The search for responsive clinical endpoints in primary progressive multiple sclerosis

Area of Science:

• Neurology
• Clinical Trials
• Biostatistics

Background:

• Primary progressive multiple sclerosis (PPMS) requires sensitive clinical endpoints to track disease progression.
• Existing scales like the Expanded Disability Status Scale (EDSS) may not fully capture the nuances of PPMS disability.
• Functional mobility and dexterity assessments are crucial for evaluating PPMS patient outcomes.

Purpose of the Study:

• To evaluate if combining EDSS scores with Timed 25-Foot Walk (T25FW) and 9-Hole Peg Test (9HPT) data yields a clinical endpoint with a higher event rate in PPMS compared to EDSS alone.
• To determine the optimal time frame for assessing meaningful clinical changes in PPMS.

Main Methods:

• A cohort of 161 PPMS patients was assessed over two years at three time points.
• Clinically meaningful deterioration or improvement was calculated for individual scales (EDSS, T25FW, 9HPT) and combined scales.
• The impact of baseline disability on endpoint definition was analyzed by stratifying patients based on EDSS levels.

Main Results:

• The T25FW demonstrated the highest event rate as a single scale at both 1 year (34%) and 2 years (46%).
• A combination of T25FW and EDSS showed the highest event rate at 2 years (57%), with fewer opposing changes compared to T25FW/9HPT at 1 year.
• The T25FW, and the T25FW/EDSS combination at two years, consistently showed the highest event rates across different baseline disability levels.

Conclusions:

• The T25FW is a robust single-scale endpoint for PPMS, irrespective of baseline disability.
• A two-year observation period is more effective for detecting meaningful changes in PPMS.
• "Worsening on either T25FW or EDSS" is identified as the most appropriate composite endpoint for PPMS clinical trials.