1. Evaluating Cocaine Use Outcome Measures: Relationships with Long Term Cocaine Use and Functioning Brian D. Kiluk, Ph.D. Kathleen M. Carroll, Ph.D. Yale University School of Medicine Supported by NIDA Supplement to R01 DA15969 MOST Meeting March 25, 2015

2. Overview Evaluate 15 candidate cocaine use treatment outcome measures Pooled data across 5 RCTs Criteria ▫Sensitivity to medication effects ▫Sensitivity to behavioral therapies ▫Relationship with post-treatment cocaine use ▫Relationship to measures of general functioning Carroll, Kiluk et al., (2014). Towards empirical identification of a clinically meaningful indicator of treatment outcome for drug addiction: Features of candidate indicators and evaluation of sensitivity to treatment effects and relationship to one year cocaine use follow-up outcomes. Drug and Alcohol Dependence, 137, 3-19.

3. Multiple cocaine treatment RCTs, 2000-present Study 1 “Cocaine-alcohol” Carroll, K.M., Nich, C., Ball, S.A., et al. 1998. Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram. Addiction 93, 713-728. Carroll, K.M., Nich, C., Ball, S.A., et al. 2000. One year follow-up of disulfiram and psychotherapy for cocaine-alcohol abusers: Sustained effects of treatment. Addiction 95, 1335-1349. Study 2 “M&M” Carroll, K.M., Fenton, L.R., Ball, S.A.,et al. 2004. Efficacy of disulfiram and cognitive- behavioral therapy in cocaine-dependent outpatients: A randomized placebo controlled trial. Archives of General Psychiatry 64, 264-272. Study 3 “TSF/Disulfiram” Carroll, K.M., Eagan, D., Nich, C., et al. 2012,. Efficacy of Twelve Step Facilitation and disulfiram for cocaine-using methadone-maintained individuals. Drug and Alcohol Dependence, 126, 224-231 Study 4 “CBT4CBT1” Carroll, K.M., Ball, S.A., Martino, S., et al. 2008. Computer-assisted cognitive-behavioral therapy for addiction. A randomized clinical trial of 'CBT4CBT'. American Journal of Psychiatry 165, 881-888. Carroll, K.M., Ball, S.A., Martino, S., et al. 2009. Enduring effects of a computer- assisted training program for cognitive-behavioral therapy: A six-month follow-up of CBT4CBT. Drug and Alcohol Dependence 100, 178-181 Study 5 “CM Disulfiram” Carroll, K.M., Nich, C., Petry, N.M., et al, under review. Disulfiram and contingency management to enhance CBT for cocaine dependence: effects on cocaine use and preliminary evidence for interactions with DBH polymorphism.

4. Common assessment approach 12 weeks outpatient treatment ▫Behavioral therapies manual guided with independent fidelity checks ▫Medications placebo controlled with riboflavin checks ▫1-3/x weekly urine toxicology screens 1 year follow-up (15 months from randomization) Substance Use Calendar ▫Day by day frequency of cocaine use during entirety of study ▫Average 13% discrepancy from urine results (urine positive, self-report negative) Follow-ups with urine collection at 1, 3, 6, 12 months >80% of the intention to treat sample Addiction Severity Index at each assessment

5. Common follow-up indicators Mean days of cocaine use 1, 3, 6, and 12 month follow ups via Substance Use Calendar Abstinent throughout full follow-up Composite measure of ‘good outcome’ ▫Days of employment problems = 0, Days of legal problems = 0, Days of psych problems=0, Days of cocaine use = 0

6. Study 1 Clinical Mangmt TSFCBT Disulfiram 250 mg/day No medication 121 cocaine- and alcohol dependent outpatients 12 weeks 1 year follow-up Weekly utox Manual guided, fidelity rated Riboflavin for med compliance Outcomes: ▫CBT, TSF > Clinical management ▫Disulfiram > no med

7. Study 2 CBTIPT Disulfiram Placebo N=121 cocaine dependent outpatients 12 weeks Utox 1x week 1 year follow-up Manual-guided with fidelity ratings Double blind placebo control, riboflavin Outcomes ▫CBT>IPT ▫Disulif>placebo

8. Study 3 TAUTAU + TSF Disulfiram Placebo N=112 cocaine-dependent methadone maintained patients 12 weeks Utox 3x week 1 year follow-up Manual-guided with fidelity ratings Double blind placebo control, riboflavin Outcomes ▫TSF>TAU alone ▫No medication effect

9. Study 4 TAUTAU + CBT4CBT N=78 mixed substance users, outpatients, 38 cocaine users. 8 weeks of treatment, 6 month follow-up Utox 2x weekly Outcomes ▫CBT4CBT>TAU alone

10. Study 5 CBTCBT+ CM Disulfiram Placebo N=99 cocaine-dependent outpatients 12 weeks Utox 3x week 1 year follow-up Manual-guided with fidelity ratings Double blind placebo control Outcome: ▫CM+CBT>CBT alone ▫No main effect for disulfiram, interaction with DBH

