Demographic Characteristics and Progression Of PPMS In The CLIMB Study Population

Background: Primary progressive multiple sclerosis (PPMS) accounts for 10-15% of the MS population and has the worst prognosis of MS subtypes. Updated understanding of PPMS disease progression, especially in the era of disease-modifying therapy, is important for improving clinical care and designing successful randomized clinical trials in this population. 

Objectives: To characterize demographic and clinical characteristics of the CLIMB study (Partners MS Center, Boston, MA) PPMS patient cohort and assess the rate of PPMS disease progression, clinically evaluated by Expanded Disability Status Scale (EDSS). Based on this data we also assess the number of PPMS patients required for clinical trials with a primary clinical endpoint of sustained progression.

Methods: Longitudinal prospective data was collected from the CLIMB study for all PPMS patients (n=73) and relapsing-onset MS (ROMS) patients (n=1541).  In each group, the time from disease onset to first EDSS 3 (Phase 1), from first EDSS 3 to first EDSS 6 (Phase 2), and from onset to first EDSS 6 was compared using survival analysis appropriate for interval censored event times. Also, time to 6-month sustained progression in PPMS patients was analyzed. Sample size calculations were made for hypothetical PPMS trials powered at 80% and alpha=0.05. 

Results: The PP group had a 1.09:1 male:female ratio, higher than the RO group (RO: 1:2.89; p<0.001), and a greater mean age of onset (PP: 44.4+/-9.6; RR: 33.6+/-10.2; p<0.0001). Presence of motor symptoms at onset was strongly associated with PPMS (p<0.001), as was spinal cord localization of first symptoms (p<0.001). Overall, median time from onset to EDSS 6.0 was faster in PPMS patients vs. RO patients (p<0.001). The PPMS patients progressed faster through Phase 1 (p<0.001) and through Phase 2 (p<0.005). Median time to sustained progression in the PP group was 4.39 years (95% confidence interval: 2.74-6.77), and this was significantly faster than in the RO group (p<0.001).

Conclusions: This PPMS cohort from the modern treatment era is demographically similar to previously studied cohorts and a representative sample of PPMS patients seen at our clinic. Faster progression through Phase 1, Phase 2, and from onset to EDSS 6 is associated with PPMS. In contrast to previous studies, we found faster Phase 2 progression to be clinically significant. Finally, reevaluation of time to sustained progression provides a basis for sample size estimates and design of new clinical trials in PPMS.