imacs history and development of myositis clinical trials muscle study group september 21, 2010...

IMACS History and Development of Myositis Clinical Trials

Muscle Study GroupSeptember 21, 2010

Chester V. Oddis, MDUniversity of Pittsburgh

Disclosures

• Genentech: Grant support

Lecture Objectives

• Overview of myositis in the past decade

• “Birth” of a clinical trial in myositis

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

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

Where Were

We Ten Years

Ago?

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

Lisa RiderFred Miller

David Isenberg

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

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

GroupAdult and pediatric rheumatologists,

neurologists, physiatrists and dermatologists organized to address these deficiencies

Myositis Clinical Trials: “Pieces of the Puzzle”

• Establishment of IMACS Adult/pediatric/multidisciplinary/international


• Sufficient sample size (IMACS)




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)

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

Domain Core 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).

LaboratoryAssessment

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



• Agreed upon outcome measures [Miller]

Step 2: Clinically Meaningful Improvement in Core Set Measures

Median % Change

Core Set Domain Adult Pediatric

MD Global Activity 20 20

Patient/Parent Global Activity

20 20

Muscle Strength 15 18

Physical Function 15 15

Muscle Enzymes 30 30

Extramuscular Activity 20 20

Rider, J Rheum, 2003

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

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




• Definition(s) of improvement for myositis clinical trials [Rider]

General Trial Design Issues1. IIM subgroups to be included in myositis clinical trials2. Classification criteria to be utilized for trial entry3. Other inclusion criteria for trial entry4. Exclusion criteria for trial entry5. Stratification of patients at outcome analysis6. Concomitant therapy allowable during myositis clinical

trial7. Trial duration/use of placebo8. Outcome and safety (drug toxicity) assessment

intervals during active treatment phase of clinical trial9. Clinical worsening to allow for change in therapy10. Drop out criteria for myositis trials11. Post-trial therapy assessments12. Definitions of complete clinical response and remission

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 2nd 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





• Multidisciplinary, international consensus on conduct of clinical trials [Oddis/Rider]

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]





• Multidisciplinary, international consensus on the conduct of adult and juvenile myositis clinical trials [Oddis/Rider]

• Assessment of disease activity and damage [Sultan/Isenberg; Rider]

Rituximab in MyositisRituximab in the Treatment of Refractory Adult and Juvenile

Dermatomyositis (DM) and Adult Polymyositis (PM)

University of PittsburghCoordinating Center

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

imacs history and development of myositis clinical trials muscle study group september 21, 2010...

Documents

myositis outcome

prospective myositis

causes of myositis slide

myositis disease activity

previous trials

outcome assessments

myositis syndromes goal

grant support slide