Diego Cadavid1, Jeffrey A Cohen2, Mark S Freedman3, Myla D Goldman4, Hans-Peter Hartung5, Eva Havrdova6, Douglas Jeffery7, Raj Kapoor8, Aaron Miller9, Finn Sellebjerg10, Deborah Kinch1, Sophia Lee1, Shulian Shang1, Daniel Mikol1. 1. Biogen, Cambridge, MA, USA. 2. Cleveland Clinic, Cleveland, OH, USA. 3. University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada. 4. University of Virginia, Charlottesville, VA, USA. 5. Department of Neurology, Medical Faculty, Heinrich- Heine University, Düsseldorf, Germany. 6. Charles University in Prague, Prague, Czech Republic. 7. Piedmont HealthCare, Huntersville, NC, USA. 8. National Hospital for Neurology and Neurosurgery, London, UK. 9. Icahn School of Medicine at Mount Sinai, New York, NY, USA. 10. Danish Multiple Sclerosis Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Abstract
BACKGROUND: The Expanded Disability Status Scale (EDSS) has wide scientific and regulatory precedent but limited ability to detect clinically relevant disability progression in secondary progressive multiple sclerosis (SPMS) patients, partly due to a lack of meaningful measurement of short-distance ambulatory and upper-extremity function. OBJECTIVE: To present a rationale for a composite endpoint adding the timed 25-foot walk (T25FW) and 9-Hole Peg Test (9HPT) to EDSS for SPMS disability progression assessment. METHODS: Using the International Multiple Sclerosis Secondary Progressive Avonex Clinical Trial (IMPACT) placebo arm ( n = 215) data, we analyzed disability progression using a novel progression endpoint, "EDSS-Plus," defined as progression on ⩾1 of 3 components (EDSS, T25FW, and/or 9HPT) confirmed ⩾24 weeks apart and with a ⩾20% minimum threshold change for T25FW and 9HPT. RESULTS: Over 2 years, subjects classified as T25FW, 9HPT (dominant hand), or 9HPT (non-dominant hand) progressors worsened on average by 103.4%, 69.0%, and 59.2%, respectively, while non-progressors' times remained largely unchanged. Using EDSS-Plus, 59.5% of the patients had 24-week confirmed disability progression versus 24.7% (EDSS), 41.9% (T25FW), and 34.4% (9HPT (either hand)) on each component alone. CONCLUSION: The 24-week confirmed minimum worsening of ⩾20% for T25FW and 9HPT clearly separates SPMS progressors from non-progressors. We propose that EDSS-Plus may represent an improved endpoint to identify SPMS disability progression.
RCT Entities:
BACKGROUND: The Expanded Disability Status Scale (EDSS) has wide scientific and regulatory precedent but limited ability to detect clinically relevant disability progression in secondary progressive multiple sclerosis (SPMS) patients, partly due to a lack of meaningful measurement of short-distance ambulatory and upper-extremity function. OBJECTIVE: To present a rationale for a composite endpoint adding the timed 25-foot walk (T25FW) and 9-Hole Peg Test (9HPT) to EDSS for SPMS disability progression assessment. METHODS: Using the International Multiple Sclerosis Secondary Progressive Avonex Clinical Trial (IMPACT) placebo arm ( n = 215) data, we analyzed disability progression using a novel progression endpoint, "EDSS-Plus," defined as progression on ⩾1 of 3 components (EDSS, T25FW, and/or 9HPT) confirmed ⩾24 weeks apart and with a ⩾20% minimum threshold change for T25FW and 9HPT. RESULTS: Over 2 years, subjects classified as T25FW, 9HPT (dominant hand), or 9HPT (non-dominant hand) progressors worsened on average by 103.4%, 69.0%, and 59.2%, respectively, while non-progressors' times remained largely unchanged. Using EDSS-Plus, 59.5% of the patients had 24-week confirmed disability progression versus 24.7% (EDSS), 41.9% (T25FW), and 34.4% (9HPT (either hand)) on each component alone. CONCLUSION: The 24-week confirmed minimum worsening of ⩾20% for T25FW and 9HPT clearly separates SPMS progressors from non-progressors. We propose that EDSS-Plus may represent an improved endpoint to identify SPMS disability progression.
Authors: Ricardo N Alonso; Maria B Eizaguirre; Leila Cohen; Cecilia Quarracino; Berenice Silva; Maria C Pita; Cecilia Yastremiz; Sandra Vanotti; Orlando Garcea Journal: Int J MS Care Date: 2020-05-15
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Authors: Ludwig Kappos; Jerry S Wolinsky; Gavin Giovannoni; Douglas L Arnold; Qing Wang; Corrado Bernasconi; Fabian Model; Harold Koendgen; Marianna Manfrini; Shibeshih Belachew; Stephen L Hauser Journal: JAMA Neurol Date: 2020-09-01 Impact factor: 18.302