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Rituximab in Myositis (RIM) Study

Rituximab in Myositis (RIM) Study. Muscle Study Group September 28, 2012. Chester V. Oddis, MD Division of Rheumatology and Clinical Immunology University of Pittsburgh. Disclosures. Genentech: Grant support and supply of study drug; Advisory Board. Where Were We in 2000?.

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Rituximab in Myositis (RIM) Study

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  1. Rituximab in Myositis (RIM) Study Muscle Study Group September 28, 2012 Chester V. Oddis, MD Division of Rheumatology and Clinical ImmunologyUniversity of Pittsburgh

  2. Disclosures • Genentech: Grant support and supply of study drug; Advisory Board

  3. Where Were We in 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 ‘current’ 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

  4. 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] • Consensus on conduct of adult and juvenile myositis clinical trials [Oddis/Rider] • Assessment of disease activity and damage [Sultan/Isenberg]

  5. Preliminary DOI for IIM Clinical Trials 3 of any 6 CSM improved by ≥ 20%, with no more than 2 CSM worsening by ≥ 25% (cannot include MMT) Rider, Arth Rheum, 2004 DOI not just a consensus definition, but partially validated using previous adult trial data (n=4) and pediatric natural history data

  6. Rituximab in Myositis Rituximab in the Treatment of Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis Chester V. Oddis, MD Ann M. Reed, MD and the RIM Study Group

  7. RIM Study: Aim To examine the efficacy of rituximab, a B cell depleting agent, in refractory adult and juvenile myositis patients in a multicenter 44-week clinical trial enrolling 76 adult PM, 76 adult DM and 50 JDM patients

  8. Inclusion Criteria • Definite or probable PM or JDM/DM (by Bohan and Peter criteria) • All patients with PM required verification of diagnosis by a 3-member Adjudication Committee • Included medical record review and muscle biopsy review by a neuropathologist

  9. Inclusion Criteria • Refractory myositis = Intolerance to or an inadequate response to corticosteroids plus at least one other immunosuppressive (IS) agent • Adult PM or DM required Manual Muscle Testing-8 (MMT-8) score ≤ 125/150 and 2 other abnormal Core Set Measures (CSM) JDM could enter by the same criteria as adults orif MMT-8 >125 then they required 3 other abnormal CSM

  10. Manual Muscle Testing-8 (MMT-8) Set of 8 muscle groups with a maximum score = 150

  11. RIM Study: 5 Additional Core Set Measures

  12. Inclusion Criteria • Stable prednisone dose for 4 weeks prior to screening visit • Background therapy with at least 1 other IS agent at stable dose for at least 6 weeks prior to screening visit was encouraged

  13. Randomized Placebo Phase Design (RPPD) Wk 0 Wk 1 Wk 8 Wk 9 Wk 4 Wk 12 Wk 44 Screen Rituximab Placebo Rtx Early Placebo-controlled Double Blind Phase Wks 12 – 44 (8 additional visits) Rtx Late Placebo Rituximab • Subjects randomly assigned, double-blind, to ‘Rtx Early’ or ‘Rtx Late’ • ½ subjects receive drug early and ½ subjects receive drug 8 wks later • Week 8: reflects a ‘randomized placebo-controlled trial’ • No corticosteroids at time of the 4 infusions • 14 visits (specimens/CSM) over 44 weeks

  14. Participant Flow Diagram MMT>125 Low IgG/IgM 200 randomized and 195 included in final analysis

  15. Rituximab Dosing • Children received 575mg/m2 up to a maximum dose of 1gm 1 week apart • Adults received 750mg/m2 BSA up to a maximum dose of 1gm 1 week apart

  16. . Patient Baseline Demographic and Clinical Characteristics

  17. Baseline Core Set Measures (Mean/SD) MMT-8 ratio refers to recorded MMT-8/total possible score for muscles tested

  18. Data Quality • Very low patient dropout • 5 pts with baseline visit and no subsequent measurements • 195 randomized pts included in analysis • Excellent quality of data • Very little missing data • Percentage of missing values = 1.2%

  19. B cell Numbers Before and After Rituximab Early Rtx LateRtx

  20. DOI for RIM Study ≥ 20% improvement in 3 of any 6 CSM, no more than 2 CSM worsening by ≥ 25% (excluding MMT) To meet DOI subjects had to satisfy criteria on 2 consecutive visits

  21. Primary Endpoint and Hypothesis • Primary Endpoint: Compare the time to DOI between the ‘Rtx Early’ and ‘Rtx Late’ groups • Hypothesis: The time to DOI will be statistically less (shorter) in early vs. late treatment groups

  22. Primary Outcome: Entire Cohort Median time to DOI: Early Rtx = 20.0 weeks Late Rtx = 20.2 weeks p = 0.74 (log rank)

  23. Primary Outcome: Adult PM Median time to DOI: Early Rtx = 21.8 weeks Late Rtx = 24.0 weeks p = 0.43 (log rank) Primary Outcome: Adult DM Median time to DOI: Early Rtx = 20.4 weeks Late Rtx = 20.3 weeks p = 0.70 (log rank)

  24. Primary Outcome: JDM Median time to DOI: Early Rtx = 11.7 weeks Late Rtx = 19.6 weeks p = 0.32 (log rank)

  25. Secondary Endpoints and Hypotheses • Secondary Endpoint II: Compare the response rates (proportion of patients achieving DOI) at week 8 in early vs. late groups Hypothesis: The response rate will be significantly higher in the early group at week 8

