At year 5, significantly lower annualized change in EDSS score, lower incidence of confirmed disability worsening, and lower annualized change in FSS pyramidal function were identified in the early initiated treatment group.
Corey C. Ford, MD, PhD
Findings from an open-label extension (OLE) of a phase 3 study completed 27 years after study initiation showed significant long-term differences favoring early start (ES) treatment of glatiramer acetate over delayed-start (DS) initiation in patients with relapsing multiple sclerosis (MS).1
The OLE represented the longest prospective study of continuous disease-modifying monotherapy in relapsing MS, with at least 25 years of glatiramer acetate monotherapy treatment experienced in a single cohort. At year 5, the annualized change from baseline in Expanded Disability Status Scale (EDSS) score was significantly lower in the ES vs DS group (mean difference, –0.278; 95% CI, –0.511 to –0.044; P = .020). Although there were no significant between-group differences in time to EDSS score of 4, proportions of those not reaching defined EDSS thresholds were numerically lower in the ES group.
Led by Corey C. Ford, MD, PhD, neurologist, University of New Mexican Health Sciences Center, the study evaluated the long-term differences of glatiramer acetate, a disease-modifying therapy approved in 1996, when initiated either immediately or delayed for up to 3 years. Of the 251 participants randomized to glatiramer acetate or placebo, 208 entered the OLE (ES, n = 101; DS, n = 107). In total, 52 (25%) participants completed the OLE (ES: n = 24 [23.8%]; DS: n 28 [26.2%]) and 74 participants (29.5%) had at least 20 years of glatiramer acetate exposure.
At randomization, mean EDSS scores were 2.8 (SD, 1.2) and 2.4 (SD, 1.3) in the ES and DS groups, respectively, which increased to 3.29 (SD, 2.13) and 3.98 (SD, 2.58) at OLE completion. Baseline-adjusted proportion of participants with stable/improved EDSS up to year 5 (odds ratio [OR], 1.934; 95% CI, 1.138-3.286; P = .0147) and up to year 20 (OR, 1.710; 95% CI, 1.016-2.880; P = .0436) was significantly higher in the ES vs DS group and remained higher throughout the OLE.
Median time to 6-month confirmed disability worsening (CDW) was 9.82 years for the ES group compared with 6.71 years for those who initiated glatiramer acetate treatment later. Similarly, median time to 12-month CDW was 18.9 and 11.6 years in the ES and DS groups, respectively. Additionally, time to the second 6-month CDW was significantly reduced by ES treatment, as shown by 76.8% of individuals who remained free of this compared with 68.3% of those in the DS group. Over the full study, baseline-adjusted proportion of disease-activity free criteria was 11.3% for ES and 5.6% for DS.
Although the overall annualized relapse rate (AAR) did not differ between ES (0.328) and DS participants (0.414; risk ratio [RR], 0.792; 95% CI, 0.586-1.069; P = .1278), the accumulated ARR over the first 3 years of treatment was significantly lower in the ES group relative to those who started treatment late (RR, 0.7613; 95% CI, 0.599-0.967; P = .0255). Baseline-adjusted proportion of participants without a relapse over the full study was 16.9% for ES and 11.7% for DS.
In total, 38 of the 232 (16.4%) study participants had at least 1 treatment-emergent adverse event (TEAE) leading to discontinuation, most of which were because of injection-site erythema and injection-site pain. Serious TEAEs were found in 37.5% (n = 87) of the cohort, the most common of which were urinary tract infection, chest pain, and dehydration. Overall, 23.7% (n = 55) of participants had at least 1 immediate post-injection reactions (IPIR), while most participants (87.1%; n = 202) had at least 1 injection-site reactions (ISRs).
Over years 0 to 3 of treatment, mean annualized TEAEs were higher in the ES group (RR, 1.213; 95% CI, 1.025-1.438; P = .0250) and were nonsignificant for the remaining period. This pattern was observed over years 0 to 3 for IPIRs (RR, 3.988; 95% CI, 1.845-8.621; P = .0004) and ISRs (RR, 2.418; 95% CI, 1.818-3.216; P <.001). Mean annualized IPIRs were similar between cohorts for the remaining period, whereas mean annualized ISRs were higher for the DS versus ES group for years 3 to 5 (RR, 0.459; 95% CI: 0.209-1.008; P = .0525) and 5 to 10 (RR, 0.366; 95% CI, 0.135-0.990; P = .0476) and similar between cohorts for the remaining period.