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NIMH Practical Trials: Implications for Practice and Policy

NIMH Practical Trials: Implications for Practice and Policy. Matthew V. Rudorfer, M.D. Division of Services & Intervention Research National Institute of Mental Health June 5, 2007. Practice. Practical Trials Clinical Trials Networks Services Research Dissemination & Implementation.

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NIMH Practical Trials: Implications for Practice and Policy

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  1. NIMH Practical Trials:Implications for Practice and Policy Matthew V. Rudorfer, M.D. Division of Services & Intervention Research National Institute of Mental Health June 5, 2007

  2. Practice Practical Trials Clinical Trials Networks Services Research Dissemination & Implementation Two Kinds of Translational Research Bench Bedside Pathophysiology Diagnostic tests Biomarkers New treatments

  3. Utility of Large Studies –“Practical Clinical Trials” • Public health perspective on clinical issues • Big questions and community effect • Chronic diseases require long term look • Longitudinal follow-up and link intermediate change to long term outcomes • Linkage of biological (biomarker, genetics – Perlis et al, STAR*D, Arch Gen Psychiatry June 2007) and clinical data; potential for targeted interventions • Identification of subgroups (differential response -- “personalized treatment”)

  4. Personalized Treatment Optimizing the Benefit:Risk Ratio

  5. Practical Clinical Trials: NIMH Approach • 1999 – 2006: Multiple large clinical trials launched under contract mechanism • 2006 – onward: With completion of practical trials, infrastructure for disorder-focused clinical trials networks formed from nucleus of high-performing sites + coordinating center

  6. Clinical Trial Design *To establish efficacy versus placebo. ‡Allowed if not depression-targeted, empirically tested therapy.

  7. Methodology Designed for High Generalizability in Practical Trials • Equipoise design, in some cases using patient preference, reflects practice, increasing generalizability of findings • Real-world patients enrolled (comorbidities OK) • Use of cutting-edge technology, e.g. Web-based quality control of treatment, ratings entry via IVR • Advances in valid and reliable clinical ratings, e.g. QIDS-C or QIDS-SR instead of traditional Hamilton score; “all-cause discontinuation” as a measure of effectiveness • Outcomes beyond symptomatic ratings, e.g. quality of life, functional measures

  8. NIMH Contracts: Practical Clinical Trials • STEP-BD (Bipolar Disorder) • 4,360 / 13 sites • Standard care and random pathways • CATIE (Schizophrenia / Alzheimer’s Disease) • 1,914 / 57 sites • 1,493 in Schizophrenia; 421 in Alzheimer’s Disease • Randomized comparison • STAR*D (Refractory Depression) • 4,041 / 41 sites • Sequential pathways

  9. Less than 1/3 of symptomatic bipolar patients reach recovery and remain well over 2 years in STEP-BD • Achieved recovery 58.5% • (< 2 mood symptoms for at least 8 weeks) • Relapse into depression 34.7% • Relapse into mood elevation 13.8% • Total relapse rate 48.5% • Total that stayed recovered over 2 years (100%-48.5%) 51.5% • Total who recovered and remained free of depressive and mood elevation recurrences over 2 years (51.5% out of 58.5% who achieved remission) 30.1% N=1469 who entered symptomatic Perlis et al,STEP-BD, Am J Psychiatry 2006 Feb;163:217-24.

  10. Anxiety comorbid conditions with higher risk of relapse in bipolar disorder in STEP-BD N=489 Overall relapse rate = 41.4% Overall Hazard Ratio (HR)= 1.764 ( 2=10.9, P=0.001) HR=1.55 for one disorder HR=2.17 for two or more disorders HR=2.07 for social anxiety disorder HR=2.45 for PTSD without anxiety with anxiety Ottoet al., STEP-BD, Br J Psychiatry 2006 Jul;189:20-5.

  11. April 26, 2007 Effectiveness of Adjunctive Antidepressant Treatment for Bipolar Depression Gary S. Sachs, M.D., Andrew A. Nierenberg, M.D., Joseph R. Calabrese, M.D., Lauren B. Marangell, M.D., Stephen R. Wisniewski, Ph.D., Laszlo Gyulai, M.D., Edward S. Friedman, M.D., Charles L. Bowden, M.D., Mark D. Fossey, M.D., Michael J. Ostacher, M.D., M.P.H., Terence A. Ketter, M.D., Jayendra Patel, M.D., Peter Hauser, M.D., Daniel Rapport, M.D., James M. Martinez, M.D., Michael H. Allen, M.D., David J. Miklowitz, Ph.D., Michael W. Otto, Ph.D., Ellen B. Dennehy, Ph.D., and Michael E. Thase, M.D.

