Varenicline vs Placebo for the Treatment of Methamphetamine Dependence

Study Overview
=================
Brief Summary
-----------------
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: reductions in methamphetamine use; treatment retention;

Detailed Description
-----------------
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: 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. To determine if varenicline results in significantly greater treatment retention than placebo among MA dependent participants when provided in conjunction with cognitive behavioral therapy. To address these aims, we recruited 20 MA dependent participants who will be randomized to receive treatment with varenicline (n=10) or placebo (n=10) for 8 weeks, in combination with cognitive behavioral therapy, followed by 4 weeks of follow up observation. 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.

Official Title
-----------------
A Randomized, Double-blind Trial of Varenicline Versus Placebo, in Conjunction With Cognitive Behavioral Therapy, for Methamphetamine Dependence

Conditions
-----------------
Methamphetamine Dependence, Substance Abuse, Methamphetamine Abuse

Intervention / Treatment
-----------------
* Drug: Varenicline
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 18 years of age or older; meet (Diagnostic and Statistical Manual of Mental Disorders) DSM-IV criteria for methamphetamine (MA) dependence; seeking treatment for MA problems; willing and able to comply with study procedures; willing and able to provide written informed consent; if female, not pregnant or lactating and willing to use an acceptable method of barrier birth control (e.g. condoms) during the trial. Exclusion Criteria: have a medical condition that, in the study physician's judgment, may interfere with safe study participation (e.g., active tuberculosis, unstable cardiac, renal, or liver disease, uncontrolled hypertension, unstable diabetes); have a current neurological disorder (e.g., organic brain disease, dementia) or a medical history which would make study agent compliance difficult or which would compromise informed consent; have a current major psychiatric disorder not due to substance abuse (e.g., schizophrenia, bipolar disorder) as assessed by the Structured Clinical Interview for DSM Disorders (SCID); have a history of attempted suicide in the past 3 years and/or serious suicidal intention or plan in the past year as assessed by the Columbia Suicide Severity Rating Scale (C-SSRS); currently on prescription medication that is contraindicated for use with varenicline; currently using any form of nicotine replacement therapy, due to potential interactions with varenicline; have current dependence on cocaine, opiates, alcohol, or benzodiazepines as defined by DSM-IV; have a history of alcohol dependence within the past three years; have a history of sensitivity to varenicline or any other circumstances that, in the opinion of the investigators, would compromise participant safety.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Varenicline<br>Varenicline: 0.5 mg daily for days 1-3 0.5 mg twice daily for days 4-7 1 mg twice daily from day 8 until end of week 8. | Drug: Varenicline<br>* Varenicline dosing will follow that which has been shown to be effective for cigarette smoking cessation. Varenicline dose will start at 0.5 mg daily for days 1-3, followed by 0.5 mg twice daily for days 4-7, followed by 1 mg twice daily from day 8 until completion of the medication period (end of week 8).<br>* Other names: CHANTIX (tm);|
| Placebo Comparator: Placebo<br>8 weeks of daily matching oral placebo in tablet form | Drug: Placebo<br>* Placebo dose will start at 0.5 mg (sugar pill) daily for days 1-3, followed by 0.5 mg twice daily for days 4-7, followed by 1 mg twice daily from day 8 until completion of the medication period (end of week 8).<br>* Other names: Sugar pill;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in MA Positive Urine Drug Screens Among Participants Randomly Assigned to Receive Varenicline Versus Placebo. | Urine samples, collected thrice weekly, were tested for metabolites of MA using radioimmunoassay. Each subject had a possible of 24 urine drug screens to provide during the 8 weeks of medication. An aggregate measure of urine drug screen results was calculated - the Treatment Effectiveness Score (TES) - which is the average of the sum of MA-free urine specimens provided during the treatment period by participants in each treatment condition. | 8-weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Retention (Completion) | Retention was determined by the proportion of participants retained for the entire trial and time until drop-out. | 8-weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
methamphetamine, crystal meth, addiction, los angeles, medication, meth