FDA alert regarding study drug safety

This project is a placebo-controlled, double-blind randomized trial evaluating the feasibility, tolerability, acceptability and adherence for lorcaserin among actively using, men who have sex with men (MSM) with cocaine use disorders.The study will enroll 45 individuals who will randomly be assigned to either the treatment (lorcaserin) arm or the placebo arm, to be taken twice a day for 12 weeks.

This is a randomized, double-blind, placebo-controlled, 12-week parallel group pilot study with 2:1 random assignment to 20 mg of extended-release oral lorcaserin versus placebo. Participants are recruited via street outreach, recruitment flyers, sexually transmitted diseases (STD) and HIV clinics, needle exchanges, community organizations, MSM bars, online Web sites, and social media. Potential participants complete a brief telephone screen to assess initial eligibility and, if eligible, are scheduled for an in-person screening visit. All participants give informed consent using University of California at San Francisco (UCSF) Institutional Review Board (IRB)-approved consent forms. A 10-item true/false questionnaire is used to verify participants' understanding of the trial. The target sample size for the study was 45 participants (The Food and Drug Administration (FDA) closed down the study early due to a long-term safety study showing that long term use of lorcaserin could be hazardous to your health). Only 22 of the 45 participants were randomized to the study.

With the proposed sample size, we estimate that proportions for our feasibility and acceptability outcomes would be estimated within margins of sampling error (Mean squared error (MSEs); i.e., half widths of 95% confidence intervals) of ≤14.4 percentage points, and means with MSEs of 0.30 standard deviations, both typical for a small pilot study.

Participants are screened for eligibility based on inclusion criteria. At Enrollment, participants are instructed to take one pill each day of extended-release lorcaserin 20mg or placebo. Medications are dispensed in bottles with Medication Events Monitoring (MEMS) caps, which are wireless medication monitoring devices that record each opening as a real-time medication event. All participants are asked about potential adverse events at each follow-up visit; symptom-driven physical exams and safety laboratory monitoring are done at weeks 4, 8, and 12. Adverse events are classified using the Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences for HIV Prevention Trials Network. Participants are seen every week for substance use counseling and urine tests for cocaine metabolites. Trained staff, supervised by a clinical psychologist, administered brief (20-30 minutes) substance use counseling at follow-up visits. Audio-computer assisted self-interviews (ACASI) are used to standardize data collection and minimize reporting bias. Standardized measures are used to assess drug and alcohol use using timeline followback, substance use treatment, craving and severity of cocaine dependence, and sexual risk behavior. Acceptability measures include questions on attitudes about trial participation, level of satisfaction with trial procedures, and trial medication.

Inclusion Criteria:

• Male gender assigned at birth and transgender men;
• self-reported anal intercourse with men in the prior six months while under the influence of cocaine;
• cocaine use disorder by (Diagnostic and Statistical Manual of Mental Health Disorders (DSM-V) and Structured clinical interviews (SCID) criteria;
• current cocaine use confirmed by urinalysis and cocaine use at least 15 days in the past 30 days;
• HIV-negative by rapid test or HIV-positive with a medical record of HIV infection;
• no current acute illnesses requiring prolonged medical care;
• no chronic illnesses that are likely to progress clinically during trial;
• able and willing to provide informed consent and adhere to visit schedule;
• age 18-65 years;
• baseline complete blood count (CBC), total protein, albumin, glucose, alkaline phosphatase, creatinine, Blood Urea Nitrogen (BUN), and electrolytes without clinically significant abnormalities as determined by study clinician in conjunction with symptoms, physical exam, and medical history

Exclusion Criteria:

• Any psychiatric condition (e.g., depression with suicidal ideation, schizophrenia) or medical condition that would preclude safe study participation;
• HIV-positive test result at screening visit but previously unaware of HIV infection (i.e., newly diagnosed with HIV infection at screening; those with a medical record of HIV infection are eligible);
• any moderate to severe alcohol or substance use disorders (other than cocaine use disorders), according to DSM-V criteria;
• known allergy or previous adverse reaction to lorcaserin;
• current T-cell count (CD4) count < 200 cells/mm3 ;
• moderate/sever liver disease (Aspartate Transferase (AST), Alanine Transaminase (ALT) > 3 times upper limit or normal);
• severely impaired renal function (creatinine clearance £ 30 ml/min);
• use of medications that affect the serotonergic neurotransmitter system (e.g., selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs));
• predisposition to priapism;
• currently participating in another longitudinal intervention research study;
• body mass index (BMI) < 15; or ≥ 30 with desire to use weight management medication, or BMI > 35;
• anticipated use of agents that are associated with valvulopathy and/or pulmonary hypertension
• Are currently treated with an opiate-substitute (buprenorphine or methadone) maintenance treatment or received therapy with any opiate-substitute within 30 days preceding screening
• Currently in court-mandated cocaine use treatment;
• Had previous history of suicidal behavior in the last 12 months ("yes" answer to the suicidal behavior question 6 of the Columbia-Suicide Severity Rating Scale (C-SSRS)); or currently have suicidal ideation as determined by 'yes' answers to questions 4 or 5 on the C-SSRS administered by a study clinician;
• Any physical condition affecting drug absorption (e.g., gastrectomy);
• 12-lead Electrocardiogram (ECG) demonstrating Corrected QT interval (QTc) > 450 or a Q wave, R wave and S wave (QRS) interval > 120 msec at screening. If Fridericia (QTcF) exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated two more times and the average of the three QTc values should be used to determine the subject's eligibility.

(Note: Participants newly diagnosed with HIV at screening who consent to be contacted for re-screening will be called in the subsequent month, or later, depending on participant preference).

Treatment and control assignments

After baseline, Adverse event data were collected weekly over the 12 week period of the study.

The study was terminated early by the FDA due to the publication of a long-term safety study that showed an increase risk for cancer by the lorcaserin arm.