Clinical trial NCT03637842
Conditions: Cannabis Use Disorder
Keywords: cannabis impulsivity
Sponsor: New York State Psychiatric Institute
Start date: 2019-08-01; Completion date: 2020-02-29
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study is to investigate the effect of lorcaserin on reductions in cannabis use and multiple constructs of impulsivity in outpatient treatment-seeking individuals with cannabis use disorder (CUD). Additionally, the investigators will make use of the technological application of ecological momentary assessments (EMA), to collect real-time data at key time intervals during the study on participants' use of cannabis and other substances in addition to measuring impulsive traits through self-initiated, fixed and random phone prompts. This will be a 13-week randomized, double-blind, placebo-controlled trial, with week 1 focused on baseline assessments of impulsivity (through EMA in vivo and at study visits), weeks 2- 3 of medication lead-in, and week 4 targeting a reduced cannabis use/quit day through week 13. The primary aims are to (1) Examine the effect of lorcaserin compared to placebo, on reductions in cannabis use among treatment-seeking outpatients with CUD, (2) Examine the effect of lorcaserin compared to placebo on behavioral and self-report measures of impulsivity among individuals with CUD during the medication lead-in phase (weeks 2-3). The secondary aim is to examine whether reductions in impulsivity (during weeks 2-3) mediates the effect of lorcaserin on cannabis use (during weeks 8-13), if the primary hypotheses are supported. Finally, the investigators will explore the effect of lorcaserin compared to placebo on (1) drop-out rates, (2) time to discontinuation from study, (3) treatment adherence, and (4) nicotine use.

Detailed description:
Cannabis use disorder (CUD) is a major public health problem associated with significant psychiatric and medical morbidity, poor performance, and legal consequences.4 4.2 million people in the United States meet criteria for CUD.5 15% of all admissions for substance abuse treatment were related to cannabis as the primary, presenting problem in 2014 and 86% of those admissions were referred for ambulatory care.6 Despite the large number of patients with CUD seeking outpatient treatment, the investigators have limited options available. While evidence-based practices (EBP), and specifically psychotherapies, have been studied to treat CUD and various approaches have been shown to have clinical utility,7-9 many patients have difficulty achieving significant reductions in their use or sustained abstinence.10 This is further complicated by patients' limited access to EBPs,11 frequent poor adherence by therapists in the community to EBP interventions,12-14 and challenges in treating CUD with EBPs when available in community settings.10 Finding effective medications for the treatment of CUD is essential. There are no FDA approved medications for CUD. A number of pharmacological treatment trials for CUD have been performed.1\* While some agents have shown promise,15-17 no medication strategy has emerged as clearly efficacious in producing abstinence.1,18 As the changing legal landscape influences patients' goals for reductions in cannabis use as compared to abstinence only, and with increasing support from the research community, future studies need to identify medications that lead to reductions in cannabis use.

Impulsivity has been linked to the predisposition,19 severity,20 and poor treatment outcomes21, 22 in cannabis users and CUD, making it a prime pharmacology target. Notably, there is an entwined relationship between cannabis and impulsivity. Impulsivity as a neurobehavioral trait is associated with cannabis use,and acute and chronic use of cannabis has been shown to exacerbate impulsivity, with some mixed evidence likely attributable to diverse constructs of impulsivity used across studies. While the investigators may not be able to fully determine which came first-the impulsivity or the cannabis use, further research is needed to demonstrate whether reductions across constructs of impulsivity can lead to improvements in CUD, and vice versa. Over the last two decades, 5HT2C receptor agonists have been shown to alter neurobiological systems of addiction and relevant drug use behavior in the preclinical literature by increasing inhibitory control on mesolimibic dopamine processes and resultant incentive motivation based behaviors,23 both directly and indirectly, particularly with regards to their impact on reducing impulsivity.24 In 2012, lorcaserin, a selective 5HT2C receptor agonist, was approved by the FDA, allowing for clinical exploration of its role in the treatment of substance use disorders, including CUD.25 Recently, a fully powered clinical trial of lorcaserin for tobacco smoking cessation was positive.26 The primary purpose of this study is therefore to investigate the effect of lorcaserin on reductions in cannabis use and multiple constructs of impulsivity in outpatient treatment-seeking individuals with CUD.

