Rituximab in Myositis (RIM) Study

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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

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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

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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

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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 (n4) and pediatric natural history data
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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
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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

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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

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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 gt125 then they required 3 other
  abnormal CSM

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Manual Muscle Testing-8 (MMT-8)
Muscle Groups Right (0 10) Left (0 10) Axial (0 10)
Axial Muscles (0 10) Axial Muscles (0 10) Axial Muscles (0 10)
Neck Flexors 0-10
Proximal Muscles (0 100) Proximal Muscles (0 100) Proximal Muscles (0 100)
Deltoid 0-10 0-10
Biceps brachii 0-10 0-10
Gluteus maximus 0-10 0-10
Gluteus medius 0-10 0-10
Quadriceps 0-10 0-10
Distal Muscles (0 40) Distal Muscles (0 40) Distal Muscles (0 40)
Wrist Extensors 0-10 0-10
Ankle dorsiflexors 0-10 0-10
MMT-8 score (0 150) 0-70 0-70 0-10
Set of 8 muscle groups with a maximum score 150
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RIM Study 5 Additional Core Set Measures
Domain Core Set Measures
Global Activity Physician global VAS 2.0 on 10cm scale
Global Activity 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
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Inclusion Criteria

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

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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

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Participant Flow Diagram
MMTgt125 Low IgG/IgM
200 randomized and 195 included in final analysis
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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

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. Patient Baseline Demographic and Clinical
Characteristics
Characteristic Early Rituximab (n96) Late Rituximab (n104) 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 (n96) 39/40/25 (n104) 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) 16 (15.8) 19 (18.8) 3 0.65
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Baseline Core Set Measures (Mean/SD)
Characteristic Early Rituximab (n96) Late Rituximab (n104) 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 (0-100 mm) 27.4 (20.4) 30.7 (19.5) 0.25
MMT-8 ratio refers to recorded MMT-8/total
possible score for muscles tested
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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

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B cell Numbers Before and After Rituximab
Early Rtx
LateRtx
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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
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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

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Primary Outcome Entire Cohort
Median time to DOI Early Rtx 20.0 weeks
Late Rtx 20.2 weeks p 0.74 (log rank)
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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)
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Primary Outcome JDM
Median time to DOI Early Rtx 11.7 weeks
Late Rtx 19.6 weeks p 0.32 (log rank)
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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

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Secondary Endpoint II
Proportions of Patients Meeting DOI at Week 8
Early Rtx Late Rtx
20.6
15
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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
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Corticosteroid Sparing Effect
p lt 0.001
There was a significant difference in the mean
corticosteroid dose at baseline compared to the
final visit
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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, n9) Weeks from DOI to DOW (mean, n9) Weeks to Re-treatment DOI (mean, n8)
12.4 16.5 19.9
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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

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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

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RIM Study Conclusions

• Overestimate of the rituximab effect
• SC postulated gt50 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)

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What about more stringent criteria for
improvement?

• At least 4 CSM improving by 40

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Entire Cohort Time to Stringent DOI
Early Rtx Late Rtx
p0.13 (Peto-Peto test) p0.18 (log rank)
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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
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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) DMTIF-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
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Median Time to Stringent DOI Jo-1 vs non-Jo-1
Median time to stringent DOI in Early 27.9 weeks
Early vs Late p0.12 (log rank)
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Other Univariate Predictors

• Caucasians showed a better response (p0.04)
• Higher baseline VAS for extramuscular activity
  was only CSM predictive of better response
  (p0.02)
• Higher baseline VAS muscle damage score predicted
  a poor response (p0.05)

Aggarwal, Arth Rheum 62 S385, 2010
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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

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Participating Centers
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Foreign Centers
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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)

• 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!!!

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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
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