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Multicenter Study
. 2024 Feb 13;102(3):e207963.
doi: 10.1212/WNL.0000000000207963. Epub 2024 Jan 18.

Multicenter Validation of the Charcot-Marie-Tooth Functional Outcome Measure

Melissa R Mandarakas  1 , Katy J Eichinger  1 , Paula Bray  1 , Kayla M D Cornett  1 , Michael E Shy  1 , Mary M Reilly  1 , Gita M Ramdharry  1 , Steven S Scherer  1 , Davide Pareyson  1 , Timothy Estilow  1 , Marnee J McKay  1 ; for ACT-CMT Study Group  1 ; David N Herrmann  1 , Joshua Burns  1
Collaborators, Affiliations
Multicenter Study

Multicenter Validation of the Charcot-Marie-Tooth Functional Outcome Measure

Melissa R Mandarakas et al. Neurology. .

Abstract

Background and objectives: Charcot-Marie-Tooth disease type 1A (CMT1A), caused by a duplication of PMP22, is the most common hereditary peripheral neuropathy. For participants with CMT1A, few clinical trials have been performed; however, multiple therapies have reached an advanced stage of preclinical development. In preparation for imminent clinical trials in participants with CMT1A, we have produced a Clinical Outcome Assessment (COA), known as the CMT-Functional Outcome Measure (CMT-FOM), in accordance with the FDA Roadmap to Patient-Focused Outcome Measurement to capture the key clinical end point of function.

Methods: Participants were recruited through CMT clinics in the United States (n = 130), the United Kingdom (n = 52), and Italy (n = 32). To derive the most accurate signal with the fewest items to identify a therapeutic response, a series of validation studies were conducted including item and factor analysis, Rasch model analysis and testing of interrater reliability, discriminative ability, and convergent validity.

Results: A total of 214 participants aged 18-75 years with CMT1A (58% female) were included in this study. Item, factor, and Rasch analysis supported the viability of the 12-item CMT-FOM as a unidimensional interval scale of function in adults with CMT1A. The CMT-FOM covers strength, upper and lower limb function, balance, and mobility. The 0-100 point scoring system showed good overall model fit, no evidence of misfitting items, and no person misfit, and it was well targeted for adults with CMT1A exhibiting high inter-rater reliability across a range of clinical settings and evaluators. The CMT-FOM was significantly correlated with the CMT Examination Score (r = 0.643; p < 0.001) and the Overall Neuropathy Limitation Scale (r = 0.516; p < 0.001). Significantly higher CMT-FOM total scores were observed in participants self-reporting daily trips and falls, unsteady ankles, hand tremor, and hand weakness (p < 0.05).

Discussion: The CMT-FOM is a psychometrically robust multi-item, unidimensional, disease-specific COA covering strength, upper and lower limb function, balance, and mobility to capture how participants with CMT1A function to identify therapeutic efficacy.

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Conflict of interest statement

M.R. Mandarakas reports no disclosures relevant to the manuscript. K.J. Eichinger reports grant support through the Charcot-Marie-Tooth Association and has served on advisory boards for Biogen, Roche, Dyne, and has received consulting fees from Fulcrum Therapeutics, Dyne, Acceleron Pharma, Avidity and Roche. P. Bray and K.M.D. Cornett report no disclosures relevant to the manuscript. M.E. Shy receives grant support from the NIH (1U01 NS109403 and U54NS065712), the Muscular Dystrophy Association, and the Charcot-Marie-Tooth Association and consulting fees from Alnylam Pharmaceuticals, Flex Pharma and Accelerant Pharmaceuticals. M.M. Reilly receives grant support from the Medical Research Council (MRC MR/S005021/1), the NIH (U54NS065712 and 1UOINS109403-01 and R21TROO3034), Muscular Dystrophy Association (MDA510281) and the Charcot Marie Tooth Association and Scientific Advisory Board or consulting fees from Alnylam, Bridgebio, Applied Therapeutics, DTx Pharma and Augustine Therapeutics. G. Ramdharry reports no disclosures relevant to the manuscript. S.S. Scherer receives grant support from the NIH (1U01 NS109403 and U54NS065712), the Muscular Dystrophy Association, the CMT Association, and Scientific Advisory Board or consulting fees from Applied Therapeutics, Disarm Therapeutics, DTx Pharma, Mitochondria in Motion, Pfizer, Takeda, and Toray Industries. D. Pareyson receives grant support from the NIH (NINDS #1U01NS109403), Telethon Italy (GPP19099, GUP15009, GUP15010), AFM Telethon (# 24110, 20667, 20821), and the Charcot-Marie-Tooth Association and reports participation in Clinical/Scientific Advisory Boards of Alnylam Pharmaceuticals, Akcea, Arvinas, Augustine Tx, DTx Pharma, Inflectis. T. Estilow receives Speakers Bureau fees from Sarepta Therapeutics, and consulting fees from Applied Therapeutics and DTx Pharma. M.J. McKay reports no disclosures relevant to the manuscript. D.N. Herrmann receives grant support from the NIH (1U01 NS109403 and U54NS065712) and Scientific Advisory Board or consulting fees from Regenacy, Applied Therapeutics, Pfizer, Passage Bio, Swan Bio, Faze Medicines, DTx Pharma, Sarepta, Neurogene, Guidepoint Global, and GLG. J. Burns receives Research Support from the University of Sydney, Sydney Children's Hospitals Network, Australian Government (NHMRC#2015970, MRFF#1152226), United States Government (NIH NINDS#1U01NS109403, NIH NCATS/NINDS# U54NS065712), Muscular Dystrophy Association, American Orthotic and Prosthetic Association, Charcot Marie Tooth Association and Charcot Marie Tooth Australia. Scientific Advisory Board fees from Faculty of Medicine Siriraj Hospital Mahidol University Thailand; Department of Rehabilitation Sciences, The Hong Kong Polytechnic University; Hereditary Neuropathy Foundation. Served as a consultant to DTx Pharma, Applied Therapeutics, Pharnext. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Person-Item Threshold Distribution for the Rasch-Derived 12-Item CMT-FOM
CMT-FOM = Charcot-Marie-Tooth Functional Outcome Measure.
Figure 2
Figure 2. Item Map for the Rasch-Derived 12-Item CMT-FOM
Chair stand = 30-second chair stand test; On line eyes closed = stance with feet apart on line with eyes closed; On line eyes open = stance with feet apart on line with eyes open; CMT-FOM = Charcot-Marie-Tooth Functional Outcome Measure; 9HPT = nine-hole peg test.
Figure 3
Figure 3. Distribution of the Rasch-Derived 12-Item CMT-FOM Scores for CMT1A
CMT-FOM = Charcot-Marie-Tooth Functional Outcome Measure.
Figure 4
Figure 4. Correlation Between the Rasch-Derived 12-Item CMT-FOM and (A) CMTES-R (r = 0.643; p < 0.001), (B) ONLS (r = 0.516; p < 0.001)
CMTES-R = Rasch-modified CMT Examination Score; CMT-FOM = Charcot-Marie-Tooth Functional Outcome Measure; ONLS = Overall Neuropathy Limitation Scale.
Figure 5
Figure 5. Rasch-Derived 12-Item CMT-FOM Data Form, Including Patient Profile Information
CMT-FOM = Charcot-Marie-Tooth Functional Outcome Measure.
See this image and copyright information in PMC

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