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. Lisa RiderFred Miller 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. DomainCore Set Measures Global Activity Physician global disease activity (Likert or VAS) Parent/patient global disease activity (Likert or VAS) Muscle Strength MMT (0 – 10 point or 0 – 5 point scale) to include proximal, distal and axial muscles in adults and children. If < 4 years of age (CMAS). Physical Function Validated patient/parent questionnaire of activities of daily living (HAQ/CHAQ). Laboratory Assessment At least two serum muscle enzyme activities from the following: CK, aldolase, LDH, ALT and AST. Extramuscular disease A validated approach that is comprehensive and assesses constitutional, cutaneous, GI, articular, cardiac and pulmonary activity. 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 Median % Change Core Set DomainAdultPediatric MD Global Activity20 Patient/Parent Global Activity20 Muscle Strength1518 Physical Function15 Muscle Enzymes30 Extramuscular Activity20 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 1.IIM subgroups to be included in myositis clinical trials 2.Classification criteria to be utilized for trial entry 3.Other inclusion criteria for trial entry 4.Exclusion criteria for trial entry 5.Stratification of patients at outcome analysis 6.Concomitant therapy allowable during myositis clinical trial 7.Trial duration/use of placebo 8.Outcome and safety (drug toxicity) assessment intervals during active treatment phase of clinical trial 9.Clinical worsening to allow for change in therapy 10.Drop out criteria for myositis trials 11.Post-trial therapy assessments 12.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 2 nd 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