Breaking the PROMISE: poor association between brain volume loss and clinical disability worsening over 2 years of follow-up in primary progressive multiple sclerosis.

Clinical Snapshot

Key Findings

• P Value: Not reported in abstract

• Effect Size: Weak and inconsistent associations reported

• Primary Outcome: Association between MRI brain volume changes and clinical disability worsening over 2 years

• Nnt Or Sensitivity: Year 1 MRI changes did not predict year 2 disability progression

• Confidence Interval: Not reported in abstract

Clinical Application

High - MRI brain volumetry increasingly available in tertiary centres, though requires specialised analysis software Relevant to Australian MS centres using MRI monitoring. May inform PBS decisions on MS therapies and guide clinical trial design for pharmaceutical companies operating in Australia Patients with primary progressive multiple sclerosis undergoing clinical monitoring or enrolled in clinical trials

Abstract

BACKGROUND: Phase 2 clinical trials in primary progressive multiple sclerosis (PPMS) often use MRI brain volume measures as their primary endpoint. Here, we investigate the longitudinal association between change in MRI outcomes and change in disability over 2 years of follow-up in a large and well-characterised PPMS trial dataset. METHODS: Using the dataset from PROMISE (n=943, mean age of 58.0 years, mean Expanded Disability Status Scale (EDSS) 5.0, and mean disease duration of 10.5 years at baseline), a phase 3 trial of glatiramer acetate in PPMS, we described the change in MRI and disability measures during follow-up and used multivariable logistic regression models to investigate whether change in four MRI outcomes (grey matter volume, white matter volume, brain fraction and total burden of disease) was associated with seven measures of clinical disability worsening (including the EDSS, Timed 25 Foot Walk, Nine-Hole Peg Test and Paced Auditory Serial Addition Test). RESULTS: We found only weak and inconsistent associations between change in MRI and physical and cognitive outcome measures over 2 years of follow-up. Change in MRI measures in year 1 of the trial did not predict change in physical nor cognitive disability in year 2. DISCUSSION: The association of the investigated volumetric MRI measures and clinical disability outcomes was noticeably weak and inconsistent. Our findings question the suitability of brain volume loss and lesion burden accumulation as functionally relevant trial endpoints in PPMS and inform the design and interpretation of clinical trials in PPMS.

References

1. 1.Koch, M., Mostert, J., Strijbis, E. M., D'Haeseleer, M., Torkildsen, Ø., Comtois, J., Repovic, P., Uitdehaag, B. M. J., Killestein, J., Mcpherson, T., & Cutter, G. (2026). Breaking the PROMISE: poor association between brain volume loss and clinical disability worsening over 2 years of follow-up in primary progressive multiple sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry. https://doi.org/10.1136/jnnp-2025-337940