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Clinical Trial
. 2025 Apr 12;272(5):338.
doi: 10.1007/s00415-025-13066-4.

Measuring cognitive change in secondary progressive MS: an analysis of the ASCEND cognition substudy

Victoria Leavitt  1 , Jop Mostert  2 , Jacynthe Comtois  3 , Ester Moral  4 , Luis Brieva  5 , Pavle Repovic  6 , James D Bowen  6 , Bernard Uitdehaag  7 , Eva Strijbis  7 , Gary Cutter  8 , Marcus W Koch  9
Affiliations
Clinical Trial

Measuring cognitive change in secondary progressive MS: an analysis of the ASCEND cognition substudy

Victoria Leavitt et al. J Neurol. .

Abstract

Background: Cognitive impairment is common in multiple sclerosis (MS). Accurate measurement of cognitive change is essential for clinical trials.

Methods: The change in cognitive scores, clinical metrics of physical disability, and neuroradiological metrics was quantified in data from a phase-3 randomized controlled trial of natalizumab in secondary progressive MS (SPMS). The adults diagnosed with SPMS for ≥ 2 years and Expanded Disability Status Scale (EDSS) scores from 3 to 6.5 were randomized to receive natalizumab or placebo for 96 weeks. We evaluated change in Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), Selective Reminding Test (SRT), Brief Visuospatial Memory Test (BVMT-R), two subjective cognitive measures, Beck Depression Inventory (BDI-FS), Timed 25-foot Walk Test, Nine Hole Peg Test, measures of brain volume, and T2 lesion volume.

Results: The outcomes were evaluated at baseline, 48-, and 96-week follow-up. There were no significant differences in cognitive change between treatment arms. SDMT and PASAT scores improved over 96-weeks: mean SDMT scores by 4.5 points (SD 9.3), mean PASAT scores by 2.4 points (SD 9.4). Verbal and visuospatial memory test performance showed no consistent change. All MRI measures showed decreased brain volumes. NHPT scores worsened little and T25FW showed steadily worsening scores.

Conclusions: Improvements in SDMT and PASAT performance were observed regardless of treatment arm. These findings are consistent with prior studies in MS. As it is unlikely that cognition improves over time in people with a chronic neurologic disease, these results support the need for cognitive outcomes that overcome practice and learning effects to accurately quantify change.

Keywords: Clinical trials; Cognition; Multiple sclerosis; Outcome measures.

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Conflict of interest statement

Declarations. Conflict of interest: Dr. Leavitt received honoraria as consultant on advisory boards, and as a reviewer for the National Institutes of Health and the United States Department of Defense. Dr. Mostert reports no disclosures. Dr. Comtois reports no disclosures. Dr. Moral received honoraria as consultant in advisory boards, and or as chairperson or lecturer in meetings, or travel support from Actelion, Almirall, Bayer, Biogen-Idec, Bristol Myers Squibb, Merck-Serono, Teva, Novartis Roche and Sanofi-Genzyme. Dr. Brieva received honoraria from serving as a speaker and / or as a consultant in advisory boards from Bayer, Teva, Celgene, Biogen, Sanofi, Merck-Serono, Novartis, Roche, Allmiral, Bristol Myers Squibb, and Janssen. Dr. Repovic received consulting and/or speaking honoraria from Alexion, Biogen, Celgene, Roche, Sanofi Genzyme, Viela, and EMD Serono. Dr. Bowen received honoraria from serving on the scientific advisory board and speaker’s bureau of Biogen, Celgene, EMD Serono, Genentech and Novartis. He has received research support from AbbVie Inc, Alexion, Alkermes, Biogen, Celgene, Sanofi Genzyme, Genentech, Novartis, and TG Therapeutics. Dr. Strijbis reports no disclosures. Prof. Cutter served on Data and Safety Monitoring Boards: Astra-Zeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Horizon Pharmaceuticals, Hisun Pharmaceuticals, Mapi Pharmaceuticals LTD, Merck, Merck/Pfizer, Opko Biologics, OncoImmune, Neurim, Novartis, Ophazyme, Sanofi-Aventis, Reata Pharmaceuticals, Teva Pharmaceuticals, VielaBio Inc, Vivus, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee). Consulting or Advisory Boards: Biodelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein-Buendel Incorporated, Medimmune, Medday, Neurogenesis LTD, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Roche, TG Therapeutics. Dr. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL. Dr. Koch received consulting fees and travel support from Biogen, Novartis, Roche, Sanofi Genzyme and EMD Serono.

References

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