Conditions: Cocaine Use Disorder
Keywords: Cocaine Use Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 29
Healthy volunteers: no

Brief summary:
The overall goal of this project is to develop initial human data on effects of novel compounds on safety (interactions with cocaine) and efficacy (subjective response to cocaine and self administration data) in non-treatment seeking cocaine use disorder subjects. The compound to be studied will be the 5-HT2CR agonist lorcaserin. Lorcaserin and other 5-HT2CR agonists have been shown to reduce cocaine self-administration and cue reactivity in rodents. In addition there is human safety data in non-cocaine using subjects for lorcaserin as it is currently FDA approved for obesity, and safety data from a cocaine interaction study in rodents , but there is no human cocaine interaction/PK data and no PD data to support potential dosages for phase II clinical trials.

Detailed description:
The overall goal of this project is to develop initial human data on effects of novel compounds on safety (interactions with cocaine) and efficacy (subjective response to cocaine and self-administration data) in non-treatment seeking cocaine use disorder subjects. This project will provide innovative data on effects of novel compounds on cocaine self-administration in addition to needed safety data on drug interactions with cocaine. This is a Phase I human drug interaction study examining the safety of concurrent administration of cocaine with novel compounds, and the effects of the novel compounds on subjective response to cocaine and cocaine self-administration in non-treatment seeking cocaine use disorder subjects. This data will provide important information for go/no-go decisions on phase II clinical trials using medications as a tool to enhance abstinence. The initial compound to be studied will be the 5-HT2CR agonist lorcaserin, which has been shown to reduce cocaine self-administration and cue reactivity in rodents. In addition there is human safety data in non-cocaine using subjects for lorcaserin as it is currently FDA approved for obesity, but there is no human cocaine interaction/PK data and no PD data to support potential dosages for phase II clinical trials.

This is a single center, double-blind, placebo-controlled, randomized, 1b/2a study. 18 of subjects are planned. Each subject will be administered a single dose of study drug three times, one week apart, consisting each time of various doses of active or placebo. Each subject will receive three of the four experimental treatments. Subjects will be assigned to the treatments in random order. Evaluations will be taken at baseline and 4 hours at each of the 3 study visits.

Screening data will be reviewed to determine subject eligibility. Subjects who meet all inclusion criteria and none of the exclusion criteria will be entered into the study. If subjects meet inclusion criteria, they will be admitted as hospital inpatients during the 14 study days to prevent drug and alcohol use and maintain complete monitoring for adverse events.

The following treatment regimens will be used:

Lorcaserin will be 10mg once daily increasing to 10mg twice daily. Placebo or Comparator - identical placebo capsules administered at the same time as lorcaserin.

Total duration of subject participation including eligibility screening (Study days -3 - 0), on-unit study days (Study days 1-14), and follow-up visits (Study days 16 and 20) will be three weeks. Total duration of the study is expected to be 18 months.

Detailed description of the in-hospital portion of study (Study days 1-14) is as follows:

After a screening cocaine infusion to determine safety, eligible subjects will be randomized to Group A -placebo only or Group B -placebo followed by an ascending dose of lorcaserin. Six subjects will be assigned to Group A (placebo) and 12 subjects will be assigned to Group B (active lorcaserin).

1. Days 1-2: All subjects will receive placebo on days 1-2 in a single blind fashion. Vital signs including heart rate, blood pressure and respiration rate will be obtained 15 minutes before and 15, 30 and 60 minutes after placebo administration. Days 1-2 will be single-blind placebo, whereas all remaining study days will be double-blind.
2. Days 3-9: On days 3-9, subject group A will receive one placebo pill twice daily, and group B will receive one placebo pill in the morning and one matching lorcaserin 10 mg pill in the evening, for a total dose of 10 mg daily. ECG with QTc will be performed daily. If the QTc is prolonged greater than 30ms over baseline lorcaserin dosage will be held.
3. Days 10-12: subjects in group B will have a blinded dosage increase to 10 mg of lorcaserin twice daily. Vital signs including heart rate, blood pressure and respiration rate will be obtained 15 minutes before and 15, 30 and 60 minutes after placebo/lorcaserin administration. ECG with QTc will be performed daily under the supervision of a study physician. If the QTc is prolonged greater than 30ms over baseline lorcaserin dosage will be held.
4. Day 13 subjects in group B will be administered 10mg of lorcaserin in the morning only, and subjects in group A will be administered matching placebo in the morning. Subjects will be discharged on day 14.
5. Cocaine Infusion Sessions (Days 1, 2, 6, and 12): All subjects will undergo an ascending dose intravenous cocaine administration after admission on day 1 to ensure safety of later cocaine studies.

To assess the safety and subjective effects of cocaine in the presence of lorcaserin, subjects will receive ascending doses of intravenous cocaine (10 mg, 20 mg, 40 mg), with each cocaine administration separated by one hour. In addition, 0 mg cocaine (saline) infusion will be randomly given after the first dose of cocaine in order to aid in blinding investigators and subjects to the order of drug administration. Infusions will be carried out at 9:00am, 10:00am, 11:00am and 12:00pm (Day 1), or at 1:00 p.m., 2:00 p.m., 3:00 p.m., and 4:00 p.m. (Days 2, 6, and 12).

Arms:
arm 1: Lorcaserin 10 mg administered orally once daily for 6 days then increasing to twice daily for 3 days.

Cocaine IV (intravenous) administered in ascending doses of 0, 10, 20, 40 mg on study days 1, 2, 6 and 12. arm 2: Dextrose placebo in gelatin capsule identical to experimental drug. Cocaine IV (intravenous) administered in ascending doses of 0, 10, 20, 40 mg on study days 1, 2, 6 and 12.

Interventions: intervention 1: Lorcaserin intervention 2: Cocaine Intravenous (IV) intervention 3: Placebo comparator
Intervention descriptions: intervention 1: Lorcaserin HCL 10mg tablets (Belviq, Arena Pharmaceuticals) intervention 2: Cocaine IV administered at doses of 10, 20 and 40 mg during 4 dosing sessions intervention 3: Dextrose in gelatin capsule

Protocol document:
Prot_SAP_000.pdf: 
 
 
Title: Phase I Drug Interaction and Self Administration Studies of Compounds for Cocaine Use Disorder 
 
NCT #: NCT02537873 
 
Document version date: August 2, 2017 
 
Document approval date: October 2, 2017 
 
Document Type: Protocol and Statistical Analysis Plan 
 
 
 


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TABLE OF CONTENTS 
 
1 
BACKGROUND 
4 
1.1 
Overview of Non-Clinical Studies 
10 
1.2 
Overview of Clinical Studies 11 
2 
STUDY RATIONALE 
11 
2.1 
Risk / Benefit Assessment 
11 
3 
STUDY OBJECTIVES 
16 
3.1 
Primary Objective 
16 
3.2 
Secondary Objectives 16 
4 
STUDY DESIGN 
16 
4.1 
Study Overview 
16 
5 
Criteria for evaluation 17 
5.1 
Primary Efficacy Endpoint 
17 
5.2 
Secondary Efficacy Endpoints 
17 
6 
SUBJECT SELECTION 
17 
6.1 
Study Population 
17 
6.2 
Inclusion Criteria 
17 
6.3 
Exclusion Criteria 
18 
7 
Concurrent Medications 
19 
7.1 
Allowed 
19 
7.2 
Prohibited 
19 
8 
STUDY TREATMENTS 
19 
8.1 
Method of Assigning Subjects to Treatment Groups 19 
8.2 
Blinding 
19 
8.3 
Test and Control Formulation  
22 
8.4 
Supply of Study Medication at the Site 
21 
8.5 
Study Medication Accountability 
21 
9 
STUDY PROCEDURES AND GUIDELINES 
21 
9.1 
Clinical Assessments 22 
9.2 
Clinical Laboratory Measurements (include sections as appropriate) 
24 
9.3 
Pharmacokinetic Measurements 
24 
10 
EVALUATIONS BY VISIT 24 
10.1 
Visit 1 (Day/Week/Month #) 24 
10.2 
Visit 2 (Day/Week/Month # include visit window) 25 
10.3 
Visit 3 (Day/Week/Month # include visit window) 25 
10.4 
Visit 4 (Day/Week/Month # include visit window) 26 
10.5 
Visit 5 (Follow-up or Day/Week/Month # include visit window) 
26 
11 
ADVERSE Experience REPORTING AND DOCUMENTATION 34 
11.1 
Adverse Events 
34 
11.2 
Serious Adverse Experiences (SAE) 35 


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11.4 
Medical Monitoring 36 
11.5 
Safety Management Plan 
4 
12 
DISCONTINUATION And Replacement of subjects 
36 
12.1 
Withdrawal of Subjects 
36 
12.3 
Replacement of Subjects 
36 
13 
PRotocol Violations 37 
14 
DATA SAFETY MONITORING (optional Section – Include when appropriate) 37 
15 
STATISTICAL METHODS AND CONSIDERATIONS 
38 
15.1 
Data Sets Analyzed 
38 
15.2 
Demographic and Baseline Characteristics 38 
15.3 
Analysis of Primary Endpoint 39 
15.4 
Analysis of Secondary Endpoints 
39 
15.5 
Interim Analysis 
39 
15.6 
Sample Size and Randomization 
39 
16 
DATA COLLECTION, RETENTION AND MONITORING 
40 
16.1 
Data Collection Instruments 40 
16.2 
Data Management Procedures 
40 
16.3 
Data Quality Control and Reporting 41 
16.4 
Archival of Data 
41 
16.5 
Availability and Retention of Investigational Records 
41 
16.7 
Subject Confidentiality 
41 
17 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 41 
17.1 
Protocol Amendments 41 
17.2 
Institutional Review Boards and Independent Ethics Committees 
41 
17.3 
Informed Consent Form 
42 
17.4 
Publications 
42 
 
 
 


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List of Abbreviations 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
ASI-lite 
Addiction Severity Index 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CFR 
 
Code of Federal Regulations 
 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CGI-I 
Clinical Global Impression Improvement 
CGI-S 
Clinical Global Impression Severity 
CNS 
Central Nervous System 
COCUD 
Cocaine Use Disorder 
COWS 
Clinical Opiate Withdrawal Scale 
CRF 
case report form 
CRP 
C-reactive protein 
CRSU 
Clinical Research Services Unit 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
ESR 
erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
 
 
FTND 
Fagerstrom Test for Nicotine Dependence 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
ICH 
IDAS 
International Conference on Harmonization 
Institute for Drug and Alcohol Studies 
IEC 
Independent Ethics Committee 
IL-8 
Interleukin-8 
IRB 
Institutional Review Board 
IV 
intravenous 


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KID-SCID 
Childhood Disorders Version of the SCID ADHD Module 
KMSK 
Kreek-McHugh-Schluger-Kellogg Scale 
LDH 
lactate dehydrogenase 
NART 
National Adult Reading Test 
PI 
Principal Investigator 
PK 
pharmacokinetic 
POMS 
Profile of Mood Sates 
SAE 
serious adverse experience 
SCID 
The Structured Clinical Interview for DSM-IV 
SCID-II 
The Structured Clinical Interview for DSM-IV Personality 
Disorders Module 
VAS 
Visual Analog Scale 
WURS 
Wender Utah Rating Scale 
 
 
 


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PROTOCOL SYNOPSIS 
TITLE 
Phase I drug interaction and self-administration studies of compounds 
for Cocaine Use Disorder (COCUD) 
SPONSOR 
F. Gerard Moeller, M.D. 
FUNDING 
ORGANIZATION 
National Institute on Drug Abuse 
NUMBER OF SITES 
1 
RATIONALE 
The overall goal of this project is to develop initial human data on 
effects of novel compounds on safety (interactions with cocaine) and 
efficacy (subjective response to cocaine and self administration data) 
in non-treatment seeking cocaine use disorder subjects. The 
compound to be studied will be the 5-HT2CR agonist lorcaserin. 
Lorcaserin and other 5-HT2CR agonists have been shown to reduce 
cocaine self-administration and cue reactivity in rodents (Cunningham 
et al., 2011; Manvich et al., 2012). In addition there is human safety 
data in non-cocaine using subjects for lorcaserin as it is currently FDA 
approved for obesity, and safety data from a cocaine interaction study 
in rodents (included below), but there is no human cocaine 
interaction/PK data and no PD data to support potential dosages for 
phase II clinical trials.  
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled phase 1b/2a 
study. 
PRIMARY OBJECTIVE 
1. Assess interaction between lorcaserin and cocaine in healthy 
cocaine using subjects. 2. Assess effects of lorcaserin on cocaine self-
administration in healthy cocaine using subjects. 3. Assess effect of 
lorcaserin on subjective response to cocaine in healthy cocaine using 
subjects. 4. Assess effect of lorcaserin on cocaine PK in healthy 
cocaine using subjects.  
SECONDARY 
OBJECTIVES 
Assess effect of lorcaserin on response inhibition in healthy cocaine 
using subjects. 
NUMBER OF 
SUBJECTS 
18 
SUBJECT SELECTION 
CRITERIA 
Inclusion Criteria: 
In order to participate in this study, subjects must: 
1. Males and females between 18 and 59 years-of-age. 
2. Understand the study procedures and provide written informed 
consent. 
3. Meet current DSM-5 criteria for cocaine use disorder, at least 
moderate severity, and current DSM-IV diagnosis of cocaine 
dependence, but are not seeking treatment. 
4. Currently using cocaine by smoking or intravenous route of 
administration as determined by self-report and have a positive urine 


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drug screen for cocaine during screening. 
5. Have vital signs as follows: resting pulse below 95 bpm, blood 
pressures  below 140 mm Hg systolic and  90 mm Hg diastolic. 
6. Have no clinically significant abnormalities in the judgment of the 
study physician in hematology and chemistry laboratory tests 
including liver function tests. 
7. Have sinus rhythm with normal conduction (including QTcF less 
than 440 ms) by ECG.  
8. Have no contraindications for study participation as determined by 
medical history and physical examination. 
9. Be able to demonstrate an understanding of study procedures and 
follow instructions including behavioral laboratory testing.  
10. No pregnant or nursing women will be permitted in the study, and 
women must either be unable to conceive (i.e., surgically sterilized, 
sterile, or postmenopausal) or be using a reliable form of 
contraception (e.g., abstinence, birth control pills, intrauterine device 
with spermicide, or condoms). Men will be advised to use condoms. 
All females must provide negative pregnancy urine tests before study 
entry, at each visit during the study, and at the end of study 
participation. 
11. Have hemoglobin/hematocrit values within normal limits based on 
age and gender. 
 