Additionally, the investigators will make use of the technological application of ecological momentary assessments (EMA), to collect real-time data at key time intervals during the study on participants' use of cannabis and other substances in addition to measuring impulsive traits through self-initiated, fixed and random phone prompts. This will be a 13-week randomized, double-blind, placebo-controlled trial, with week 1 focused on baseline assessments of impulsivity (through EMA in vivo and at study visits), weeks 2-3 of medication lead-in, and week 4 targeting a reduced cannabis use/quit day through week 13. This "proof of concept" study will provide Dr. Brezing with training in randomized controlled trial operations, multiple constructs to measure impulsivity, utilization of technology as a measurement tool, and identification of outcomes that may prove important to reductions in cannabis use.

Primary Aims:

(Aim 1) Examine the effect of lorcaserin compared to placebo, on reductions in cannabis use among treatment-seeking outpatients with CUD, with the primary outcome measured by average weekly mean episodes of any cannabis use (including edibles, vaping, and other variable potency cannabinoid products) per day. (Aim 2) Examine the effect of lorcaserin compared to placebo on behavioral and self-report measures of impulsivity among individuals with CUD during the medication lead-in phase (weeks 2-3).

Secondary Aim: If the hypotheses of the Primary Aims are supported, the investigators will examine whether reductions in impulsivity (during weeks 2-3) mediates the effect of lorcaserin on cannabis use (during weeks 8-13).

Exploratory Aims: To explore the effect of lorcaserin compared to placebo on (1) drop-out rates, (2) time to discontinuation from study, (3) treatment adherence, and (4) nicotine use.

Arms: arm 1: Lorcaserin XR 20mg daily arm 2: Placebo Oral Capsule
Interventions: intervention 1: Lorcaserin intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: Lorcaserin XR 20mg per day intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
Study: #7662 “A randomized controlled trial of Lorcaserin for Cannabis Use Disorder” 
 
PI: Christina Brezing, MD 
NCT# NCT03637842 
Protocol approved: 9-21-2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

























































