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.

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.

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.

Coded IPD will become available upon reasonable request. Procedures have not yet been determined.

Not yet determined.

Not yet determined.