1. 2013 CTN Web Seminar Series Produced by: NIDA CTN CCC Training Office "This training has been funded in whole or in part with Federal funds from the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, under Contract No.HHSN271201000024C." DEVELOPING MEDICATION ASSISTED TREATMENT (MAT) PROTOCOLS Presented by: Andrew J. Saxon, MD July 17, 2013

2. Objectives: Consider some of the prior medication assisted treatment protocols conducted in the CTN for lessons learned. Identify design decisions that need to be made concerning medication assisted treatment protocols, including considerations about blinding and adherence strategies. Describe regulatory aspects of medication assisted treatment protocols. 2

3. DESIGNING MEDICATION ASSISTED PROTOCOLS 3

4. Specific Topics to Consider Investigational New Drug Application (NDA) from FDA? Open label or blinded MAT trial? Placebo or active comparator? Dosing strategy—Fixed or flexible? Adherence strategy? More exclusive or more inclusive enrollment criteria? What, if any, behavioral platform? Safety monitoring plan 4

5. REGULATORY CONSIDERATIONS 5

6. IND An Investigator IND is submitted by a physician who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. A physician might submit a research IND to propose studying an unapproved drug, or an approved product for a new indication or in a new patient population. 6

7. IND CDER's Pre-Investigational New Drug Application (IND) Consultation Program 5 fosters early communications between sponsors and new drug review divisions to provide guidance on the data necessary to warrant IND submission. The review divisions are organized generally along therapeutic class and can each be contacted using the designated Pre-IND Consultation List (PDF - 19KB) 6.Pre-Investigational New Drug Application (IND) Consultation ProgramPre-IND Consultation List (PDF - 19KB) 7

8. IND Examples Injectable risperidone for methamphetamine dependence –Drug company sponsor – wanted IND –Use in new population – FDA requested IND Prazosin for Alcohol Dependence –University/NIH sponsor – no position on IND –Given widespread use of prazosin, has probably been used by patients with AUD –No plans to seek a change in labeling or advertising –Exempt from IND 8

9. Controlled Substances Obtain appropriate DEA licensure Obtain licensure specific to each state 9

10. BLINDING AND PLACEBO STRATEGIES 10

11. Open Label vs. Blinded Study Enck et al., 2013 11

12. Open Label Advantages Good for pilot studies to test: – tolerability – safety – possibly dose effects More real world For some medications expectancies are component of efficacy –Disulfiram (Antabuse) Less complex/costly 12

13. Blinding Advantage Accounts for expectancy effects –Patients –Research staff Double blind vs. single blind 13

14. Benedetti et al., 2005 14

15. Placebo Response Benedetti et al., 2005 15

16. Placebo vs. Active Comparator If active medication has profound, observable effects, inert placebo may break blind Active “placebo” possible If an already approved medication for indication exists, head to head comparison informative 16

17. PRIOR MEDICATION ASSISTED TREATMENT PROTOCOLS Lessons Learned in the CTN 17

18. START Study Schema 1920Number screened for participation 1269Randomized 740Buprenorphine/Naloxone529Methadone 340Evaluable 400 Failed to remain on assigned medication for 24 wks 0Failed to provide ≥ 4 LT samples 391Evaluable 136Failed to remain on assigned medication for 24 wks 2Failed to provide ≥ 4 LT samples 261 Completed 32-week follow-up330 Completed 32-week follow-up 18

19. CTN 0028 OROS-Methylphenidate ADHD/SUD Riggs et al., 2011 19 Titrated to 72 mg per day

20. CTN 0048 CURB Study Schema 20

21. Fixed vs. Flexible Dosing Fixed dosing –requires less physician time –Fixed dosing may miss optimum dose Flexible dosing –Titrate to effects/side effects –Need algorithm to guide study physician –More real world –More complex analytic approach may be needed 21

22. CTN 0003 Buprenorphine Taper Total Stabilization Dose 8 mg48 (9.3%) 16 mg141 (27.3%) 24 mg327 (63.4%) Total516 (100%) 22

23. ADHERENCE STRATEGIES 23

24. Potential Adherence Measures Observed dosing Pill counts Biologic marker Electronic monitoring Self report Plasma or urine drug concentrations 24

25. PRIOR MEDICATION ASSISTED TREATMENT PROTOCOLS Lessons Learned in the CTN 25

26. 0053 Achieving Cannabis Cessation - Evaluating N-Acetylcysteine Treatment (ACCENT) The primary objective is to evaluate impact of N-acetylcysteine (NAC) 1200 mg versus matched placebo (PBO) twice daily, added to compliance enhancement (CE) and contingency management (CM), on cannabis use among treatment-seeking cannabis- dependent adults. Medication adherence will be assessed using self- report, blister pack pill counts, and urine riboflavin testing. 26

