Greater sensitivity to multiple sclerosis disability worsening and progression events using a roving versus a fixed reference value in a prospective cohort study

Abstract

Background: Confirmed Expanded Disability Status Scale (EDSS) progression occurring after a fixed-study entry baseline is a common measure of disability increase in relapsing-remitting multiple sclerosis (RRMS) studies but may not detect all disability progression events, especially those unrelated to overt relapses.

Objective: To evaluate possible measures of disability progression unrelated to relapse using EDSS data over ≈5.5 years from the Tysabri^® Observational Program (TOP).

Methods: TOP is an ongoing, prospective, open-label study in RRMS patients receiving intravenous 300 mg natalizumab every 4 weeks. Measures of increasing disability were assessed using as a reference either study baseline score or a "roving" system that resets the reference score after ⩾24- or ⩾48-week confirmation of a new score.

Results: This analysis included 5562 patients. Approximately 70% more EDSS progression events unrelated to relapse and 50% more EDSS worsening events overall were detected with a roving reference score (cumulative probability: 17.6% and 29.7%, respectively) than with a fixed reference baseline score (cumulative probability: 10.1% and 20.3%, respectively).

Conclusion: In this long-term observational RRMS dataset, a roving EDSS reference value was more efficient than a study baseline EDSS reference in detecting progression/worsening events unrelated to relapses and thus the transition to secondary progressive disease.

Keywords: Expanded Disability Status Scale; Multiple sclerosis; disease progression; natalizumab; relapsing-remitting; secondary progressive multiple sclerosis.

Figure 1.

Schematic of the roving Expanded Disability Status Scale (EDSS) reference system. Confirmed EDSS worsening (a) ⩾24 or (b) ⩾48 weeks apart using a roving reference is illustrated. Also shown are hypothetical examples of confirmed EDSS worsening (c) ⩾24 or (d) ⩾48 weeks apart that would be captured using a roving EDSS reference and not accounted for using the conventional study baseline as EDSS. *Increase in EDSS score of ⩾1.5 points from a score of 0.0, ⩾1.0 point from a score of 1.0–5.5, or ⩾0.5 points from a score ⩾6.0.

Figure 2.

Schematic of methodological assessment of Expanded Disability Status Scale (EDSS) progression unrelated to relapses confirmed (a) ⩾24 or (b) ⩾48 weeks apart using a roving EDSS reference. t: time following EDSS increase with no concurrent relapse. *Increase in EDSS score of ⩾1.5 points from a score of 0.0, ⩾1.0 point from a score of 1.0–5.5, or ⩾0.5 points from a score ⩾6.0.

Figure 3.

Cumulative probabilities (Kaplan–Meier analysis) of 24-week-confirmed Expanded Disability Status Scale (EDSS) overall worsening or progression and of 24-week-confirmed EDSS progression unrelated to relapses identified using a conventional study baseline reference for events occurring (a) ⩾24 weeks apart or (b) ⩾48 weeks apart or using a roving reference for events occurring between two EDSS assessments (c) ⩾24 weeks apart or (d) ⩾48 weeks apart. *Defined as a relapse that was recorded from ⩽30 days prior to the reference EDSS assessment to ⩽30 days post progression assessment. †Defined as a relapse that was recorded from ⩽30 days prior to the reference EDSS assessment to ⩽12 weeks post progression assessment.

Figure 4.

Cumulative probabilities (Kaplan–Meier analysis) of 24-week-confirmed Expanded Disability Status Scale (EDSS) overall worsening or progression and of 24-week-confirmed EDSS progression unrelated to relapses using sensitivity analysis criteria (roving baseline confirmed at 12 weeks). Kaplan–Meier plots show the cumulative probability of events occurring between two EDSS assessments: (a) ⩾24 weeks apart or (b) ⩾48 weeks apart. *Defined as a relapse that was recorded from ⩽30 days prior to the reference EDSS assessment to ⩽30 days post progression assessment. †Defined as a relapse that was recorded from ⩽30 days prior to the reference EDSS assessment to ⩽12 weeks post progression assessment.