  12. Intensive psychosocial interventions for bipolar depression better than collaborative care, but over a third never reach recovery 1-year recovery rate for intensive group, 105/163 [64.4%]; for CC, 67/130 [51.5%]; log-rank 2(1) = 6.20, p = 0.013; hazard ratio (HR) = 1.47; 95% CI = 1.08-2.00 Miklowitz et al., STEP-BD, Arch Gen Psychiatry, April 2007

  13. Volume 353:1209-1223September 22, 2005Number 12 Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia Jeffrey A. Lieberman, M.D., T. Scott Stroup, M.D., M.P.H., et al. for the Clinical Antipsychotic Trials of Intervention Effectiveness(CATIE) Investigators

  14. CATIE:Primary Questions Addressed • How do the atypical antipsychotic medications compare with an older, less expensive conventional antipsychotic? • How do the atypical antipsychotics compare to one another? • Are the atypical antipsychotics cost-effective? Stroup TS et al. Schizophr Bull. 2003;29:15-31.

  15. Use of Atypical Antipsychotic Medications in U.S. TRx (000s) Source: IMS NPA Plus, Dec 05. Lieberman – Presentation to NIMH Advisory Council, Sept 2006

  16. ARIPIPRAZOLE • CLOZAPINE • FLUPHENAZINE DECANOATE • OLANZAPINE • PERPHENAZINE • QUETIAPINE • RISPERIDONE • ZIPRASIDONE • 2 of the antipsychotics above CATIE Schizophrenia Trial Design Phase 3 Phase 2 Phase 1* Participants who discontinue Phase 1 choose either the clozapine or the ziprasidone randomization pathways Participants who discontinuePhase 2 choose one of the following open-label treatments Double-blind, random treatment assignment. CLOZAPINE (open-label) OLANZAPINE OLANZAPINE, QUETIAPINE or RISPERIDONE R QUETIAPINE 1500 participants with schizo- phrenia R RISPERIDONE ZIPRASIDONE R OLANZAPINE, QUETIAPINE or RISPERIDONE ZIPRASIDONE PERPHENAZINE No one assigned to same drug as in Phase 1 Responders stay on assigned medication for duration of 18-month treatment period * Phase 1A: participants with tardive dyskinesia do not get randomized to perphenazine Phase 1B: participants who fail perphenazine will be randomized to an atypical (olanzapine, quetiapine, or risperidone) before they are eligible for Phase 2 Stroup et al 2003

  17. ▬▬▬ Olanzapine (n=330) ▬▬▬ Risperidone (n=333) ▬▬▬ Perphenazine (n=257) ▬▬▬ Ziprasidone (n=183) ▬▬▬ Quetiapine (n=329) PHASE 1: Time to Discontinuation for Any Reason 36% 26% 25% 21 % 18%

  18. Problems with Movement During the Trial Percent (%) Perphenazine Risperidone Quetiapine Olanzapine Ziprasidone Prolactin: Change from Baseline Exposure-adjusted Mean (ng/mL) Perphenazine Risperidone Quetiapine Olanzapine Ziprasidone

  19. Body Weight: Change from Baseline Weight Gain >7% Perphenazine Risperidone Quetiapine Olanzapine Ziprasidone Fasting Glucose: Change from Baseline Exposure-adjusted Mean (mg/dL) Perphenazine Risperidone Quetiapine Olanzapine Ziprasidone Fasting Triglycerides: Change from Baseline Exposure-adjusted Mean (mg/dL) Perphenazine Risperidone Quetiapine Olanzapine Ziprasidone

  20. American Journal of Psychiatry 163:600-610, April 2006 Effectiveness of Clozapine Versus Olanzapine, Quetiapine, and Risperidone in Patients With Chronic Schizophrenia Who Did Not Respond to Prior Atypical Antipsychotic Treatment Joseph P. McEvoy, M.D., Jeffrey A. Lieberman, M.D., T. Scott Stroup, M.D., M.P.H., Sonia M. Davis, Dr.P.H., Herbert Y. Meltzer, M.D., Robert A. Rosenheck, M.D., Marvin S. Swartz, M.D., Diana O. Perkins, M.D., M.P.H., Richard S.E. Keefe, Ph.D., Clarence E. Davis, Ph.D., Joanne Severe, M.S., John K. Hsiao, M.D. for the CATIE Investigators

  21. CATIE Phase 2: Preference Pathways (for people who discontinue Phase 1) Clozapine—open-label Efficacy Pathway Randomized Olanzapine, Quetiapine, or Risperidone—drug not taken in Phase 1 Randomized Tolerability Pathway Ziprasidone Stroup TS et al. Schizophr Bull. 2003;29:15-31.

