Rituximab in Myositis (RIM) Study

Muscle Study GroupSeptember 28, 2012

Chester V. Oddis, MDDivision of Rheumatology and Clinical ImmunologyUniversity of Pittsburgh

Disclosures

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

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

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]

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

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

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

Inclusion Criteria

1. 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

Inclusion Criteria

2. Refractory myositis = Intolerance to or an inadequate response to corticosteroids plus at least one other immunosuppressive (IS) agent

3. 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

Muscle Groups Right (0 – 10) Left (0 – 10) Axial (0 – 10)

Axial Muscles (0 – 10)

Neck Flexors 0-10

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)

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

Manual Muscle Testing-8 (MMT-8)

Domain Core Set Measures

Global ActivityPhysician global VAS ≥ 2.0 on 10cm scale

Patient/Parent global VAS ≥ 2.0 on 10cm scale

Physical Function CHAQ/HAQ disability index ≥ 0.25

LaboratoryAssessment

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

RIM Study: 5 Additional Core Set Measures

Inclusion Criteria

4. Stable prednisone dose for 4 weeks prior to screening visit

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

Randomized Placebo Phase Design(RPPD)

Rituximab

Placebo

Wk 0 Wk 1Wk 4

Wk 8 Wk 9

Placebo

Rituximab

Screen

Placebo-controlled Double Blind Phase

Wks 12 – 44(8 additional visits)

Rtx Early

Rtx Late

Wk 12 Wk 44

• 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

Participant Flow Diagram

200 randomized and 195 included in final analysis

MMT>125Low IgG/IgM

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

. Patient Baseline Demographic and Clinical Characteristics

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 (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

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%

B cell Numbers Before and After Rituximab

Early Rtx

LateRtx

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

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

Primary Outcome: Entire CohortPrimary Outcome: Entire Cohort

Median time to DOI: Early Rtx = 20.0 weeks Late Rtx = 20.2 weeks

p = 0.74 (log rank)

Primary Outcome: Adult PM

Median time to DOI: Early Rtx = 21.8 weeks Late Rtx = 24.0 weeks

p = 0.43 (log rank)

Median time to DOI: Early Rtx = 20.4 weeks Late Rtx = 20.3 weeks

p = 0.70 (log rank)

Primary Outcome: Adult DM

Primary Outcome: JDM

Median time to DOI: Early Rtx = 11.7 weeks Late Rtx = 19.6 weeks

p = 0.32 (log rank)

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

Secondary Endpoint IISecondary Endpoint II

Proportions of Patients Meeting DOI at Week 8

15%

20.6%

Early Rtx Late Rtx

Patients Meeting DOI During TrialPatients Meeting DOI During Trial

Overall, 83% (161/195) of subjects met the DOI during the course of the 44-week clinical trial

80% 85%

Early Rtx Late Rtx

Corticosteroid Sparing Effect

p < 0.001

There was a significant difference in the mean corticosteroid dose at baseline compared to the final visit

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

(mean, n=9)

Weeks to Re-treatment DOI

(mean, n=8)

12.4 16.5 19.9

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

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

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)

What about more stringent criteria for improvement?

• At least 4 CSM improving by 40%

p=0.13 (Peto-Peto test) p=0.18 (log rank)

Entire Cohort: Time to Stringent DOI

Early Rtx Late Rtx

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

Baseline Autoantibodies Predict Outcome

no autoAb (21%)

anti-SRP (13%)

other autoAb (14%)

DM:TIF-1/MJ/Mi-2 (33%)

anti-syn Ab (14%)

Autoantibody subsetsAutoantibody subsets• anti-SynAb anti-SynAb - HR 2.3 (1.3 – 4.2), p value = 0.01 - HR 2.3 (1.3 – 4.2), p value = 0.01 • DM Abs: TIF-1/MJ/Mi-2DM Abs: TIF-1/MJ/Mi-2 - HR 1.9 (1.2 – 3.1), p value = 0.01- HR 1.9 (1.2 – 3.1), p value = 0.01

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Time in weeks

Anti-syn & DM Abs predicted a better outcome, but anti-SRP and those without MAAs had a worse outcome

Median Time to Stringent DOI: Jo-1 vs non-Jo-1

Early vs Latep=0.12 (log rank)

Median time to stringent DOI in Early = 27.9 weeks

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

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

Participating Centers

Foreign Centers

Participating CentersAdult 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!!!

AcknowledgementsCoordinating 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

Study PartnersStudy PartnersSupported by:

Steering CommitteeAnn Reed, MDSteve Ytterberg, MDDana Ascherman, MDDavid Lacomis, MDBrian Feldman, MDFred Miller, MD, PhDLisa Rider, MDTodd Levine, MDSteve Belle, PhDHoward Rockette, PhDMichael Harris-Love,MPT

Other CollaboratorsThe RIM Study GroupRIM Study CoordinatorsDavid Isenberg, MD, FRCPMyositis Working GroupThe Myositis AssociationRIM Publication Committee

Data CenterHoward Rockette, PhDSteven Belle, PhDSharon Lawlor, MBAStephanie Kelley, MS

IMACS