Exclusion Criteria: 
In order to participate in the study, subjects must not: 
1. Meet current DSM-5 diagnosis of any psychoactive substance use 
disorder other than cocaine, opioids, marijuana, or nicotine. Diagnosis 
of mild to moderate use disorder for alcohol will not be considered 
exclusionary. 
2. Have a DSM-5 axis I psychiatric disorder other than substance use 
disorder including but not limited to Bipolar Disorder, Major 
Depressive Disorder, ADHD, or Schizophrenia or a neurological 
disorder requiring ongoing treatment and/or making study 
participation unsafe. 
3. Have any previous medically adverse reaction to cocaine, including 
loss of consciousness, chest pain, or epileptic seizure. 
4. Have any clinically significant medical disorder including 
cardiovascular (including hypertension), pulmonary, CNS, hepatic, or 
renal disorder.  
5. Have a history of seizures (excluding childhood febrile seizures), or 
clinically significant head injury. 
6. Have significant current suicidal or homicidal ideation or a history 
of suicide attempt within the past 6 months. 
7. Have conditions of probation or parole requiring reports of drug use 
to officers of the court. 


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8. Have impending incarceration.  
9. Have a positive HIV test by self-report or history.  
10. Be pregnant or nursing or not using a reliable form of 
contraception if able to conceive. All females must provide negative 
pregnancy urine tests at screening, and at each study visit. 
11. Have any other illness, or condition, which in the opinion of the PI 
would preclude safe and/or successful completion of the study. 
12. Have a positive breath alcohol test or urine drug screening 
positive for drugs of abuse with the exception of cocaine, cocaine 
metabolites, opioids, and marijuana. 
13. Subjects who are allergic to lorcaserin. 
14. Subjects who have taken any investigational drug within 90 days 
prior to baseline. 
15. Subjects who have symptoms of opioid withdrawal during 
screening. 
 
 
TEST PRODUCT, 
DOSE, AND ROUTE OF 
ADMINISTRATION 
Lorcaserin 10mg  
Product will be administered orally once daily for 6 days then 
increasing to twice daily for 3 days.   
CONTROL PRODUCT, 
DOSE AND ROUTE OF 
ADMINISTRATION 
Placebo 
Subjects who are randomized to placebo will receive identical 
capsules to the test product at the same time administered orally.  
DURATION OF 
SUBJECT 
PARTICIPATION AND 
DURATION OF STUDY 
Screening:  up to 7 days 
Treatment in CRSU and IDAS:  12 days  
Follow-up:  7 days  
The total duration of the study is expected to be 4 years.  
CONCOMMITANT 
MEDICATIONS 
Allowed: Non-CNS Active medications 
 
Prohibited: CNS active medications 
Medications which could potentially interact with lorcaserin or 
cocaine 
Efficacy Evaluations 
Primary outcome measures:  
1. Safety: Heart rate (HR) and blood pressure (BP) measures during 
saline infusions will be compared to HR and BP after each cocaine 
infusion (20 mg and 40 mg doses).  Changes in HR and BP induced 
by cocaine infusion along with lorcaserin will be compared to those 
without lorcaserin, by cocaine dose level (20 mg and 40 mg doses), 
using repeated measures analysis of variance (ANOVA). Changes in 
ECG readings during saline infusion as compared to those taken 
during cocaine infusions will be reported as summary statistics. 
Adverse event data will be compiled for lorcaserin and placebo 


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cohorts and presented as summary statistics.  
2. Cocaine Self-administration: Repeated measures ANOVA with 
cocaine dose (0mg, 25mg) and lorcaserin dose (0mg, 10mg, 20mg) as 
within subject factors will be used to examine differences in mean 
cocaine choice selection. In addition, a Bayesian analysis will be 
carried out as described below. 
3. Subjective response to cocaine: Subjective response measures 
(VAS) obtained during saline infusions will be compared between 
lorcaserin and placebo subjects to those during cocaine infusions by 
cocaine dose level to determine the extent to which these measures are 
modified by the administration of lorcaserin using repeated measures 
ANOVA. 
4. Cocaine PK: Plasma concentration-time profiles of cocaine after 
cocaine infusion during placebo administration (Day 2) will be 
analyzed to obtain pharmacokinetic parameter estimates of cocaine 
(Tmax, AUC, apparent t½, CL) by individual. These parameters will 
be compared within subjects on sessions with lorcaserin (Days 6 and 
10). 
Secondary Outcome Measure: Response inhibition: Commission 
errors on the IMT will be compared between lorcaserin and placebo 
subjects to determine the extent to which this measure is modified by 
the administration of lorcaserin using repeated measures ANOVA. 
 
Planned Interim Analyses  When approximately 50% of patients have completed the study, an 
interim analysis for safety will be conducted by the DSMB. Serious 
adverse events will be monitored by the committee on an ongoing 
basis throughout the study. 
STATISTICS 
Primary Analysis Plan 
Initial analyses will evaluate group differences on demographic and 
baseline variables, will use contingency tables with chi-square testing, 
ANOVA’s, and examination of correlations between baseline 
variables subjective responses and clinical results. General data 
analysis procedures: Urn randomization will be used for gender to 
reduce any potential between-group differences (lorcaserin vs. 
placebo) on baseline variables. Prior to data analysis procedures, 
groups will be examined for differences in other baseline 
characteristics that could potentially influence treatment outcome. 
Any variables that differ between groups and are related to outcome 
measures will be examined as potential covariates in subsequent data 
analyses.  
 
Primary outcome measures:  
1. Safety: Heart rate (HR) and blood pressure (BP) measures during 
saline infusions will be compared to HR and BP after each cocaine 
infusion (20 mg and 40 mg doses).  Changes in HR and BP induced 
by cocaine infusion along with lorcaserin will be compared to those 
without lorcaserin, by cocaine dose level (20 mg and 40 mg doses), 


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using repeated measures analysis of variance (ANOVA). Changes in 
ECG readings during saline infusion as compared to those taken 
during cocaine infusions will be reported as summary statistics. 
Adverse event data will be compiled for lorcaserin and placebo 
cohorts and presented as summary statistics.  
2. Cocaine Self-administration: Repeated measures ANOVA with 
cocaine dose (0mg, 25mg) and lorcaserin dose (0mg, 10mg, 20mg) as 
within subject factors will be used to examine differences in mean 
cocaine choice selection. In addition, a Bayesian analysis will be 
carried out as described below. 
3. Subjective response to cocaine: Subjective response measures 
(VAS) obtained during saline infusions will be compared between 
lorcaserin and placebo subjects to those during cocaine infusions by 
cocaine dose level to determine the extent to which these measures are 
modified by the administration of lorcaserin using repeated measures 
ANOVA. 
4. Cocaine PK: Plasma concentration-time profiles of cocaine after 
cocaine infusion during placebo administration (Day 2) will be 
analyzed to obtain pharmacokinetic parameter estimates of cocaine 
(Tmax, AUC, apparent t½, CL) by individual. These parameters will 
be compared within subjects on sessions with lorcaserin (Day 6 and 
Day 10). 
Secondary Outcome Measure: Response inhibition: Commission 
errors on the IMT will be compared between lorcaserin and placebo 
subjects to determine the extent to which this measure is modified by 
the administration of lorcaserin using repeated measures ANOVA. 
.   
Rationale for Number of 
Subjects 
Power Calculation and Sample Size: 
Rationale for sample size: Sample size for effect of lorcaserin on 
cocaine self-administration was based on previous research showing 
effects of medication on human cocaine self-administration (Hart et 
al., 2008). In an effort to increase the power of the study, a Bayesian 
approach will also be utilized that incorporates information from 
previous studies.  This approach will use a Bayesian hierarchical 
model with subject at the lowest level of the hierarchy and treatment 
group at the second level.  This model is analogous to the repeated 
measures ANOVA except that prior information will be introduced.  
Since many similar studies have been conducted with cocaine users 
and the same outcome measures we will assign an informative prior 
distribution on the control group where the mean and standard 
deviation are educated guesses from the information provided in 
previous study of Hart et al. (2008).  For the treatment group we will 
assume a priori no change in the mean from the control group and the 
standard deviation are similar to those as the experimental group of 
the study by Hart et al. (Hart et al., 2008).  The model will be 
calculated using standard Markov Chain Monte Carlo (MCMC) 
packages such as WinBUGS, OpenBUGS, JAGS or MCMCpack in R.  


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Because MCMC sampling techniques are being employed the quality 
of the samples from the posterior distribution will be checked using 
trace plots, effective sample size, potential scale reduction factor and 
Hellinger distances (for more on Bayesian analyses and MCMC 
sampling see (Gelman et al., 2013).  As necessary techniques such as 
discarding burn-in samples, thinning and over-disperse starting points 
will be employed in order to obtain a set of samples from the posterior 
distribution that have an effective sample size of 10,000 on all 
parameters.  All inferences will be made from this set of samples from 
the posterior distribution. 
 
To calculate the power for the acute effects of the study three 
analyses are considered using the paired differences of subjects at 
baseline and acute time points.  A two-sample test on the means is 
performed using: Wilcoxon test (non-parametric), T-test (parametric) 
and a Bayesian (parametric) approach.  While from a Bayesian 
paradigm the notion of power does not exist in the traditional sense, 
one can create a decision rule and loss function in such a way that the 
associated risk is analogous to the notion of power.  To understand the 
power of each of the methods a Monte Carlo study was performed 
utilizing 1,000 separate datasets for likely effect sizes and sample 
sizes.  The power was calculated as the proportion of datasets in 
which the test “rejected” the null hypothesis.  The table below gives 
the power for each test across percent change in effect size and control 
group sample sizes, here the treatment group sample size was n2 = 12. 
Based on the table at left, an n of 6 was chosen as the sample size for 
the placebo group. 
 
 
 
BACKGROUND 
Lorcaserin is a 5-HT2CR agonist (Trade Name Belviq) approved for treatment of obesity.  
Overview of Non-Clinical Studies 
Lorcaserin and other 5-HT2CR agonists have been shown to reduce cocaine self-administration and cue 
reactivity in rodents (Cunningham et al., 2011; Manvich et al., 2012). We have collected preliminary data to 


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indicate that lorcaserin dose-dependently suppresses cue reactivity. Male Sprague-Dawley rats (n=11) were 
trained to self-administer cocaine on an FR5 schedule of reinforcement (0.75 mg/kg/inf; 3 hrs/d) for 14 days 
(Anastasio et al, 2014b). Rats were returned to their home cage for 1 day of forced abstinence (no extinction 
training) and were then reintroduced to the chambers. To assess cue reactivity, presses on the previously active 
lever were reinforced contingently by the discrete cue complex on an FR1 for one hour (active lever responses); 
inactive lever presses were recorded but produced no scheduled consequences. As predicted by studies with 
other selective 5-HT2cR agonists in extinction/reinstatement models, lorcaserin effectively suppressed cue 
reactivity. In addition there is human safety data in non-cocaine using subjects for lorcaserin as it is currently 
FDA approved for obesity, and safety data from a cocaine interaction study in rodents (See included full study 
report)., 
Overview of Clinical Studies 
BELVIQ (lorcaserin hydrochloride) tablets, for oral use. BELVIQ is a serotonin 2C receptor agonist indicated 
as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults 
with an initial body mass index (BMI) of: 30 kg/m2 or greater (obese) or 27 kg/m2 or greater (overweight) in 
the presence of at least one weight-related comorbid condition, (e.g., hypertension, dyslipidemia, type 2 
diabetes). 
In a preliminary report of a smoking cessation study, Eisai Inc. and Arena Pharmaceuticals Inc. announced 
results from a Phase 2 trial investigating lorcaserin HCl for smoking cessation. The trial demonstrated 
statistically significant improvement over placebo in reducing the number of patients who smoke after 12 weeks 
of treatment.  
Based on Arena media report dated November 3, 2014, the 12-week, randomized, double-blind, placebo-
controlled trial assessed the efficacy and safety of lorcaserin as a potential aid to smoking cessation. In the trial, 
603 active smokers were randomized to receive lorcaserin 10 mg once daily, 10 mg twice daily or placebo in a 
1:1:1 ratio. At baseline subjects were dependent on nicotine averaging 18 cigarettes per day. Patients received 
medication for two weeks prior to attempting to quit around Day 15 of the trial. Subjects also received smoking 
cessation counseling during the trial. Results showed that the carbon monoxide confirmed continuous 
abstinence rate (CAR), was achieved by 5.6%, 8.7%, and 15.3% of patients in the placebo, once daily and twice 
daily groups, respectively (p-value = 0.003 and odds ratio = 3.02 for twice daily vs. placebo; the result for once 
daily vs. placebo was not statistically significant). 
Safety and tolerability data showed that there was a statistically significant difference in weight between 
lorcaserin twice daily and placebo (-0.98 kg and -0.01 kg, respectively, p-value = 0.0004). The most common 
adverse events during the study were headache, nausea, constipation, dizziness and dry mouth, similar to 
previous trials of lorcaserin. 
For more detail refer to Belviq prescribing information.  
STUDY RATIONALE 
The overall goal of this project is to develop initial human data on effects of novel compounds on safety 
(interactions with cocaine) and efficacy (subjective response to cocaine and self- administration data) in non-
treatment seeking cocaine use disorder subjects. The compound to be studied will be the 5-HT2CR agonist 
lorcaserin. Lorcaserin and other 5-HT2CR agonists have been shown to reduce cocaine self-administration and 
cue reactivity in rodents (Cunningham et al., 2011; Manvich et al., 2012). In addition there is human safety data 
in non-cocaine using subjects for lorcaserin as it is currently FDA approved for obesity, and safety data from a 
cocaine interaction study in rodents (included below), but there is no human cocaine interaction/PK data and no 
PD data to support potential dosages for phase II clinical trials. 
Risk / Benefit Assessment 
Potential risks are listed below. The primary risks to participate in this study are those involved from potential 
unexpected serious adverse events due to receiving cocaine or lorcaserin. The risks of the medications are 
provided below. 


