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Methamphetamine (MA) abuse is the fastest growing drug problem in the United States and is responsible for significant public health complications, including HIV infection. As a result effective treatments for MA dependence are urgently needed. There are currently no efficacious medications for MA dependence, although results from preliminary randomized trials of bupropion for MA dependence found bupropion to be more effective than placebo, but only among subgroups of participants, including those with lower frequency of MA use at baseline. A growing body of preclinical and clinical studies suggest that cholinergic mechanisms play an important role in the neurobiology of MA and other stimulant dependence, such as nicotine dependence. Mechanistically, cholinergic medications may alleviate MA-associated cognitive dysfunction, thereby improving outcomes of treatment for MA dependence. Varenicline is a partial agonist at α4β2 nicotinic receptors and a full agonist at α7 nicotinic receptors that has been approved as an anti-cigarette smoking medication. In order to assess the potential efficacy of varenicline for methamphetamine dependence, we will perform a clinical trial to assess if varenicline compared to placebo results in greater:
1. reductions in methamphetamine use;
2. treatment retention;
3. MA withdrawal symptoms;
4. reductions in ad libitum cigarette smoking; and
5. to determine if baseline cognitive function is associated with treatment outcomes regardless of treatment assignment.
Methamphetamine (MA) abuse is the fastest growing drug problem in the United States and is responsible for significant public health complications, including HIV infection1. As a result effective treatments for MA dependence are urgently needed. There are currently no efficacious medications for MA dependence, although results from preliminary randomized trials of bupropion for MA dependence found bupropion to be more effective than placebo, but only among subgroups of participants, including those with lower frequency of MA use at baseline 2, 3. A growing body of preclinical and clinical studies suggest that cholinergic mechanisms play an important role in the neurobiology of MA and other stimulant dependence, such as nicotine dependence 4. Mechanistically, cholinergic medications may alleviate MA-associated cognitive dysfunction, thereby improving outcomes of treatment for MA dependence 5. Varenicline is a partial agonist at α4β2 nicotinic receptors and a full agonist at α7 nicotinic receptors that has been approved as an anti-cigarette smoking medication. In order to assess the potential efficacy of varenicline for methamphetamine dependence, we will perform a clinical trial to assess the following aims:
1. To determine if varenicline results in significantly greater reductions in methamphetamine use than placebo, as determined via the proportion of methamphetamine-free urine specimens provided by participants throughout treatment, when provided to methamphetamine dependent participants in conjunction with cognitive behavioral therapy.
Exploratory Aim 1a. To determine whether reductions in methamphetamine use with varenicline versus placebo are greater among methamphetamine dependent participants with baseline light MA use (MA use on 18 or fewer of the past 30 days at baseline) versus heavy MA use (MA use on more than 18 of the past 30 days).
Exploratory Aim 1b. To determine if varenicline results in a greater proportion of methamphetamine dependent participants achieving methamphetamine abstinence defined as self-reported MA abstinence, confirmed via urine drug screens (all available urine drug screens are MA-metabolite free and at least one urine drug screen available per week and no more than two missed visits between urine drug screens) during the final two weeks of the study medication period (weeks 7 and 8) relative to placebo when provided in conjunction with cognitive behavioral therapy.
2. To determine if varenicline results in significantly greater treatment retention than placebo among MA dependent participants when provided in conjunction with cognitive behavioral therapy.
3. To determine if varenicline results in significantly greater reductions in MA withdrawal symptoms than placebo, as determined via the Amphetamine Cessation Symptoms Assessment Scale (ACSA), among MA dependent participants when provided in conjunction with cognitive behavioral therapy.
4. To determine if baseline cognitive function, as determined via our cognitive battery is associated with subsequent treatment outcomes (MA use and retention) among MA dependent participants overall regardless of treatment group assignment.
Aim 4a. To determine if treatment outcomes with varenicline versus placebo differ among participants with baseline higher versus lower cognitive function, as assessed via our cognitive battery.
5. To determine if varenicline results in greater reductions in ad libitum cigarette smoking compared to placebo among MA dependent participants.
Exploratory Aim 5a. To determine whether reductions in methamphetamine use correlate significantly with reductions in ad libitum cigarette smoking among cigarette smoking MA dependent participants who receive varenicline as compared to placebo.
We will also perform additional exploratory analyses examining whether (1) variation in genes related to MA abuse and/or response to varenicline, such as dopaminergic (e.g. COMT, DAT, DRD2, and VMAT2) and/or cholinergic (e.g. CHRNA3-CHRNA5-CHRNB4 gene cluster) signaling system genes baseline frequency of methamphetamine use and/or treatment outcomes (MA use, retention). To address these aims, we will recruit 70 MA dependent participants who will be randomized to receive treatment with varenicline (n=35) or placebo (n=35) for 8 weeks, in combination with cognitive behavioral therapy, followed by 4 weeks of follow up observation.
As in other pilot trials conducted under the UCLA Medication Development P50 Center, the study is powered to identify effects of a putative medication that has moderate or greater effect size along a set of a priori specified hypotheses in order to determine whether there is a signal for the medication that can be followed with an adequately powered confirmatory study. The primary aim comparing potential reductions in MA use, as determined via thrice-weekly urine drug screen results, will be used to determine the power for this study (See Power Analysis below). Results of this study have the potential to provide additional safety data and to yield preliminary evidence that may support a fully powered late Phase II trial of the efficacy of varenicline for the treatment of methamphetamine dependence. Findings also have potential to provide insights into the influence of cognitive dysfunction, and medications with potential cognitive enhancing effects, on the pathogenesis of MA dependence and treatment outcomes.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
UCLA Vine Street Clinical Research Site
National Institute on Drug Abuse (NIDA)
Published on BioPortfolio: 2014-08-26T22:18:03-0400
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