IMACS History and Development of
Myositis Clinical Trials
Muscle Study Group
September 21, 2010
Chester V. Oddis, MD
University 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
Fred Miller
Lisa Rider
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 Group
Adult 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
Areas to Address in Myositis Trials
• Sufficient sample size (IMACS)
• Relevant outcomes for clinical trials
• Special aspects of myositis influencing
trial design:

Heterogeneity

Clinical diversity

Activity vs. damage
• Barriers to studying novel therapies
Areas to Address in Myositis Trials
• Sufficient sample size (IMACS)
• Relevant outcomes for clinical trials
• Special aspects of myositis influencing
trial design:

Heterogeneity

Clinical diversity

Activity vs. damage
• Barriers to studying novel therapies
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
Domains of Disease Activity and Core Set
Measures for Assessing Outcome in Myositis
Domain
Global Activity
Core Set Measures
Physician global disease activity (Likert or
VAS)
Parent/patient global disease activity (Likert or
VAS)
Muscle Strength
Physical
Function
Laboratory
Assessment
Extramuscular
disease
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).
Validated patient/parent questionnaire of
activities of daily living (HAQ/CHAQ).
At least two serum muscle enzyme activities
from the following: CK, aldolase, LDH, ALT and
AST.
A validated approach that is comprehensive
and assesses constitutional, cutaneous, GI,
articular, cardiac and pulmonary activity.
Miller, Rheumatology, 2001
Myositis Clinical Trials:
“Pieces of the Puzzle”
•
Establishment of IMACS

•
Adult/pediatric/multidisciplinary/international
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
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]
Areas to Address in Myositis Trials
• Sufficient sample size (IMACS)
• Relevant outcomes for clinical trials
• Special aspects of myositis influencing
trial design:

Heterogeneity

Clinical diversity

Activity vs. damage
• Barriers to studying novel therapies
General Trial Design Issues
1.
2.
3.
4.
5.
6.
IIM subgroups to be included in myositis clinical trials
Classification criteria to be utilized for trial entry
Other inclusion criteria for trial entry
Exclusion criteria for trial entry
Stratification of patients at outcome analysis
Concomitant therapy allowable during myositis clinical
trial
7. Trial duration/use of placebo
8. Outcome and safety (drug toxicity) assessment intervals
during active treatment phase of clinical trial
9. Clinical worsening to allow for change in therapy
10. Drop out criteria for myositis trials
11. Post-trial therapy assessments
12. 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)

•
Step 4: Resolution of controversial trial design issues using
nominal group technique ( 70% agreement)

•
38 adult and 31 pediatric specialists responded to 2nd Email survey
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
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]
•
Multidisciplinary, international consensus
on conduct of clinical trials [Oddis/Rider]
Areas to Address in Myositis Trials
• Sufficient sample size (IMACS)
• Relevant outcomes for clinical trials
• Special aspects of myositis influencing
trial design:

Heterogeneity

Clinical diversity

Activity vs. damage
• Barriers to studying novel therapies
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]
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]
•
Multidisciplinary, international consensus on the
conduct of adult and juvenile myositis clinical
trials [Oddis/Rider]
•
Assessment of disease activity and damage
[Sultan/Isenberg; Rider]
Areas to Address in Myositis Trials
• Sufficient sample size (IMACS)
• Relevant outcomes for clinical trials
• Special aspects of myositis influencing
trial design:

Heterogeneity

Clinical diversity

Activity vs. damage
• Barriers to studying novel therapies
Rituximab in Myositis
Rituximab in the Treatment of Refractory Adult and Juvenile
Dermatomyositis (DM) and Adult Polymyositis (PM)
University of Pittsburgh
Coordinating 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