Modafinil vs Placebo for the Treatment of Methamphetamine Dependence - Full Text View

Sponsor:	National Institute on Drug Abuse (NIDA)
Information provided by:	National Institute on Drug Abuse (NIDA)
ClinicalTrials.gov Identifier:	NCT00469508

Purpose

Methamphetamine abuse and dependence have for some time been significant issues in other parts of the world, including several southeast Asian countries, and have now become one of the most significant substance abuse problems in the United States, gaining recent national attention in Congressional hearings and network news programs. Modafinil is a non-amphetamine type stimulant that acts as a wakefulness-promoting drug, and is approved for managing symptoms of narcolepsy (i.e., daytime somnolence). Its precise mechanism of action in promoting wakefulness remains unclear, but it is pharmacologically distinct from stimulants that are sympathetic amines (Ferraro et al 1999; Jasinski 2000; Mignot et al 1994; Saper and Scammell 2004; Walsh et al 2004). Modafinil is a medication warranting evaluation as a treatment for MA dependence. It has a half-life of approximately 15 hours and reaches steady state in 2-4 days (Package insert) and will likely require once daily dosing, which reduces problems with medication adherence.

This application proposes a placebo-controlled double-blind trial of modafinil, on a platform of contingency management (CM) and individual cognitive-behavioral (CBT) counseling, for the treatment of methamphetamine dependence.

Participants in this study will complete a 2-week baseline screening period during which they will provide urine samples and complete physical and psychological assessments to establish their eligibility for the study. In addition, participants will be asked to provide a blood or saliva specimen for genetic testing in order to identify genetic variations that influence response to methamphetamine and to treatment with modafinil. If participants agree, genetic specimens will also be stored at UCLA and may be used in future studies to examine additional genes and/or shared with other investigators. Upon successful completion of this period, participants will be randomly assigned to receive either modafinil (400mg qd) or placebo during the 12 weeks of the study. Neither the participants nor study staff will know who is receiving active medication or placebo. Regardless of medication condition, all participants will receive CM and weekly individual CBT counseling sessions to help them stop using methamphetamine and prevent relapse. They will attend the clinical research site (either at the UCLA Hollywood Clinic, or the Rancho Cucamonga site) three times per week, providing urine samples at each visit, completing data measures, and receiving individual CBT counseling on one visit each week. At the end of the 12-week study, the medication or placebo will be discontinued. Participants will return to the research site approximately 30 days following medication discontinuation for a brief health check to assess any possible lingering side effects and complete brief data measures.

Condition	Intervention	Phase
Methamphetamine Dependence	Drug: Modafinil Drug: Placebo	Phase II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Investigator), Active Control, Parallel Assignment, Efficacy Study
Official Title:	A Randomized, Double-Blind, Placebo-Controlled Evaluation of Modafinil vs Placebo for the Treatment of Methamphetamine Dependence

Resource links provided by NLM:

MedlinePlus related topics: Methamphetamine Urine and Urination

Drug Information available for: Methamphetamine hydrochloride Modafinil Amphetamine Methamphetamine

U.S. FDA Resources

Further study details as provided by National Institute on Drug Abuse (NIDA):

Primary Outcome Measures:

Urine toxicology [ Time Frame: 3/wk over 14 wks ] [ Designated as safety issue: No ]
Beck Depression Inventory [ Time Frame: 15 times over 18 wks ] [ Designated as safety issue: No ]
Clinical Global Impressions [ Time Frame: 3 times/18 wks ] [ Designated as safety issue: No ]
Brief Symptom Inventory [ Time Frame: 15 times over 18 wks ] [ Designated as safety issue: No ]

Enrollment:	73
Study Start Date:	April 2007
Study Completion Date:	January 2009
Primary Completion Date:	January 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Active Comparator	Drug: Modafinil 400mg pills taken orally daily for 12 wks.
2: Placebo Comparator	Drug: Placebo 400mg pills taken orally daily for 12 wks

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Detailed Description:

