A Consensus Hybrid Definition Using a Conjoint Analysis Is the Proposed As Response Criteria for Minimal and Moderate Improvement for Adult Polymyositis and Dermatomyositis Clincal Trials

Rohit Aggarwal¹, Lisa G. Rider², Nicolino Ruperto³, Nastaran Bayat², Brian Erman⁴, Brian M. Feldman⁵, Adam M. Huber⁶, Chester V. Oddis⁷, Ingrid E. Lundberg⁸, Anthony A. Amato, MD^9,10, Robert G. Cooper, MD, FRCP¹¹, Hector Chinoy¹², Maryam Dastmalchi¹³, David Fiorentino¹⁴, David Isenberg¹⁵, James D. Katz¹⁶, Andrew L. Mammen¹⁷, Marianne de Visser¹⁸, Steven R. Ytterberg¹⁹, Katalin Danko²⁰, Luca Villa²¹, Mariangela Rinaldi²¹, Howard Rockette²², Peter A. Lachenbruch², Frederick W. Miller² and Jiri Vencovsky, MD, DSc²³, ¹Medicine, University of Pittsburgh, Pittsburgh, PA, ²Environmental Autoimmunity Group, NIEHS, NIH, Bethesda, MD, ³Pediatria II,, Istituto Giannina Gaslini, Genoa, Italy, ⁴Social and Scientific Systems, Inc., Durham, NC, ⁵Rheumatology, The Hospital for Sick Children, Toronto, ON, Canada, ⁶IWK Health Centre, Halifax, NS, Canada, ⁷Rheum/Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, ⁸Rheumatology Unit, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden, ⁹Brigham and Women's Hospital and Harvard Medical School, Boston, MA, ¹⁰Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, ¹¹MRC/ARUK Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom, ¹²Centre for Musculoskeletal Research, University of Manchester, Manchester, United Kingdom, ¹³Rheumatology Unit, Department of Medicine, Karolinska University Hospital in Solna, Karolinska Institutet, Stockholm, Sweden, ¹⁴Dermatology, Stanford University, Redwood City, CA, ¹⁵Centre for Rheumatology Research, Arthritis Research UK Centre for Adolescent Rheumatology, University College London, London, United Kingdom, ¹⁶NIAMS, NIH, Bethesda, MD, ¹⁷Neurology and Medicine, Johns Hopkins University, Baltimore, MD, ¹⁸Department of Neurology, Academic Medical Centre, Amsterdam, Netherlands, ¹⁹Rheumatology Division, Mayo Clinic, Rochester, MN, ²⁰Institute of Rheumatology, University of Debrecen, Hungary, Debrecen, Hungary, ²¹Pediatria II, Reumatologia, PRINTO, IRCCS Istituto G. Gaslini, Genova, Italy, ²²University of Pittsburgh, Pittsburgh, PA, ²³Institute of Rheumatology, Charles University, Prague, Czech Republic

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Clinical research, Clinical Response, dermatomyositis, myositis and polymyositis

Session Information

Title: Muscle Biology, Myositis and Myopathies

Session Type: Abstract Submissions (ACR)

Background/Purpose: To develop consensus on definitions of improvement (DOIs) for minimal and moderate improvement (and draft preliminary criteria for major improvement) in adult dermatomyositis (DM) and polymyositis (PM) for therapeutic trials.

Methods: Patient profiles from natural history and/trial data were rated by myositis experts. Consensus (³70%) was reached in 91%; 157 rated with minimal, 72 moderate and 12 major improvement. Conjoint analysis was performed on forced-choice surveys (using 1000Minds software) that were administered to myositis experts. Candidate DOIs based on changes in IMACS core set measures (CSMs) were generated for minimal, moderate and major improvement: A) 23 previously-published DOIs; B) 408 new DOIs (called “Base”) using expert survey and variations of published DOIs; C) 56 DOIs derived from logistic regression; D) 6 DOIs derived from a Conjoint Analysis survey that yielded scores with different levels of improvement in different CSMs; E) 8 DOIs drafted by combining changes in each CSM with respective Conjoint Analysis weights; and F) 194 DOIs drafted by applying weights from Conjoint Analysis to the base DOIs. Relative and absolute percentage change DOIs were tested for minimal, moderate and major improvement. The consensus-rated patient profiles were then used to: a) validate DOIs (including definitions A, B, D, E, F) for their sensitivity, specificity, kappa, odds ratio, and area under the curve (AUC); and b) develop logistic regression DOIs (definition C using 2/3^rd of data) and then internal validation (using 1/3^rd data). High performing DOIs were externally validated using Rituximab in Myositis (RIM) trial data (N=152 DM/PM), followed by a consensus meeting using nominal group technique (NGT). The 17 highest performing candidate DOIs with AUC ³ 0.90 in profile data and with good validation (AUC > 0.70) in RIM, some from each category A-F, were discussed for their performance characteristics and clinical face validity at a consensus conference.

