The COMBINE Study: Results and ImplicationsThe COMBINE Study: Results and Implications

Social Work Research and Multidisciplinary Studies: Findings Social Work Research and Multidisciplinary Studies: Findings from Major Landmark Studiesfrom Major Landmark Studies

SSWR Annual ConferenceSSWR Annual ConferenceSan Francisco, CA San Francisco, CA January 13, 2007January 13, 2007

Allen Zweben, DSWAllen Zweben, DSWAssociate Dean and Professor Associate Dean and Professor

Columbia University School of Social WorkColumbia University School of Social Work

Primary Outcome Manuscript Writing Group

Raymond F. Anton, MD (Study Chair) Richard Longabaugh, EdD

Stephanie S. O’Malley, PhD (Former Study Chair)

Barbara J. Mason, PhD

Domenic A. Ciraulo, MD Margaret E. Mattson, PhD (NIAAA)

Ron A. Cisler, PhD William R. Miller, PhD

David Couper, PhD Helen M. Pettinati, PhD

Dennis M. Donovan, PhD Carrie L. Randall, PhD

David R. Gastfriend, MD Robert Swift, MD

James D. Hosking, PhD Roger D. Weiss, MD

Bankole A. Johnson, MD, PhD Lauren D. Williams, MD

Joseph S. LoCastro, PhD Allen Zweben, DSW

Primary Outcome Manuscript Writing Group

• Raymond F. Anton, MD– Center for Alcohol Programs, Medical University of South Carolina,

Charleston, SC • Stephanie S. O’Malley, PhD

– Substance Abuse Treatment Unit, Yale University School of Medicine, New Haven, CT

• Domenic A. Ciraulo, MD– Boston University School of Medicine, Boston, Massachusetts

• James D. Hosking, PhD– Collaborative Studies Coordinating Center, University of North Carolina,

Chapel Hill, NC• Dennis M. Donovan, PhD

– Addictions Treatment Center, University of Washington, Seattle, WA

Principal Investigators

Primary Outcome Manuscript Writing Group (continued)

• David R. Gastfriend, MD– Formerly: Massachusetts General Hospital, Boston, MA; currently:

Alkermes, Inc. • Bankole A. Johnson, MD, PhD

– Formerly: University of Texas Health Science Center at San Antonio, TX; currently: University of Virginia Health Systems, Charlottesville, VA

• Richard Longabaugh, EdD– Roger Williams Medical Center, Brown University, Providence, RI

• Barbara J. Mason, PhD– Formerly: University of Miami School of Medicine, Miami, FL; currently:

The Scripps Research Institute, La Jolla, CA

• Margaret E. Mattson, PhD– National Institute of Alcohol Abuse and Alcoholism, Bethesda, MD

Primary Outcome Manuscript Writing Group (continued)

• William R. Miller, PhD– Center on Alcoholism, Substance Abuse and Addiction, University of

New Mexico, Albuquerque, NM • Helen M. Pettinati, PhD

– Treatment and Research Center, University of Pennsylvania, Philadelphia, PA

• Robert Swift, MD – Roger Williams Medical Center, Brown University, Providence, RI

• Roger D. Weiss, MD– Harvard University/McLean Hospital, Belmont, MA

• Lauren D. Williams, MD– University of Miami School of Medicine, Miami, FL

• Allen Zweben, DSW– Formerly: University of Wisconsin - Milwaukee, Milwaukee, WI;

currently: Columbia University School of Social Work, New York, NY

Primary Outcome Manuscript Writing Group (continued)

• Ron A. Cisler, PhD– University of Wisconsin - Milwaukee, Milwaukee, WI

• David Couper, PhD– Collaborative Studies Coordinating Center, University of North Carolina,

Chapel Hill, NC• Joseph S. LoCastro, PhD

– VA Boston Healthcare System/Boston University School of Medicine, Boston, MA

• Carrie L. Randall, PhD – Center for Alcohol Programs, Medical University of South Carolina,

Charleston, SC

Co-Investigators

COMBINE Centers

Rationale for COMBINE

• Recent advances have occurred in the development of pharmacological and behavioral treatments for alcohol dependence

• The hypothesis that pharmacological and behavioral treatments may enhance each other and yield optimal improvement rates requires investigation

• COMBINE evaluated the efficacy of naltrexone, acamprosate, and specialized behavioral counseling individually and in combination.

