Efficacy and Safety of Sustained-release Dexamphetamine in Patients With Moderate to Severe Cocaine Use Disorder

Efficacy and Safety of 24 Weeks Sustained-release Dexamphetamine in Patients With Moderate to Severe Cocaine Use Disorder With Comorbid Opioid Use Disorder - A Multicenter Randomized, Double-blind, Placebo-controlled Study

In The Netherlands, each year, about 15 thousand people come into treatment because of problems with cocaine use. There is no approved medication for treatment of cocaine addiction and the psychosocial treatment patients receive is not successful for everyone; many return to treatment several times. There is evidence that agonist ("replacement") medications are effective in treating addiction: methadone for heroin addiction; nicotine replacement for smokers. Dexamphetamine is a stimulant medication registered for treatment of ADHD. It may also be effective as agonist treatment for people with cocaine addiction.

It will be investigated whether sustained-release dexamphetamine in people with cocaine addiction, participating in routine methadone maintenance treatment for their comorbid opioid use disorder, (1) reduces cocaine use and (2) improves their health and quality of life.

Study Overview

• Status: Recruiting
• Conditions: Cocaine Use Disorder
• Intervention / Treatment: Drug: Sustained-release Dexamphetamine; Drug: Placebo

Detailed Description

RESEARCH QUESTION/RATIONALE: Treatment for patients with cocaine use disorder is modestly effective and there is an urgent need for more effective treatments. Several randomized controlled trials, including our previous proof of principle study (Nuijten et al., 2016, The Lancet), suggest that sustained-release dexamphetamine is the most promising medication for the treatment of cocaine use disorder.

HYPOTHESIS & OBJECTIVES: Therefore, it is hypothesized that sustained-release dexamphetamine is effective in patients with cocaine use disorder in terms of reducing cocaine use and improving health and quality of life.

STUDY DESIGN: Multicentre randomized, double-blind, placebo-controlled study in 204 patients with cocaine use disorder - participating in routine methadone maintenance treatment for their comorbid opioid use disorder. In the 1st study phase (24 weeks) the efficacy and safety of sustained-release dexamphetamine is compared with placebo. In the 2nd double-blind, placebo-controlled randomized treatment discontinuation phase (6 weeks), we assess the consequences of discontinuation of sustained-release dexamphetamine treatment.

STUDY POPULATION: Patients with moderate/severe cocaine use disorder participating in routine oral methadone maintenance treatment for their comorbid opioid use disorder .

INTERVENTION: The investigational product is in tablets, containing 30 mg dexamphetamine sulphate in sustained-release formulation. Patients will be titrated to the target dose of 90 mg/day, if tolerated. Medication is dispensed twice weekly.

OUTCOME PARAMETERS: Primary endpoint: number of days of cocaine abstinence in the final 4 weeks of treatment, assessed by combined self-report and urinalysis. Key secondary endpoint: Good or improved overall health status (in terms of physical and mental health, and social functioning).

SAMPLE SIZE/DATA-ANALYSIS: Assuming 5 days difference in cocaine abstinent days in the final 4 weeks of the study to be clinically relevant requires 102 patients per treatment group in order to detect these 5 days difference (pooled standard deviation: 11 days; two-sided alpha=0.05; power=0.90). Primary analysis: As cocaine abstinence is assessed throughout the trial, the numbers of days of cocaine abstinence in the sequential 4 week periods will be treated as repeated measure. The primary analysis will be a likelihood-based mixed model of repeated measures (MMRM) approach, including treatment, fixed timepoints (periods of 4 weeks, categorical) and their interaction as fixed factors and subject as random effect. Treatment center and overall health status (both stratification factors) will be included as covariates. The contrast between the two groups at week 24 will be the primary comparison.

