
• Timing of the study drug:  Did the AE/SAE follow in a reasonable temporal sequence from 
administration of the drug test? 
 
• Consistency with study drug profile:  Known pharmacology and toxicology of the study 
drug in animals and man; reaction of similar nature having been previously described with 
the study drug. 
 
• Alternative explanations for the adverse event such as concomitant medications, concurrent 
illness, non-medicinal therapies, diagnostic tests, procedures or other confounding findings. 
 
• Response to discontinuation of the study drug. 
 
Terms and definitions to be used in assessing the study drug relationship to the AE/SAE are: 
 
• Definitely Related:  The adverse event is clearly related to the investigational 
agent/procedure – i.e., an event that follows a reasonable temporal sequence from 
administration of the study intervention, follows a known or expected response 
pattern to the suspected intervention, that is confirmed by improvement on stopping 
and reappearance of the event on repeated exposure and that could not be reasonably 
explained by the known characteristics of the subject’s clinical state. 
• Possibly Related:  An adverse event that follows a reasonable temporal sequence 
from administration of the study intervention follows a known or expected response 
pattern to the suspected intervention, but that could readily have been produced by a 
number of other factors. 
• Not Related:  The adverse event is clearly not related to the investigational 
agent/procedure – i.e., another cause of the event is most plausible; and/or a clinically 


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plausible temporal sequence is inconsistent with the onset of the event and the study 
intervention and/or a causal relationship is considered biologically implausible.  
 
D. SPECIFIC INSTRUCTIONS – LABORATORY/ECG ADVERSE EVENT 
 
A laboratory or ECG AE is any clinically significant worsening in a test variable that occurs 
during the course of the study, whether or not considered to be attributable to the study drug. For 
each such change, provide the information requested on date of test, severity, likelihood of a 
relationship to study drug, change in study drug dosage due to the AE, and treatment required. 
 
All laboratory AEs should be specified as an increased or decreased test result (e.g., “increased 
glucose”, “decreased potassium”) or as a term that implies an abnormality (e.g., hypercalcemia, 
azotemia, hypokalemia, or bradycardia). Any abnormal laboratory value that is considered not 
clinically significant will be recorded as such on the clinical laboratory report along with a 
comment providing justification for that determination. 
 
E. SPECIFIC INSTRUCTIONS – PREGNANCY 
 
1. Record results of pregnancy test on subject’s source documentation and enter the results 
on the electronic case report form (eCRF).   
2. Document the pregnancy as an adverse event in the subject’s source documentation and 
enter the adverse event on the electronic case report form (eCRF). 
3. Primary responsibility will be to follow the pregnancy through until its completion. There 
are several possible outcomes: 
a. The mother chooses to have an abortion. In that case NIDA will report to FDA 
that the pregnancy was intentionally terminated by the mother and that there is no 
further follow-up required. NIDA will also include this in the final clinical study 
report. 
b. The mother experiences a spontaneous abortion. In that case NIDA will report to 
FDA that the pregnancy resulted in a spontaneous abortion and it will be recorded 
as an SAE and at least possibly related. At that point there is no further follow-up 
required. NIDA will also include this in the final clinical study report and in the 
SAE listings. 
c. The baby goes to term and is born healthy. In that case NIDA will report to FDA 
that the birth was without issue and that there is no further follow-up required. 
NIDA will obtain the hospital record of the birth, if possible, and also include it in 
the final clinical study report.  
d. The baby goes to term and is born with a congenital anomaly. In that case NIDA 
will report to FDA that the pregnancy resulted in a congenital anomaly and it will 
be recorded as an SAE and at least possibly related. At that point there may be 
further follow-up required depending upon what the anomaly was. NIDA will 
obtain the hospital record of the birth, if possible, and also include it in the final 
clinical study report and in the SAE listings. 
4. NIDA will submit an Information Amendment to the IND reporting any pregnancy and 
follow-up thereafter.  
 


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F. THE HUNTER SEROTONIN SYNDROME (DIAGNOSTIC CRITERIA) 
 
Subjects that meet one of the following conditions to be considered for serotonin syndrome: 
 
• Spontaneous clonus 
• Inducible clonus PLUS agitation or diaphoresis 
• Ocular clonus PLUS agitation or diaphoresis 
• Tremor PLUS hyperreflexia 
• Hypertonia PLUS temperature above 38oC PLUS ocular clonus or inducible clonus 
 
G. SERIOUS ADVERSE EVENT AND UNEXPECTED ADVERSE EVENT REPORTING 
 
24 hour Reporting Requirements 
 
Any SAEs due to any cause, that occur during the course of this investigation, whether or not 
related to the investigational agent, must be reported to the Study Medical Monitor and the 
NIDA Project Manager within 24-hours by phone or email with receipt confirmation to these two 
individuals is required: 
 
NIDA Medical Monitor: Tanya Ramey, M.D., Ph.D. Tel: 301-827-5944, email: 
tanya.ramey@nih.gov 
 
NIDA Project Manager: Liza Zeinert, M.A., Tel: 301-443-1138, email: liza.zeinert@nih.gov 
 
The following information must be provided with the initial report of an SAE or unexpected AE: 
 
• Name of person reporting the SAE/unexpected AE 
• Subject's ID number & ALPHA Code 
• Name of the SI and institution 
• Date the subject signed informed consent 
• Date of first dose of study drug 
• Description of the SAE/unexpected AE 
• Date and time of onset 
• Date/time of administration of last dose of study drug prior to the SAE/unexpected AE 
• Severity of the SAE/unexpected AE 
• SI's assessment of the relationship of the SAE/unexpected AE to study drug (related, possibly 
related, probably related, unlikely related, not related) 
• Any action taken with the study drug, alteration to protocol defined schedule, diagnostics, 
and treatments secondary to the SAE/unexpected AE. 
 
