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Jeffrey A. Cohen, MD; Gary R. Cutter, PhD; Jill S. Fischer, PhD; Andrew D. Goodman, MD; Fedor R. Heidenreich, MD; Amy J. Jak, MA; Judith E. Kniker, MA; Mariska F. Kooijmans, MD, PhD; Julia M. Lull, BA; Alfred W. Sandrock, MD, PhD; Jack H. Simon, MD; Nancy A. Simonian, MD; John N. Whitaker, MD; for the IMPACT Investigators

Arch Neurol. 2001;58:961-967.

Background  The Multiple Sclerosis Functional Composite (MSFC) is a multidimensional clinical outcome measure that includes quantitative tests of leg function/ambulation (Timed 25-Foot Walk), arm function (9-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test). The MSFC is the primary outcome measure in the ongoing multinational phase 3 trial of interferon beta-1a (Avonex) in patients with secondary progressive MS.

Objective  To assess the practice effects, reliability, and validity of the MSFC clinical outcome measure.

Design  Examining technicians underwent formal training using standardized materials. The MSFC was performed according to a standardized protocol. The 436 patients enrolled in the International Multiple Sclerosis Secondary Progressive Avonex Controlled Trial underwent 3 prebaseline MSFC testing sessions before randomization.

Results  Practice effects were evident initially for the MSFC but stabilized by the fourth administration. The Paced Auditory Serial Addition Test demonstrated the most prominent practice effects. The reliability of the MSFC was excellent, with an intraclass correlation coefficient for session 3 (final prebaseline session) vs session 4 (baseline) of 0.90. The MSFC at baseline correlated moderately strongly with the Kurtzke Expanded Disability Status Scale. Among the MSFC components, the Timed 25-Foot Walk correlated most closely. Correlations among the 3 MSFC components were weak, suggesting they assess distinct aspects of neurologic function in patients with MS.

Conclusions  The MSFC demonstrated excellent intrarater reliability in this multinational phase 3 trial. Three prebaseline testing sessions were sufficient to compensate for practice effects. The pattern of correlations among the MSFC, its components, and the Kurtzke Expanded Disability Status Scale supported the validity of the MSFC.

From the Mellen Center for Multiple Sclerosis Treatment and Research and the Department of Neurology, The Cleveland Clinic Foundation, Cleveland, Ohio (Drs Cohen and Fischer and Mss Jak and Kniker); the Center for Research Methodology and Biometrics, AMC Cancer Center, Lakewood, Colo (Dr Cutter); the Departments of Neurology, University of Rochester, Rochester, NY (Dr Goodman), Hannover Medical School, Hannover, Germany (Dr Heidenreich), and the University of Alabama at Birmingham (Dr Whitaker); Biogen, Inc, Cambridge, Mass (Drs Kooijmans, Sandrock, and Simonian and Ms Lull); and the Department of Radiology, University of Colorado, Denver (Dr Simon). Drs Kooijmans, Sandrock, and Simonian and Ms Lull are full-time employees of Biogen, Inc. None of the other authors has a personal financial investment, ownership, equity, or other financial holdings with Biogen, Inc. Dr Fischer and Mss Jak and Kniker supervised the training of examining technicians and were reimbursed through a contract with Biogen, Inc, which was paid to The Cleveland Clinic. Drs Cohen, Cutter, Goodman, Heidenreich, Simon, and Whitaker have served as consultants for, received honoraria from, or received research support from Biogen, Inc.

Corresponding author and reprints: Jeffrey A. Cohen, MD, The Mellen Center-U10, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195 (e-mail: cohenj{at}ccf.org).

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