• Study Type: Interventional
• Enrollment (Estimated): 204
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Vincent Hendriks, PhD.; Phone Number: +31651154583; Email: vincent.hendriks@brijder.nl
• Study Contact Backup: Name: Tjitske Colenbrander, MsC, MD.; Phone Number: +31616046159; Email: t.colenbrander@brijder.nl

Study Locations

• Netherlands
  • The Hague, Netherlands, 2512 HN
    • Recruiting
    • Brijder Den Haag
    • Contact: Tjitske Colenbrander, MD; Phone Number: +31616046159; Email: t.colenbrander@brijder.nl

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• male and female patients between 18 years and over;
• actively participating in opioid agonist treatment with oral methadone;
• with moderate or severe cocaine use disorder according to DSM-5;
• with regular use of cocaine in the previous month (i.e., ≥8 days/month);
• with snorting, inhaling or injecting cocaine use as primary route of administration;
• express the intention to reduce or stop their cocaine use;
• be able and willing to attend the treatment center for 2 days per week;
• be able and willing to co-operate with the required study assessments and study procedures; and
• have provided written informed consent.

Exclusion Criteria:

• severe medical (e.g., severe renal or hepatic insufficiency/failure) or severe psychiatric problems (e.g. previous or acute severe psychotic episode, acute suicidality, current bipolar disorder);
• cardiovascular problems: clinically relevant ECG abnormalities suggestive of channelopathy or structural or ischemic heart disease, or a prolonged QTc interval (≥500 msec); moderate to severe hypertension (i.e., SBP>140; DBP>90); HR>100, known coronary artery disease (i.e., angina pectoris, acute myocardiac infarction), known cardiomyopathy, CVA;
• glaucoma;
• Gilles-de-la-Tourette syndrome;
• pheochromocytoma;
• hyperthyroid status;
• pregnancy or continued lactation;
• use of monoamine oxidase inhibitor(s) (MAOI): currently or in the past 14 days;
• treatment with other prescription psychostimulants that might potentially be effective for stimulant use disorder (i.e., (immediate release) dexamphetamine, lisdexamphetamine, methylphenidate, or modafinil);
• anticipated need for inpatient treatment (clinical judgement);
• (expected) inability to complete the 30 weeks study (e.g., planned holidays, expected incarceration or hospitalization);
• insufficient command of the Dutch language; and
• current participation in another addiction treatment study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sustained-release Dexamphetamine; Tablets of 30 mg sustained-release dexamphetamine sulphate. Target dose: 90 mg/day, if tolerated. Tablets have to be taken daily, in the morning, per os for 24 weeks.	Drug: Sustained-release Dexamphetamine; During the first week, patients will be individually titrated to the target dose of 90 mg/day, if tolerated. From the second week onwards, patients are prescribed 3 tablets (30 mg) per day, if tolerated. Titration can be slower but should be finished at the end of week 4. After 4 weeks dosages can no longer be increased, and only be reduced. Patients will visit the treatment centre 2 times per week to take their study medication under supervision of the treatment staff and to receive take-home medication for the days in between study visits. After 24 weeks patients will be randomized to either (double-blind) continuation or discontinuation (placebo) of SR-Dexamphetamine treatment to assess the consequences of discontinuation, during a 6 weeks period.
Placebo Comparator: Placebo; Identical matched placebo, dispensed under the same conditions and with similar frequency as the investigational product (see above).	Drug: Placebo; Dispensed under the same conditions and with similar frequency as the investigational product (see above). After 24 weeks study medication will be discontinued in the placebo group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary outcome measure for the primary study objective (to evaluate the efficacy of 24 weeks SR-dexamphetamine, compared with 24 weeks placebo): the number of days cocaine abstinence.	The number of days of cocaine abstinence in the final 4 weeks of treatment, assessed by combined self-report and urinalysis.	Final 4 weeks of treatment (first study phase; i.e., week 21-24)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Key secondary outcome measure for the primary study objective ("good or improved overall health status", in terms of physical health, mental health, and social functioning).	Good or improved overall health is defined as follows: In patients with physical health problems (Maudsley Addiction Profile; MAP-HSS), or mental health problems (Brief Symptom Inventory; BSI) or problematic social functioning (Social functioning, criminality; European Addiction Severity Index; EuropASI) at baseline, good or improved overall health is defined as: at least 40% improvement in at least one of the 'problematic' health domains, compared with baseline status, assessed at week 24.; In patients without physical health problems, or mental health problems or problematic social functioning at baseline, good or improved overall health is defined as: no deterioration of 40% or more in any of the 'non-problematic' health domains, compared with baseline status, that results in crossing the threshold of health problems, again assessed at week 24. This endpoint concerns the 24-week efficacy of SR-dexamphetamine in terms of overall health.	Final 4 weeks of treatment (i.e. week 21 - week 24) compared with baseline