Promising BehavioralTreatments: Moderate Intensity Models

• Project MATCH designed three treatments to be nonoverlapping in terms of content. COMBINE will incorporate the putative strengths of each of these treatments.

– Motivational enhancement– Cognitive behavioral skills training– Facilitation in mutual-help groups

• Patients receiving CBI could have a maximum of 20 sessions (50 min.) over 16 weeks of manual driven therapy by masters level, trained and certified counselors.

Medical Management (MM)

• Ecological validity• Enhancement of medication compliance and support for

sobriety• Prior support for effectiveness• Cost effective alternative to CBI• Lower intensity to produce differential effects• Available manuals• All subjects (except one group – CBI only) received 9

sessions (15-20 min.) of MM by a health care professional (physician, nurse, physician assistant)

Rationale For Choice Of Drugs

• Strong evidence of efficacy for both naltrexone and acamprosate

• Clinical observations suggest that the drugs may work differently. – Acamprosate may be effective early in treatment

(treatment of prolonged withdrawal or cue-induced craving)

– Naltrexone may block positive reinforcing effects of ethanol and reduce craving.

COMBINE: Standardization of Psychosocial Interventions

• Permits a carefully controlled evaluation of the efficacy of the medications and of the behavioral interventions

• Published research on acamprosate has not specified the intensity or content of the psychosocial component of treatment

• Published studies of naltrexone have used more intensive behavioral treatments, and the effectiveness of naltrexone with less intensive treatment is unknown.

Primary Objective• The primary objective of COMBINE is to assess the

efficacy of combinations of behavioral and pharmacological interventions in the treatment of alcohol dependence.

Are naltrexone and acamprosate effective in a large, well controlled, multi-center trial?

Is a specialist delivered behavioral intervention more effective than an intervention provided by health care professionals?

Study Design

• Randomized clinical trial

• 11 clinical centers

• 1,383 participants with DSM-IV alcohol dependence

Study Design

• COMBINE used an additive design to test whether combinations of behavioral and pharmacological interventions are more effective than medical management and placebo in the treatment of alcohol problems.

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

Primary Outcome Measures

• Percent Days Abstinent during treatment period

• Time to relapse (number relapsed) to heavy drinking– Males: 5 drinks / day; Females: 4 drinks / day

Secondary Outcome MeasuresGlobal Clinical Outcome -No more than 2 heavy drinking days, 11 (women) or 14 drinks (men) per week, and no alcohol problems in a given follow-up interval

Dosing• Target Doses

– Naltrexone 100 mg daily, given as two 50 mg tablets orally in AM

– Acamprosate 3 grams (3000 mg) given as two 500 mg tablets orally in AM, mid-day, and PM

Schedule of Assessments

• Pre-Intake Screening• Baseline (Drinking, Physical, Social, Lab)• Within Treatment – weekly drinking, craving,

adverse medication events• Within Treatment -- Month 2 • Post-Treatment Follow-Up

– Weeks 16, 26, 52, and 68 after randomization

Statistical Methods

• Mixed effect linear models for PDA– Intention to treat population: all randomized patients

with any post-randomization drinking data

• Proportional hazards models for time to relapse to heavy drinking– Intention to treat population: all randomized patients

(loss to follow-up treated as relapse)

Study Sample

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 28.8

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

Retention and Adherence

Adherence and Validity Measures

• 94% of 16 week, and 82% of 1 year follow-up drinking data were obtained

• Dose reductions: 8% placebo, 12% acamprosate, 12% naltrexone, 21% naltrexone plus acamprosate

• Mean medication adherence: naltrexone 85.4% , acamprosate 84.2%

• Median visits: CBI = 10, MM = 9• Therapist (CBI and MM) protocol adherence on

random tapes by independent raters was 6 on a 7 point scale

PDA during Treatment (16 weeks)

Acamprosate Main Effect

Placebo (n=616)

Acamprosate (n=605)

P

Adj. mean (s.d.)* 77.6 (25.32) 78.4 (25.31) 0.61

Naltrexone Main Effect

Placebo (n=610)

Naltrexone (n=611)

P

Adj. mean (s.d.) 77.2 (25.42) 78.8 (25.46) 0.25

CBI Main Effect

No CBI (n=609)

CBI (n=614)

P

Adj. mean (s.d.) 77.8 (25.36) 78.2 (25.52) 0.82

*Least-squares means (standard deviation) adjusting for clinical center, and baseline PDA, fitting all main effects and two- and three-factor interactions.