3-day Supporting Documentation Requirements 
 
Documentation for all SAEs/unexpected AEs must be received by the NIDA Medical Monitor 
and the NIDA Project Manager within 3 days of reporting the event. Required documents that 


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must be submitted include the following: 
• SAE CRF 
 
Additional documentation may include: 
 
• Copies of source documents pertinent to the event (lab reports, ECG tracings, medical chart 
notes, etc.) 
• Any other relevant information necessary to facilitate the SI’s judgment regarding the SAE’s 
relatedness to the severity OR by request of the Medical Monitor/Alternate 
 
These documents may be submitted by facsimile, as email attachments, or via overnight courier. 
Any personally identifiable information (i.e., names, birthdates, etc.) should be 
removed/obscured before sending. Subject ID and ALPHA-NUMERIC code are allowable. 
 
Follow-Up of All Adverse Events/Serious Adverse Events 
 
All adverse medical events must be followed until they are resolved, or until all attempts to 
determine the resolution of the AE/SAE are exhausted. This may require an extended 
hospitalization period or a change in status from outpatient to inpatient. All treatments, outcomes 
and information regarding whether or not the subject was referred to their Primary Care Provider 
for additional follow-up must be recorded in the source document. All serious and unexpected 
adverse events occurring at any time (up to and including the Week 16 visit) must be reported. 
All follow-up Week 16 AEs will be recorded and followed to resolution, only if they are serious, 
or if the study physician assesses them to be clinically significant. 
 
The SI is required to provide the Medical Monitor and the NIDA Project Manager with all 
relevant follow-up information necessary to facilitate a thorough understanding of the event and 
judgment regarding the relationship to the study drug. 
 
Reporting to the FDA 
 
The IND sponsor is required to report SAEs to the FDA: 
 
• in 7 days if the SAE is unexpected (or, if expected, unusually serious or rarely seen), life-
threatening or lethal, and at least possibly related to the study drug, with a follow-up 
written report in 8 days; 
 
• in 15 days if the SAE is unexpected (or, if expected, unusually serious or rarely seen), but 
not immediately life-threatening; and  
 
• in an annual report in all other cases. 
 
 
 
 
 


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APPENDIX II: Procedure for Applying for a Certificate of Confidentiality 
 
The only people who will know the identity of the subjects are members of the research team 
and, if appropriate the physicians and nurses. No information about the subjects, or provided by 
the subjects during the research, will be disclosed to others without the subjects’ written 
permission, except:  
 
- 
if necessary to protect subjects’ rights or welfare 
 
When the results of the research are published or discussed in conferences, no information will 
be included that would reveal subjects’ identity. Authorized representatives of the FDA and 
NIDA study monitors may need to review records of individual subjects. As a result, they may 
know subjects’ names, but they are bound by rules of confidentiality not to reveal their identity 
to others. The results of this study including laboratory results and clinical information collected 
during this study will be submitted to the FDA and may be used for research purposes. The 
results of this study may be published but will not personally identify any subjects. All records 
will be kept in locked storage locations that will be accessible only to authorized study 
personnel.  
 
NIDA will apply for a Certificate of Confidentiality for all participating sites. 
 
This Certificate of Confidentiality helps researchers protect the privacy of subjects in health 
research projects against compulsory legal demands (e.g., court orders and subpoenas) that seek 
the names or other identifying characteristics of research subjects. The certificate was developed 
to protect against the involuntary release of personally identified research information of a 
sensitive nature sought through any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings. This authority was granted under the Comprehensive Drug 
Abuse Prevention and Control Act of 1970, Public Law No. 91-513, Section 3(a).  
 
This certificate is necessary for SIs to avoid being required to involuntarily disclose personally 
identifiable research information about individual study subjects. Under this statute: 
 
"The Secretary [of the Department of Health and Human Services] may authorize persons 
engaged in biomedical, behavioral, clinical, or other research (including research on mental 
health, and on the use and effect of alcohol and other psychoactive drugs) to protect the privacy 
of individuals who are the p subject of such research by withholding from all persons not 
connected with the conduct of such research the names or other identifying characteristics of 
such individuals. Persons so authorized to protect the privacy of such individuals may not be 
compelled in any Federal, State, or local civil, criminal, administrative, legislative, or other 
proceedings to identify such individuals" (Public Health Service Act 301 (d), 42 U. S. C. 241  
(d), as amended by Public Law No. 100-607, Section 163 (November 4, 1988)).” 
 
Accordingly, this special privacy protection can be granted only to research (i.e., a systematic 
investigation, designed to develop or contribute to generalizable knowledge). It is granted only 
when the research is of a sensitive nature where the protection is judged necessary to achieve the 
research objectives. 


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The study subjects should be informed that a Certificate is in effect, and be given a fair and clear 
explanation of the protection it affords, including the limitations and exceptions. This 
information will be included in the informed consent. Please see below some suggested wording: 
“We have received a Certificate of Confidentiality from the National Institute on Drug Abuse, 
which will help us protect your privacy. The Certificate protects against the involuntary release 
of information about your participation in this study. The researchers involved in this project 
cannot be forced to disclose your identity or your participation in this study in any legal 
proceedings at the federal, state, or local level, regardless of whether they are criminal, 
administrative, or legislative proceedings. However, you or the researcher may choose to 
voluntarily disclose the protected information under certain circumstances. For example, if you 
or your guardian requests disclosure of your participation, the researchers will provide research 
data. The Certificate does not protect against that voluntary disclosure. 
 
Furthermore, federal agencies may review our records under limited circumstances, such as a 
DHHS request for information for an audit or program evaluation or a Food and Drug 
Administration request under the Food, Drug and Cosmetics Act.”