  26. Secondary Endpoint II Proportions of Patients Meeting DOI at Week 8 Early Rtx Late Rtx 20.6% 15%

  27. Patients Meeting DOI During Trial Early Rtx Late Rtx 85% 80% Overall, 83% (161/195) of subjects met the DOI during the course of the 44-week clinical trial

  28. Corticosteroid Sparing Effect p < 0.001 There was a significant difference in the mean corticosteroid dose at baseline compared to the final visit

  29. Retreatment With Rituximab • 10 subjects (9 evaluable) met criteria for re-treatment with Rtx • 4 were in ‘Early’ and 5 in ‘Late’ Rtx groups

  30. Adverse Events • 52/200 (26%) subjects had 68 serious adverse events (SAE) • 40% of those were reported as related to treatment • Most common SAEs included: • infection (25%) • musculoskeletal (18%) • GI (12%) • cardiac (7%) • 1 death (unrelated to drug) • No cases of PML

  31. Summary • The primary and secondary endpoints were not achieved in the RIM Study • 83% of refractory adult and juvenile myositis patients met the DOI in this trial • There was a significant corticosteroid sparing effect noted in this trial between the baseline dose and the dose at study conclusion • Rituximab was generally well tolerated

  32. RIM Study Conclusions • Overestimate of the rituximab effect • SC postulated >50% would meet DOI by 8 weeks • One-half responded by 20 weeks (lower potency) • Underestimate of placebo effect • Short placebo phase of 8 weeks • Heterogeneity of myositis • Increased variance around time to DOI in both arms • Subjective CSM (partially validated)

  33. What about more stringent criteria for improvement? • At least 4 CSM improving by 40%

  34. Entire Cohort: Time to Stringent DOI Early Rtx Late Rtx p=0.13 (Peto-Peto test) p=0.18 (log rank)

  35. RIM Study Autoantibodies

  36. Baseline Autoantibodies Predict Outcome • Autoantibody subsets • anti-SynAb • - HR 2.3 (1.3 – 4.2), p value = 0.01 • DM Abs: TIF-1/MJ/Mi-2 • - HR 1.9 (1.2 – 3.1), p value = 0.01 no autoAb (21%) anti-SRP (13%) other autoAb (14%) DM:TIF-1/MJ/Mi-2 (33%) anti-synAb (14%) Survival distribution function Time in weeks Anti-syn & DM Abs predicted a better outcome, but anti-SRP and those without MAAs had a worse outcome

  37. Median Time to Stringent DOI: Jo-1 vs non-Jo-1 Median time to stringent DOI in Early = 27.9 weeks Early vs Late p=0.12 (log rank)

  38. Other Univariate Predictors • Caucasians showed a better response (p=0.04) • Higher baseline VAS for extramuscular activity was only CSM predictive of better response (p=0.02) • Higher baseline VAS muscle damage score predicted a poor response (p=0.05) Aggarwal, Arth Rheum 62: S385, 2010

  39. Future Directions • Study the ‘immunology’ of the response in the specimens obtained from RIM and correlate this to the clinical outcomes • Assess other biomarkers from the specimen repository • Re-examination of the DOI and the response criteria

  40. Participating Centers

  41. Foreign Centers

  42. Participating Centers Adult Sites Alabama (Fessler) Boston (Narayanaswami) Czechoslovakia (Vencovsky) Dallas (Olsen) Kansas City (Barohn/Latinis) Kentucky (Crofford) London (Isenberg) Mayo Clinic (Ytterberg) Miami (Sharma) Michigan (Seibold/Schiopu) Michigan State (Martin/Eggebeen) Milwaukee (Cronin) New York: North Shore (Marder) New York: HSS (DiMartino) NIH (Miller) Philadelphia (Kolasinski) Phoenix (Levine) Pittsburgh (Oddis/Ascherman) Stanford (Chung/Fiorentino) Sweden (Lundberg) UCLA (Weisman/Venuturupalli) Pediatric Sites Boston (Kim) Cincinnati (Lovell) Duke (Rabinovich) Mayo Clinic (Reed) Miami (Rivas-Chacon) Michigan State (Martin/Eggebeen) NIH (Rider) Nova Scotia (Huber) Philadelphia (Sherry) Pittsburgh (Kietz) Stanford (Sandborg) Toronto (Feldman) Our Patients!!!

  43. Acknowledgements Coordinating Center Dana Ascherman, MD Rohit Aggarwal, MD Sherrie Pryber, Project Manager Diane Koontz, Project Manager Noreen Fertig, BS Kelly Reckley, BS Maureen Laffoon, BS Xinyan Gu IDS Pharmacy David Lacomis, MD Jonette Werley, BA, HT, HTL Christopher Bise, MS, PT Steering Committee Ann Reed, MD Steve Ytterberg, MD Dana Ascherman, MD David Lacomis, MD Brian Feldman, MD Fred Miller, MD, PhD Lisa Rider, MD Todd Levine, MD Steve Belle, PhD Howard Rockette, PhD Michael Harris-Love,MPT Data Center Howard Rockette, PhD Steven Belle, PhD Sharon Lawlor, MBA Stephanie Kelley, MS Other Collaborators The RIM Study Group RIM Study Coordinators David Isenberg, MD, FRCP Myositis Working Group The Myositis Association RIM Publication Committee IMACS Supported by:

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