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Risks of Lorcaserin Administration 
Lorcaserin is FDA approved for the treatment of obesity. According to the FDA briefing document on 
lorcaserin based on the clinical trials in patients with obesity, “the most common adverse events with an 
incidence in the lorcaserin group that clearly exceeded placebo were headache (16.8 vs. 10.1%), dizziness (8.5 
vs. 3.8%), nausea (8.3 vs. 5.3%), fatigue (7.2 vs. 3.6%), and dry mouth (5.3 vs. 2.3%). These events were 
typically dose-related, mild or moderate in severity and transient. Furthermore, the excess over placebo 
occurred primarily within the first several days of treatment for headache and dizziness. Rates of 
discontinuation for adverse events were similar for lorcaserin 10 mg BID (8.6%), 10 mg QD (7.5%), and 
placebo (6.8%). Serious adverse events were as expected for the population, and similar in both character and 
frequency in the lorcaserin and placebo populations.” Because lorcaserin has the potential to impair cognitive 
function, patients should be cautioned about operating hazardous machinery, including automobiles, until they 
are reasonably certain that lorcaserin therapy does not affect them adversely. In preclinical studies abnormalities 
in thyroid function and liver tests have been seen in animals, but no changes in thyroid function or liver function 
have been noted in humans. In patients with diabetes, a drop in blood sugar has been seen. Weight loss may 
increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and/or insulin 
secretagogues (e.g., sulfonylureas); hypoglycemia was observed in clinical trials with lorcaserin. Lorcaserin has 
not been studied in combination with insulin. In other populations, lorcaserin has been associated with a modest 
increase in blood pressure.  
Other Potential Risks of Lorcaserin but not seen in Clinical Trials 
Risk of serotonin syndrome: As lorcaserin is a serotonergic medication, it carries the risk of serotonin syndrome 
associated with all serotonergic compounds. This risk could be increased by combining lorcaserin with other 
serotonergic compounds. Our own research experience using another serotonergic drug, citalopram with 
cocaine dependent subjects (Moeller et al., 2007) and another ongoing clinical trial has not seen any episodes of 
serotonin syndrome. Risk of valvular heart disease: Valvular heart disease has been seen in compounds that are 
5-HT2B agonists (Hutcheson et al., 2011). Lorcaserin is a 5-HT2C agonist, with minimal affinity for the 5-
HT2B receptor (see table 1 below). In addition, occurrence of valvular heart disease was examined in clinical 
trials with lorcaserin. In 3451 subjects who took lorcaserin 10mg twice daily for 1 year, 2.4% of patients who 
received lorcaserin and 2.0% of patients who received placebo developed valvular regurgitation on 
echocardiography (Belviq prescribing information). 
 
Table 1. Lorcaserin 5-HT Receptor Affinity (Belviq Prescribing Information) 
 
Risk of Priapism: Other medications that have 5-HT2C receptor affinities have been shown to produce 
priapism. Due to this risk subjects will be warned regarding the need for prompt treatment of prolonged 
erections lasting more than four hours. 
 
Abuse Potential: Lorcaserin is a Schedule IV medication due to studies in humans showing that 
supratherapeutic doses of lorcaserin produced a rating of “high”. In a published study (Shram et al., 2011) 
subjective measures of drug response were obtained in recreational polydrug users after 20mg, 40mg, and 60mg 
of lorcaserin and compared with zolpidem (15mg and 30mg) and ketamine (100mg). Results of that study 
showed that on the visual analog scale (VAS) rating of “drug liking”, overall, the mean scores for zolpidem and 
ketamine were in the “liking” range of greater than 50 on a 100 point scale, whereas, ratings for lorcaserin were 
in the “disliking” range (less than 50). The effects were primarily due to higher doses of lorcaserin. On other 


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VAS ratings, lorcaserin 40mg and 60mg produced a significant increase in the “high” rating but also produced a 
significant increase in the “feeling sick” rating. In contrast, zolpidem and ketamine were liked by the subjects. 
The authors’ conclusions regarding this study were that “This study demonstrated that lorcaserin has a very low 
potential for abuse by recreational polydrug users with a history of using perception-altering and central 
nervous system depressant drugs. Supratherapeutic doses of lorcaserin were significantly disliked, as 
demonstrated by the bipolar Drug Liking VAS (primary measure), and was associated with prominent negative 
effects.” (Shram et al, 2011). 
Based on the safety and abuse potential data from human studies described above, as well as the preclinical data 
on interaction with cocaine described below, a dosage regimen of 10mg daily escalating to a maximum dose of 
10mg twice daily was chosen for this study. 
Risks of Cocaine Administration 
Cocaine exposure: Medical complications that have been reported with cocaine use include heart attack, rupture 
of major blood vessels, stroke, difficulty breathing, swelling, cessation of bowel function, and death. However, 
none of these complications have been observed during our previous experience using I.V. cocaine 
administration for a similar protocol with GBR12909 at the University of Texas Medical Branch, or another 
study at UTMB using another study medication, SYN117. Cocaine is a potent sympathomimetic and has been 
associated with adverse cardiovascular events, including myocardial infarction and stroke, when taken illicitly.  
While these consequences have never been observed following controlled experimental administration, we will 
limit these potential risks in several ways: (1) We will enroll only physically healthy cocaine using subjects 
with no evidence of cardiovascular disease based on history, physical examination, ECG, and laboratory tests – 
all prospective subjects will be seen a Cardiologist on staff prior to the initiation of the study. (2) We will 
administer a dose shown to be safe in our hands that was selected to produces scientifically valid results. (3) We 
will monitor subjects closely in a hospital setting throughout the duration of action of the drug, under the 
supervision of medical personnel trained in basic and advanced cardiac life support. We will also employ 
continuous non-invasive hemodynamic monitoring using the Nexfin finger cuff (Edwards Scientific) that 
provides real-time assessment of blood pressure, heart rate, stroke volume, stroke volume variability, systemic 
vascular resistance, and cardiac output. Hemodynamic data will be continuously visible at bedside and stored 
for off-line analysis via the finger cuff.  We have an intervention plan in place to deal with any adverse events 
that may occur, as described in the following paragraph. In the event of an adverse event, the research team and 
the hospital is fully prepared to respond to any situation that may arise. The general and psychiatric emergency 
rooms are located minutes away.  There is a 24-hour medical emergency code team in the hospital. Physicians 
and their designated medical staff are fully trained to respond to all types of medical and psychiatric 
emergencies. A fully equipped crash cart is located on the unit. Study days 1, 2, 3, 6, 7, 10, and 11 of this study 
will be conducted at the CRS unit, a specialized research unit at VCU Medical Center. This unit has previously 
conducted phase I studies, including cocaine studies in humans (Baker et al., 2007). In the highly unlikely event 
of a suspected of medical emergency (i.e. chest pain, uncontrolled hypertension, cardiac arrhythmia, respiratory 
distress) the subject will be promptly evaluated by one of the research physicians and either transferred to Step 
Down Unit, ICU or Emergency Department or prescribed the appropriate treatment and monitoring level. Low 
risk subjects such as those with resolution of symptoms, normalization of vital signs, non-diagnostic ECG, and 
lack of potentially lethal arrhythmias may be monitored in the CRSU (see Immediate Evaluation of Adverse 
Event form).  
 
Effects on addiction: An additional concern is possible exposure to intravenous route of cocaine administration. 
In recruiting our subjects, the inclusion criteria include intravenous and/or smoked cocaine use. It is possible 
that some subjects might be exposed to intravenous cocaine for the first time. One concern will be whether this 
experience will lead to a change in route of drug administration, i.e. cocaine smoking subject becoming 
intravenous drug users. Previous research has shown that this event is not likely to occur. In the case of cocaine, 
users of smoked cocaine rarely switch to intravenous cocaine use even after exposure to intravenous cocaine. 


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Thus, we do not think that administering intravenous cocaine to crack users will encourage intravenous drug 
use. In fact, human laboratory studies comparing the smoked and intravenous administered cocaine have shown 
that pharmacokinetics are very similar with these routes of administration. That is, time to reach peak plasma 
levels as well as onset and duration of effect are comparable between intravenous and smoked cocaine 
administration in humans.  
 
In addition, some of subjective effects of cocaine such as feelings of "stimulated" and "high" were greater for 
smoked than those for intravenous cocaine at comparable plasma levels. In addition, smoked cocaine seems to 
be associated with more craving than the comparable intravenous dose. Therefore, there is little evidence to 
support the view that intravenous cocaine is more addicting than smoked cocaine; in fact, the current evidence 
supports the opposite view. The risk of cocaine administration on craving in general will be minimized through: 
1) To enroll in this study, cocaine use disorder subjects must not be seeking treatment. 2) Subjects will remain 
in the controlled environment after the last dose of cocaine. 3) At the time study completion, risks of ongoing 
cocaine use and opportunities for treatment are discussed with all subjects. 
Risks of Lorcaserin Combined with Cocaine 
In a recent NIDA funded preclinical study (NIDA Study Report 1812-12132, Sep. 20, 2013), lorcaserin was 
administered to rodents in combination with cocaine without any significant toxicity. Final results of this study 
are summarized here and provided in detail in an attached document. In short, at human equivalent doses in rats 
(i.e., 5 mg/kg, equivalent to 20 mg/day in humans, based on systemic exposures), there were no 
additive/synergistic effects of PO lorcaserin on IV cocaine-induced mortality or convulsions.  However, at 5-
fold higher doses (i.e., 25 mg/kg in rats, equivalent to 100 mg/day in humans – substantially beyond what is 
proposed in this study), there are indications of increased sensitivity to cocaine-induced convulsions due to 
lorcaserin. The combination of lorcaserin and cocaine has not been studied in humans. We will guard against 
potential toxicity of cocaine combined with lorcaserin by dosing cocaine using an ascending dose approach, and 
we have specific stopping criteria in place to stop the cocaine dose escalation if warranted by excessive 
cardiovascular responses.  If in spite of these precautions cocaine toxicity is observed (significant hypertension, 
tachycardia, symptoms of ischemia or evidence of arrhythmias) we have established treatment protocols in 
place and a code team will respond if needed.  We have never required such assistance in the past. Moreover, 
additional blood samples will be drawn 4-6 hours on the days of escalating cocaine infusions to measure high-
sensitivity troponin I (hsTnI) and N-terminal pro-brain natriuretic peptide (NT-pro-BNP). Although not 
routinely utilized in clinical practice, these markers will be stored for batch analysis upon completion of the 
study to detect the presence cardiac strain and/or stress to the myocardium related to cocaine in the absence of 
overt clinical disease (Gaggin and Januzzi, 2014; Gualandro et al., 2014). This data will be used as a potential 
biomarker of subclinical effects of cocaine on heart for future clinical trials. The total amount of blood for the 
entire study will not exceed 550ml in an 8 week period. 
Potential Risks Not Due to Study Medication 
Potential risks to participating in this study not involving medication include: unauthorized disclosure of 
confidential information; discomfort or embarrassment related to urine collection or questionnaires dealing with 
personal habits, lifestyle, drug or alcohol use; possible unwanted encounters with friends or associates in the 
treatment setting. 
Phlebotomy: There is the potential risk of bruising at the site of the blood draw  for the blood chemistries and 
complete blood count. This risk will be minimized by having blood drawn by a trained phlebotomist. 
Adequacy of Protection Against Risks 
Informed Consent Procedures. The informed consent process involves a detailed verbal description of the study, 
the behavioral intervention, and the study medication provided by a study staff member.  Staff will emphasize 
that participation is voluntary. Next, the Project Director or study coordinator will conduct an item-by-item 
reading of the consent form while the participant reads along. The participant then meets with a physician 


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investigator to ask questions about the risks of the medical procedures in the study. In this initial interview, 
participants will be informed of the following: 
They have an opportunity for research participation involving a program to evaluate effects of the study 
medication on effects produced by administration of cocaine in the hospital.   
Subjects in the studies will be randomly assigned to receive study medication or placebo. All assignments are 
based on chance. 
As with all medications, there are risks to treatment with the study medication. These are enumerated in the 
section above describing potential risks to the medication. 
All participants will be asked to complete questionnaires and answer questions related to drug and alcohol use, 
personal habits, lifestyle and feelings.  The initial information collection will take approximately 2 hours; 
shorter data collection sessions will occur weekly. 
All participants will be asked to provide a urine specimen for drug screening at each clinic visit.  
Participants may drop out at any time without penalty or loss of benefits to which they are otherwise entitled. 
Participants will be informed of procedures for ensuring their confidentiality, including: the issuance of a 
“Certificate of Confidentiality” by the federal government; the use of numbers, codes and/or pseudonyms rather 
than participants’ names; and the placement of all data in locked files.  
Participants will be informed that, despite participant confidentiality protections, research staff, under current 
state law, are required to report certain communicable diseases, and any incidents of sexual or physical abuse of 
a child or elder.   
Participants will be given the contact numbers of both the Principal Investigator and IRB to answer questions 
about the study or one’s rights as a human subject. 
 
A copy of the signed form is made and given to the subject, another copy is held in the Principal Investigator’s 
records, and the original signed consent is kept in a separate, locked file accessible to the Institutional Review 
Board (IRB) upon request. Individuals who decide that they are interested in treatment for cocaine dependence 
will be assisted in selecting treatment services and self-help meetings from the community resource listings. 
Assessment of Adverse Events. Participants will be asked daily how they are doing and if they are having any 
problems. Any spontaneously reported symptoms or complaints will be recorded and reported to the IRB and 
NIDA and the FDA if events are classified as serious.  
 
Data monitoring to ensure subject safety and confidentiality.  A potential risk in studies involving drug-
dependent volunteers is breach of confidentiality. This will be limited by maintaining data files on the medical 
histories of subjects to be kept in a locked file cabinet in the P.I.’s offices, accessible only to the study P.I. and 
designated study personnel as needed. Electronic media (i.e., computer-stored data, and data stored on CDs) 
will be password protected via encrypted code key known only to the designated study personnel.  
Furthermore, all subject information is coded with a unique numerical identifier. Protections of privacy of 
subjects’ medical information will be described to the prospective subjects as part of the enrollment interview 
and the informed consent procedures.  
 
