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IMACS History and Development of Myositis Clinical Trials

IMACS History and Development of Myositis Clinical Trials. Muscle Study Group September 21, 2010. Chester V. Oddis, MD University of Pittsburgh. Disclosures. Genentech: Grant support. Lecture Objectives. Overview of myositis in the past decade “Birth” of a clinical trial in myositis.

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IMACS History and Development of Myositis Clinical Trials

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  1. IMACS History and Development of Myositis Clinical Trials Muscle Study Group September 21, 2010 Chester V. Oddis, MD University of Pittsburgh

  2. Disclosures • Genentech: Grant support

  3. Lecture Objectives • Overview of myositis in the past decade • “Birth” of a clinical trial in myositis

  4. Idiopathic Inflammatory Myopathy • Rare disease • Affect children and adults • Paucity of controlled trials • Unreliable and insensitive outcome measures • 2-specialty disease (neurology/rheumatology) • Systemic disease

  5. Areas to Address in Myositis Trials • Sufficient sample size • Relevant outcomes for clinical trials • Special aspects of myositis influencing trial design: • Heterogeneity • Clinical diversity • Activity vs. damage • Barriers to studying novel therapies

  6. Where Were We Ten Years Ago?

  7. Summary: Published Trials in IIM (2000) • Lack of consistent design in published trials • 26 prospective myositis trials reviewed • 14 adult PM-DM; 5 adult IBM; 5 JDM; 2 adult PM/DM/IBM • Problems with published trials • different myositis classification criteria used • lack of uniformity with inclusion/exclusion criteria • variability in concomitant therapies • variability in trial durations and subsequent follow-up • different intervals of assessment • lack of uniformity in measures for outcome assessments

  8. Fred Miller Lisa Rider David Isenberg

  9. IMACS • Coalition of health care providers with experience and interest in the myositis syndromes • Goal: Improve the lives of children and adults with myositis • Discover better therapies through understanding the causes of myositis

  10. Idiopathic Inflammatory Myopathy • Rare disease • Affect children and adults • Paucity of controlled trials • Unreliable and insensitive outcome measures • 2-specialty disease (neurology/rheumatology) • Systemic disease • IMACS: International Myositis Assessment and Clinical Studies Group • Adult and pediatric rheumatologists, neurologists, physiatrists and dermatologists organized to address these deficiencies

  11. Myositis Clinical Trials: “Pieces of the Puzzle” • Establishment of IMACS • Adult/pediatric/multidisciplinary/international

  12. Areas to Address in Myositis Trials • Sufficient sample size (IMACS) • Relevant outcomes for clinical trials • Special aspects of myositis influencing trial design: • Heterogeneity • Clinical diversity • Activity vs. damage • Barriers to studying novel therapies

  13. Areas to Address in Myositis Trials • Sufficient sample size (IMACS) • Relevant outcomes for clinical trials • Special aspects of myositis influencing trial design: • Heterogeneity • Clinical diversity • Activity vs. damage • Barriers to studying novel therapies

  14. Step 1:Development of Preliminary Core Set Measures for Myositis Outcome in Clinical Trials • Evaluate measures used in previous trials • Assess the validation of published instruments • Discuss at international consensus conference • Further refine using IMACS group (Delphi method)

  15. Assessing Outcome in Myositis • Proposed core set measures to assess 5 domains that were determined to capture myositis disease activity • 5 domains include: • Global disease activity • Muscle strength • Physical function • Laboratory evaluation • Extramuscular manifestations

  16. Domains of Disease Activity and Core Set Measures for Assessing Outcome in Myositis Miller, Rheumatology, 2001

  17. Myositis Clinical Trials: “Pieces of the Puzzle” • Establishment of IMACS • Adult/pediatric/multidisciplinary/international • Agreed upon outcome measures [Miller]

  18. Step 2: Clinically Meaningful Improvement in Core Set Measures Rider, J Rheum, 2003

  19. Step 3:Definition of Improvement in a Clinical Trial • Tedious process including face to face meetings of adult and pediatric experts (n=29) • Review of 102 adult and 102 juvenile paper patient profiles using nominal group techniques • Experts’ consensus ratings as a gold standard and their judgment of clinically meaningful change in the core set measures • Candidate DOIs developed from this consensus