  22. PHASE 2E: Time to Discontinuation for Any Reason 44% 29% 14% 7%

  23. PHASE 2T: Time to Discontinuation for Any Reason 36% 33% 23% 16%

  24. Negative Symptoms and Cognitive Function • No differences between atypical antipsychotics and a conventional antipsychotic (perphenazine) on negative symptoms and cognitive functions

  25. December 1, 2006 Older Medication May Be More Cost-Effective for Some Patients with Schizophrenia A new study analyzing the economic implications of CATIE concludes that the older (first generation) antipsychotic medication perphenazine was less expensive and no less effective than the newer (second generation) medications used in the trial during initial treatment, suggesting that older antipsychotics still have a role in treating schizophrenia. Total monthly health costs, a figure that includes both average medication costs and inpatient and outpatient costs, were up to30 percent lower for those taking perphenazine than for those taking the second generation medications. -- NIMH Press Release Re: Rosenheck et al, Am J Psychiatry, December 2006

  26. CATIE HIGHLIGHTS • All antipsychotic medications studied are effective but have substantial limitations reflected by high discontinuation rates • Olanzapine and Clozapine show the best efficacy but the worst side effects • Perphenazine was surprisingly comparable to atypicals • Differences in types and severity of side effects • Ziprasidone has least weight and metabolic side effects (Aripiprazole was released later)

  27. “CATIE has opened the door to more choice in treatment options." -- Robert Rosenheck, M.D. Treatments for persons with schizophrenia must be individualized. Doctors and patients must carefully evaluate the tradeoffs between efficacy and side effects and past treatment history in choosing an appropriate medication. Lieberman – Presentation to NIMH Advisory Council, Sept 2006

  28. Issues in Schizophrenia Treatment Research Still Needing Attention • Need for strategies beyond clozapine or alternatives to clozapine for patients with refractory symptoms • Rational antipsychotic polypharmacy? • What are optimal strategies for first-episode psychosis? • How to enhance treatment adherence ? Lieberman – Presentation to NIMH Advisory Council, Sept 2006

  29. 355:1525-1538October 12, 2006Number 15 Effectiveness of Atypical Antipsychotic Drugs in Patients with Alzheimer's Disease Lon S. Schneider, M.D., Pierre N. Tariot, M.D., Karen S. Dagerman, M.S., Sonia M. Davis, Dr.P.H., John K. Hsiao, M.D., M. Saleem Ismail, M.D., Barry D. Lebowitz, Ph.D., Constantine G. Lyketsos, M.D., M.H.S., J. Michael Ryan, M.D., T. Scott Stroup, M.D., David L. Sultzer, M.D., Daniel Weintraub, M.D., Jeffrey A. Lieberman, M.D., for the CATIE-AD Study Group

  30. "The antipsychotic medications may be effective against some symptoms in Alzheimer's patients compared to placebo, but their tendency to cause intolerable adverse side effects in this vulnerable population offsets their benefits." Lon Schneider, MD Schneider et al, CATIE-AD, N Engl J Med, Oct 2006

  31. Psychotherapy in NIMH Effectiveness Trials – completed • STEP-BD (Bipolar Depression) –3 types of structured psychotherapy are effective adjuncts to pharmacotherapy (Miklowitz et al, Arch Gen Psychiatry, April 2007) • STAR*D (Refractory Depression) – Only 26% of patients agreed to treatment with cognitive therapy (CT) as a second-line treatment after inadequate response to citalopram. Responses to CT, as monotherapy or augmenting citalopram, were equivalent to medication-only groups. Time to remission was slower with CT but with fewer side effects (Thase et al, & Wisniewski et al, Am J Psychiatry, May 2007)

  32. Psychotherapy in NIMHEffectiveness Trials – in progress • Research Evaluating the Value of Augmenting Medication with Psychotherapy(REVAMP / Chronic Major Depression) – Does CBASP or supportive psychotherapy add to pharmacotherapy in the treatment of chronic forms of major depression? (Kocsis et al) • Coordinated Anxiety Learning and Management(CALM / Anxiety Disorders) – Does computer-based individualized CBT add to pharmacotherapy for anxiety disorders in primary care? (Roy-Byrne et al)

  33. What Questions Should Be Pursued Next? • Widely used treatments and treatment combinations that are untested? • New molecules ready for wider testing? • Patient attrition? • Longer-term outcomes? • Tailoring treatment to individuals? • Enhancing cost efficiency? • Practice procedures that are controlled by payor costs without regard to patient outcomes? Rush – Presentation to NIMH Advisory Council, Sept 2006

  34. What’s Next at NIMH • Three new clinical trials networks (Depression, Bipolar Disorder, Schizophrenia), building upon completed Practical Clinical Trials • Platform funding • Central data management • Collaboration with new partners • Identify challenging public mental health questions suitable for study on Networks • Continue regular grant support of non-Network services and interventions research

  35. www.nimh.nih.gov/ncdeu/index.cfm For complete details of NIMH-supported Clinical Trials, please see http://www.nimh.nih.gov/studies/index.cfm

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