11. Overview of trials MedicationBehav therapy N for follow- up sample (all > 80%) % female % ethnic minority Mean days cocaine use/past 28 % not working % criminal justice referred Study 1: Coc-Alcohol, Disulfiram v no med CBT v TSF v clinical management 9129%60%1455%24% Study 2: M&M Disulfiram v placebo CBT v IPT 1082535145722 Study 3: TSF- Disulifram, Disulfiram v placebo TSF v no TSF 112413616462 Study 4: CBT4CBT No medCBT4CBT v TAU 38**477688042 Study 5: CM-Dis Disuflriam v placebo CM + CBT v CBT 85316014695 TOTAL4343348135316

12. Outcomes across trials DesignPlatformUrine schedule/ % cocaine free Mean % days abstinent during tx % completely abstinent during treatment 6 month follow-up % good outcome composite 1Coc- Alcohol 3 x 2 RCT Outpatient Coc+alcohol 2x/ 55% 85%19%13% 2 M&M 2 x 2 RCT Outpatient cocaine 1x/ 68% 811213 3 TSF Dis 2 x 2 RCT Methadone cocaine 3x/ 18% 60518 4 CBT4CBT 2 group RCT Outpatient cocaine subgroup only 2x/ 50% 82924 5.CM Disulf 2 x 2 RCT Outpatient cocaine 3X/ 44% 761727

13. Medication effects across indicators No medication Placebo Disulfiram n=36 n=148n=212 Outcome Indicator Type mean or N sd or % mean or N sd or % mean or N sd or % F/X 2 pTukey/phi Days retained in treatment protocol C 37.532.1 53.735.6 58.332.6 6.26.00 Disulf, Placebo >No med Percent negative cocaine urine specimens C 42.641.1 37.536.0 38.936.8 0.37.70 Maximum consecutive days abstinent C 19.518.6 19.123.4 25.726.2 3.2.04 Disulf > Placebo Percent days of abstinence from cocaine C 83.118.0 76.425.3 70.926.9 5.61.00 No med>Placebo Maximum days of continuous abstinence during last two weeks of treatment* C 7.64.5 8.94.7 4.83.03 Disulfiram > Placebo Completely abstinent last two weeks of treatment D 1036% 2924% 7524% 10.39.01 No med > Disulf, placebo 3 or more weeks of continuous abstinence D 925% 6141%9344% 4.52.10 2 or more weeks of continuous abstinence D 1542% 6846%11353% 2.86.24 1 or more weeks of continuous abstinence D 2261% 10672%15875% 2.84.26 Completely abstinent from cocaine during treatment D 514% 1710%2914% 0.26.88 Completed treatment and abstinent in last week D 719% 3524% 7437% 8.27.02 Disulf > no med % reduction (28 days prior/days last 4 weeks) C 62.236.0 60.237.352.839.3 1.78.17 50% reduction in frequency of cocaine use D 925% 0.5437%7033% 1.78.41 75% reduction in cocaine use D 411% 2819%3617% 1.25.54 Report no cocaine use, legal, employment, or psychological problems last 28 days of treatment – ‘good outcome’ D 217% 1913% 1819% 1.18.55

14. Indicators across behavioral therapies Comparison (1) TSF (2)CBT (3)CM (4) n=195n=97n=105n=37 Outcome indicator Mean or n sd or % Mean or n sd or % Mean or n sd or % Mean or n sd or % F/ X 2 pTukey Days retained in treatment protocol 54.233.156.93351.6330.8646.0834.051.13.34 ns Proportion cocaine negative urine specimens.36.37.26.29.49.38.56.388.130.00 1v3, 1v4 2v3, 2v4 Maximum consecutive days abstinent 20.124.323.722.9725.723.5823.7627.721.26.29 ns Percent days of abstinence.72.27.75.24.82.21.81.264.200.011v3 Maximum days of continuous abstinence during participant's last two weeks of treatment 8.14.77.94.539.354.3810.274.632.540.06 ns Completely abstinent last 2 weeks of treatment 5433%2427%4246%14.0054%11.61.009 4 v other, 3 v 2 3+ weeks of continuous abstinence 7438%3435%4543%27.0073%17.85.00 4 v other 2+ weeks of continuous abstinence 9046%4041%5754%29.0078%16.82.001 4 v other 1+ weeks of continuous abstinence 13971%6668%7370%32.0071%4.85.18 ns Completely abstinent from cocaine during treatment 2513%1111%1615%8.0024%3.55.31 ns Completing treatment and abstinent in last week 5631%2628%3537%11.0030%2.15.54 ns % reduction in frequency of cocaine use (28 days prior/days last 4 weeks) 0.530.380.58.39.65.37.62.322.15.09 ns 50% reduction 60.031%2627%3836%15.0041%3.43.33 ns 75% reduction 2312%99%2524%12.0032%18.12.00 3 v other, 4 v other ‘Good outcome’ 2011%812%56%9.0024%8.9.03 4 v other

