Marcus W Koch1,2, Jop Mostert3, Pavle Repovic4, James D Bowen4, Jacynthe Comtois5,6, Eva Strijbis7, Bernard Uitdehaag7, Gary Cutter8. 1. Department of Clinical Neurosciences, University of Calgary, Calgary, Canada. mwkoch@ucalgary.ca. 2. Department of Community Health Sciences, University of Calgary, Calgary, Canada. mwkoch@ucalgary.ca. 3. Department of Neurology, Rijnstate Hospital, Arnhem, The Netherlands. 4. Multiple Sclerosis Center, Swedish Neuroscience Institute, Seattle, USA. 5. Department of Medicine, Neurology Service, Hôpital Maisonneuve-Rosemont, Montreal, Canada. 6. Département de neurosciences, Faculté de médecine, Université de Montréal, Montreal, Canada. 7. Department of Neurology, MS Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, The Netherlands. 8. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, USA.
Abstract
BACKGROUND: Clinical trials in primary progressive MS (PPMS) generally use the Expanded Disability Status Scale (EDSS) as their primary outcome measure, although different clinical outcomes may be more useful. Disability worsening in PPMS trials may be influenced by baseline factors, such as age, sex, and contrast-enhancing lesions. METHODS: We used the dataset of PROMISE, a large randomized controlled trial of glatiramer acetate (GA) versus placebo, to compare the clinical outcomes EDSS, timed 25-foot walk (T25FW), and nine-hole peg test (NHPT). We used Cox regression analyses to investigate the association of the baseline factors age, sex, treatment arm, contrast-enhancing lesions (CELs), and EDSS on the time to 3-month confirmed disability worsening (3MCDW) on the EDSS and the T25FW. RESULTS: PROMISE included 943 participants. Worsening on the T25FW or EDSS or occurred much more frequently than on the NHPT. Having CELs at baseline was associated with a shorter time to 3MCDW on both the EDSS and T25FW. An additional resampling experiment using the PROMISE dataset showed that increasing representation of participants with CELs at baseline increases the likelihood of having a positive trial result in favor of GA treatment. CONCLUSION: Our investigation suggests that the T25FW may be a more useful primary outcome measure than the EDSS in PPMS trials, and that its use may shorten clinical trials. Our findings on the impact of CELs at baseline on disability outcomes inform the critical appraisal of clinical trials in PPMS.
BACKGROUND: Clinical trials in primary progressive MS (PPMS) generally use the Expanded Disability Status Scale (EDSS) as their primary outcome measure, although different clinical outcomes may be more useful. Disability worsening in PPMS trials may be influenced by baseline factors, such as age, sex, and contrast-enhancing lesions. METHODS: We used the dataset of PROMISE, a large randomized controlled trial of glatiramer acetate (GA) versus placebo, to compare the clinical outcomes EDSS, timed 25-foot walk (T25FW), and nine-hole peg test (NHPT). We used Cox regression analyses to investigate the association of the baseline factors age, sex, treatment arm, contrast-enhancing lesions (CELs), and EDSS on the time to 3-month confirmed disability worsening (3MCDW) on the EDSS and the T25FW. RESULTS: PROMISE included 943 participants. Worsening on the T25FW or EDSS or occurred much more frequently than on the NHPT. Having CELs at baseline was associated with a shorter time to 3MCDW on both the EDSS and T25FW. An additional resampling experiment using the PROMISE dataset showed that increasing representation of participants with CELs at baseline increases the likelihood of having a positive trial result in favor of GA treatment. CONCLUSION: Our investigation suggests that the T25FW may be a more useful primary outcome measure than the EDSS in PPMS trials, and that its use may shorten clinical trials. Our findings on the impact of CELs at baseline on disability outcomes inform the critical appraisal of clinical trials in PPMS.
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