As part of the Data and Safety Monitoring Plan, a Data and Safety Monitoring Board (DSMB) will monitor 
study processes and findings; part of the role of the DSMB will be to intercede to recommend halting 
enrollment of subjects if results definitively indicate that the study medication or protocol is harmful or in any 
way would negatively impact those individuals.   
 


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Approval by other interested agencies, including the FDA, is required prior to initiating studies investigating 
new indications of approved medications. This will provide further safeguard against unanticipated risks. An 
IND for drug and cocaine administration will be obtained well in advance of project start-up. 
Potential Benefits of the Proposed Research to the Subjects and Others 
Subjects in the study will receive close psychiatric attention. The potential benefits to society include decreased 
cocaine use if the study medications prove beneficial, with a resultant decrease in cocaine morbidity and 
mortality, as well as a reduction in the overall social costs for cocaine dependence. 
Risk-Benefit Ratio 
The primary risks to participation to this research are those that result from exposure to the study medications. 
These risks are seen as reasonable since there are in place numerous procedures, ongoing and periodic, designed 
to detect adverse experiences that occur both at the level of the individual and at the level of the medication 
condition. Once detected, there are adequate procedures in place to determine the most appropriate method for 
addressing adverse events that occur to the individual or to a group of individuals in a specific medication 
condition. There are few anticipated physical, psychological, social, or legal risks. However, some possible 
risks to participating in these studies include: unauthorized disclosure of confidential information; discomfort or 
embarrassment related to urine collection or questionnaires dealing with personal habits, lifestyle, drug or 
alcohol use; and possible unwanted encounters with friends or associates in the study setting. If participants 
were to find any aspects of their involvement in the study psychologically or otherwise uncomfortable, they will 
first meet with the study physician to discuss the situation and determine if modifications can be made to 
accommodate them. If there is no apparent resolution available, the decision will be made whether or not to 
discontinue the participant from the study.  
Importance of the Knowledge to be Gained 
The risks to participants are reasonable in relation to the anticipated benefits because: 
Staff will be trained and supervised to identify participants who are of danger to themselves or others.  Those 
participants found to be seeking treatment will be referred for appropriate care. 
The identification of effective treatments for cocaine dependence would be a great benefit to society. 
 
If any Psychiatric or non-Psychiatric medical illness (other than substance abuse) is discovered during the study, 
subjects will be referred for additional treatment in the community. 
STUDY OBJECTIVES 
Primary Objective 
The primary objectives are to provide safety and PK information on drug interactions between lorcaserin and 
cocaine in subjects with cocaine use disorder, to provide information on effects of lorcaserin on subjective 
response to cocaine and cocaine self-administration in subjects with cocaine use disorder, and to provide safety, 
PK information, and cocaine self-administration and subjective response to cocaine information for compounds 
chosen based on results of current project and discussions with NIDA program staff. 
Secondary Objectives 
The secondary objective is to examine effects of lorcaserin on behavioral laboratory measures of impulsivity in 
cocaine dependent subjects. 
STUDY DESIGN 
Study Overview 
The overall goal of this project is to develop initial human data on effects of novel compounds on safety 
(interactions with cocaine) and efficacy (subjective response to cocaine and self-administration data) in non-
treatment seeking cocaine use disorder subjects. This project will provide innovative data on effects of novel 
compounds on cocaine self-administration in addition to needed safety data on drug interactions with cocaine. 
This is a Phase I human drug interaction study examining the safety of concurrent administration of cocaine 


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with novel compounds, and the effects of the novel compounds on subjective response to cocaine and cocaine 
self-administration in non-treatment seeking cocaine use disorder subjects. This data will provide important 
information for go/no-go decisions on phase II clinical trials using medications as a tool to enhance abstinence. 
The initial compound to be studied will be the 5-HT2CR agonist lorcaserin, which has been shown to reduce 
cocaine self-administration and cue reactivity in rodents. In addition there is human safety data in non-cocaine 
using subjects for lorcaserin as it is currently FDA approved for obesity, but there is no human cocaine 
interaction/PK data and no PD data to support potential dosages for phase II clinical trials.  
This is a single center, double-blind, placebo-controlled, randomized, 1b/2a study. 18 subjects are planned.   
Screening data will be reviewed to determine subject eligibility.  Subjects who meet all inclusion criteria and 
none of the exclusion criteria will be entered into the study.  
The following treatment regimens will be used: 
Lorcaserin will be 10mg once daily increasing to 10mg twice daily. 
Placebo or Comparator – identical placebo capsules administered at the same time as lorcaserin. 
Subject participation will consist of 12 active study days and 2 follow-up visits, divided into multiple scheduled 
study visits.  Total duration of the study is expected to be 4 years. 
Criteria for evaluation 
Primary Efficacy Endpoint 
1. Safety: Heart rate (HR) and blood pressure (BP) measures during saline infusions will be compared to HR 
and BP after each cocaine infusion (20 mg and 40 mg doses).  Changes in HR and BP induced by cocaine 
infusion along with lorcaserin will be compared to those without lorcaserin, by cocaine dose level (20 mg and 
40 mg doses), using repeated measures analysis of variance (ANOVA). Changes in ECG readings during saline 
infusion as compared to those taken during cocaine infusions will be reported as summary statistics. Adverse 
event data will be compiled for lorcaserin and placebo cohorts and presented as summary statistics.  
2. Cocaine Self-administration: Repeated measures ANOVA with cocaine dose (0mg, 25mg) and lorcaserin 
dose (0mg, 10mg, 20mg) as within subject factors will be used to examine differences in mean cocaine choice 
selection. In addition, a Bayesian analysis will be carried out as described below. 
3. Subjective response to cocaine: Subjective response measures (VAS) obtained during saline infusions will be 
compared between lorcaserin and placebo subjects to those during cocaine infusions by cocaine dose level to 
determine the extent to which these measures are modified by the administration of lorcaserin using repeated 
measures ANOVA. 
4. Cocaine PK: Plasma concentration-time profiles of cocaine after cocaine infusion during placebo 
administration (Day 2) will be analyzed to obtain pharmacokinetic parameter estimates of cocaine (Tmax, AUC, 
apparent t½, CL) by individual. These parameters will be compared within subjects on sessions with lorcaserin 
(Days 6 and 10). 
Secondary Efficacy Endpoints 
Response inhibition: Commission errors on the IMT will be compared between lorcaserin and placebo subjects 
to determine the extent to which this measure is modified by the administration of lorcaserin using repeated 
measures ANOVA. 
SUBJECT SELECTION 
Study Population 
Subjects with a diagnosis of cocaine use disorder who meet the inclusion and exclusion criteria will be eligible 
for participation in this study.   
Inclusion Criteria 
Males and females between 18 and 59 years-of-age. 
Understand the study procedures and provide written informed consent. 


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Meet current DSM-5 criteria for cocaine use disorder, at least moderate severity, and current DSM-IV diagnosis 
of cocaine dependence, but are not seeking treatment. 
Currently using cocaine by smoking or intravenous route of administration as determined by self-report and 
have a positive urine drug screen for cocaine during screening. 
Have vital signs as follows:  resting pulse below 95 bpm, blood pressures  below 140 mm Hg systolic and  90 
mm Hg diastolic. 
 
Have no clinically significant abnormalities in the judgment of the study physician in hematology and chemistry 
laboratory tests including liver function tests. 
Have sinus rhythm with normal conduction (including QTcF less than 440 ms) by ECG.   
Have no contraindications for study participation as determined by medical history and physical examination. 
Be able to demonstrate an understanding of study procedures and follow instructions including behavioral 
laboratory testing.  
No pregnant or nursing women will be permitted in the study, and women must either be unable to conceive 
(i.e., surgically sterilized, sterile, or postmenopausal) or be using a reliable form of contraception (e.g., 
abstinence, birth control pills, intrauterine device with spermicide, or condoms). Men will be advised to use 
condoms. All females must provide negative pregnancy urine tests before study entry, at each visit during the 
study, and at the end of study participation. 
Have hemoglobin/hematocrit values within normal limits based on age and gender. 
 
Exclusion Criteria 
Meet current DSM-5 diagnosis of any psychoactive substance use disorder other than cocaine, opioids, 
marijuana, or nicotine.  Diagnosis of mild to moderate use disorder for alcohol will not be exclusionary. 
Have a DSM-5 diagnosis of any psychoactive substance use disorder including but not limited to Bipolar 
Disorder, Major Depressive Disorder, ADHD, or Schizophrenia or a neurological disorder requiring ongoing 
treatment and/or making study participation unsafe. 
Have any previous medically adverse reaction to cocaine, including loss of consciousness, chest pain, or 
epileptic seizure. 
Have any clinically significant medical disorder including cardiovascular (including hypertension), pulmonary, 
CNS, hepatic, or renal disorder.  
Have a history of seizures (excluding childhood febrile seizures), or clinically significant head injury. 
Have significant current suicidal or homicidal ideation or a history of suicide attempt within the past 6 months. 
Have conditions of probation or parole requiring reports of drug use to officers of the court. 
Have impending incarceration.  
Have a positive HIV test by self-report or history.  
Be pregnant or nursing or not using a reliable form of contraception if able to conceive. All females must 
provide negative pregnancy urine tests at screening, and at each study visit. 
Have any other illness, or condition, which in the opinion of the PI would preclude safe and/or successful 
completion of the study. 
Have a positive breath alcohol test or urine drug screening positive for drugs of abuse with the exception of 
cocaine, cocaine metabolites, opiates and marijuana. 
Have a score > 5 on the Clinical Opiate Withdrawal Scale on any screening, monitoring, or study visit. 
Subjects who are allergic to lorcaserin. 
Subjects who have taken any investigational drug within 90 days prior to baseline. 


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Concurrent Medications 
All subjects should be maintained on the same medications throughout the entire study period, as medically 
feasible, with no introduction of new chronic therapies. 
Allowed Medications and Treatments 
Non-CNS active medications which are not known to have a potential interaction with cocaine or lorcaserin 
would be allowed in this study. 
Prohibited Medications and Treatments 
The following medications are prohibited during the study and administration will be considered a protocol 
violation. 
Any CNS active medications 
Any medications with a known interaction with cocaine or lorcaserin 
STUDY TREATMENTS 
Method of Assigning Subjects to Treatment Groups 
Up to 18 eligible patients will be randomly assigned to lorcaserin or placebo treatment groups in a 1:2 ratio 
using a SAS-based computer-generated randomization scheme developed by the study data management 
provider.   
Blinding 
Due to the objectives of the study, the identity of test and control treatments will not be known to investigators, 
research staff, or patients.  The following study procedures will be in place to ensure double-blind 
administration of study treatments.  
Access to the randomization code will be strictly controlled.   
Packaging and labeling of lorcaserin and placebo will be identical to maintain the blind.  
Lorcaserin concentrations will not be analyzed till the end of the study. 
The study blind will be broken on completion of the clinical study and after the study database has been locked.  
During the study, the blind may be broken only in emergencies when knowledge of the patient’s treatment 
group is necessary for further patient management. Unblinding will occur by the PI contacting the research 
pharmacy to break the blind in case of emergency. 
Formulation of Test Product 
Lorcaserin HCL 10mg tablets (Belviq, Arena Pharmaceuticals) will be used for this study. To ensure blinding, 
tablets will be placed in gelatin capsules by the research pharmacist prior to administration.   
Commercially available sterile normal saline for human use will be used as a matched 
placebo for cocaine. Cocaine is packaged in 2 mL vials containing 20 mg per mL. 
Cocaine for IV human use will be obtained from a NIDA contractor under a letter of 
authorization to allow cross reference to NIDA’s DMF for cocaine obtained and 
submitted to the IND. 
The pharmacist will prepare the cocaine according to instructions supplied by the NIDA 
contractor and dispense according to the randomization. The labels on the cassettes of 
cocaine and matching placebo will conform to internal Pharmacy and CRSU SOPs and 
instructions. 
The doses of cocaine will be prepared by diluting cocaine with 20 mL normal saline. 
Cocaine administration: Cocaine will be administered by a study nurse under the direct supervision of a 
physician. The drug is given intravenously (IV) over a 2 minute period in a cassette via a pump delivery system. 
Formulation of Control Product 


