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

Study Overview
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Brief Summary
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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.

Detailed Description
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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: The primary endpoint is modelled in a negative binomial regression analysis, with treatment group as independent variable and stratification variables (treatment centre, overall health status, and (nearly) daily cocaine use) as covariates.

Official Title
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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

Conditions
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Cocaine Use Disorder

Intervention / Treatment
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* Drug: Sustained-release Dexamphetamine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: male and female patients between 18 and 65 years of age; active participation in opioid agonist treatment with oral methadone; moderate or severe cocaine use disorder according to DSM-5; regular use of cocaine in the previous month (i.e., ≥8 days/month); snorting, inhaling or injecting cocaine use as primary route of administration; the intention to reduce or stop cocaine use; able and willing to attend the treatment centre for 2 days per week; able and willing to co-operate with the required study assessments and study procedures; and provide written informed consent. Exclusion Criteria: severe medical (e.g., severe renal or kidney insufficiency/failure) or severe psychiatric problems (e.g. acute psychosis, current major depression, current bipolar disorder, acute suicidality); cardiovascular problems: clinically relevant ECG abnormalities, moderate to severe hypertension (SBP>140; DBP>90; HR>100), angina pectoris, history with myocardial infarction, CVA, heart failure; glaucoma; Gilles-de-la-Tourettesyndrome; pheochromocytoma; hyperthyroid status; current dyspnea; pregnancy or continued lactation; (indication for) treatment with other medications that might potentially be effective for stimulant use disorder (e.g., methylphenidate, disulfiram, bupropion, or modafinil); anticipated need for inpatient treatment (clinical judgement); (expected) inability to complete the 30 weeks study (e.g., due to expected incarceration or hospitalization); insufficient command of the Dutch language; and current participation in another addiction treatment study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sustained-release Dexamphetamine<br>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<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Identical matched placebo, dispensed under the same conditions and with similar frequency as the investigational product (see above). | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of days of 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 |
| --- | --- | --- |
| Physical health | Physical health; self-reported, Maudsley Addiction Profile - Health Symptoms Scale (MAP-HSS) | Final 4 weeks of treatment compared with baseline | 
| Mental health | Mental health; self-reported, Brief Symptom Inventory (BSI) | Final 4 weeks of treatment compared with baseline | 
| Social functioning | Social functioning, criminality; self-reported, European Addiction Severity Index (EuropASI) | Final 4 weeks of treatment compared with baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cocaine use disorder, sustained-release dexamphetamine, agonist pharmacotherapy, opioid use disorder, methadone maintenance treatment, randomized controlled trial (RCT), placebo-controlled, double-blind