SAP_001.pdf: 
Study: #7662 “A randomized controlled trial of Lorcaserin for Cannabis Use Disorder”  
PI: Christina Brezing, MD  
NCT# NCT03637842 
SAP originally created: 11‐07‐2017 as part of grant submission. 
SAP unchanged and approved 9/21/2018 when protocol approved. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Data Analysis:  
Outcome measures: Primary Cannabis Outcomes: (1) Weekly average dollar value of cannabis use per 
day (continuous; longitudinal,); Secondary Cannabis Outcomes: (1) number of days of abstinence per 
week (continuous; longitudinal); (2) Weekly THC‐COOH urine levels (continuous; longitudinal). Primary 
lmpulsivity Outcomes: (1) Premature responses on the 4‐CSRTT (continuous, longitudinal); Secondary 
lmpulsivity Outcomes: (1) changes in calculated k values from the Monetary Choice Questionnaire 
(continuous, longitudinal); (2) number of beads drawn prior to decision for the Beads Task (continuous, 
longitudinal); (3) top Signal Reaction Time (SSRT) from the Stop Signal Task (continuous, longitudinal); 
(4) Total and subscale scores on the UPPS‐P (continuous, longitudinal); (5) daily BIS‐7 report through 
EMA (continuous, longitudinal). Exploratory Outcomes: Drop‐out rates, time to discontinuation of study, 
FTND total scores, self‐report of missed doses of medication, % response completed of EMA, and study 
visits attended. Covariates: Demographics (including age, gender) and baseline cannabis use measured 
by dollar amount of cannabis pen using day at baseline. Sample size and randomization: 60 participants 
will be randomly allocated (1 :1) to receive either lorcaserin or placebo, using random block sizes of 4, 6, 
and 8, stratified by baseline severity of cannabis use (dichotomized by dollars spent per day >$10) as we 
have previously done in CUD treatment trials. Intent to Treat/Drop outs and missing data: The primary 
analyses will be on the intent‐to‐treat (ITT) sample of all randomized participants. Those participants will 
be included in the ITT analysis of primary and secondary outcomes. Significance testing and preliminary 
analyses: Tests for main effects will be performed at a two‐tailed significance a=0.05. We will examine 
all variables for outliers before performing analyses. The distributions for all continuous variables will be 
checked for normality, and transformations will be employed, if necessary, before applying specific 
parametric techniques. The distribution of demographic variables and measures of symptomatology at 
baseline will be examined and described in terms of means, standard deviations, proportions and 95% 
confidence intervals. We will examine the associations between key baseline variables (demographics, 
cannabis use severity) and the primary outcome measures. Baseline variables strongly associated with 
outcome will be included as covariates in models used to test the study hypotheses. We will also explore 
effect moderation; i.e., baseline covariate by treatment interactions.  
Hypotheses:  
Primary hypotheses:  
Aim 1 hypothesis: Lorcaserin will show greater reductions in (1) dollars and (2) the number of abstinent 
days of cannabis use reported by TLFB and (3) reductions in THC‐COOH urine levels as compared to 
placebo. The following longitudinal mixed effects model will be used:  
(1) Yijt = β0 + β1li + β2t + β3t*li + β4Uii + Si + Eijt 
where Yiit is the daily amount of cannabis used (either (1) dollar value, (2) number of abstinent days, or 
(3) ifHC‐COOH urine level averaged over a one‐week period) by the i1h subject in the treatment group j 
at week t (t=2, ... 13); Ui is the vector of covariates; Ii is the indicator variable for treatment with 
lorcaserin; si is a random intercept for subject i and Eiit is a random error term. Significant interaction 
t*li indicates that the effect of each treatment group is different over time (that corresponds to 
rejecting the null hypothesis that β3=0). If so, the effect of time will be estimated for each group 


separately and the groups will be compared (using contrast) at the last time point t=13. If the interaction 
term is not significant, we will refit the model without the interaction term and test the main effect of 
treatment.  
Aim 2 hypothesis: During the medication lead‐in (weeks 2‐3), lorcaserin will significantly reduce action 
impulsivity (4‐CSRTT premature responding and SSRT), choice impulsivity (MCQ calculated k values and# 
of beads drawn), and UPPS‐P scores and self‐report on BIS‐7 through EMA as compared to placebo.  
For all impulsivity measures collected at study visits, a similar model as used to test Aim 1 will be used.  
Secondary hypothesis:  
Reductions in impulsivity will mediate the effects of lorcaserin on cannabis use. If lorcaserin is shown to 
reduce different constructs of impulsivity, then these measures will be evaluated as potential mediators 
through the Baron and Kenny mediation framework for their effects on cannabis use outcomes.  
Exploratory hypotheses: The effect of lorcarserin as compared to placebo on the proportion of 
participants who drop out will be explored using a Chi‐square test. Time to discontinuation between 
treatment groups will be examined using survival analysis and Cox models. The effects of lorcaserin on 
treatment adherence and nicotine use will be examined using regression analysis and longitudinal mixed 
effects models, respectively.  
Power: The primary purpose of this proposed study is to estimate effect size of lorcaserin on cannabis 
use. This will be done using 95% confidence interval methodology. The resulting 95% confidence interval 
provides considerably more information than testing a specific null hypothesis: it gives a range of 
plausible parameter estimates for the difference of cannabis use between the placebo and lorcaserin 
groups. Such range of plausible effect sizes can be used to estimate the potential effect size in larger 
clinical trials. The following power calculations are only in support of the study proposal and for the 
purpose of sample size calculation. With 30 participants per group the study prrovides 80% Rower to 
detect significant effect size = .74 or larger.