Trial Of NS2359 For The Treatment of Cocaine Dependence

A Phase II, Double-Blind, Placebo-Controlled, Trial Of NS2359 For The Treatment of Cocaine Dependence

NS2359 attenuates the euphoria associated with cocaine use. In a manner parallel to cocaine, NS2359 blocks the reuptake of dopamine (DA), norepinephrine (NE), and serotonin (5HT) with nanomolar affinities at the 3 transporters. In primates NS2359 significantly attenuated cocaine self-administration. In several phase II clinical trials for major depressive disorder and adult attention deficit disorder, NS2359 did not cause euphoria. NS2359 exhibited no abuse potential in a human laboratory study comparing NS2359 with amphetamine. In a phase I human laboratory interaction study, NS2359 showed no toxicity after 20 or 40 mg of cocaine, but it attenuated the both the rewarding and cardiovascular effects of intravenous cocaine. On the basis of these promising studies, investigators propose a Phase II double-blind clinical trial of NS2359 in cocaine addiction (CA). The proposed trial will involve 100 CA subjects participating in an eight week trial, including a 1-week baseline and 8 weeks of NS2359 or placebo treatment. Four weeks after completing the medication phase, there will be one follow-up visit. Subjects will be randomly assigned to treatment with placebo or 2 mg NS2359 daily, with a possible decrease to 1 mg daily for adverse events. This dose range is selected on the basis of phase I and II evidence of tolerability and NS2359 plasma levels which were associated with blockade of cocaine reward. This project has the potential to identify the first effective pharmacotherapy for CA.

Study Overview

• Status: Completed
• Conditions: Cocaine Use Disorder
• Intervention / Treatment: Drug: NS2359; Drug: placebo

Detailed Description

In this phase II randomized double-blind, placebo-controlled trial, 40 persons will be randomized to NS2359 and 40 to placebo. The primary hypothesis is: more NS2359-treated subjects (compared to placebo-treated subjects) will achieve 3 consecutive weeks of cocaine abstinence, as measured by urine benzoylecgonine (BE) assay, during the last three weeks of the trial. The study is 9 weeks: one week of screening, followed by an 8-week double-blind, placebo-controlled trial. All subjects will receive weekly cognitive behavioral therapy (CBT) to encourage abstinence during their 3 times weekly clinic visits. Investigators expect ~ 20% dropout rate, based on our recent CA clinical trials (eg, Kampman et al, 2015 and 2013), so 80 randomized patients will yield ~ 64 study completers. There will be a 1 month start-up period, followed by 20 months of recruitment for the study. The 1 month start-up period will allow for training of staff, preparation of study capsules, placement of study advertisements, etc. Penn IRB approval has been obtained. There will be a 2-month termination period to allow the final patients to complete the study. Data cleaning, statistical analyses and preparation of reports will be done in the final two months. Based on recent cocaine pharmacotherapy trials conducted by our team, monthly enrollment of ~4 CA participants (respondents to flyers and advertisements) is feasible.

Recruitment will occur at the University of Pennsylvania's Treatment Research Center (TRC), led by Kyle Kampman, MD, and Wade Berrettini, MD, PhD, Professors of Psychiatry at Penn. At the TRC, CA patients are respondents to advertisements for free treatment of CA. The ethnicity is 90% African-American, 9 % European-American, 70% male, mean age 47 (+/- 12).

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male and females, 18-65 years old.
2. Meets diagnostic criteria (DSM-V) for current diagnosis of cocaine use disorder, moderate to severe, by semi-structured interview.
3. In the past 30 days, used no less than $100-worth of cocaine
4. Speaks, understands, and prints in English.

Exclusion Criteria:

1. Meets DSM-V criteria for substance use disorder, moderate to severe, for a substance other than cocaine, alcohol or nicotine. Subjects with comorbid alcohol use disorder will be accepted if their alcohol use disorder is not severe enough to require a medical alcohol detoxification.
2. Needs treatment with any psychoactive medications (with the exception of diphenhydramine or melatonin, if necessary, for sleep).
3. Meets current or lifetime DSM-V criteria for schizophrenia or any psychotic disorder, or organic mental disorder.
4. Has another Axis I psychiatric disorder that in the opinion of the physician will interfere with completion of the study or place the patient at heightened risk through participation in the trial.
5. Has evidence of a history of significant hematological, pulmonary, endocrine, cardiovascular, renal or gastrointestinal disease.
6. Use of an investigational medication in the 30 days prior to randomization.

7. Is female and has a positive pregnancy test, is contemplating pregnancy in the next 6 months, is nursing, or is not using effective contraception (if relevant).

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Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NS2359; The initial dose of the NS2359 will be two mg once daily. Patients with difficult adverse events at the 2 mg dose will be allowed to reduce to 1 mg once daily. Subjects will participate in weekly cognitive behavioral relapse prevention psychotherapy from week 2 through week 9.	Drug: NS2359; NS2359 is a small molecule which inhibits the reuptake of dopamine, norepinephrine and serotonin with equal affinity.
Placebo Comparator: placebo; Placebo pills matched to NS2359 pills will be given once daily. Patients with difficult adverse events at the 2 mg placebo will be allowed to reduce to 1 mg placebo once daily. Subjects will participate in weekly cognitive behavioral relapse prevention psychotherapy from week 2 through week 9.	Drug: placebo; Placebo pills identical in appearance to the NS2359 will be provided

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Number of Participants Who Achieved Abstinence From Cocaine During the Last Three Weeks of the Trial	Number of Participants Who Report no Cocaine Use and Have no Cocaine Positive Urine Drug Screens in the NS2359 Group Versus the Placebo Group Comparator During the Last Three Weeks of the Trial [ Time Frame: weeks 6,7.8 of the trial ] Number of subjects with cocaine abstinence as measured through three-times-weekly urine benzoylecgonine (BE) levels in urine drug screen (UDS) and self-reports of use from the Time Line Follow Back. UDS results and TLFB reports combined to yield weekly use/no-use indicators for each week of treatment.	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Weekly Cocaine Craving Scores NS2359 Group Versus the Placebo Group Comparator [ Time Frame: Once Per Week in Weeks 2 Through 8 ]	As measured by average weekly scores for cocaine craving on the brief substance craving scale combining cocaine craving frequency, intensity and duration. Minimum value 0 maximum value 12 higher scores indicate worse craving.	8 weeks

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: Saniona; The Dana Foundation
• Investigators: Principal Investigator: Wade Berrettini, MD, PhD, University of Pennsylvania Perelman School of Medicine, Department of Psychiatry

Study record dates

Study Major Dates

• Study Start: May 1, 2016
• Primary Completion (Actual): March 1, 2020
• Study Completion (Actual): October 1, 2020

Study Registration Dates

• First Submitted: May 17, 2016
• First Submitted That Met QC Criteria: June 8, 2016
• First Posted (Estimate): June 14, 2016

Study Record Updates

• Last Update Posted (Actual): May 24, 2021
• Last Update Submitted That Met QC Criteria: May 19, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Cocaine-Related Disorders
• Other Study ID Numbers: 824109

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No