Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence

(The COMBINE Study): A Randomized Controlled Trial

Overview of Within Treatment Primary Outcomes

Raymond F. Anton, MD

for

The COMBINE Study Research Group

JAMA Vol. 295,17. 2003-2017, 2006 (May 3rd)

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 Measures

Global Clinical Outcome Craving – OCDS

Other Drinking MeasuresBiological Markers (%CDT, GGT)

Participant Adherence / Retention

Medication Adherence

(%)

Treatment Withdrawals

*(%)

Drop out or Lost to follow-up

(%)

Placebo 80.1 22.2 1.3

Acam 77.7 28.9 2.6

Nal 80.1 24.0 1.9

Acam+Nal 75.9 23.0 2.0

Placebo+CBI 79.2 13.5 3.2

Acam+CBI 79.2 16.6 0.7

Nal+CBI 77.5 14.8 2.6

Acam+Nal+CBI 75.1 20.4 3.2

CBI, No Pills 27.4 2.5

*MM vs. CBI, p=0.05

Completion of Drinking Assessments

% Complete

Placebo 94.1

Acam 95.4

Nal 92.2

Acam+Nal 95.3

Placebo+CBI 94.2

Acam+CBI 95.4

Nal+CBI 95.5

Acam+Nal+CBI 92.4

CBI, No pills 94.9

Reasons for Treatment Withdrawal

Adverse

Event (%)

Serious Adverse

Event (%)

Taking Disallowed Medication

(%)

Clinical Deterioration

(drinking) (%)

Placebo 1.3 0.7 0.7 0.7

Acam 3.3 2.0 0.0 2.6

Nal 3.9 1.3 0.0 0.0

Acam+Nal 2.7 0.7 0.7 0.0

Placebo+CBI 0.6 1.3 0.0 1.3

Acam+CBI 0.0 2.0 0.7 2.0

Nal+CBI 4.0 0.7 1.3 1.3

Acam+Nal+CBI 4.6 1.3 0.0 1.3

Adverse Events (SAFTEE Interview)

Placebo

(n=309)

Acamprosate

(n=303)

Naltrexone

(n=309)

Acamprosate + Naltrexone

(n=305)

Event % % % % P

Nausea 21 24 34 42*** <0.001

Vomiting 9 9 15* 18 ** <0.001

Diarrhea 35 65 *** 31 * 56 *** <0.001

Decreased Appetite

13 19 21 25 *** 0.002

Somnolence 24 31** 37*** 31 * 0.003

AST or ALT

5 times upper limit normal

0 0 2 * 2 * 0.02

Withdrawals due to adverse events

1 3 4 4 * 0.09

* Nominal p-values for placebo vs. active drug comparisons: *p<0.05, **p<0.01, ***p<0.001

Results

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

Relapse to Heavy Drinking, Naltrexone Effect

Relapse to Heavy Drinking, Naltrexone x CBI Interaction

Relapse to Heavy Drinking at Week 16

Relapse to Drinking (first drink), Acamprosate Effect

Acamprosate Secondary Outcomes Effect Size

Naltrexone Secondary Outcomes Effect Size

CBI Secondary Outcomes Effect Size

Secondary Outcomes Naltrexone x CBI

Composite Clinical Outcome* during Last 8 Weeks of Treatment

Naltrexone by CBI interaction, p=0.02

*No more than 2 daysheavy drinking over eight weeks and no more than 11 (women) or 14 (men) drinks per week and no alcohol problems

% Good Clinical Outcomes (16w)

58.2

73.7

60.8

78.4

71.3

74.4 74.473.5

60.6

56

58

60

62

64

66

68

70

72

74

76

78

80

Placebo N A

N+A

CBI+P

CBI+N

CBI+A

CBI+N+A

CBI

CBI X Naltrexone interaction: p = .02

Odds Ratios for Good Clinical OutcomeNaltrexone Comparisons

Odds Ratios for Good Clinical OutcomeOdds ratios for Good Clinical Outcome Acamprosate Comparisons

Summary

• There was marked improvement in all groups• Acamprosate showed no greater efficacy than placebo• In the context of medical management both naltrexone and

CBI were more efficacious than placebo• There was no increase in efficacy by combining acamprosate

with naltrexone or by adding either medication to CBI

Implications

• Alcohol dependent patients may benefit from being treated by a health care professional who adopts medical management and utilizes either naltrexone and/or refers to a specialized alcohol counselor using CBI-like techniques.

• This broadens options for treatment for those not previously being treated.

Limitations

• Select sample of outpatient alcoholics – generalizability to others needs to be done with caution

• Doses used were higher than those in the NDA for FDA approval

• MM delivered in the context of substance abuse facilities not in “primary care settings”

• Potential of assessment effects adding to overall response

• Only a few subjects were in need of medical alcohol detoxification - ? Implications for acamprosate

• Therapists were trained and monitored - ? Implications for CBI in clinical settings

Future Data

• Evaluating predictors of treatment response including genetic markers of response

• Evaluation of the Economic Impact of the Treatments over an extended period of time-Cost Effectiveness Study

• Evaluating what components of the therapies accounted for greater response including compliance and adherence

• Data presented in this presentation were collected as part of the multisite COMBINE trial sponsored by:

National Institute on Alcohol Abuse and Alcoholism

• 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/.

Acknowledgements