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Gelatin placebo capsules identical to capsules that enclose the study drug will be used for placebo. Dextrose 
powder will be used as a filling in the capsules. 
Packaging and Labeling 
Each pill bottle of study drug will be labeled with the required FDA warning statement, the protocol number, a 
treatment number, the name of the study physician, and directions for patient use and storage.   
Administration of Study Drug 
Dosage/Dosage Regimen 
 If subjects meet inclusion criteria, they will be seen both in the hospital and at IDAS clinic for a total of 12 
active study days and monitoring procedures will be in place to detect drug and alcohol use and assess for 
adverse events at each visit. In addition, the hospital cocaine administration procedures will reduce the 
likelihood of increased cocaine craving after cocaine administration. Subjects will undergo procedures as 
described below. Subjects will not be allowed to smoke cigarettes, as smoking is not allowed in the hospital or 
anywhere on the VCU campus. Subjects will have the option to use a nicotine patch dosed based on the amount 
of daily cigarettes smoked. Subjects will not be allowed to leave the CRS Unit nor receive visitors during their 
study visits. Subjects who are unable to comply with these restrictions will be dropped from the study. After a 
screening cocaine infusion to determine safety, eligible subjects will be randomized to Group A –placebo only 
or Group B –placebo followed by an ascending dose of lorcaserin. Six subjects will be assigned to Group A 
(placebo) and 12 subjects will be assigned to Group B (active lorcaserin).  
Study Drug Dosage: Lorcaserin will be 10mg once daily increasing to 10mg twice daily.  
Outcome Measures: The primary outcome measures are adverse events, cardiovascular responses (Heart rate 
(HR), blood pressure (BP), ECG measurements, subjective response to cocaine, cocaine self-administration, and 
cocaine blood PK. Secondary outcome measures will be impulsivity as measured by the immediate memory 
task (IMT).  
1) Days 1-2: All subjects will be seen on the CRSU. All subjects will receive placebo on days 1-2 in a single 
blind fashion. Vital signs including heart rate, blood pressure and respiration rate will be obtained after placebo 
administration. Days 1-2 will be single-blind placebo, whereas all remaining study days will be double-blind. 
All subjects will leave the CRSU at the end of each study day. 
2) Days 3-6: All subjects will be seen on the CRSU on days 3 and 6, and at the IDAS clinic on days 4 and 5. On 
days 3-6, subject group A will receive one placebo pill twice daily, and group B will receive one placebo pill in 
the morning and one matching lorcaserin 10 mg pill in the evening, for a total dose of 10 mg daily. ECG with 
QTc will be performed daily. If the QTc is prolonged greater than 30ms over baseline lorcaserin dosage will be 
held.  
3) Day 7: All subjects will receive one placebo pill in the morning in single blind fashion. Following Cocaine 
Self-administration sessions and impulsivity testing the subjects will leave the unit. 
4) Days 8-10: All subjects will be seen at the  IDAS clinic on Days 8 and 9 and subjects in group B will have a 
blinded dosage increase to 10 mg of lorcaserin twice daily for Days 8-11 (Days 10 and 11 will take place at the 
CRSU). Vital signs including heart rate, blood pressure and respiration rate will be obtained before 
placebo/lorcaserin administration. ECG with QTc will be performed daily under the supervision of a study 
physician. If the QTc is prolonged greater than 30ms over baseline lorcaserin dosage will be held. 
5) Day 11: All subjects will be seen on the CRSU and receive placebo/lorcaserin in the morning followed by the 
last cocaine self-administration session. 
6) Day 12: Subjects will be seen at IDAS for study procedures.   
5) Cocaine Infusion Sessions (Days 1, 2, 6, and 10): All subjects will undergo an ascending dose intravenous 
cocaine administration after admission on day 1 to ensure safety of later cocaine studies.  
To assess the safety and subjective effects of cocaine in the presence of lorcaserin, subjects will receive 
ascending doses of intravenous cocaine (10 mg, 20 mg, 40 mg), with each cocaine administration separated by 


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one hour. In addition, 0 mg cocaine (saline) infusion will be randomly given after the first dose of cocaine in 
order to aid in blinding investigators and subjects to the order of drug administration. Infusions will be carried 
out hourly starting from 1 hour after placebo/lorcaserin for 4 times (on Day 1, 2, 6, and 10). An example dose 
by session diagram is shown below. Note that the 0 mg dose is randomly given after the first dose of cocaine. 
Monitoring will be continued for 1 hour after the last dose of cocaine. 
 
Dose 
Dose Session 1 
Dose Session 2 
Dose Session 3 
Dose Session 4 
1 
10 mg Cocaine 
10 mg Cocaine 
10 mg Cocaine 
10 mg Cocaine 
2 
20 mg Cocaine 
0 mg Cocaine 
20 mg Cocaine 
0 mg Cocaine 
3 
0 mg Cocaine 
20 mg Cocaine 
40 mg Cocaine 
20 mg Cocaine 
4 
40 mg Cocaine 
40 mg Cocaine 
0 mg Cocaine 
40 mg Cocaine 
 
Dispensing 
Study drugs will be dispensed by the research pharmacist and administered by the research nurse on the CRS 
unit (cocaine) or trained research personnel (lorcaserin) at IDAS. 
Supply of Study Drug at the Site 
Study drug will be provided to the CRS research unit after an order from the study physician. 
Storage 
At the testing facility, all lorcaserin, placebo, and cocaine must be kept in a secure, locked storage place with 
access limited to authorized study personnel only. Lorcaserin bottles must be 
kept at room temperature (15°C–25°C) until ready for administration. Cocaine must be 
stored in accordance with regulations for controlled substances and per pharmacy 
policy. 
Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for each subject will be 
maintained on an ongoing basis by a member of the study site staff.  The number of study drug dispensed and 
returned by the subject will be recorded on the Investigational Drug Accountability Record. The study staff 
must record an accurate accounting of each lorcaserin, and Cocaine/placebo dispensation and assignment 
number, as well as the date dispensed. 
Both used and cocaine/placebo cassettes and IV cocaine vials must be accounted for on a drug disposition and 
accountability form, including the amount of cocaine that was not dispensed and was wasted from the 2mg/mL 
vial. 
 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the duration of the study 
is diagrammed in Appendix 1. While it will be preferable to schedule all of the study days consecutively, the 
modular design allows Day 1 and Day 2 to be scheduled independently in advance of the Day 3-7 and Day 8-12 
study visits. The Day 3-7 and Day 8-12 hospital visits will be for 5 days each. In addition these 2 study visits 
may be scheduled separately to accommodate the availability of participants. However, all study days must be 
completed with a 90-day period. In the event that all study days are not scheduled consecutively, participants 
will be required to come into the research clinic for weekly monitoring  (including UDS, vitals, and 
questionnaires). 
 


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Prior to conducting any study-related activities, written informed consent and the Health Insurance Portability 
and Accountability Act (HIPAA) authorization must be signed and dated by the subject.  If appropriate, assent 
must also be obtained prior to conducting any study-related activities. 
Clinical Assessments 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at screening and study days (Days 1-
11) and Follow-Up days (Days 12, 15 and 19).  Dose, route, unit frequency of administration, and indication for 
administration and dates of medication will be captured. 
Clinical Opiate Withdrawal Scale (COWS) 
This scale will be administered each study day during screening, monitoring and at each of the study visits for 
subjects who meet criteria for opioid dependence to determine the presence of symptoms indicative of opiate 
withdrawal. A score  > 5 on the scale would prohibit study participation. In the event of a positive urine drug 
screen for opiates the study physician will review the COWS and the subject’s drug use history to determine the 
likelihood of opiate withdrawal which would also prohibit study participation. 
Demographics  
Demographic information (date of birth, gender, race) will be recorded at screening. 
Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory history, and 
information regarding underlying diseases will be recorded at screening. 
Physical Examination 
A complete physical examination will be performed by qualified staff (MD, NP,).  New abnormal physical 
exam findings must be documented and will be followed by a physician or other qualified staff at the next 
scheduled visit. 
Vital Signs 
Body temperature, blood pressure, pulse and respirations will be performed after resting for 5 minutes at 
screening and at study visits (Days 1-12) and Follow-Up visits (Days 15 and 19). 
The Structured Clinical Interview for DSM-IV (SCID) 
The SCID (First et al, 2002) will be used to collect diagnostic information used to make eligibility 
determinations. This interview will be conducted by staff who will be trained by experienced SCID interviewers 
using standardized training videotapes from Biometrics Research, NY. This interview will be conducted at 
screening. 
Structured Clinical Interview for DSM-IV Personality Disorders Module (SCID-II) 
This instrument provides a DSM-IV axis II diagnosis, and will be used to determine a diagnosis of Antisocial 
Personality Disorder and Borderline Personality Disorder (First et al, 1997). This interview will be conducted at 
screening by trained staff. 
Childhood Disorders Version of the SCID (KID-SCID) ADHD Module 
A version of the KID-SCID modified for adults will be used to aid in the determination of a diagnosis of adult 
attention deficit hyperactivity disorder (ADHD). This interview will be conducted at screening by trained staff. 
Wender Utah Rating Scale (WURS) 
This 61-item scale for adults (Almaric and Koob, 1993) describes their own childhood behavior to aid in the 
determination of ADHD in adults. This will be conducted at screening by trained staff. 
Kreek-McHugh-Schluger-Kellogg Scale (KMSK) 
This scale (Kellogg et al, 2003) will be used to quantify use of opioids, cocaine, marijuana, alcohol, and other 
substances of abuse by assessing the frequency, amount, and duration of use of the particular substance during 


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the individual’s period of greatest consumption. The scale also assesses the mode of use, whether the substance 
use is current or past, and whether each substance is the substance of choice. This will be conducted at 
screening by trained staff. 
Addiction Severity Index (ASI-lite) 
This scale (Cacciola et al, 2007) will be used in conjunction with the KMSK as measures of baseline severity of 
substance use. This will be conducted at screening by trained staff. 
Fagerström Test for Nicotine Dependence (FTND) 
This is a short self-report questionnaire (Heatherton et al, 1991) designed to measure the construct of nicotine 
dependence, will be included to explore the potential moderating effects of tobacco dependence in relation to 
cocaine use and response to treatment. This will be conducted at screening by trained staff. 
National Adult Reading Test (NART) 
The NART-R is a 61-item vocabulary test (Nelson and O’Connell, 1978) will be used to estimate general 
intellectual ability and to control for individual differences in subject’s premorbid level of intelligence. This test 
has been shown to have high inter-rater (.96-.98) and test-retest reliability (.98) and predictive validity (.74) 
with the WAIS-R IQ.  This will be conducted at screening. 
Attentional Bias (modified Stroop task) 
This is a widely-used implicit task in which the subject is presented with words printed in color, and asked to 
discriminate the color of each stimulus and to ignore the meaning of the words. There are ten cocaine-related 
words (e.g., "cocaine", "crack"), and ten neutral words consisting of household features (eg., "table", "kitchen"). 
The word sets are matched in length or frequency of use using typical procedures. Subjects are instructed that 
words written in different colors (blue, green, or red) will be presented on the screen, one after the other, and 
that their task is to indicate the color in which the word is written as quickly and as accurately as possible, 
ignoring the meaning of the word itself. A new word is presented 500ms after a response (or 500ms after the 
timeout of 3 sec). In this block design protocol a block (60s) of neutral words alternates with a block (60s) of 
cocaine words and each run is approximately 10 min. Subjects first respond to a practice sequence (50 trials) of 
letter strings (e.g, HHHH). Within each Stroop task, the program randomly determines the presentation order of 
words and colors for each participant under the constraint that the same color does not appear on two 
consecutive trials. 
Conditioned Distracter XY Go-No Go task 
This task is based on the XY-GoNo Task of Hugh Garavan and colleagues: 
http://www.ncbi.nlm.nih.gov/pubmed/12944513 
In this task, the subject sees the letters X and Y alternating once per second (white letter on black background) 
in a large font, e.g. 400 ms of letter presentation, alternating with 600 ms blank screen.  The subject is to emit a 
press each time the letter is different from the one before (an alternation).  Since most of the time X alternates 
with Y, this builds up a prepotent tendency of the subject to press every second.  However, the subject is to 
NOT press if the same letter is presented twice in a row, 
e.g.   ..X.…Y…..X….X.....  or   X….Y…..X….Y….X….Y….Y…   The presentation of the same letter twice in 
a row in the series is a called a LURE, and these represent 10% of the stimuli, and lures never occur in rapid 
succession. The task will be divided into 15 blocks, each 30 seconds long. Each block will thus have 30 letters 
shown, three of which will be identical to the letter before it (i.e. three lures per block. Five blocks will be "non-
distractor" control blocks, where the background will be black as in the original Garavan task. Five blocks will 
be "unconditioned distractor) control blocks, where the subject will see a continuous thick yellow border at the 
periphery of the screen. Five blocks will be the "conditioned distractor" blocks, where the subject will see a 
continuous teal-colored thick border that was previously seen in the cocaine self-administration task.  
 
 


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Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. Duration (start and 
stop dates and times), severity, outcome, treatment and relation to study drug will be recorded on the case report 
form (CRF). 
Clinical Laboratory Measurements  
Hematology 
Blood will be obtained and sent to each site’s clinical hematology lab a complete blood count (hemoglobin, 
hematocrit, red blood cell count, white blood cell count, white blood cell differential, and platelet count). 
Blood Chemistry Profile 
Blood will be obtained and sent to each site’s clinical chemistry lab for determination of serum sodium, 
potassium, chloride, bicarbonate, random glucose, BUN, creatinine, aspartate aminotransferase (AST/SGOT), 
alanine aminotransferase (ALT/SGPT), alkaline phosphatase, total bilirubin, direct bilirubin, albumin and LDH. 
Pregnancy Test 
A urine pregnancy test will be obtained from female subjects who are of childbearing age prior to their 
participation in the study. 
Urinalysis 
Urine will be obtained and sent to each site’s clinical laboratory for determination of color, specific gravity, pH, 
protein, glucose, ketones, and blood. 
Urine Drug Screen 
Urine will be obtained from all subjects to be tested for cocaine (benzoylecgonine), opiates and opioids, 
benzodiazepines, amphetamine, methamphetamine, and THC. 
Breathalyzer 
Breath alcohol level will be obtained from all subjects. Subjects who have a positive breath alcohol will be told 
that they must return at a later date with a negative breath alcohol in order to take part in study procedures. 
Pharmacokinetic Measurements 
Pharmacokinetic samples for analysis of cocaine (PK): Blood samples for analysis of the pharmacokinetics of 
10 mg IV cocaine will be collected during treatment with 0 mg Lorcaserin (on study day 2) and during 
treatment with lorcaserin at 10 mg once daily (study day 6) and lorcaserin 10mg twice daily (study day 10). 
Plasma cocaine levels at these time points for each of those days: -15, 5, 10, 20, 30, 45 60, 90, 120, 180, 240 
minutes. Plasma levels of cocaine and metabolites will be assayed by liquid chromatography-tandem mass 
spectrometry. Benzoylecgonine and ecgonine methyl ester both peak at approximately 120 minutes, with 
expected concentrations of 170 and 15 ng/mL at 480 minutes, respectively. Determinations of cocaine, 
benzoylecgonine, ecgonine methyl ester, and norcocaine (if detectible) will be measured. Blood will be 
collected into Vacutainer tubes that contain fluoride to inhibit hydrolysis of cocaine by plasma cholinesterases. 
After separation of plasma by routine methods, samples will be frozen at -70°C until ready for analysis.  
 
EVALUATIONS BY VISIT (see table 2. below for overview of time course) 
 
Screening (Days -7 to 0) Conducted at IDAS  
Review the study with the subject and obtain written informed consent. 
Assign the subject a unique screening number. 
Record demographics data. 
Record medical history.  
Record concomitant medications. 


