Table 2: Active-comparator clinical studies with GA in MS.

Study overview
StudyDesign (risk of bias)TreatmentPatientsDuration, Percent withdrawals Key dataCommentReference

REGARDMulticenter, randomized, comparative, parallel-group, open-label, assessor-blinded
GA 20 mg SC QD vs IFNβ-1a 44 μg SC TIWRelapsing-remitting MS
96 wk,
IFN: 21
GA: 14
No significant difference between groups for time to first relapse (HR 0.94 [95% CI 0.74 to 1.21]; p=0.64) No significant differences between groups for no. and change in volume of T2-active lesions or for change in volume of Gd+ lesionsFewer Gd+ lesions in patients treated with IFNβ-1a (0.24 lesions/patient/scan vs 0.41 for GA; p=0.0002) Significantly greater reduction in brain volume with IFNβ-1a (-1.24%) vs GA (-1.07%; p=0.018)(i) Relapse rates in the trial were lower than predicted, thus limiting prediction of clinical superiority. This may be a fault of the trial design due to a limited number of patient contacts and also site selection
(ii) Brain volume data indicate that brain atrophy precedes/is correlated with disability progression
Mikol et al. [51]

BECOMERandomized, single-blind (low)GA 20 mg SC QD vs IFNβ-1b 250 μg EOD SCTreatment-naïve relapsing-remitting MS or CIS
2 y,
IFN: 19.4
GA: 10.3
Similar median [75th percentile] combined active lesions/patient/scan (GA: 0.58 [2.45], IFNβ-1a: 0.63 [2.76]) No differences in new lesions or clinical relapses over 2 y(i) Similar MRI and clinical activity following GA or IFNβ-1a treatment
(ii) Greater subclinical disease activity than previously observed was also reported in this study. However, these data should be interpreted with caution as the small trial size limits conclusions
Cadavid et al [52]

BEYONDMulticenter, randomized, parallel-group
GA 20 mg SC QD vs IFNβ-1b SC (250 μg or 500 μg) EODTreatment-naïve relapsing-remitting MS
2–3.5 y
IFN 250 μg: 11.6
IFN 500 μg: 17.9
GA: 15.8
No differences between groups in relapse risk, disability (EDSS) progression, T1-hypointense lesion volume, or normalized brain volumeSignificant decrease in T2 lesion volume observed with both IFNβ-1b groups vs GA at Year 1 but not during Years 2 and 3(i) Similar clinical efficacy for GA and IFNβ-1b
(ii) GA and IFNβ-1b have different adverse-event profiles; however, overall tolerability is similar
O’Connor et al [53]

CONFIRMMulticenter, randomized, double-blind (low)GA 20 mg SC QD vs DMF 240 mg BID PO, 240 mg TID PO, or PBO PORelapsing-remitting MS
2 y,
DMF BID: 29.5
DMF TID: 27.8
GA: 24.6
PBO: 35.5
ARR significantly lower vs PBO with all active treatments (GA: 0.29; DMF BID: 0.22, TID: 0.20; PBO: 0.40) No significant differences in reduction of disability progression for GA or DMF vs PBOPost hoc comparison revealed a significantly greater treatment effect for DMF vs GA for ARR (TID dose), no. of new or enlarging hyperintense lesions on T2-weighted images (both BID and TID), and T1-weighted images (TID dose)(i) Apparent convenience of oral therapies complicated by issues including adverse events and monitoring requirements
(ii) Study was not powered to test the superiority or noninferiority of DMF vs GA. Post hoc comparisons are therefore not informative
(iii) Markedly higher drop-out rate with oral DMF vs GA owing to adverse events
Fox et al [54]

CombiRxDouble-blind, randomized, placebo-controlled
IFNβ-1a 30 μg IM weekly
GA 20 mg SC QD
Combination IFNβ-1a + GA
Relapsing-remitting MS
3 y,
IFN: 22.4
GA: 13.9
Combination: 20.4
Combination was not superior to GA for ARR or 6-mo confirmed progression of disability (EDSS) Compared with IFN, both combination (25%; p=0.022) and GA alone (31% reduction, p=0.027) significantly improved ARR; no differences in disability (EDSS) progressionCombination superior to IFN or GA alone in reducing new lesion activity and accumulation of total lesion volumesNo unexpected safety issues observed with combination(i) Similar results were observed after a further 4 y of follow-up
(ii ) The reduction in MRI activity in the 3-y study did not result in a later clinical advantage at 7 y
Lubin et al. [55, 56]

ARR: annualized relapse rate; BID: twice daily; CI: confidence interval; CIS: clinically isolated syndrome; DMF: dimethyl fumarate; EDSS: Expanded Disability Status Scale; EOD: every other day; GA: branded glatiramer acetate; Gd+: gadolinium-enhancing; HR: hazard ratio; IFN: interferon; IM: intramuscular; MRI: magnetic resonance imaging; MS: multiple sclerosis; PBO: placebo; PO: oral; QD: once daily; SC: subcutaneous; TID: three-times daily; TIW: three times per week.
Based on assessment of risk of bias with regard to randomization; baseline characteristics; blinding; withdrawal/discontinuation; outcome selection, reporting, and other sources of bias; and statistical analysis [57]. Low risk of bias for all aspects other than randomization (not reported) [57]. Patients receiving GA were aware of their treatment allocation. Dose not Food and Drug Administration approved.