Results: A final ranking of the top DOIs from the adult working group yielded 92% consensus (among 12 adult PM/DM experts) for a Conjoint Analysis hybrid DOI using relative % change in CSMs with different cutpoints for minimal, moderate and major improvement. NGT discussion with the adult and pediatric working groups yielded consensus (91% agreement) in use of a different Conjoint Analysis hybrid DOI (Table 1) for both adult DM/PM and JDM clinical trials using absolute % change with different cutpoints for minimal, moderate and major improvement.

Conclusion: A Conjoint Analysis-driven hybrid DOI with a continuous score of improvement based on absolute % change in CSMs with different cut points for minimal, moderate and major improvement (prelim) was selected by a data and consensus-driven process as a final DOI to be used for clinical trials in adult DM/PM. Criteria for major improvement is considered preliminary.

Table 1. Final Myositis Response Criteria Model

1000Minds Model (absolute % change)
Core Set Measure	Improvement score for each level of CSM
MD Global Absolute % Change
Up to <=5%	0
>5% up to <=15%	7.5
>15% up to <=25%	15
>25% up to <=40%	17.5
>40%	20
Patient Global/Parent Global Absolute % Change
Up to <=5%	0
>5% up to <=15%	2.5
>15% up to <=25%	5
>25% up to <=40%	7.5
>40%	10
MMT/CMAS Absolute % Change
Up to <=2%	0
>2% up to <=10%	10
>10% up to <=20%	20
>20% up to <=30%	27.5
>30%	32.5
HAQ/CHAQ Absolute % Change
Up to <=5%	0
>5% up to <=15%	5
>15% up to <=25%	7.5
>25% up to <=40%	7.5
>40%	10
Muscle Enzyme/CHQ-PF50 Absolute % Change
Up to <=5%	0
>5% up to <=15%	2.5
>15% up to <=25%	5
>25% up to <=40%	7.5
>40%	7.5
Extra Muscular VAS/DAS Absolute % Change
Up to <=5%	0
>5% up to <=15%	7.5
>15% up to <=25%	12.5
>25% up to <=40%	15
>40%	20
Total Improvement Score is sum of score achieved in each CSM
Total improvement score >= cut points determines Minimal, Moderate and Major Improvement
Profile	Improvement Category	Cut point on total improvement score
Adult	Minimal	>=20
	Moderate	>=40
	Major (prelim)	>=60

Disclosure:

R. Aggarwal,

Questcor,

Pfizer Inc,

NIEHS-NIH,

Questcor,

aTyr Pharma,

L. G. Rider,

NIEHS-NIH,

NIAMS-NIH,

National Center for Translational Science-NIH,

Cure JM Foundation,

N. Ruperto,

European League Against Rheumatism,

N. Bayat,

Cure JM Foundation,

B. Erman,

NIEHS-NIH,

B. M. Feldman,
None;

A. M. Huber,
None;

C. V. Oddis,

Novartis Pharmaceutical Corporation,

I. E. Lundberg,
None;

A. A. Amato, MD,

MedImmune,

Biogen Idec,

Neuromuscular Disorders textbook,

R. G. Cooper, MD, FRCP,
None;

H. Chinoy,
None;

M. Dastmalchi,
None;

D. Fiorentino,
None;

D. Isenberg,
None;

J. D. Katz,
None;

A. L. Mammen,
None;

M. de Visser,
None;

S. R. Ytterberg,

Questcor,

K. Danko,
None;

L. Villa,
None;

M. Rinaldi,
None;

H. Rockette,
None;

P. A. Lachenbruch,
None;

F. W. Miller,

NIEHS-NIH,

NIAMS-NIH,

National Center for Advancing Translational Science-NIH,

J. Vencovsky, MD, DSc,

European League Against Rheumatism, Myositis Support Group, The Myositis Association,

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