The COMBINE Study: Design and Methodology Stephanie S. O’Malley, Ph.D. for The COMBINE Study Research Group JAMA Vol. 295, , 2006 (May 3 rd )

Study Design Randomized clinical trial 11 clinical centers 1,383 participants with DSM-IV alcohol dependence Participants were randomized to one of 9 treatment conditions

Two Types of Counseling during 16 weeks of treatment Medical Management (MM) Combined Behavioral Intervention (CBI)

Medication Conditions: 8 Cells Acamprosate + Naltrexone Acamprosate Only (+ Naltrexone placebo) Naltrexone Only (+ Acamprosate placebo) Double Placebo All received Medical Management (MM) Half also got behavioral counseling (CBI) Medications were administered double blind

Cell 9: No Pills, No MM Besides the 8 groups taking medications One group received: –Behavioral counseling –No pills –No medical management

Treatment Group Combinations (1383 Randomized participants)

Study Sample

Inclusion Criteria DSM IV alcohol dependence At least 4, but no more than 21, abstinence days prior to randomization Drinking more than 21 drinks per week with at least 2 heavy drinking days in last 30 Major Axis 1 Psych diagnosis Psych disorder requiring medication Other substance abuse (except MJ, nicotine) in last 90 days and clean UDS Unstable medical conditions including LFT’s greater than 3x normal Exclusion Criteria

Participant (n=1383) Characteristics at Baseline

Drinking and Severity Measures at Baseline

Medication Dosing Target Doses and Procedures –Naltrexone 100 mg daily or placebo, given as two 50 mg tablets orally in AM –Acamprosate 3 grams (3000 mg) or placebo given as two 500 mg tablets orally in AM, mid-day, and PM –Blister packed to enhance compliance –Pill counts for compliance were obtained Rationale For Doses –Naltrexone: 100 mg doses may reduce effects of missed doses and provide greater efficacy than 50 mg –Acamprosate: 3 gram dose found effective in Lipha U.S. clinical trial –Pilot work demonstrated that the combination was well tolerated at these doses (Johnson et al., 2003;Combine Research Group, 2003)

Medication Dosing (continued) –Dose reductions were allowed to try to retain patients in treatment and we re-challenged them when practical –Patients who discontinued meds (or therapy) were not dropped from the protocol and continued to be assessed

Behavioral Interventions Medical Management Sessions –By a licensed health care professional 14 physicians, 28 nurses, 1 physician assistant, 1 clinical pharmacist –Initial visit 45 minutes modeled after a new patient visit –Subsequent visits were 20 minutes on average –Up to 9 sessions scheduled weekly for 1 month, bi- weekly for 3 months and once in the final month –Median number of sessions attended = 9

Behavioral Interventions Combined Behavioral Intervention –Licensed behavioral health specialists, all with at least a masters degree –Up to twenty 50-minute sessions, the frequency and number negotiated with the patient –Median number of sessions attended =10

Schedule of Assessments Baseline In-treatment at 9 MM visits In-treatment: 2, 4 months Post-treatment follow-up: 8, 12, 16 months

Assessment Domains Screening / Eligibility Medical / Physiological / Laboratory Treatment-Related Expectancies Alcohol Consumption Alcohol / Drug Involvement Craving Motivation Psychological / Psychiatric Mutual Help Involvement Quality of Life Service Utilization Treatment Compliance and Process

Primary Outcome Measures Percent Days Abstinent (not drinking) (PDA) Time to first heavy drinking day –Males: 5 drinks in one day –Females: 4 drinks in one day

Statistical Methods PDA: Mixed effect linear models –Intention to treat population: all randomized patients with any post-randomization drinking data Time to Relapse to Heavy Drinking: Proportional hazards models –Intention to treat population: all randomized patients (loss to follow-up treated as relapse) Family-wise error control:  =.05, two-tailed for each main effect and interaction Bonferroni correction for two co-primary endpoints leading to an  =.025 for each primary measure

Statistical Analysis Primary analyses –Based on 16 week treatment period Secondary analysis for –CBI without pills comparisons –1 year post-treatment period Primary efficacy analysis –Traditional factorial ANOVA model fitting and evaluating main effects and interactions

Treatment Group Combinations Acamprosate Main Effect

Treatment Group Combinations Naltrexone Main Effect

Treatment Group Combinations CBI Main Effect

Treatment Group Combinations Naltrexone x CBI Interaction