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Administer COWS if opioid user 
Perform a complete physical examination. 
Perform a complete neurological exam. 
Perform a 12-Lead ECG. 
Collect urine for clinical laboratory tests (urine drug screen, pregnancy test, urinalysis). 
Perform and record vital signs. 
Perform and record Breathalyzer. 
Collect blood for clinical laboratory tests (serum chemistry and hematology). 
Perform psychiatric interviews (SCID, SCID-II, KID-SCID). 
Conduct clinical assessments (KMSK, FTND, NART, ASI-lite, POMS, CGI-S, C-SSRS). 
Record brief substance craving scale, timeline follow back cocaine use, and drug use history. 
Verify inclusion and exclusion. 
Schedule subject for Day 1 visit  as soon as possible. 
 
 
 
Study Day 1  
Arrive at CRS unit. 
Collect urine for pregnancy test and urine drug screen. 
Perform and record Breathalyzer. 
Administer COWS if opioid user.  
Perform and record vital signs. 
Perform a 12-Lead ECG. 
Perform a brief physical exam and continuous cardiovascular monitoring. 
Administer placebo in morning. 
Administer cocaine for Dosing session 1. 
Record brief substance craving scale. 
Update concomitant medications. 
Record Visual Analog Scale (VAS). 
Record adverse events. 
Conduct clinical assessments (POMS, CGI-I, C-SSRS). 
Administer Immediate Memory Task (IMT). 
 Leave CRS unit. 
 
Study Day 2  
Arrive on CRS unit. 
Collect urine for pregnancy test and urine drug screen. 
Perform and record Breathalyzer and vital signs. 
Administer COWS if opioid user. 
Perform a 12-Lead ECG. 
Perform a brief physical exam and continuous cardiovascular monitoring. 


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Administer placebo in morning. 
Administer cocaine for PK. 
Record brief substance craving scale. 
Update concomitant medications. 
Record VAS and adverse events. 
Administer cocaine for Dosing session 2. 
Conduct clinical assessments (POMS, CGI-I). 
Leave CRS unit. 
 
Study Day 3  
Arrive on CRS unit. 
Collect urine for pregnancy test and urine drug screen. 
Perform and record Breathalyzer and vital signs. 
Administer COWS if opioid user. 
Perform a 12-Lead ECG, brief physical exam, and continuous cardiovascular monitoring. 
Administer placebo in morning 
Self -Administered cocaine session 1 in morning. 
Self-Administered cocaine session 2 in afternoon. 
Record brief substance craving scale. 
Update concomitant medications. 
Record VAS and AE. 
Conduct clinical assessments (POMS, CGI-I). 
Administer placebo/lorcaserin in evening 
Leave CRS unit. 
 
Study Day 4  
Arrive at IDAS 
Administer placebo in morning 
Collect urine for pregnancy test and urine drug screen 
Perform and record Breathalyzer and vital signs. 
Perform a 12-Lead ECG. 
Record brief substance craving scale and AE. 
Administer COWS if opioid user. 
Update concomitant medications. 
Conduct clinical assessments (POMS, CGI-I). 
Administer IMT task 
Administer placebo/lorcaserin in evening 
Leave IDAS. 
 
Study Day 5  
Arrive at IDAS  


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Administer placebo in morning 
Collect urine for pregnancy test and urine drug screen. 
Perform and record Breathalyzer and vital signs. 
Perform a 12-Lead ECG. 
Record brief substance craving scale and AE. 
Administer COWS if opioid user. 
Update concomitant medications. 
Conduct clinical assessments (POMS, CGI-I, and C-SSRS). 
Administer placebo/lorcaserin in evening 
Leave IDAS. 
 
Study Day 6  
Arrive on CRS unit  
Administer placebo in morning 
Collect urine for pregnancy test and urine drug screen. 
Perform and record Breathalyzer and vital signs. 
Perform a 12-Lead ECG and continuous cardiovascular monitoring. 
Record brief substance craving scale, VAS, and AE. 
Administer COWS if opioid user. 
Update concomitant medications. 
Administer cocaine for PK. 
Measure lorcaserin PK 
Administer cocaine for Dosing session 3. 
Conduct clinical assessments (POMS, CGI-I). 
Administer placebo/lorcaserin in evening 
Leave CRS unit. 
 
Study Day 7  
Arrive on CRS unit  
Administer placebo in morning 
Collect urine for pregnancy test and urine drug screen. 
Perform and record Breathalyzer and vital signs. 
Perform a 12-Lead ECG and brief physical exam. 
Record brief substance craving scale, VAS and AE. 
Administer COWS if opioid user. 
Update concomitant medication. 
Self -Administered cocaine session 3 in morning. 
Self -Administered cocaine session 4 in afternoon. 
Conduct clinical assessments (POMS, CGI-I). 
Administer IMT task. 
Leave CRS unit 


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Study Day 8  
Arrive at IDAS  
Administer placebo/lorcaserin in morning 
Collect urine for pregnancy test and urine drug screen. 
Perform and record Breathalyzer and vital signs. 
Administer COWS if opioid user. 
Perform a 12-Lead ECG and brief physical exam. 
Record brief substance craving scale, VAS and AE. 
Update concomitant medications. 
Conduct clinical assessments (POMS, CGI-I, and C-SSRS). 
Administer placebo/lorcaserin in evening. 
Leave IDAS. 
 
Study Day 9  
Arrive at IDAS 
Administer placebo/lorcaserin in morning 
Collect urine for pregnancy test and urine drug screen. 
Perform and record Breathalyzer and vital signs. 
Perform a 12-Lead ECG. 
Record brief substance craving scale and AE. 
Administer COWS if opioid user. 
Update concomitant medications. 
Conduct clinical assessments (POMS, CGI-I, and C-SSRS). 
Administer placebo/lorcaserin in evening. 
Leave IDAS. 
 
Study Day 10   
Arrive on CRS unit  
Administer placebo/lorcaserin in morning 
Collect urine for pregnancy test and urine drug screen. 
Perform and record Breathalyzer and vital signs. 
Perform a 12-Lead ECGand continuous cardiovascular monitoring. 
Record brief substance craving scale, VAS, and AE. 
Administer COWS if opioid user. 
Update concomitant medications. 
Administer cocaine for PK. 
Measure lorcaserin PK. 
Conduct clinical assessments (POMS, CGI-I). 
Administer cocaine for Dosing session 4. 
Administer IMT task 


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Administer placebo/lorcaserin in evening 
Leave CRS unit. 
 
Study Day 11  
Arrive on CRS unit  
Administer placebo/lorcaserin in morning 
Collect urine for pregnancy test and urine drug screen. 
Collect blood for clinical laboratory tests (serum chemistry and hematology). 
Perform and record Breathalyzer and vital signs. 
Perform a 12-Lead ECG and continuous cardiovascular monitoring. 
Record brief substance craving scale, VAS and AE. 
Administer COWS if opioid user. 
Update concomitant medication. 
Self -Administered cocaine session 5 in morning. 
Self -Administered cocaine session 6 in afternoon. 
Conduct clinical assessments (POMS, CGI-I). 
Leave CRS unit. 
 
 Study Day 12   
Arrive at IDAS 
Collect urine for pregnancy test and urine drug screen. 
Perform and record Breathalyzer and vital signs. 
Perform a 12-Lead ECG. 
Record brief substance craving scale and AE.  
Administer COWS if opioid user. 
Update concomitant medication. 
Conduct clinical assessments (POMS,CGI-I, Stroop, and XY Go-No Go). 
PI (or designee) conduct assessment for lorcaserin side effects. 
Leave IDAS 
 
Follow-Up Days (Day 15, 19) Conducted at IDAS 
Collect urine for pregnancy test and urine drug screen. 
Perform and record Breathalyzer and vital signs. 
Perform a 12-Lead ECG and brief physical exam (Day 19 only). 
Record brief substance craving scale and timeline follow back cocaine use. 
Update concomitant medication. 
Conduct clinical assessments (POMS, CGI-I, and C-SSRS). 
 
 
 
 


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Table 2.   Overview of Study Procedures 
Study Day 
Day 1 
Day 2 
Study Visit 
One 
Two 
Procedure Morning 
Session 
Arrive  at CRS, Three Screening 
Doses of Cocaine (NexFin 
monitoring) 
Arrive at CRS 
10mg Cocaine for PK  
Procedure Afternoon 
Session 
Impulsivity Testing 
Depart from CRS 
Three Doses of Cocaine, Cardiovascular 
(NexFin monitoring) 
Cardiac Biomarkers (4-6 hrs from last dose) 
Subjective Ratings 
Depart from CRS 
Study Drug 
Placebo 8:00 a.m. 
Placebo 8:00 a.m 
 
Study Day 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Study Visit 
Three 
Four 
Five 
Six 
 
Seven 
Arrive at CRS 
ECG 
Procedure 
Morning Session 
Arrive at CRS 
Cocaine Self 
Administration 
Arrive at 
IDAS 
ECG 
Impulsivity 
Testing 
Arrive at 
IDAS 
 
ECG 
Arrive at CRS  
ECG 
10mg Cocaine for PK, 
Lorcaserin blood levels 
Cocaine Self 
Administration 
Procedure 
Afternoon Session 
Cocaine Self 
Administration 
Depart from 
CRS 
  
  
Three Doses of Cocaine  
(NexFin monitoring) 
Cardiovascular& 
Subjective Ratings 
Cardiac Biomarkers (4-
6 hrs from last dose) 
Depart from CRS 
Cocaine Self 
Administration 
Impulsivity Testing 
Depart from CRS 
Study Drug 
Placebo 8:00 
a.m., Lorcaserin 
10mg p.m. prior 
to departure  or 
Placebo 8:00 
a.m., Placebo 
p.m. prior to 
Placebo 8:00 
a.m., 
Lorcaserin 
10mg p.m. 
prior to 
departure  or 
Placebo 8:00 
Placebo 
8:00 a.m., 
Lorcaserin 
10mg p.m. 
prior to 
departure  
or Placebo 
Placebo 8:00 a.m., 
Lorcaserin 10mg p.m. 
prior to departure, or 
Placebo 8:00 a.m., 
placebo   p.m. prior to 
departure 
Placebo 8:00 a.m. 


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departure 
a.m., 
placebo p.m. 
prior to 
departure 
8:00 a.m., 
placebo 
p.m. prior 
to departure 
 
 


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Study Day 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Study Visit 
Eight 
Nine 
Ten 
Eleven 
Twelve 
Procedure 
Morning Session Arrive at 
IDAS 
ECG 
 
 Arrive at 
IDAS 
ECG 
 
Arrive at CRS 
ECG 
10mg Cocaine for 
PK, Lorcaserin blood 
levels 
Arrive at CRS 
ECG 
Cocaine Self 
Administration 
Arrive at IDAS 
ECG 
Impulsivity 
Testing 
 
Procedure 
Afternoon 
Session 
  
 
Three Doses of 
Cocaine (NexFin 
monitoring) 
Cardiovascular & 
Subjective Ratings 
Cardiac Biomarkers 
(4-6 hrs from last 
dose) 
Impulsivity Testing 
Depart from CRS 
Cocaine Self 
Administration 
 
Depart from CRS 
Physical exam 
Study Drug 
Lorcaserin 
10mg 8:00 
a.m., 
Lorcaserin 
10mg p.m. 
prior to 
departure. or 
Placebo 8:00 
a.m., placebo 
p.m. prior to 
departure 
Lorcaserin 
10mg 8:00 
a.m., 
Lorcaserin 
10mg p.m. 
prior to 
departure or 
Placebo 8:00 
a.m., placebo 
p.m. prior to 
departure 
Lorcaserin 10mg 
8:00 a.m., Lorcaserin 
10mg p.m. prior to 
departure or Placebo 
8:00 a.m., placebo 
p.m. prior to 
departure 
Lorcaserin 10mg 
8:00 a.m. or Placebo 
8:00 a.m.,  
  
 
Self-Administration Session (Days 3, 7, and 11)  
On days 3, 7, and 11, subjects participate in two self-administrative sessions and will make six choices for 
cocaine or $5. The first session will begin at 10 am and the second at 1 pm (see Table 3 below), with each 
session being 2.5 hours long.  
 
Table 3. Schedule of Cocaine Self Administration Procedure 
Time 
Choices 
8 patients 
8 patients 
10:00 am 
Baseline: VAS, BP/HR, EKG 
10:20 am 
Choice 1 
0 mg cocaine IV or $ 5 
25 mg cocaine IV or $ 5 
10:35 am 
Choice 2 
0 mg cocaine IV or $ 5 
25 mg cocaine IV or $ 5 


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10:50 am 
Choice 3 
0 mg cocaine IV or $ 5 
25 mg cocaine IV or $ 5 
11:05 am 
Choice 4 
0 mg cocaine IV or $ 5 
25 mg cocaine IV or $ 5 
11:20 am 
Choice 5 
0 mg cocaine IV or $ 5 
25 mg cocaine IV or $ 5 
11:35 am  
Choice 6 
0 mg cocaine IV or $ 5 
25 mg cocaine IV or $ 5 
 
 
 
 
1:00 pm 
Baseline: VAS, BP/HR, EKG 
1:20 pm 
Choice 1 
25 mg cocaine IV or $ 5 
0 mg cocaine IV or $ 5 
1:35 pm 
Choice 2 
25 mg cocaine IV or $ 5 
0 mg cocaine IV or $ 5 
1:50 pm 
Choice 3 
25 mg cocaine IV or $ 5 
0 mg cocaine IV or $ 5 
2:05 pm 
Choice 4 
25 mg cocaine IV or $ 5 
0 mg cocaine IV or $ 5 
2:20 pm 
Choice 5 
25 mg cocaine IV or $ 5 
0 mg cocaine IV or $ 5 
2:35 pm  
Choice 6 
25 mg cocaine IV or $ 5 
0 mg cocaine IV or $ 5 
 
In one session subjects will make six choices between 0 mg i.v. cocaine or money. During the other self-
administration session, subjects will make six choices between 25 mg i.v. cocaine or money. The dose of 
cocaine was chosen based on previous studies showing a significant medication effect on cocaine self-
administration (Hart et al, 2008). Sessions begin with a baseline period in which participants complete 
computerized subjective-effects questionnaires, and vital signs are monitored.  
The session begins with one “sample” choice, where participant respond on a keyboard under a fixed ratio 
schedule (FR200; participants are required to press the spacebar 200 times to receive the option). The 
subsequent five trials are spaced 15-min apart, in which participants had the opportunity to self-administer the 
same dose of cocaine as the sample dose, or to receive money. A modified progressive ratio of responding is 
used, in which the first response requirement is a FR200. Following each choice, the response requirement for 
the chosen option increases by 400, while the response requirement for the non-chosen option does not 
change. Thus, if a participant only chose cocaine or only chose money, the response requirements would 
escalate progressively through 600, 1,000, 1,400,1,800, and 2,200 bar presses (Haney et al, 2011).  
The subject would make a series of choices using the PR schedule between ascending value money 
options ($5) or cocaine (0 mg or 25 mg/i.v. infusion) using a patient controlled (PCA pump). Choices for money 
will be verbally indicated to the investigator. Infusions will be made over a 2 min period followed by a 13 min 
time-out period. Subjects will receive the cash or cocaine doses (0 or 25 mg) immediately after they meet the 
progressive ratio criteria for each choice, providing vital signs remain within the preset intervals. If the subject 
chooses all cocaine options in the cocaine choice session and no money, they will receive a maximum of 120 
mg cocaine, i.v. Money choices will be given directly to the patient after choice session, but this can only be 
spent after departing from the CRS. All infusions on this day will be double-blinded and counterbalanced in 
their presentation among subjects. 
 
