Confirmed 6-Month Disability Improvement and Worsening Correlate with Long-term Disability Outcomes in Alemtuzumab-Treated Patients with Multiple Sclerosis: Post Hoc Analysis of the CARE-MS Studies

Abstract

Introduction: In the 2-year CARE-MS trials (NCT00530348; NCT00548405) in patients with relapsing-remitting multiple sclerosis, alemtuzumab showed superior efficacy versus subcutaneous interferon beta-1a. Efficacy was maintained in two consecutive extensions (NCT00930553; NCT02255656). This post hoc analysis compared disability outcomes over 9 years among alemtuzumab-treated patients according to whether they experienced confirmed disability improvement (CDI) or worsening (CDW) or neither CDI nor CDW.

Methods: CARE-MS patients were randomized to receive two alemtuzumab courses (12 mg/day; 5 days at baseline; 3 days at 12 months), with additional as-needed 3-day courses in the extensions. CDI or CDW were defined as ≥ 1.0-point decrease or increase, respectively, in Expanded Disability Status Scale (EDSS) score from core study baseline confirmed over 6 months, assessed in patients with baseline EDSS score ≥ 2.0. Improved or stable EDSS scores were defined as ≥ 1-point decrease or ≤ 0.5-point change (either direction), respectively, from core study baseline. Functional systems (FS) scores were also assessed.

Results: Of 511 eligible patients, 43% experienced CDI and 34% experienced CDW at any time through year 9 (patients experiencing both CDI and CDW were counted in each individual group); 29% experienced neither CDI nor CDW. At year 9, patients with CDI had a -0.58-point mean EDSS score change from baseline; 88% had stable or improved EDSS scores. Improvements occurred across all FS, primarily in sensory, pyramidal, and cerebellar domains. Patients with CDW had a +1.71-point mean EDSS score change; 16% had stable or improved EDSS scores. Patients with neither CDI nor CDW had a -0.10-point mean EDSS score change; 98% had stable or improved EDSS scores.

Conclusion: CDI achievement at any point during the CARE-MS studies was associated with improved disability at year 9, highlighting the potential of alemtuzumab to change the multiple sclerosis course. Conversely, CDW at any point was associated with worsened disability at year 9.

Keywords: Alemtuzumab; Confirmed disability improvement; Confirmed disability worsening; Disease-modifying therapy; Expanded Disability Status Scale; Functional systems; Multiple sclerosis.

Fig. 1

Disposition of pooled CARE-MS I and II patients stratified by 6-month CDI, 6-month CDW, or neither CDI nor CDW over 9 years. CDI and CDW were defined as a ≥ 1.0-point decrease and a ≥ 1.0-point increase, respectively, in EDSS score from core study baseline confirmed over 6 months, and were assessed only in patients with EDSS score ≥ 2.0 at core study baseline. Patients who experienced both CDI and CDW events during the 9-year period were counted in both groups. CDI confirmed disability improvement, CDW confirmed disability worsening, EDSS Expanded Disability Status Scale

Fig. 2

EDSS scores over 9 years in patients stratified by a 6-month CDI, b 6-month CDW, or c neither CDI nor CDW. Line charts represent EDSS scores through 9 years and bar charts represent improvement or stability in EDSS scores at year 9 relative to core study baseline, both in pooled CARE-MS I and II patients who had 6-month CDI, 6-month CDW, or neither CDI nor CDW at any time during the 9-year study. CDI and CDW were defined as a ≥ 1.0-point decrease and a ≥ 1.0-point increase, respectively, in EDSS score from core study baseline confirmed over 6 months, and were assessed only in patients with EDSS score ≥ 2.0 at core study baseline. Improved and stable EDSS scores were defined as ≥ 1-point decrease and ≤ 0.5-point change in either direction, respectively, from core study baseline at a single time point (year 9), and did not require confirmation over time. CDI confirmed disability improvement, CDW confirmed disability worsening, EDSS Expanded Disability Status Scale

Fig. 3

FS scores over 6 years in patients stratified by a 6-month CDI, b 6-month CDW, or c neither CDI nor CDW. Includes pooled CARE-MS I and II patients who had 6-month CDI, 6-month CDW, or neither CDI nor CDW at any time during the 9-year study. CDI and CDW were defined as a ≥ 1.0-point decrease and a ≥ 1.0-point increase, respectively, in EDSS score from core study baseline confirmed over 6 months, and were assessed only in patients with EDSS score ≥ 2.0 at core study baseline. FS scores were collected through the end of the CARE-MS extension (year 6), and were not recorded in the TOPAZ extension (years 7–9). Improved and stable FS scores were defined as ≥ 1-point decrease and ≤ 1-point change in either direction, respectively, from core study baseline at a single time point (year 6), and did not require confirmation over time. Sum of percentages with improved and stable FS scores may differ due to rounding. CDI confirmed disability improvement, CDW confirmed disability worsening, EDSS Expanded Disability Status Scale, FS functional systems