Transdermal Rotigotine as Adjunct to Behavioral Therapy for Cocaine Use Disorder

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled phase 2b pilot clinical trial to determine whether non-ergoline D3/D2/D1 dopamine (DA) receptor agonist rotigotine (RTG), in combination with treatment as usual, including individual or group behavioral therapy can a) reduce cocaine use and also b) increase brain activity in frontocortical areas of the brain, and, as a reflection of that - improve top-down cognitive control in persons with cocaine use disorder (CocUD). Rotigotine is a marketed non-ergoline D3/D2/D1 DA agonist (RTG, Neupro®) in the form of a transdermal patch that is FDA-approved for the treatment of Parkinson's Disease and Restless Legs Syndrome. The premise of this project was based on apparent beneficial effects of RTG in a different human population characterized by executive function (EF) impairment. In light of the deficits in EF common in persons with CocUD, RTG may hold the potential for cognitive improvement in persons with CocUD who are in treatment as usual to both attend to and retain psychoeducation concepts better. In addition, rotigotine may help these individuals in recovery maintain goals better, where goal maintenance is a crucial integrative product of successful EF.

Detailed Description
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Among different substance use disorders, stimulant use disorders are more consistently linked with impaired executive function (EF) of the brain, which is a set of cognitive skills like working memory that operate to enable self-control over behavior and long-term planning. Medications such as stimulants that increase function of the frontal cortex dopamine (DA) system can improve EF. However, stimulants such as amphetamine have abuse potential. Of interest is determining whether a multiple DA receptor medication like rotigotine could improve brain function in persons with stimulant use disorder who are in therapy, to help them retain educational concepts and strategies better. Rotigotine has been shown to improve cognition-related quality of life in persons with Alzheimer's Disease. This is a roughly six week trial of rotigotine (given in a skin patch) to determine whether it not only reduces cocaine use in persons in treatment for cocaine use disorder, but actually improves cognitive performance itself, and increases activity in the frontal cortex of the brain, compared to placebo. It is hypothesized that rotigotine will be specifically helpful for cognition and abstinence in those participants whose cognitive performance ability tested at baseline is below the median.

Official Title
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Phase 2a Double-Blind Placebo-Controlled Trial of Transdermal Rotigotine as Adjunct to Behavioral Therapy for Cocaine Use Disorder

Conditions
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Substance-Related Disorders

Intervention / Treatment
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* Drug: Rotigotine Transdermal System [Neupro]
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects between 18 and 55 years of age. Meet current DSM-5 criteria for Cocaine Use Disorder (CocUD), moderate or severe Currently undergoing treatment as usual for CocUD (such as individual or group therapy sessions), or slated for enrollment in a program for CocUD treatment as usual. Able to understand and comply with study procedures Have positive urine result for cocaine metabolite benzoylecgonine (BE) during at least one screening visit (out of up to three visits, depending on participants' preference). Have hematology and chemistry laboratory tests that are within normal limits, except that liver function tests must be no more than 2x of the upper limit of normal (if any elevation is above the limit - must be judged by the study physician to be clinically insignificant). No clinically significant abnormalities on baseline ECG. Be able to demonstrate an understanding of study procedures and follow instructions including behavioral laboratory and fMRI testing. Women must either be unable to conceive (i.e., surgically sterilized, sterile, or postmenopausal) or be using a reliable form of contraception (e.g., abstinence, birth control pills, intrauterine device with spermicide, or condoms). Men will be advised to use condoms. All females must provide negative pregnancy urine tests before study entry, at each visit during the study, and the end of study participation. Exclusion Criteria: Have concurrent secondary DSM-5 diagnosis of any psychoactive substance use disorder other than cocaine, alcohol, methamphetamine, nicotine, opioid, or marijuana use disorder. Have a DSM-5 axis I psychiatric disorder other than substance use disorder, including but not limited to Bipolar I Disorder, Schizophrenia, or other psychotic disorder that require treatment with antipsychotics, or a neurological disorder requiring ongoing treatment and/or making study participation unsafe. Comorbid PTSD, Generalized Anxiety Disorder and Major Depressive Disorder will be allowed. Use of medications contraindicated for concurrent use along with rotigotine. These include dopamine antagonists such as antipsychotic medications (especially neuroleptics) or metoclopramide. Subjects with evidence or history of any clinically significant medical disorder including biliary obstruction, hepatic disease, severe cardiovascular or pulmonary disease, bronchial asthma, renal, or endocrine disease. However, controlled hypertension, controlled hypothyroidism, and cancer in remission over 5 years will not be excluded. Have a history of seizures (excluding childhood febrile seizures) or loss of consciousness (e.g. from traumatic brain injury) for more than 30 minutes. Have significant current suicidal or homicidal ideation or a suicide attempt within the past 6 months. Be HIV positive by self-report or history. Be pregnant or nursing or not using a reliable form of contraception if able to conceive. All females must provide negative pregnancy urine tests before study entry, at each visit during the study, and the end of study participation Have any other illness, or condition, which in the opinion of the clinical co-investigator (Arias) would preclude safe and/or successful completion of the study. Have metal fragments or other bodily metal (e.g., pacemaker) or significant claustrophobia that would put the subjects at risk for MRI scanning. Be allergic to rotigotine. Have taken any investigational drug within 45 days prior to baseline Show clinically significant symptoms of cocaine or opioid withdrawal Demonstrate intolerance to, poor adherence to, or extreme skin irritation by daily application of known placebo practice skin patches during the screening phase Current/pending criminal charges that may result in incarceration within the next 60 days

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Active Rotigotine (RTG)<br>Participants who are randomized to the active RTG arm will receive Neupro® RTG patches | Drug: Rotigotine Transdermal System [Neupro]<br>* Neupro® 2mg/24h transdermal patches for the first seven days, followed by the target 4mg dose for the subsequent 35 days (five weeks) of dosing up to the follow-up assessments, followed by two days of 2mg/24h ramp-down dose.<br>|
| Placebo Comparator: Placebo<br>Participants who are randomized to placebo will receive transdermal patches that match the size and color of active Neupro®. | Drug: Placebo<br>* Placebo drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cocaine-positive urine samples | comparison of cocaine-positive urine samples between participants randomized to transdermal RTG relative to participants randomized to placebo patches | weeks 5 - 6 of transdermal patch treatment | 
| self-reported cocaine use | comparison of cocaine cocaine use (by self report) between participants randomized to transdermal RTG relative to participants randomized to placebo patches | weeks 5 - 6 of transdermal patch treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| executive function (change) | Change in CNS-VS Neurocognition Index (NCI) scores | change from baseline to study week 6 | 
| QoLI total score (change) | Change in QoLI total scores | change from baseline to study week 6 | 
| dorsolateral prefrontal cortex (DLPFC) | Change in recruitment of dorsolateral prefrontal cortex (DLPFC) | study day 1 to study week 6 | 
| stop signal task (SST) | Change in recruitment of right anterior insula by stop-signals in the SST | study day 1 to study week 6 | 
| EC from DLPFC to striatum during working memory demands | change in EC from DLPFC to striatum during working memory demands in the EFNBk and during resting state | study day 1 to study week 6 |