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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
204
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.
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.
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.
Time frame: Final 4 weeks of treatment (first study phase; i.e., week 21-24)
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Final 4 weeks of treatment discontinuation phase (second study phase; i.e., week 27-30)
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