PDA during Treatment (continued)Acamprosate x Naltrexone Interaction

Placebo Acamprosate Placebo

(n=307) Naltrexone

(n=309) Placebo (n=303)

Naltrexone (n=302)

P

Adj. mean (s.d.) 77.0 (25.82) 78.2 (25.31) 77.3 (25.37) 79.5 (25.37) 0.74

Acamprosate x CBI Interaction

No CBI CBI Placebo

(n=307) Acamprosate

(n=300) Placebo (n=309)

Acamprosate (n=305)

P

Adj. mean (s.d.) 77.3 (25.41) 77.9 (24.90) 78.4 (25.84) 78.4 (25.50) 0.84

Naltrexone x CBI Interaction

No CBI CBI Placebo

(n=305) Naltrexone

(n=302) Placebo (n=305)

Naltrexone (n=309)

P

Adj. mean (s.d.) 75.1 (25.46) 80.6 (25.37) 79.2 (25.32) 77.1 (25.49) 0.009

PDA Effect Size at Week 16

Relapse to Heavy Drinking During Treatment (16 weeks)

Acamprosate Main Effect

Placebo (n=618)

Acamprosate (n=608)

P

Percent 70.1 69.6 0.23

Naltrexone Main Effect

Placebo (n=612)

Naltrexone (n=614)

P

Percent 71.4 68.2 0.02

CBI Main Effect

No CBI (n=607)

CBI (n=619)

P

Percent 69.7 70.0 0.16

Relapse to Heavy Drinking by Week 16 (continued)

Acamprosate x Naltrexone Interaction

Placebo Acamprosate Placebo

(n=309) Naltrexone

(n=309) Placebo (n=303)

Naltrexone (n=305)

P

Percent 73.4 67.0 69.6 69.5 0.40

Acamprosate x CBI Interaction

No CBI CBI Placebo

(n=307) Acamprosate

(n=300) Placebo (n=311)

Acamprosate (n=308)

P

Percent 71.3 68.0 68.8 71.1 0.66

Naltrexone x CBI Interaction

No CBI CBI Placebo

(n=305) Naltrexone

(n=302) Placebo (n=307)

Naltrexone (n=312)

P

Percent 73.1 66.2 69.7 70.2 0.15

Composite Clinical Outcome* during Last 8 Weeks of Treatment

*No more than 2 daysheavy drinking and nomore than 11 (women)or 14 (men) drinks perweek and no alc. problems

*Naltrexone by CBI interaction, p=0.02

Summary

• There was marked improvement in all groups

• Acamprosate showed no greater efficacy than placebo. This is surprising since previous studies suggested otherwise

• There was no increase in efficacy by combining acamprosate with naltrexone

• Adding naltrexone to CBI did not prove to be more effective as indicated in previous studies

• In the context of medical management both naltrexone and CBI were more efficacious than placebo

• Effects observed during treatment were still present but waned during the one year follow-up

Implications

Take Home Message:

• Alcohol dependent patients may benefit Alcohol dependent patients may benefit from being treated by a health care from being treated by a health care professional who adopts medical professional who adopts medical management and utilizes either naltrexone management and utilizes either naltrexone and/or refers to a specialized alcohol and/or refers to a specialized alcohol counselor using CBI-like techniques. This counselor using CBI-like techniques. This broadens options for treatment for those broadens options for treatment for those not previously being treatednot previously being treated. .

Data presented in this report were collected as part of the multisite COMBINE trial sponsored by the National Institute on Alcohol Abuse and Alcoholism, in collaboration with the COMBINE Study Research Group.

Acamprosate, naltrexone and their matching placebos were kindly donated by Lipha Pharmaceuticals.

Data and Safety Monitoring was conducted by: R Hingson ScD C Meinert PhDR Kadden PhD R Saitz MD MPHM McCaul PhD Gerard Connors PhD

A full listing of the staff of the COMBINE Study can be found at http://www.cscc.unc.edu/combine/.