the combine study: design and methodology stephanie s. o’malley, ph.d. for the combine study...
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The COMBINE Study:Design and Methodology
Stephanie S. O’Malley, Ph.D.
for
The COMBINE Study Research Group
JAMA Vol. 295,17. 2003-2017, 2006 (May 3rd)
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 Counselingduring 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)
Medical Management (n=607)
Placebo Acamprosate Placebo 153 152 Naltrexone 154 148
Medical Management + CBI (n=619)
Placebo Acamprosate No Pills Placebo 156 151 Naltrexone 155 157 No Pills 157
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
Mean s.d.
Age 44 10.2
N %
Male 955 69.1
Married 581 42.0
Education > H.S. 398
71.2
Employed 1006 72.7
Non-minority 1055 76.3
Drinking and Severity Measures at Baseline
Mean s.d.
Drinking days, % in last 30 days 74.9 24.92
Drinks per drinking day 12.5 7.81
ADS Score 16.7 7.44
DSM-IV symptoms 5.5 1.49
Total OCDS Score 20.0 9.59
Total DrInC Score 47.6 20.45
GGT, % > normal (63 IU/L) 31.4
CDT, % > normal (2.6%) 52.1
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 CombinationsAcamprosate Main Effect
Medical Management (n=607)
Placebo Acamprosate Placebo 153 152 Naltrexone 154 148
Medical Management + CBI (n=619)
Placebo Acamprosate Placebo 156 151 Naltrexone 155 157
Treatment Group CombinationsNaltrexone Main Effect
Medical Management (n=607)
Placebo Acamprosate Placebo 153 152 Naltrexone 154 148
Medical Management + CBI (n=619)
Placebo Acamprosate Placebo 156 151 Naltrexone 155 157
Treatment Group CombinationsCBI Main Effect
Medical Management (n=607)
Placebo Acamprosate Placebo 153 152 Naltrexone 154 148
Medical Management + CBI (n=619)
Placebo Acamprosate Placebo 156 151 Naltrexone 155 157
Treatment Group CombinationsNaltrexone x CBI Interaction
Medical Management (n=607)
Placebo Acamprosate Placebo 153 152 Naltrexone 154 148
Medical Management + CBI (n=619)
Placebo Acamprosate Placebo 156 151 Naltrexone 155 157