This application proposes a placebo-controlled double-blind trial of modafinil, on a platform of contingency management (CM) and individual cognitive-behavioral counseling (CBT once weekly individual session), for the treatment of methamphetamine dependence. Modafinil is a medication warranting evaluation as a treatment for MA dependence. It has a half-life of approximately 15 hours and reaches steady state in 2-4 days (Package insert) and will likely require once daily dosing, which reduces problems with medication adherence. Modafinil has potent psychiatric and behavioral effects that include brightening mood (Menza et al., 2000; Ninan et al., 2004), improving cognition (Turner et al., 2004a, b; 2003), improving impulse control (Turner et al., 2003; Turner et al., 2004a), and countering fatigue (Beusterien et al., 1999, Stahl et al., 2003). These effects neatly counterbalance effects produced by MA withdrawal (Newton et al., 2004) and may have particular value in ameliorating the negative reinforcing properties of MA, i.e., when MA is used to immediately relieve depressed mood due to recent abstinence (Peck et al., 2005b). CM is a behavioral intervention that effectively helps substance abusers to initiate abstinence, particularly from cocaine (Higgins et al., 1993; Higgins et al., 2000; Higgins et al., 1991) and from methamphetamine (Roll & Shoptaw, in press; Shoptaw et al., 2005). As well, CM has been shown to reduce substance abuse and optimize the effects of medications in reducing substance abuse (Carroll, 2004; Shoptaw et al., 2002). The objective of this study is to determine whether modafinil reduces methamphetamine use and concomitant physical and psychological symptoms more effectively than placebo when administered in conjunction with CM and CBT. The purpose of this project is to evaluate whether methamphetamine abusers seeking outpatient treatment demonstrate significantly significant reductions of methamphetamine when randomly assigned to receive modafinil (400mg qd) in combination with CM and weekly CBT compared their peers randomly assigned to receive placebo in combination with CM and weekly CBT.

Research Hypotheses:

Participants receiving active experimental drug (modafinil 400mg) will demonstrate statistically significant reductions in methamphetamine use over participants receiving placebo. Methamphetamine use outcomes will be measured using urine samples and analyzed with the following indices: Treatment Effectiveness Score, the Joint Probability Index, self-report of methamphetamine use verified by urine drug screening, and the longest uninterrupted period of methamphetamine abstinence. Primary analyses will be conducted using modeling approaches (Generalized Estimation Equations, Markov Chain Transition Models) depending upon the structure of the dataset. Self-report of methamphetamine use will be analyzed using the Addiction Severity Index drug composite scale and Substance Use Inventory (SUI).
Participants receiving active experimental drug will remain in treatment for significantly longer periods compared to participants receiving placebo. Retention will be measured by the number of days in the protocol and analyzed using survival analysis.

a. Specifically, participants with mild cognitive dysfunction (as measured as <=1 SD below the published mean for the MicroCog assessments) receiving modafinil (400mg) will demonstrate significantly greater overall retention, and attendance to CBT sessions than those participants with cognitive function measured at greater than 1 SD below the mean for the MicroCog assessments who are receiving placebo.
Participants receiving active experimental drug (modafinil 400mg) will demonstrate statistically significant reductions in reported methamphetamine craving over participants receiving placebo. Craving outcomes will be measured using a visual analogue scale.
Participants receiving active experimental drug (modafinil 400mg) will demonstrate statistically significant reductions in withdrawal symptoms and somatic complaints compared to participants receiving placebo. These outcomes will be measured using the BSI, the Beck Depression Inventory-II, and the Quality of Well-Being scale.
Participants receiving active experimental drug (modafinil 400mg) will demonstrate statistically significant improvements in mood and global ratings of functioning compared to participants receiving placebo. Global rating outcomes will be completed at baseline, treatment termination, and follow-up by both the research staff and participants.
Participants receiving active experimental drug (modafinil 400mg) will demonstrate improved neurocognitive functioning, particularly impulse control, as measured via response inhibition using the Stop-Signal Task, compared to participants receiving placebo.

