Efficacy and Safety of Sustained-Release Dexamphetamine and Piracetam in Cocaine Use Disorder with Comorbid Opioid Use Disorder: A Randomized Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of 24 weeks of sustained-release dexamphetamine, individually titrated to a maximum dosage of 90 mg/day, compared with a placebo, in patients with moderate to severe **cocaine use disorder** who are undergoing routine opioid agonist treatment with oral methadone for comorbid opioid dependence. The evaluation focuses on the number of days of cocaine abstinence and overall health status, which are clinically relevant as they address the effectiveness of the treatment in reducing cocaine use and improving patient health outcomes.

Secondary objectives include assessing the acceptance, tolerability, and safety of the 24-week sustained-release dexamphetamine treatment. Additionally, the study aims to evaluate the effect of discontinuing the sustained-release dexamphetamine after 24 weeks of treatment. These objectives are important for understanding the broader implications of the treatment regimen, including patient adherence, potential side effects, and the impact of treatment cessation on patient outcomes.

The clinical trial focuses on individuals diagnosed with **cocaine use disorder**, specifically those with moderate to severe conditions as per DSM-5 criteria. The study population includes both male and female participants, with an age range encompassing adults and older adults. Participants are actively engaged in opioid agonist treatment with oral methadone for comorbid opioid dependence. The trial does not involve a vulnerable population. Participants were selected based on their regular use of cocaine in the previous month, with snorting, inhaling, or injecting as the primary routes of administration. They must express an intention to reduce or cease cocaine use and demonstrate the ability and willingness to attend the treatment center twice weekly, as well as cooperate with study assessments and procedures. Written informed consent is a prerequisite for participation. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the **efficacy** and safety of sustained-release dexamphetamine in patients with moderate to severe **cocaine use disorder** who are also undergoing routine opioid agonist treatment with oral methadone. This study is a multicenter, randomized, double-blind, placebo-controlled trial. The trial will span a total duration of 24 weeks, with an estimated recruitment start date in November 2024 and an estimated end date in December 2026. Participants will be randomly assigned to receive either the active treatment, dexamphetamine sulfate/piracetam sustained release tablets, or placebo tablets containing a subtherapeutic dose of piracetam as an adherence marker.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are assessed, including active participation in opioid agonist treatment, a diagnosis of moderate or severe cocaine use disorder according to DSM-5, and regular cocaine use in the previous month. Participants must express the intention to reduce or stop cocaine use and be able to attend the treatment center twice a week. Following the screening, participants will undergo regular follow-up visits throughout the 24-week treatment period to monitor efficacy and safety outcomes. The primary endpoint is the number of days of cocaine abstinence in the final four weeks of treatment, assessed by self-report and urinalysis. Secondary endpoints include overall health status, safety assessments, and the number of days of cocaine abstinence during the discontinuation phase.

The expected length of participant involvement is 24 weeks, with conditions for early termination including non-compliance with study procedures, withdrawal of consent, or adverse events that necessitate discontinuation. The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted to evaluate the primary and secondary endpoints. Participants' involvement may be terminated early if they fail to adhere to the study protocol or if safety concerns arise. The trial aims to provide valuable insights into the potential benefits of sustained-release dexamphetamine for individuals with cocaine use disorder, contributing to the development of effective treatment strategies.

The clinical trial involves the administration of **dexamphetamine sulfate/piracetam sustained release tablets** as the experimental medication. These tablets are formulated as modified-release tablets, containing 30.0 mg of dexamphetamine sulfate and 1.25 mg of piracetam. The route of administration is oral. The dosage is individually titrated to a maximum of 90 mg per day, as tolerated by the participant. The treatment period is set for a maximum of 30 days. The pharmaceutical form is designed to ensure a sustained release of the active substances, optimizing therapeutic efficacy and minimizing potential side effects. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

The study also includes the use of **placebo tablets** as a comparator treatment. These placebo tablets contain a subtherapeutic dose of 1.25 mg piracetam, serving as an adherence marker. The placebo is administered orally, in a manner identical to the experimental medication, to maintain the double-blind nature of the study. The placebo is used to evaluate the efficacy of the experimental treatment by providing a baseline for comparison. The inclusion of a placebo group is critical for assessing the true therapeutic effects of the dexamphetamine sulfate/piracetam combination in patients with moderate to severe cocaine use disorder, who are also receiving routine opioid agonist treatment with oral methadone for comorbid opioid dependence.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoint, which is the number of days of cocaine abstinence in the final 4 weeks of treatment (weeks 21–24). This will be measured using a combination of self-reported data and urinalysis. Additionally, a key secondary endpoint will assess "good or improved overall health status," encompassing physical health, mental health, and social functioning.

Secondary endpoints include the number and proportion of patients starting and completing the 24-week treatment, the maximum dose received, and the dose at various time points, such as the end of week 4 and the final 4 weeks of study phases 1 and 2. Safety assessments will include monitoring vital signs, body weight, ECG, and laboratory parameters, as well as recording adverse events and serious adverse events. Other secondary endpoints will evaluate the total number of days of cocaine abstinence during the first 12 weeks and the entire 24-week treatment period, complete abstinence from cocaine, and achieving sustained abstinence for at least 21 consecutive days. The study will also measure at least a 40% reduction in cocaine use in the final 4 weeks of treatment compared to baseline, the number of weeks of uninterrupted cocaine abstinence, the average number of cocaine administrations on days of use, and cocaine craving.