1. One-Year Post-Treatment COMBINE Study Drinking Outcomes Dennis M. Donovan, Ph.D. for the COMBINE Study Research Group Research Society on Alcoholism Baltimore, Maryland June 27, 2006

2. Rationale for Examining Outcomes from Pharmaco- and Behavioral Therapies Beyond the Active Treatment Phase Most pharmacotherapy trials for alcoholism have focused on outcomes over a relatively brief 8 to 16 week active treatment phase The longer term effects of such medications, once they have been discontinued, have not been widely studied, especially when there are possible interactions with psychosocial interventions Existing data suggest that the effectiveness of naltrexone (e.g., O’Malley, et al., 1996; Anton, et al, 2001) and acamprosate (e.g., Poldrugo, 1997; Tempesta, et al., 2000) wanes over time once active use is discontinued As a public health issue it would be important to know the effectiveness of these medications and behavioral therapies alone and in combination over the longer term

3. Naltrexone as an Adjunctive Treatment to Cognitive Behavioral Therapy for Outpatient Alcoholics During treatment Nonrelapse (%) Naltrexone (n=68) (44.1%) Placebo (n=63) (31.8%) P=.048P=.015 TreatmentFollow-up Post-treatment Days Anton RF et al. J. Clin. Psychopharmacol. 21: 72-77, 2001.

4. Follow-Up Assessment Points in COMBINE Active Treatment 1- 16 26 52 68 Follow-Up Assessment Points Weeks from Randomization

5. Completion Rates for Form-90 Drinking Data During 1-Year Follow-up Period Week 26 – 91.8% Week 52 – 88.0% Week 68 – 82.3% There were no significant differences across groups at any of the three follow-up points (p>.25).

6. Comparison Across Groups on Potential Post- Treatment Confounding Variables Received treatment in a hospital or other facility Visited emergency department for alcohol treatment Received medication for drinking Received psychiatric medication Received medication for detoxification Attended AA meetings 11% 6% 11% 17% 6% 33.2% No differences were found across treatment combinations on the percent of subjects who during the 1-year follow-up period:

7. 1-year Post-Treatment Drinking Outcomes in the COMBINE Study InterventionMM OnlyCBI Treatment CellN PlaceboNalt.Acam.Nalt. + Acam. PlaceboNalt.Acam.Nalt.+ Acam. No Pills Number randomized1383 153154152148156155151157 Drinking Outcomes Percent Days Abstinent, mean (s.d.) 59.4 (32.4) 68.1 (31.5) 62.7 (31.5) 64.4 (31.7) 67.5 (32.9) 66.0 (31.4) 64.2 (31.4) 68.6 (31.7) 60.9 (32.6) Return to Heavy drinking, % 84.378.680.982.480.878.777.578.386.6 Good Clinical Outcome, % 37.748.244.445.847.150.448.7 48.746.8

8. Percent Days Abstinent (PDA) Overall, PDA declined in all groups over the 1-year follow-up period There were no main effects for naltrexone or acamprosate There was a trend (p =.08) for those receiving CBI to have achieved a higher PDA (66.9%) than those not receiving CBI (63.8%) Exploratory “time slice” analyses indicated that there was a significant difference between those receiving and not receiving CBI at the Week 26 follow-up, but this difference is no longer significant at the 52 or 68 Week follow-ups While the direction of the differences were the same as in the active treatment phase, the naltrexone x CBI interaction was no longer significant (p =.28) No other interaction effects were significant

9. Time Slice Comparison of PDA for CBI versus No CBI P <.03 PDA P =.21 P =.31

10. Acamprosate Main Effect

11. Naltrexone Main effect HR = 0.77, 97.5% CI, 0.58 – 1.02, p =.04: Those receiving naltrexone had less risk of returning to at least one heavy drinking day over time

12. CBI Main Effect

13. Percent of Clients with “Good Clinical Outcomes” Based on Receiving or Not Receiving CBI Follow-Up Point Percent of Subjects OR = 0.80 (0.65 – 0.99), p =.04