Secondary outcome measures for the primary study objective: Cocaine use related secondary endpoints: (1) Total number of days cocaine abstinence.		During first 12 weeks treatment (i.e., 0-84 days)
Secondary outcome measures for the primary study objective: Cocaine use related secondary endpoints: (2) Total number of days cocaine abstinence.		During 24 weeks treatment (i.e., 0-168 days)
Secondary outcome measures for the primary study objective: Cocaine use related secondary endpoints: (3) Complete abstinence from cocaine.		During 24 weeks treatment
Secondary outcome measures for the primary study objective: Cocaine use related endpoints: (4) Achieving a period of sustained abstinence from cocaine for at least 21 consecutive days.	Proportion of subjects achieving sustained cocaine abstinence of at least 21 consecutive days as measured by the Timeline Follow-Back Method (TLFB): SR-dexamphetamine versus placebo. Higher proportion means better outcome.	During 24 weeks treatment
Secondary outcome measures for the primary study objective: Cocaine use related endpoints: (5) At least 40% reduction in cocaine use (days/month) in the final 4 weeks of treatment (weeks 21-24), compared with baseline.		The final 4 weeks of treatment (weeks 21-24)
Secondary outcome measures for the primary study objective: Cocaine use related endpoints: (6) Number of weeks of uninterrupted cocaine abstinence sustained till abstinence during final treatment week in study phase 1.		Final treatment week in study phase 1
Secondary outcome measures for the primary study objective: Cocaine use related endpoints: (7) Average number of cocaine administrations on days that cocaine was used.		During 24 weeks treatment
Secondary outcome measures for the primary study objective: Cocaine use related endpoints: (8) Cocaine craving.	Cocaine craving is measured using the Obsessive Compulsive Drug Use Scale (OCDUS, Franken et al., 2002), with a score range of 0 to 20. Higher scores mean worse outcome.	During 24 weeks treatment
Secondary outcome measure for the secondary study objective (to assess the acceptance, tolerability, and safety of 24 weeks SR-dexamphetamine): treatment completion; medication adherence; adverse events, and serious adverse events.	The number and proportion of patients starting and completing 24 weeks treatment;; Maximum dose received; dose at the end of week 4; dose in final 4 weeks of study phase 1 (weeks 21-24); dose in final 4 weeks of study phase 2 (weeks 27-30) (all: mean(std.dev), and median/IQR).; Safety will be assessed and reported in terms of:; Vital signs (heart rate, blood pressure) and body weight.; ECG and safety laboratory parameters (NT-proBNP, and hs-Troponine T).; Adverse events (AEs; solicited and unsolicited) and serious adverse events (SAEs).	The first 24 weeks of treatment
Secondary outcome measure for the secondary study objective (to evaluate the effect of discontinuation of SR-dexamphetamine after 24 weeks treatment): days cocaine abstinence.	Days cocaine abstinence in the final 4 weeks of the discontinuation phase of the study (i.e., weeks 27-30), assessed by combined self-report and urinalysis. A decrease of ≥5 days/month in cocaine abstinent days, compared with the number of cocaine abstinent days/month at the end of study phase 1 (weeks 21-24) is considered to be a clinically relevant deterioration.	Final 4 weeks of treatment discontinuation phase (second study phase; i.e., week 27-30)
Secondary outcome measure for the secondary study objective (to evaluate the effect of discontinuation of SR-dexamphetamine after 24 weeks treatment): overall health status.	The overall health status of patients in the final 4 weeks of the discontinuation study phase 2 (weeks 27-30), - defined as "deteriorated overall health status", in terms of physical health, mental health, and social functioning - thereby using the overall health status at the end of study phase 1 (weeks 21-24) as reference. More specifically, deteriorated overall health status is defined as follows: In patients without physical health problems, or mental health problems or problematic social functioning at week 24, deteriorated overall health status is defined as: a deterioration of 40% or more in any of the 'non-problematic' health domains, compared with status at week 24, that results in crossing the threshold of health problems, assessed at week 30.	Final 4 weeks of treatment discontinuation phase (second study phase; i.e., week 27-30)
Secondary outcome measure for the secondary study objective (to evaluate the effect of discontinuation of SR-dexamphetamine after 24 weeks treatment): dichotomous outcome of deterioration.	A dichotomous outcome of deterioration (yes versus no) based on the composite outcome of (1) a clinically relevant decrease of ≥5 days/month in cocaine abstinent days and/or (2) deterioration in overall health status.	Final 4 weeks of treatment discontinuation phase (second study phase; i.e., week 27-30)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Outcome measure for the exploratory study objective (to explore the cost-utility of 24 weeks SR-dexamphetamine treatment, compared with 24-weeks placebo):	For this purpose, we will use the following exploratory outcomes: QALYs.; Costs related to treatment, additional health care consumption, and criminality.	The first 24 weeks of treatment

