Methods

1. Use of an Adaptive Treatment Research Design in a CTN study of prescription opioid dependence treatment • RD Weiss1,2, JS Potter2,3, M Byrne4, C Sullivan4, W Ling5 • McLean Hospital, Belmont, MA, USA • Department of Psychiatry, Harvard Medical School, Boston, MA, USA • University of Texas Health Science Center, San Antonio, TX, USA • West Virginia University School of Medicine, Morgantown, WV, USA • UCLA School of Medicine, Los Angeles, CA, USA Conclusions Aims Results Abstract The NIDA Clinical Trials is conducting the Prescription Opioid Addiction Treatment Study (POATS) – a multi-site trial examining different lengths and intensities of buprenorphine and drug counseling for subjects with prescription opioid dependence. The primary study aim is to determine whether adding individual drug counseling (e.g., Enhanced Medical Management (EMM)) to buprenorphine plus Standard Medical Management (SMM) improves outcome in this population during Phase 1, an initial 4-week taper, and Phase 2, a subsequent 12-week stabilization treatment for those who relapsed during or soon after Phase 1. (Figure 1) POATS presents a unique opportunity to evaluate a treatment strategy for prescription opioid dependence, rather than a discrete treatment intervention. Researchers need to weigh the advantages and challenges when considering an ATRD applied to drug abuse studies. Recruitment is complete for POATS. 653 subjects were randomized to Phase 1. 360 subjects were randomized to Phase 2. Conducting POATS revealed some advantages and challenges of an ATRD in the context of a drug abuse study. Advantages include 1) the ecological validity associated with a study designed to approximate real-world clinical practice (i.e., start with a relatively non-intensive approach, then instituting more intensive treatment if the first treatment fails), and 2) the ability to answer multiple research questions in one study4. Challenges include 1) masking from subjects the eligibility criteria that trigger randomization into Phase 2; 2) establishing a threshold for deciding when it is clinically necessary to rescue subjects who respond poorly to the Phase 1 treatment; and 3) powering a study for Phase 2 when there is uncertainty about how many participants from the original population will be eligible for and enter Phase 2. We managed the first challenge by emphasizing the importance of not disclosing Phase 1 failure criteria during initial training and booster sessions with study staff. The second challenge was addressed after extensive consultation and feedback from clinical experts in the field. To address the third challenge, conservative assumptions were made a priori that about 50% of subjects randomized to Phase 1 will meet treatment failure criteria and agree to be randomized in Phase 2. Aims: The NIDA Clinical Trials is conducting the Prescription Opioid Addiction Treatment Study (POATS) – a multi-site trial examining different lengths and intensities of buprenorphine and drug counseling for subjects with prescription opioid dependence. The primary aim is to determine whether adding counseling to buprenorphine plus medical management improves outcome in this population during Phase 1, an initial 4-week taper, and Phase 2, a subsequent 12-week stabilization treatment for those who relapsed during or soon after Phase 1. Methods: This study employs an adaptive treatment research design (ATRD). Subjects with poor outcomes in Phase 1 enter Phase 2, at which time they are randomized to a new treatment. Results: This study has completed recruitment: Phase 1 (N = 653); Phase 2 (N = 360). Conducting POATS has revealed some advantages and challenges to using an ATRD. Advantages include being able to approximate real-world clinical practice and simultaneously answer multiple research questions. Challenges include 1) masking the eligibility criteria for Phase 2 from subjects; 2) developing a clinical threshold for when to respond to subjects who respond poorly to Phase 1; and 3) powering the study based on uncertain estimates for Phase 2 enrollment. Conclusions: ATRD, applied to the POATS study, presents an opportunity to evaluate a treatment strategy rather than a discrete intervention. This research design has advantages and challenges that researchers need to consider in both the design and implementation stages of a clinical trial. Bibliography • Tunis, S.R., D.B. Stryer, and C.M. Clancy, Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy. JAMA, 2003. 290(12): p. 1624-32. • Rush, A.J., et al., Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Control Clin Trials, 2004. 25(1): p. 119-42. • Materson, B.J., et al., Response to a second single antihypertensive agent used as monotherapy for hypertension after failure of the initial drug. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Arch Intern Med, 1995. 155(16): p. 1757-62. • Brown, C.H., et al., Adaptive designs for randomized trials in public health. Annu Rev Public Health, 2009. 30: p. 1-25. Methods POATS employs an adaptive treatment research design (ATRD1); in an ATRD, subjects receive an initial treatment (pre-specified or randomly assigned), with a plan to evaluate treatment response and potentially make clinical adjustments when a pre-specified time point or clinical status (e.g., remission or relapse) is reached. ATRD has been used elsewhere in psychiatry2 and in general medicine3, but has been used infrequently in drug abuse studies. In POATS, subjects with poor outcomes in Phase 1 (Table 1) enter Phase 2, at which time they are randomized to a new treatment. The advantages and known challenges to employing an ATRD were considered in the design of POATS. Anecdotal reports of unforeseen challenges were collected from study sites during the course of the trial. Support NIDA Grants DA15831, DA022288, DA022297, DA013045, DA020036 Table 1: Phase 1 Treatment Failure Criteria Figure 1: Study Design Conflict of Interest Dr. Weiss has consulted to Titan Pharmaceuticals; Dr. Sullivan has spoken for Pfizer and Reckitt-Benckiser. • Injection drug use • Participation in other formal substance abuse treatment • Beginning on Study Day 15: • Opioid use > 4 days in the last 28 days • Opioid-positive urine drug screens for 2 consecutive visits • >1 missing urine sample Contact Information Roger D. Weiss, M.D. McLean Hospital Division of Alcohol and Drug Abuse 115 Mill Street Belmont, MA 02478 Email: rweiss@mclean.harvard.edu Phone: 617-855-2242