15. Outcome indicator Days of Cocaine Use in Follow-Up Month Complete Abstinence in FU Good Functioning Status at Follow-Up Month 13612136 Days retained in treatment protocol r -.12-.06-.08.02.05.10.05.08.04 p.01.23.09.76.33.04.35.12.47 Percent cocaine negative urine specimens r -.31-.28-.30-.16.33.29.25.22 p.00.01.00 Maximum consecutive days of abstinence r -.30-.24-.26-.12.30.34.26.24.17 p.00.02.00 Percent days of abstinence r -.39-.37-.35-.24.19.23.21.18.14 p.00.01 Maximum days of consecutive abstinence during last two weeks of treatment r -.46-.35-.30-.21.32.31.33.19.24 p.00 Completely abstinent last two weeks of treatment r -.30-.25-.19-.07.28.29.31.21.19 p.00.25.00 3+ weeks of abstinence r -.33-.30-.28-.16.25.26.24 p.00 2+ weeks of abstinence r -.26 -.28-.14.24.26.22.20 p.00.01.00 1+ week of abstinence r -.27-.22-.24-.10.11.21.17.15.17 p.00.05.02.00 Completely abstinent during treatment r -.14-.08-.11-.09.23.28.17.14.19 p.00.12.03.09.00 Completed treatment and abstinent in the last week r -.30-.24-.22-.09.23.22.23.19.12 p.00.09.00.03 % reduction in frequency of cocaine use r -.32-.26-.22-.11.18.24.22.17.14 p.00.07.00.01 50% reduction r -.02-.01.02.04-.16-.04-.05-.09.00 p.65.76.67.49.00.40.30.06.94 75% reduction r -.08-.07-.04-.01-.11-.04.00-.01.07 p.08.14.42.92.02.39.94.88.21 Good outcome r -.20 -.15-.08.29.37.28.24.21 p.00.16.00 Relationship with Post-Treatment Cocaine Use and Functioning

16. Outcome Indicator Sensitivity to disulfiram effects Sensitivity to behavioral therapies Relationship with post tx cocaine use Relationship to measures of general functioning/ Days retained in treatment protocolX Percent negative cocaine urine specimens XXX Maximum consecutive days abstinent XXX Percent days of abstinence from cocaine XXX Maximum days of continuous abstinence during last two weeks of treatment XXX Completely abstinent last two weeks of treatment XXXX 3 or more weeks of continuous abstinence XXXX 2 or more weeks of continuous abstinence X 1 or more weeks of continuous abstinence Completely abstinent from cocaine during treatment Completed treatment and abstinent in last week XX % reduction (28 days prior/days last 4 weeks) X 50% reduction in cocaine use 75% reduction in cocaine use X “Good outcome” XXX

17. Does cocaine abstinence have effect on functional problems? Evaluate the relationship between within-treatment cocaine use and problems in major life areas other than cocaine use (e.g., medical, legal, employment, family/social, psychological) following treatment Latent growth curve model to evaluate within-tx cocaine use on change in ‘global problems’ over time Kiluk, B.D., Nich, C., Witkiewitz, K., Babuscio, T.A., & Carroll, K.M. (2014). What happens in treatment doesn’t stay in treatment: Cocaine abstinence during treatment is associated with fewer problems at follow-up. Journal of Consulting and Clinical Psychology, 82, 619-627.

18. ‘Global Problems’ construct Created latent measure of ‘global problems’ ▫Used longitudinal confirmatory factor analysis to evaluate equivalence of ASI problem subscales over time ▫Used ‘Days of Problems’ item rather than composite score ▫Examined whether factor structure was metric invariant over time Unconditional latent growth curve modeling used to examine changes in ‘global problems’ over time Conditional latent growth curve modeling used to examine association between within-tx cocaine use and follow-up levels of global problems over time (controlling for baseline problems)

19. Latent growth curve model of within-tx cocaine use and change in global problems during follow-up period β = -.43** β = -.17** β =.32** ** p<.001

20. Summary, so far Existing widely used continuous measures are consistent predictors of cocaine use and good general functioning in follow up: ▫Percent days abstinent, maximum days of consecutive abstinence, percent positive urines, max days abstinence in last 2 weeks Good performance of urine measures and abstinence at termination measures offset by limits to availability of data (80% of samples) Poorer performance for ‘reduction’ measures, as well as ‘complete abstinence during treatment” End of treatment abstinence, 3+ weeks abstinence very consistent predictor of long term cocaine use and functioning, sensitive to effects of medication and behavioral therapies Higher levels of cocaine abstinence during tx associated with fewer problems during follow-up (controlling for baseline level of problems)