27. 0052 Randomized Controlled Evaluation of Buspirone for Relapse-Prevention in Adults with Cocaine Dependence (BRAC) 27

28. 0052 Randomized Controlled Evaluation of Buspirone for Relapse-Prevention in Adults with Cocaine Dependence (BRAC) The primary objective is to evaluate the efficacy of buspirone, relative to placebo, in preventing relapse in cocaine-dependent adults in inpatient/residential treatment who are planning to enter outpatient treatment upon inpatient/residential discharge. MEMS, pill count, and participant self-report of medication adherence will be collected. Urine samples will be shipped to a central lab, and samples from the buspirone group will be assayed for buspirone and/or its metabolite. 28

29. MEMS The Medication Event Monitoring System, (MEMS) is a medication bottle cap with a microprocessor that records the occurrence and time of each bottle opening. 29

30. INCLUSION/EXCLUSION STRATEGIES 30

31. Enrollment Criteria More restrictive –Increase safety –Possibly increase likelihood of effect Less restrictive –Increase generalizability –Interventions found efficacious in clinical trials often fail in real world 31

32. PRIOR MEDICATION ASSISTED TREATMENT PROTOCOLS Lessons Learned in the CTN 32

33. Exclusions 0027 START ALT or AST values > 5 times the upper limit of normal Known diagnosis of acute psychosis, severe depression or imminent suicide risk Poor venous access such that venipuncture could not be accomplished from a vein in an extremity during eligibility 33

34. Exclusions 0052 BRAC Medical or psychiatric condition that, in the judgment of the study physician, would make study participation unsafe or which would make treatment compliance difficult. Medical conditions that may compromise participant safety or study conduct include, but are not limited to: –AIDS –liver function tests greater than 3X upper limit of normal –serum creatinine greater than 2 mg/dL Psychiatric disorder requiring continued treatment with a psychotropic medication 34

35. Potential Behavioral Platforms Medications alone not expected to be fully efficacious for SUD More intensive behavioral intervention –Could overwhelm medication effects –Could provide sufficient support and/or synergy to allow medication to work Less intensive behavioral intervention –Less likely to overwhelm medication effects –May not hold patients in treatment sufficiently to allow medication to work 35

36. PRIOR MEDICATION ASSISTED TREATMENT PROTOCOLS Lessons Learned in the CTN 36

37. Behavioral Interventions from CTN MAT Trials Bup Taper and START –Counseling as usual OROS-methylphenidate ADHD/SUD –CBT (highly efficacious) ACCENT –compliance enhancement (CE) and contingency management (CM) 37

38. CTN 0028 OROS-Methylphenidate ADHD/SUD Riggs et al., 2011 38

39. SAFETY MONITORING 39

40. Safety Monitoring Data Safety Monitoring Board –Established for CTN MAT Trials Plan to assess adverse events and serious adverse events Laboratory monitoring –e.g., liver tests, glucose, CBC Cardiac monitoring –ECG 40

41. Recap / Highlights Designing MAT trials involves numerous decision points and trade-offs MAT trials conducted in CTN can provide considerable guidance in making these decisions for design of future MAT trials 41

42. Q&A – Questions / Comments Alternatively, questions can be directed to the presenter by sending an email to CTNtraining@emmes.com. 42

43. References Saxon et al., Buprenorphine/Naloxone and methadone effects on laboratory indices of liver health: A randomized trial. Drug and Alcohol Dependence 128:71- 76, 2013. Riggs et al., Randomized controlled trial of osmotic- release methylphenidate with cognitive-behavioral therapy in adolescents with attention deficit/hyperactivity disorder and substance use disorders. Journal of the American Academy of Child & Adolescent Psychiatry 50:903-914, 2011. Ling et al., Buprenorphine tapering schedule and illicit opioid use. Addiction 104:256-265, 2009. 43

44. Survey Reminder Upcoming Webinar The NIDA CCC encourages all to complete the survey issued to participants directly following this webinar session. Watch for the email notification! Also, please visit the Training Suggestion Box to post general comments: https://www.surveymonkey.com/s/CTNTrainingSuggestionBox Social Media – Using Social Media as a Clinical Trials Research Tool Wednesday, August 21, 2013 1:00 pm to 2:00 pm ET Social Media – Using Social Media as a Clinical Trials Research Tool Wednesday, August 21, 2013 1:00 pm to 2:00 pm ET 44

45. A copy of this presentation will be available electronically after this session. http://ctndisseminationlibrary.org 45

46. Thank you for participating. NIDA CTN Web Seminar Series 46