Cardiovascular Monitoring During Cocaine Infusions and Cocaine Self-Administration Procedure 
Cardiovascular monitoring by continuous measuring heart rate/ECG and blood pressure starting 15 minutes 
prior to each of the 4 cocaine infusions and continued for at least 60 minutes following each dose. PI/Co-I or 
their medically qualified designees will be present during all cocaine infusions to monitor and intervene if 
necessary. For the sessions of cocaine infusions on Day 1, 2, 6, and 10, non-invasive monitoring of cardiac 
hemodynamics will be performed with the NexFin finger cuff system (Edwards Life Sciences). 
 
Criteria for withholding Cocaine Administration 
Cocaine administration will not be initiated if: 


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• 
Clinically significant arrhythmias 
• 
Resting pulse > 130 bpm 
• 
QTc increase of greater than 30ms over baseline  
• 
Blood pressure above 165mm Hg systolic and 100mm Hg diastolic. 
• 
Behavioral manifestations of cocaine toxicity (agitation, psychosis, inability to 
cooperate with study procedures). 
 
If cardiovascular measures have not returned to acceptable levels (heart rate 
<130 bpm, diastolic pressure <100mmHg, and systolic pressure <165 mmHg, QTc <30ms over baseline), the 
next session will be delayed by 15 min, after which these measures will be repeated. 
 
Stopping Criteria for Subject Participation 
Subject participation will be terminated if any of the following events occur: 
The following values do not return to acceptable limits within appropriate time frames 
(approximately 30 minutes); 
• Systolic BP > 180 mm Hg 
• Diastolic BP > 120 mm Hg 
• Heart rate > (220 – age x 0.85) bpm 
• QTc > 470ms 
• Participants must continue to meet other inclusion criteria in order to remain in the 
protocol  
 
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
Adverse Events 
Adverse Events (AEs) will be identified through daily interviews with participants and noted at any visit. The 
data will be entered on the standard VCU IRB AE and SAE forms. Continuous logs of all SAEs and AEs will 
be maintained. SAEs will be reported to the VCU IRB, the NIDA PO, the DSMB and the US FDA (when 
appropriate) as described above. In addition to immediate reports where appropriate, there will be annual 
reports and descriptions in the results section of publications. 
 
Table 4.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no 
medical intervention or therapy required. The subject may be 
aware of the sign or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy 
required, hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 


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AE Relationship to Study Drug 
The relationship of an AE to the study drug will be assessed using the following the guidelines in 5. 
Table 5.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from administration of the drug; that follows a known or 
expected response pattern to the suspected drug; that is confirmed by stopping 
or reducing the dosage of the drug; and that is not explained by any other 
reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to the suspected 
drug; that is confirmed by stopping or reducing the dosage of the drug; and 
that is unlikely to be explained by the known characteristics of the subject’s 
clinical state or by other interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to that suspected 
drug; but that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the 
study drug. 
Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 
• death 
• a life-threatening adverse experience 
• inpatient hospitalization or prolongation of existing hospitalization 
• a persistent or significant disability/incapacity 
• a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on appropriate medical judgment, 
they jeopardize the subject or require intervention to prevent one of the outcomes listed.  
 
 
Serious Adverse Experience Reporting 
All adverse events (AEs) occurring during the course of the study will be collected, documented, and reported 
to the PI. The occurrence of AEs will be assessed at baseline and each clinic visit during the treatment phase of 
the study.  
 
AE’s deemed to be serious (SAEs), as defined by the FDA, will be systematically evaluated at each clinic visit. 
Any SAE, whether or not related to study, will be reported to the VCU IRB, the NIDA Program Officer (Aidan 
Hampson, and the FDA (when appropriate) within 24-48 hours. A full written report to all institutions will 
follow as soon as possible but in no more than three days.  The written report will be in the format required by 
the local IRB and will contain information regarding the date of the SAE, description of the SAE, severity 
rating (Grade 1 to 4), assessment of cause, whether the SAE indicates an increased risk for current or future 
subjects, and whether changes to the informed consent form will be necessary.   
 


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In cases of early termination from the study due to SAE, the participant will have appropriate follow-up medical 
monitoring. Monitoring will continue until the problem has resolved or stabilized with no further change 
expected, is clearly unrelated to study medication, or results in death.  Outcome of SAEs will be periodically 
reported to NIDA. A summary of the SAEs that occurred during the previous year will be included in the annual 
progress report to NIDA. 
 
Medical Monitoring 
Dr. F. Gerard Moeller should be contacted directly at these numbers to report medical concerns or questions 
regarding safety. 
Phone: (804) 828-4134 
Pager: (804) 828-4999, pager 3479 
   
DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject, the investigator, or the Sponsor 
feels that it is not in the subject’s best interest to continue.  The following is a list of possible reasons for study 
treatment discontinuation:  
Subject withdrawal of consent (or assent) 
Subject is not compliant with study procedures 
Adverse event that in the opinion of the investigator would be in the best interest of the subject to discontinue 
study treatment 
Protocol violation requiring discontinuation of study treatment 
Lost to follow-up 
Sponsor request for early termination of study 
Positive pregnancy test (females) 
Chest discomfort or shortness of breath consistent with ischemia 
Systolic BP > 180 mmHg 
Diastolic BP > 110 mmHg 
Heart rate > Maximum predicted heart rate (> 220 – age x 0.85) bpm. 
If a subject is withdrawn from treatment due to an adverse event, the subject will be followed and treated by the 
Investigator until the abnormal parameter or symptom has resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early discontinuation visit as soon as 
possible and then should be encouraged to complete all remaining scheduled visits and procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified or unspecified, and 
without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals.  The reason 
for the subject’s withdrawal from the study will be specified in the subject’s source documents Refer to Section 
10 for early termination procedures. 
Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or the Sponsor feels that 
it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified or unspecified, and 
without prejudice. 


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Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals.  The reason 
for the subject’s withdrawal from the study will be specified in the subject’s source documents.   
Replacement of Subjects 
Subjects who withdraw from the study treatment will be replaced.   
Subjects who withdraw from the study will be replaced.   
 
Protocol Violations 
A protocol violation occurs when the subject, investigator, fails to adhere to significant protocol requirements 
affecting the inclusion, exclusion, subject safety and primary endpoint criteria.  Protocol violations for this 
study include, but are not limited to, the following: 
Failure to meet inclusion/exclusion criteria 
Use of a prohibited concomitant medication 
Failure to follow study procedures as described in the study protocol. 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol violation. The 
investigator will determine if a protocol violation will result in withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol Violation Form 
detailing the violation will be generated. A copy of the form will be filed in the site’s regulatory binder. 
 
DATA SAFETY MONITORING  
a. The Data Safety and Monitoring Board includes, Michael J. Lennon (M.D., Richmond VA Hospital), and 
Ananda Pandurangi (M.D., VCU school of Medicine), and John M. Hettema (M.D., Ph.D., VCU school of 
Medicine), Roshanak Markley, (M.D. Cardiology VCU school of Medicine), Brandon Willis (DO, Emergency 
medicine and toxicology VCU school of medicine), Spencer Hays, (statistician, VCU department of statistics). 
Members are individuals who are completely independent of the investigators and who have no financial, 
scientific, or other conflict of interest with the trial.  Each member will provide written documentation attesting 
to absence of conflict of interest.  
 
b.  Frequency of meetings 
The first meeting will take place face-to-face to discuss the protocol, any modifications of the trial, and to 
establish guidelines to monitor the study. The DSMB Chairperson and the PI will prepare the agenda to address 
the review of manual of operating procedures, modification of the study design, initiation of the trial, reporting 
of adverse events, stopping rules, interim analysis plan, etc.  
 
Meetings of the DSMB will be held at time points corresponding with annual progress reports.  Open DSMB 
meetings will be attended by the PI, co-investigators, and research staff member (as appropriate).  A closed 
DSMB session will be held at study completion and attendance will be limited to DSMB members and the PI.  
Meetings may be convened as conference calls as well as in person, although the initial meeting and meetings to 
discuss interim analysis will be face-to-face. An emergency meeting of the DSMB (open, closed, or executive 
session) may be called at any time by the Chairperson should questions of patient safety arise.  
 
Issues discussed at DSMB sessions will include conduct and progress of the study, patient accrual, compliance 
with protocol, and problems encountered. As patient-specific data and treatment group data may be presented at 
DSMB sessions, the discussion will be regarded as completely confidential.   
 


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c.  Conflict of interest 
All participating investigators and DSMB members will declare any conflicts of interest before the study is 
initiated, annually, and in the event of changing circumstances. Beyond this, the investigators are blind to the 
conditions and the PI does not make active decisions about assignment or subject care or participation. This 
separation of activities diminishes the risk of harm to either science or subjects due to conflicts of interest.  
 
d.  Protection of confidentiality 
All materials, discussions and proceedings of the DSMB are completely confidential. Members and other 
participants in DSMB meetings will be expected to maintain confidentiality.  
 
e.  Monitoring activities 
After initial review and approval of the project, the monitoring activities of the DSMB will be to evaluate the 
progress of the trial, including periodic assessments of data quality and timeliness, participant recruitment, 
accrual and retention, participant risk versus benefit, performance of the trial site, and other factors that can 
affect study outcome. 
 
f.  Communication plans to IRB, NIDA, and FDA 
The DSMB will make recommendations to the PI, who will then communicate the recommendations to the 
NIDA PO, and if necessary, to the FDA.  Recommendations of the DSMB will be sent to the IRB as well.   
 
 
STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will be written describing 
all analyses that will be performed.  The SAP will contain any modifications to the analysis plan described 
below.   
Data Sets Analyzed 
Initial analyses will evaluate group differences on demographic and baseline variables, will use contingency 
tables with chi-square testing, ANOVA’s, and examination of correlations between baseline variables subjective 
responses and clinical results. General data analysis procedures: Urn randomization will be used for gender to 
reduce any potential between-group differences (lorcaserin vs. placebo) on baseline variables. Prior to data 
analysis procedures, groups will be examined for differences in other baseline characteristics that could 
potentially influence treatment outcome. Any variables that differ between groups and are related to outcome 
measures will be examined as potential covariates in subsequent data analyses. 
Demographic and Baseline Characteristics 
Women, minorities, and children (18-21 years of age) will be included to the extent they are reflected in this 
non-treatment seeking population.  In our previous cocaine clinical trials, the percentage of females and males is 
approximately 30% and 70% respectively. We will continue recruitment efforts to achieve a 50-50 balance and 
thus permit meaningful analyses by sex across groups.  
 
The ethnic representation has been 55% Black, 44% White, 15% Hispanic, and <1% Asian in previous research 
by our group. Nevertheless, we are prepared to implement recruitment procedures to ensure a more diverse 
patient population.  These procedures include: 1) Targeted advertising in newspapers which serve minority 
communities (e.g., Hispanic or Latino communities). 2) Distribution of flyers and notices in neighborhoods 
known to have a high minority population. 3) Engaging in outreach activities on an ongoing basis, e.g., 


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contacting church and community leaders in the Hispanic communities to provide educational material about 
cocaine dependence and its consequences; providing contact information to aid in referrals to our clinic.  
 