Exploratory analyses will also be conducted to identify potential genetic variants associated with treatment response to modafinil for MA dependence. Candidate genes implicated by previous research as being involved in the pathogenesis of MA dependence and/or the molecular mechanism of modafinil (for example, genes for neurotransmitter receptors and transporters, including dopamine, norepinephrine, GABA, and glutamate, as well as genes for enzymes involved in the metabolism of these neurotransmitter, such as catechol-O-methyltransferase and monoamine oxidase A) will be sequenced in order to determine the frequency of known single nucleotide polymorphisms (SNPs), as well as potentially identify novel SNPs, in these genes among MA dependent participants. Initial analyses will focus on genes involved in the dopaminergic pathway, given the importance of dopamine in the neurobiology of MA dependence, but additional genes may also be assessed. SNPs associated with response to modafinil will be identified in order to generate hypotheses for future pharmacogenomic studies.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

18 years of age or older;
meet DSM-IV criteria for methamphetamine dependence;
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 and for one month after discontinuation of study medication (modafinil may reduce the effectiveness of steroidal contraceptives both during administration and for one month after discontinuation).

Exclusion Criteria:

have a medical condition that, in the study physician's judgment, may interfere with safe study participation (e.g., active TB, unstable cardiac, renal, or liver disease, unstable diabetes, or elevated liver enzymes (SGOT or SGPT) greater than 4 times the upper limit of normal);
have a current neurological disorder (e.g., organic brain disease, dementia) or major psychiatric disorder not due to substance abuse (e.g., schizophrenia or bipolar illness) as assessed by the SCID and a medical history which would make study agent compliance difficult or which would compromise informed consent, or recent (past 30 days) history of suicide attempts and/or current serious suicidal intention or plan as assessed by the SCID and the BDI-II;
currently on prescription medication that is known to interact with the study drug;
have current dependence on cocaine, opiates, alcohol, or benzodiazepines, as defined by DSM-IV-TR criteria;
have a history of alcohol dependence within the past three years;
have a history of mitral valve prolapse, left ventricular hypertrophy, cardiac arrhythmias, angina, myocardial infarction, acute coronary syndrome (unstable angina), cardiac syncope or presyncope, or any EKG abnormalities that suggests the presence of one of these conditions;
have a systolic blood pressure greater than 160, a diastolic blood pressure greater than 100 (i.e. cutoffs for stage 2 hypertension), and a heart rate greater than 70% of the maximum heart rate expected for their age (0.70(220-age)) at any of the study visits.
any other circumstances that, in the opinion of the investigators, would compromise participant safety;
have a history of sensitivity to modafinil.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00469508

Locations

United States, California
UCLA Hollywood Clinic
Hollywood, California, United States, 90038

Sponsors and Collaborators

National Institute on Drug Abuse (NIDA)

Investigators

Principal Investigator:

Steve Shoptaw, Ph.D.

University of California, Los Angeles

More Information

No publications provided

Responsible Party:	UCLA Department of Family Medicine ( Steven Shoptaw )
Study ID Numbers:	P50 DA018185-03, P50 DA018185-03, DPMCDA
Study First Received:	May 3, 2007
Last Updated:	September 3, 2009
ClinicalTrials.gov Identifier:	NCT00469508 History of Changes
Health Authority:	United States: Food and Drug Administration; United States: Data and Safety Monitoring Board; United States: Research Advisory Panel of California; United States: UCLA Human Subjects Protection Committee (Institutional Review Board); United States: National Institute on Drug Abuse

Keywords provided by National Institute on Drug Abuse (NIDA):

Methamphetamine
Modafinil
Medication development
Contingency Management

Additional relevant MeSH terms:

Dopamine Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Neurotransmitter Agents
Adrenergic Agents
Molecular Mechanisms of Pharmacological Action
Adrenergic Uptake Inhibitors
Sympathomimetics
Physiological Effects of Drugs
Central Nervous System Stimulants
Protective Agents

Neuroprotective Agents
Modafinil
Pharmacologic Actions
Methamphetamine
Autonomic Agents
Therapeutic Uses
Amphetamine
Dopamine Agents
Peripheral Nervous System Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on November 22, 2009