  20. Preliminary Definition of Improvement for IIM Clinical Trials Three of any 6 of the core set measures improved by ≥ 20%, with no more than 2 worse by ≥ 25% (which cannot include MMT) Rider, Arth Rheum, 2004

  21. Myositis Clinical Trials: “Pieces of the Puzzle” • Establishment of IMACS • Adult/pediatric/multidisciplinary/international • Agreed upon outcome measures [Miller] • Definition(s) of improvement for myositis clinical trials [Rider]

  22. Areas to Address in Myositis Trials • Sufficient sample size (IMACS) • Relevant outcomes for clinical trials • Special aspects of myositis influencing trial design: • Heterogeneity • Clinical diversity • Activity vs. damage • Barriers to studying novel therapies

  23. General Trial Design Issues • IIM subgroups to be included in myositis clinical trials • Classification criteria to be utilized for trial entry • Other inclusion criteria for trial entry • Exclusion criteria for trial entry • Stratification of patients at outcome analysis • Concomitant therapy allowable during myositis clinical trial • Trial duration/use of placebo • Outcome and safety (drug toxicity) assessment intervals during active treatment phase of clinical trial • Clinical worsening to allow for change in therapy • Drop out criteria for myositis trials • Post-trial therapy assessments • Definitions of complete clinical response and remission

  24. Step 4: Strategy to Develop Consensus for IIM Clinical Trials • Step 1: Ascertain expert opinion on key trial design questions (Delphi approach: Survey #1) • 41 adult and 27 pediatric specialists responded to Email survey • Included rheumatologists, neurologists, dermatologists, physiatrists • Step 2: Establish both areas of consensus (set at  2/3 agreement) and controversy through review of surveys • Step 3: Address unresolved clinical trial design issues (Survey #2) • 38 adult and 31 pediatric specialists responded to 2nd Email survey • Step 4: Resolution of controversial trial design issues using nominal group technique ( 70% agreement) • Completed at 2003 IMACS Workshop • Step 5: Develop and publish a consensus document: “Guidelines for Clinical Trials in Adult and Juvenile Myositis” Oddis, Arth Rheum, 2005

  25. Myositis Clinical Trials: “Pieces of the Puzzle” • Establishment of IMACS • Adult/pediatric/multidisciplinary/international • Agreed upon outcome measures [Miller] • Definition(s) of improvement for myositis clinical trials [Rider] • Multidisciplinary, international consensus on conduct of clinical trials [Oddis/Rider]

  26. Areas to Address in Myositis Trials • Sufficient sample size (IMACS) • Relevant outcomes for clinical trials • Special aspects of myositis influencing trial design: • Heterogeneity • Clinical diversity • Activity vs. damage • Barriers to studying novel therapies

  27. Activity and Damage Tools in Myositis • Myositis Disease Activity and Assessment Tool (MDAAT) • Reliable and valid instrument to assess myositis activity • Extra muscular manifestations (constitutional, cutaneous, articular, GI, pulmonary, cardiac) [Sultan/Isenberg, Arth Rheum, 2008] • Myositis Damage Index (MDI) [Rider, Arth Rheum, 2009]

  28. Myositis Clinical Trials: “Pieces of the Puzzle” • Establishment of IMACS • Adult/pediatric/multidisciplinary/international • Agreed upon outcome measures [Miller] • Definition(s) of improvement for myositis clinical trials [Rider] • Multidisciplinary, international consensus on the conduct of adult and juvenile myositis clinical trials [Oddis/Rider] • Assessment of disease activity and damage [Sultan/Isenberg; Rider]

  29. Areas to Address in Myositis Trials • Sufficient sample size (IMACS) • Relevant outcomes for clinical trials • Special aspects of myositis influencing trial design: • Heterogeneity • Clinical diversity • Activity vs. damage • Barriers to studying novel therapies

  30. Rituximab in Myositis Rituximab in the Treatment of Refractory Adult and Juvenile Dermatomyositis (DM) and Adult Polymyositis (PM) University of Pittsburgh Coordinating Center

  31. Summary • Significant progress in myositis clinical trials over the past decade • Ability to test some of these advances by analyzing data in the ‘RIM Study‘ and ‘Etanercept in DM Study’ • Proactive in design of upcoming trials using novel agents and novel biomarkers

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