Children as defined by NIH (age 18-21years) will be included in this research.  The incidence of severe cocaine 
abuse/dependence is relatively small in the population of youth less than 18 years old.  From a safety 
perspective, risks of exposure to the proposed study medication and cocaine administration in substance-
dependent children under 18 have not been established.   
Analysis of Primary Endpoint 
1. Safety: Heart rate (HR) and blood pressure (BP) measures during saline infusions will be compared to HR 
and BP after each cocaine infusion (20 mg and 40 mg doses).  Changes in HR and BP induced by cocaine 
infusion along with lorcaserin will be compared to those without lorcaserin, by cocaine dose level (20 mg and 
40 mg doses), using repeated measures analysis of variance (ANOVA). Changes in ECG readings during saline 
infusion as compared to those taken during cocaine infusions will be reported as summary statistics. Adverse 
event data will be compiled for lorcaserin and placebo cohorts and presented as summary statistics.  
2. Cocaine Self-administration: Repeated measures ANOVA with cocaine dose (0mg, 25mg) and lorcaserin 
dose (0mg, 10mg, 20mg) as within subject factors will be used to examine differences in mean cocaine choice 
selection. In addition, a Bayesian analysis will be carried out as described below. 
3. Subjective response to cocaine: Subjective response measures (VAS) obtained during saline infusions will be 
compared between lorcaserin and placebo subjects to those during cocaine infusions by cocaine dose level to 
determine the extent to which these measures are modified by the administration of lorcaserin using repeated 
measures ANOVA. 
4. Cocaine PK: Plasma concentration-time profiles of cocaine after cocaine infusion during placebo 
administration (Day 2) will be analyzed to obtain pharmacokinetic parameter estimates of cocaine (Tmax, AUC, 
apparent t½, CL) by individual. These parameters will be compared within subjects on sessions with lorcaserin 
(Day 6 and 10). 
Analysis of Secondary Endpoints 
Response inhibition: Commission errors on the IMT will be compared between lorcaserin and placebo subjects 
to determine the extent to which this measure is modified by the administration of lorcaserin using repeated 
measures ANOVA. 
Safety and tolerability data will be summarized by treatment group.   
Adverse event rates will be coded by body system and MedDra classification term.  Adverse events will be 
tabulated by treatment group and will include the number of patients for whom the event occurred, the rate of 
occurrence, and the severity and relationship to study drug.   
Interim Analysis 
When approximately 50% of patients have completed the study, an interim analysis for safety will be conducted 
by the DSMB. Serious adverse events will be monitored by the committee on an ongoing basis throughout the 
study. 
Sample Size and Randomization 
This project requires a final sample size of 18 subjects (Six subjects assigned to Group A (placebo) and 12 
subjects assigned to Group B (active lorcaserin). This sample size for effect of lorcaserin on cocaine self-
administration was based on previous research showing effects of medication on human cocaine self-
administration (Hart et al, 2008). In an effort to increase the power of the study, a Bayesian approach will also 
be utilized that incorporates information from previous studies.  This approach will use a Bayesian hierarchical 
model with subject at the lowest level of the hierarchy and treatment group at the second level.  This model is 
analogous to the repeated measures ANOVA except that prior information will be introduced.  Since many 
similar studies have been conducted with cocaine users and the same outcome measures we will assign an 


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informative prior distribution on the control group where the mean and standard deviation are educated guesses 
from the information provided in previous study of Hart et al. (2008).  For the treatment group we will assume a 
priori no change in the mean from the control group and the standard deviation are similar to those as the 
experimental group of the study by Hart et al. (Hart et al, 2008).  The model will be calculated using standard 
Markov Chain Monte Carlo (MCMC) packages such as WinBUGS, OpenBUGS, JAGS or MCMCpack in R.  
Because MCMC sampling techniques are being employed the quality of the samples from the posterior 
distribution will be checked using trace plots, effective sample size, potential scale reduction factor and 
Hellinger distances (for more on Bayesian analyses and MCMC sampling see (Gelman et al, 2013). As 
necessary techniques such as discarding burn-in samples, thinning and over-disperse starting points will be 
employed in order to obtain a set of samples from the posterior distribution that have an effective sample size of 
10,000 on all parameters.  All inferences will be made from this set of samples from the posterior distribution. 
 
To calculate the power for the acute effects of the study three analyses are considered using the paired 
differences of subjects at baseline and acute time points.  A two-sample test on the means is performed using: 
Wilcoxon test (non-parametric), T-test (parametric) and a Bayesian (parametric) approach.  While from a 
Bayesian paradigm the notion of power does not exist in the traditional sense, one can create a decision rule and 
loss function in such a way that the associated risk is analogous to the notion of power.  To understand the 
power of each of the methods a Monte Carlo study was performed utilizing 1,000 separate datasets for likely 
effect sizes and sample sizes.  The power was calculated as the proportion of datasets in which the test 
“rejected” the null hypothesis.  The table below gives the power for each test across percent change in effect 
size and control group sample sizes, here the treatment group sample size was n2 = 12. Based on the table at 
left, an n of 6 was chosen as the sample size for the placebo group. 
 
DATA COLLECTION, RETENTION AND MONITORING 
Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents designed to record all 
observations and other pertinent data for each subject treated with the study drug.   
Study personnel at each site will enter data from source documents corresponding to a subject’s visit into the 
protocol-specific paper CRF when the information corresponding to that visit is available.  Subjects will not be 
identified by name in the study database or on any study documents to be collected by the Sponsor (or 
designee), but will be identified by a subject number. 
The Investigator is responsible for all information collected on subjects enrolled in this study.  All data collected 
during the course of this study must be reviewed and verified for completeness and accuracy by the 
Investigator.  
Data Management Procedures 


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The data will be entered into a REDCap database.  The Data Management group will be responsible for data 
processing, in accordance with procedural documentation.  Database lock will occur once quality assurance 
procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good computing practices meeting 
FDA guidelines for the handling and analysis of data for clinical trials. 
Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation checks will be 
implemented and applied to the database on a regular basis. The study database will be updated in accordance 
with the resolved queries.  All changes to the study database will be documented. 
Archival of Data 
The database is safeguarded against unauthorized access by established security procedures; appropriate backup 
copies of the database and related software files will be maintained.  Databases are backed up by the database 
administrator in conjunction with any updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final reports), data for analysis is 
locked and cleaned per established procedures. 
Availability and Retention of Investigational Records 
The Investigator will make study data accessible to IRB, and Regulatory Agency (e.g., FDA) inspectors upon 
request.  A file for each subject must be maintained that includes the signed Informed Consent, HIPAA 
Authorization and Assent Form and copies of all source documentation related to that subject.  The Investigator 
will ensure the reliability and availability of source documents from which the information on the CRF was 
derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study File Notebook, etc.) 
will be kept secured for a period of six years after study completion and the IND has been discontinued.   
Subject Confidentiality 
In order to maintain subject confidentiality, only a subject number will identify all study subjects on CRFs and 
other documentation submitted to the Sponsor.  In addition, a Certificate of Confidentiality will be obtained 
from NIDA to protect subject confidentiality. 
 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human Volunteers (21 CFR 
50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records will be 
identified by a coded number and initials only.  All study records will be kept in a locked file cabinet and code 
sheets linking a patient’s name to a patient identification number will be stored separately in another locked file 
cabinet.  Clinical information will not be released without written permission of the subject, except as necessary 
for monitoring by the FDA.  The Investigator must also comply with all applicable privacy regulations (e.g., 
Health Insurance Portability and Accountability Act of 1996, EU Data Protection Directive 95/46/EC). 
Protocol Amendments 
Any amendment to the protocol will be written by the investigator  Protocol amendments cannot be 
implemented without prior written IRB approval except as necessary to eliminate immediate safety hazards to 
patients.  A protocol amendment intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately, provided the IRBs are notified within five working days. 
Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the VCU IRB prior to study initiation.  
Serious adverse experiences regardless of causality will be reported to the IRB in accordance with the standard 


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operating procedures and policies of the IRB, and the Investigator will keep the IRB informed as to the progress 
of the study.  The Investigator will obtain assurance of IRB compliance with regulations. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol amendments, 
Investigator’s Brochure, consent forms, information concerning patient recruitment, payment or compensation 
procedures, or other pertinent information) will be submitted to the IRB.  The IRBs written unconditional 
approval of the study protocol and the informed consent form will be in the possession of the Investigator 
before the study is initiated.   
Protocol and/or informed consent modifications or changes may not be initiated without prior written IRB 
approval except when necessary to eliminate immediate hazards to the patients or when the change(s) involves 
only logistical or administrative aspects of the study.  Such modifications will be submitted to the IRB and 
written verification that the modification was submitted and subsequently approved should be obtained.   
The IRB must be informed of revisions to other documents originally submitted for review; serious and/or 
unexpected adverse experiences occurring during the study in accordance with the standard operating 
procedures and policies of the IRB; new information that may affect adversely the safety of the patients of the 
conduct of the study; an annual update and/or request for re-approval; and when the study has been completed. 
Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US Code of 
Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, and CFR Part 56, 
Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, if applicable), and local 
regulations. 
The Investigator will prepare the informed consent form and HIPAA authorization. The written consent 
document will embody the elements of informed consent as described in the International Conference on 
Harmonization and will also comply with local regulations.  
A properly executed, written, informed consent will be obtained from each subject prior to entering the subject 
into the trial.  Information should be given in both oral and written form and subjects must be given ample 
opportunity to inquire about details of the study. A copy of the signed consent form will be given to the subject 
and the original will be maintained with the subject’s records. 
Publications  
The publication or presentation of any study results shall comply with all applicable privacy laws, including, but 
not limited to, the Health Insurance Portability and Accountability Act of 1996.  
 
 
References: 
Baker, J.R., Jatlow, P., McCance-Katz, E.F., 2007. Disulfiram effects on responses to intravenous cocaine 
administration. Drug Alcohol Depend 87, 202-209. 
Cunningham, K.A., Fox, R.G., Anastasio, N.C., Bubar, M.J., Stutz, S.J., Moeller, F.G., Gilbertson, S.R., 
Rosenzweig-Lipson, S., 2011. Selective serotonin 5-HT(2C) receptor activation suppresses the reinforcing 
efficacy of cocaine and sucrose but differentially affects the incentive-salience value of cocaine- vs. sucrose-
associated cues. Neuropharmacology. 
Gaggin, H.K., Januzzi, J.L., Jr., 2014. Natriuretic peptides in heart failure and acute coronary syndrome. Clinics 
in laboratory medicine 34, 43-58, vi. 
Gelman, A., Carlin, J., Stern, H., Dunson, D.B., Vehtari, A., Rubin, D.B., 2013. Bayesian Data Analysis, Third 
Edition. Chapman and Hall/CRC, Boca Raton, Florida. 
Gualandro, D.M., Puelacher, C., Mueller, C., 2014. High-sensitivity cardiac troponin in acute conditions. 
Current opinion in critical care 20, 472-477. 


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Hart, C.L., Haney, M., Vosburg, S.K., Rubin, E., Foltin, R.W., 2008. Smoked cocaine self-administration is 
decreased by modafinil. Neuropsychopharmacology 33, 761-768. 
Hutcheson, J.D., Setola, V., Roth, B.L., Merryman, W.D., 2011. Serotonin receptors and heart valve disease--it 
was meant 2B. Pharmacol Ther 132, 146-157. 
Manvich, D.F., Kimmel, H.L., Howell, L.L., 2012. Effects of serotonin 2C receptor agonists on the behavioral 
and neurochemical effects of cocaine in squirrel monkeys. J Pharmacol Exp Ther 341, 424-434. 
Moeller, F.G., Schmitz, J.M., Steinberg, J.L., Green, C.M., Reist, C., Lai, L.Y., Swann, A.C., Grabowski, J., 
2007. Citalopram combined with behavioral therapy reduces cocaine use: a double-blind, placebo-controlled 
trial. American Journal of Drug and Alcohol Abuse 33, 367-378. 
Shram, M.J., Schoedel, K.A., Bartlett, C., Shazer, R.L., Anderson, C.M., Sellers, E.M., 2011. Evaluation of the 
abuse potential of lorcaserin, a serotonin 2C (5-HT2C) receptor agonist, in recreational polydrug users. Clin 
Pharmacol Ther 89, 683-692. 
 


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APPENDIX 1.  DETAILED TIMELINE OF MEASURES 
 
Screening 
Day 
Study Day 
 
Follow-
up 
Procedure 
-90 to 0 
1 
2 3 4 5 
6 
7 
8 
9 
10 
11 
12 
15, 19 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
Chemistry 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Hematology 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
History, 
Physical 
Exam, and 
Neurological 
Exam 
X 
X 
X  
 
 
 
 
 
 
 
X 
 
 
Urine 
Pregnancy 
test 
(females) 
X 
X 
X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Psychiatric 
Interview 
(SCID) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kreek-
McHugh-
Schluger-
Kellogg 
scale 
(KMSK) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fagerstrom 
Test for 
Nicotine 
Dependence 
(FTND) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
National 
Adult 
Reading Test 
(NART) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Addiction 
Severity 
Index (ASI-
lite) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Brief 
Substance 
Craving 
Scale 
X 
X 
X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Timeline 
Follow Back 
Cocaine Use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Drug Use 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical 
Opiate 
Withdrawal 
Scale 
(COWS) 
X 
X 
X X X X 
X 
X 
X 
X 
X 
X 
X 
 
Urine drug 
screen 
X 
X 
X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Breathalyzer 
X 
X 
X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Verify 
Inclusion & 
Exclusion 
X 
X 
X  
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead 
ECG 
(baseline 
triplicate) 
and singlet 
thereafter) 
X 
X 
X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Continuous 
Cardiovascul
ar 
Monitoring 
 
X 
X X  
 
X 
 
 
X 
 
 
X 
 
Brief 
Physical 
Exam 
 
X 
X X  
 
 
 
X 
 
 
 
X 
X (Day 
19 only) 
Cocaine 
Administrati
on for 3 
Doses 
 
X 
X  
 
 
X 
 
 
 
X 
 
 
 


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Adverse 
Events 
Inventory 
 
X 
X X X X 
X 
X 
X 
X 
X 
X 
X 
 
Visual 
Analog 
Scale (VAS) 
 
X 
X X  
 
X 
X 
 
 
X 
X 
 
 
Profile of 
Mood States 
(POMS) 
X 
X 
X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical 
Global 
Impression 
Severity & 
Improvemen
t (CGI-S&I) 
( baseline 
CGI-S, and 
CGI-I 
thereafter) 
X 
X 
X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Columbia 
Suicide 
Severity 
Rating Scale 
(C-SSRS) 
(Lifetime 
version at 
screening 
and since 
last visit 
version 
thereafter) 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
Cocaine for 
PK 
 
 
X  
 
 
X 
 
 
 
X 
 
 
 
Lorcaserin 
PK 
measurement 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Cardiac 
biomarkers 
(baseline and 
4-6 hours 
after last 
dose) 
 
 
X  
 
 
X 
 
 
 
X 
 
 
 


Protocol Number 
Confidential 
 
Version #: 7 
Version Date 08/02/17 
Page 47 of 48 
 
Lorcaserin 
or Placebo 
 
X 
X X X X 
X 
X 
X 
X 
X 
 
 
 
Cocaine 
Self-
administratio
n 
 
 
 
X  
 
 
X 
 
 
 
X 
 
 
Immediate 
Memory 
Task (IMT) 
 
X 
 
 
X  
 
X 
 
 
X 
 
 
 
Stroop 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
XY Go-
NoGo 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 


Protocol Number 
Confidential 
 
Version #: 7 
Version Date 08/02/17 
Page 48 of 48