1. Rituximab in Myositis (RIM) Study
Muscle Study Group
September 28, 2012
Chester V. Oddis, MD
Division of Rheumatology and Clinical Immunology University 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
Problem of PM mimics and to exclude IBM

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 or if MMT-8 >125 then they required 3 other abnormal CSM

10. Manual Muscle Testing-8 (MMT-8)
Muscle Groups
Right (0 – 10)
Left (0 – 10)
Axial (0 – 10)
Axial Muscles (0 – 10)
Neck Flexors
0-10
Proximal Muscles (0 – 100)
Deltoid
Biceps brachii
Gluteus maximus
Gluteus medius
Quadriceps
Distal Muscles (0 – 40)
Wrist Extensors
Ankle dorsiflexors
MMT-8 score (0 – 150)
0-70
Set of 8 muscle groups with a maximum score = 150

11. Extramuscular Disease
RIM Study: 5 Additional Core Set Measures
Domain
Core Set Measures
Global Activity
Physician global VAS ≥ 2.0 on 10cm scale
Patient/Parent global VAS ≥ 2.0 on 10cm scale
Physical Function
CHAQ/HAQ disability index ≥ 0.25
Laboratory
Assessment
At least one muscle enzyme (CK/AST/ALT/LDH/aldolase) ≥ 1.3x ULN
Extramuscular Disease
Global extramuscular disease activity VAS ≥ 1.0 on the Myositis Disease Activity Assessment Tool (MDAAT)
– constitutional, cutaneous, articular, GI, pulmonary, cardiac

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
Early Rituximab (n=96)
Late Rituximab (n=104)
p value
Caucasian race (%)
62 (65)
81 (78)
0.05
Mean age (SD)
43 (18.2)
40 (18.4)
0.36
Female sex (%)
68 (71)
78 (75)
0.61
IIM subset (PM/DM/JDM)
37/36/23 (n=96)
39/40/25 (n=104)
0.99
Mean disease duration (SD)
5.2 yrs (6.5)
5.4 years (6.0)
0.78
Mean prednisone dose (SD)
19.7 (12.1)
21.4 (14.4)
0.39
Non-corticosteroid immunosuppressive use (%)
84 (88)
89 (86)
0.85
Myositis autoantibody positivity (%)
Anti-synthetase
Anti-SRP
DM-associated*
Other autoantibody#
None of the above
Undefined autoantibody+
16 (17.8)
13 (14.4)
33 (36.7)
8 (8.9)
20 (22.2) 6
16 (15.8)
12 (11.9)
38 (37.6)
19 (18.8) 3
0.65

17. Baseline Core Set Measures (Mean/SD)
Characteristic
Early Rituximab (n=96)
Late Rituximab (n=104)
p value
MMT-8 ratio
71 (11.4)
71.7 (13.0)
0.70
MD Global VAS
(0-100 mm)
51.4 (17.6)
49.2 (17.4)
0.37
Patient/Parent Global VAS
(0-100mm)
65.4 (20.3)
65.6 (21.7)
0.94
HAQ/CHAQ Disability Index (0-3)
1.55 (.7)
1.53 (0.8)
0.84
Muscle enzyme x ULN
9.5 (14.9)
5.5 (9.0)
0.03
Extramuscular Score VAS
27.4 (20.4)
30.7 (19.5)
0.25
MMT-8 ratio refers to recorded MMT-8/total possible score for muscles tested

18. Data Quality Very low patient dropout Excellent quality of data
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. To meet DOI subjects had to satisfy criteria on 2 consecutive visits
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. Proportions of Patients Meeting DOI at Week 8
Secondary Endpoint II
Proportions of Patients Meeting DOI at Week 8
Early Rtx Late Rtx
20.6%
15% 26

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 27

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

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
Weeks to Initial DOI
(mean, n=9)
Weeks from DOI to DOW
Weeks to Re-treatment DOI
(mean, n=8)
12.4
16.5
19.9

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
Autoantibody
Number (%)
Synthetase
32 (16%)
- 28 Jo-1
SRP
25 (13%)
DM-associated
71 (35%)
- 26 Mi-2
- 23 TIF1-gamma
- 22 MJ
Overlap/other autoAb
24 (12%)
No MAA
40 (20%)
Undefined
9 (4%)
Total
200

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-syn Ab (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!!!
Made changes:
Michigan should be changed to Seibold and Schiopu
The 2 adult New York sites should be distinguished from each other – i.e. location ; Marder-North Shore; DiMartino: HSS
Stanford is spelled wrong and should be Chung and Fiorentino
UCLA should be Weisman and Venuturupalli 42

43. Acknowledgements Supported by: 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: