Adaptive Treatment Strategies

1. Adaptive Treatment Strategies S.A. Murphy CCNIA Proposal Meeting 2008

2. Outline • What are Adaptive Treatment Strategies? • What are SMART trials? • SMART Designing Principles and Analysis

3. Adaptive Treatment Strategies are individually tailored sequences of treatments, with treatment type and dosage adapted to the patient. • Generalization from a one-time decision to a sequence of decisions concerning treatment • Operationalize clinical practice.

4. Why use an Adaptive Treatment Strategy? • High heterogeneity in response to any one treatment • What works for one person may not work for another • What works now for a person may not work later • Improvement often marred by relapse • Remitted is not the same as cured. • Co-occurring disorders/adherence problems are common

5. Example of an Adaptive Treatment Strategy Treatment of alcohol dependence. Goal is to achieve and maintain remission. Provide Naltrexone for up to 8 weeks. If the patient experiences 2 heavy drinking days prior to the end of the 8 weeks, then switch the patient to CBI. If the patient makes the 8 weeks with at most 1 heavy drinking day, then maintain Naltrexone and add TDM.

6. What are Sequential Multiple Assignment Randomized Trials? • Pinpoint a small number of critical decisions per patient to investigate. • A randomization takes place at each critical decision (multiple randomizations for each patient). • Goal is to inform the construction of an adaptive treatment strategy.

7. Remitter/Non-Remitter Trial

8. From a Remitter/Non-Remitter Trial to a SMART

9. SMART Designing Principles • KEEP IT SIMPLE: At each stage, restrict class of treatments only by ethical, feasibility or strong scientific considerations. Use a summary (responder status) instead of all intermediate outcomes (time until nonresponse, adherence, burden, stress level, etc.) to restrict class of next treatments. • Collect intermediate outcomes that might be useful in ascertaining for whom each treatment works best; information that might enter into the adaptive treatment strategy.

10. SMART Designing Principles • Choose primary hypotheses that are both scientifically important and aid in developing the adaptive treatment strategy. • Power trial to address these hypotheses.

11. SMART Designing Principles: • Primary Hypothesis • EXAMPLE 1: (sample size is highly constrained): Hypothesize that the initial decision, NTX with early trigger for non-response to lower levels of symptoms over entire study than the initial decision, NTX with a late trigger for non-response (controlling for subsequent treatments via experimental design). • EXAMPLE 2: (sample size is less constrained): Hypothesize that non-responders will experience fewer symptoms if provided NTX + CBI as opposed to only NTX. (embedded non-responder trial).

12. Ex. 1: Two-Group Comparison

13. Ex. 2: Two-Group Comparison

14. SMART Designing Principles • Choose secondary hypotheses that further develop the adaptive treatment strategy and use the randomization to eliminate confounding. • EXAMPLE: Hypothesize that non-adhering non-responders to NTX will do better on NTX + CBI as opposed to CBI only.

15. Regression using stage 1 non-adherence as a moderator

16. Discussion • Secondary analyses can use patient characteristics/outcomes to provide evidence for a more sophisticated adaptive treatment strategy. • SMART studies and analyses targeted at scientific goal of informing the construction of a high quality adaptive treatment strategy

17. Extra slides follow Acknowledgements: This presentation is based on work with many individuals including Linda Collins, Kevin Lynch, Jim McKay, David Oslin, and Tom Ten Have. Email address: samurphy@umich.edu Slides with notes at: http://www.stat.lsa.umich.edu/~samurphy/ Click on seminars > health science seminars

18. Oslin ExTENd Naltrexone 8 wks Response Randomassignment: TDM + Naltrexone Early Trigger for Nonresponse CBI Randomassignment: Nonresponse CBI +Naltrexone Randomassignment: Naltrexone 8 wks Response Randomassignment: TDM + Naltrexone Late Trigger for Nonresponse Randomassignment: CBI Nonresponse CBI +Naltrexone

19. Adaptive Treatment for ADHD • Ongoing study at the State U. of NY at Buffalo (B. Pelham) • Goal is to learn how best to help children with ADHD improve functioning at home and school.

20. ADHD Study A1. Continue, reassess monthly; randomize if deteriorate Yes 8 weeks A. Begin low-intensity behavior modification A2. Add medication;bemod remains stable butmedication dose may vary Assess- Adequate response? Randomassignment: No A3. Increase intensity of bemod with adaptive modifi-cations based on impairment Randomassignment: B1. Continue, reassess monthly; randomize if deteriorate 8 weeks B2. Increase dose of medication with monthly changes as needed B. Begin low dose medication Assess- Adequate response? Randomassignment: B3. Add behavioral treatment; medication dose remains stable but intensityof bemod may increase with adaptive modificationsbased on impairment No

21. Studies under review • H. Jones study of drug-addicted pregnant women (goal is to reduce cocaine/heroin use during pregnancy and thereby improve neonatal outcomes) • J. Sacks study of parolees with substance abuse disorders (goal is reduce recidivism and substance use)

22. Jones’ Study for Drug-Addicted Pregnant Women rRBT 2 wks Response Randomassignment: tRBT tRBT tRBT Randomassignment: Nonresponse eRBT Randomassignment: aRBT 2 wks Response Randomassignment: rRBT rRBT Randomassignment: tRBT Nonresponse rRBT

23. Sack’s Study of Adaptive Transitional Case Management Standard TCM 4 wks Response Standard TCM Nonresponse Augmented TCM Randomassignment: Randomassignment: Standard TCM Standard Services

24. Example 2: Classical Continuation Trial Subjects who have responded are randomized to one of three groups: • Continue on lower intensity version of treatment for 24 additional weeks as long as there is no relapse • Continue on lower intensity version of treatment for 12 additional weeks as long as there is no relapse • No treatment as long as there is no relapse

25. Example 2: Continuation Trial

26. Example 2: Continuation to SMART

27. The Big Questions • What is the best sequencing of treatments? • What is the best timing of alterations in treatments? • What information do we use to make these decisions?

28. Classical Non-Remitter Trial Patients who have not remitted following an adequate course of an SSRI are randomized to one of two groups: • Augment with Med C OR • Switch to Med D

29. Remitter/Non-Remitter Trial

30. From a Remitter/Non-Remitter Trial to a SMART

31. From a Remitter/Non-Remitter Trial to a SMART

32. SMART Designing Principles: • Primary Hypothesis • EXAMPLE 1: (sample size is highly constrained): Hypothesize that the initial treatment SSRI + WebCBT leads to lower levels of symptoms over entire study than the initial treatment, SSRI alone (controlling for subsequent treatments via experimental design). • EXAMPLE 2: (sample size is less constrained): Hypothesize that subjects who do not remit at the first stage of treatment will exhibit higher remission rates if provided a switch to med D as opposed to augmenting by med C. (embedded non-remitter trial).

33. Ex. 1: Two-Group Comparison

34. Ex. 2: Two-Group Comparison

35. SMART Designing Principles • Choose secondary hypotheses that further develop the adaptive treatment strategy and use the randomization to eliminate confounding. • EXAMPLE: Hypothesize that patients who have experienced less than a 50% improvement in response in the first stage will be more likely to remit if they receive a switch to Med D as opposed to augmentation by Med C.

36. Regression using Response Level during Stage 1