14. “CBI without Pills or MM” Analysis

15. Overall Percent Days Abstinent Comparing CBI Only to Placebo+MM and Placebo+MM+CBI p = 0.08 Percent Days Abstinent

16. Time to Relapse: Placebo+MM vs Placebo+MM+CBI vs CBI Only P = 0.18.

17. Percent of Clients with “Good Clinical Outcomes”: Placebo+MM vs Placebo+MM+CBI vs CBI Only Follow-Up Point Percent of Subjects

18. Summary Overall, there is a significant time effect, in which post-treatment drinking increases over time The relative efficacy of naltrexone demonstrated in the active treatment phase persists into the post-treatment period There appears to be an emergence of an effect for CBI in the period following the active treatment phase The differences between the CBI only condition (“Cell 9” ) and its comparison groups dissipated following treatment and were no longer significant

19. Implications Alcohol dependence is a chronic disease and thus may require chronic treatment for long-term management Naltrexone, either as continued daily use or potentially as targeted medication only when craving alcohol, may serve as an important adjunct as part of this long-term management The emergent benefits of CBI began to diminish beyond Week 26, suggesting that some form of continuing care or “booster sessions,” potentially as minimal as periodic phone contacts, would be warranted to help maintain these benefits.

21. Completion Rates for Form-90 Drinking Data During 1-Year Follow-up Period Treatment ConditionWeek 26Week 52Week 68 Placebo91.587.681.9 Acamprosate92.187.582.8 Naltrexone89.086.478.5 Acamp+Naltrex93.987.881.9 Placebo+CBI Therapy92.389.184.9 Acamp+CBI Therapy93.490.786.0 Naltrex+CBI Therapy92.989.783.6 Acamp+Naltrex+CBI Therapy 89.885.479.1 Overall91.888.082.3  2, df=7 8.877.158.21 p-value0.260.410.52

22. 6-month Follow-up of Naltrexone and Psychotherapy Some, but not all benefits from short-term treatment persist after discontinuation of treatment Effect of naltrexone on abstinence lasted only 1 month post-treatment Alcohol dependence is a chronic disease and thus may require chronic treatment for long-term management O’Malley SS et al. Arch Gen Psychiatry. 1996;53:217-224.

23. 26 Mean no. of heavy drinking days Group x Change in Slope, P <.08 Group x Slope, P<.03 TreatmentFollow-up Naltrexone as an Adjunctive Treatment to Cognitive Behavioral Therapy for Outpatient Alcoholics Week Naltrexone Placebo Predictions based on piecewise random regression model. Anton RF et al. J. Clin. Psychopharmacol. 21: 72-77, 2001 Heavy Drinking Days by Study Week

24. Nonrelapse (%) Within CBT: NTX better than PLC P<.05 Treatment Follow-up Naltrexone as an Adjunctive Treatment to Cognitive Behavioral Therapy for Outpatient Alcoholics Days Anton RF unpublished data. Time to First Relapse (heavy drinking day) Naltrexone main effect P<.05 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 115294357718599113127141155169183197211225239253267281 Naltrexone/CBT Naltrexone/MET Placebo/CBT Placebo/MET

25. Survival Analysis to First Relapse* Over 1-year Follow-up Period Rubio, et al., 2001 *Five or more drinks per day

26. Percentage of Days of Heavy Drinking from Baseline to 1-year Follow-up Rubio, et al., 2001

27. Comparison Across Groups on Potential Post-Treatment Confounding Variables No differences were found across treatment combinations with respect to the percent of subjects who during the follow-up period: – Received treatment in a hospital or other facility –Visited emergency departments for alcohol treatment –Received medication for drinking –Received psychiatric medication –Received medication for detoxification –Attended AA meetings

28. Adjusted Mean Percent Days Abstinent at Week 68 for Combinations of Pharmacotherapies and CBI Percent Days Abstinent (PDA) Combinations of Acamprosate and Naltrexone

29. Percent of Clients with “Good Clinical Outcomes” Based on Receiving or Not Receiving CBI Follow-Up Point Percent of Subjects OR = 0.80 (0.65 – 0.99), p =.04

30. Percent Days Abstinent Comparing CBI Only to Placebo+MM and Placebo+MM+CBI p = 0.08 Percent Days Abstinent

31. Percent of Clients with “Good Clinical Outcomes” Placebo+MM vs Placebo+MM+CBI vs CBI Only Follow-Up Point Percent of Subjects