Collaborators and Investigators

• Sponsor: Parnassia Addiction Research Centre
• Collaborators: Radboud University Medical Center; Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); The Netherlands Cancer Institute; Leiden University Medical Center; Het Zwarte Gat
• Investigators: Principal Investigator: Vincent Hendriks, PhD., Parnassia Addiction Research Centre

Publications and helpful links

General Publications

• Nuijten M, Blanken P, van de Wetering B, Nuijen B, van den Brink W, Hendriks VM. Sustained-release dexamfetamine in the treatment of chronic cocaine-dependent patients on heroin-assisted treatment: a randomised, double-blind, placebo-controlled trial. Lancet. 2016 May 28;387(10034):2226-34. doi: 10.1016/S0140-6736(16)00205-1. Epub 2016 Mar 22.
• Blanken P, Nuijten M, van den Brink W, Hendriks VM. Clinical effects beyond cocaine use of sustained-release dexamphetamine for the treatment of cocaine dependent patients with comorbid opioid dependence: secondary analysis of a double-blind, placebo-controlled randomized trial. Addiction. 2020 May;115(5):917-923. doi: 10.1111/add.14874. Epub 2020 Jan 6.

Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2026
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): October 1, 2029

Study Registration Dates

• First Submitted: August 19, 2022
• First Submitted That Met QC Criteria: September 6, 2022
• First Posted (Actual): September 7, 2022

Study Record Updates

• Last Update Posted (Actual): May 29, 2026
• Last Update Submitted That Met QC Criteria: May 26, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: opioid use disorder; placebo-controlled; double-blind; cocaine use disorder; sustained-release dexamphetamine; agonist pharmacotherapy; methadone maintenance treatment; randomized controlled trial (RCT)
• Additional Relevant MeSH Terms: Narcotic-Related Disorders; Mental Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Opioid-Related Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Membrane Transport Modulators; Central Nervous System Stimulants; Dopamine Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Dopamine Agents; Dextroamphetamine
• Other Study ID Numbers: 10140262110025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Coded IPD will become available upon reasonable request. Procedures have not yet been determined.
• IPD Sharing Time Frame: Not yet determined.
• IPD Sharing Access Criteria: Not yet determined.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No