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. 2020 Aug 24;78(1):1-13.
doi: 10.1001/jamaneurol.2020.2950. Online ahead of print.

Efficacy and Safety of 2 Fingolimod Doses vs Glatiramer Acetate for the Treatment of Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial

Bruce A C Cree  1 , Myla D Goldman  2 , John R Corboy  3 , Barry A Singer  4 , Edward J Fox  5 , Douglas L Arnold  6 , Corey Ford  7 , Bianca Weinstock-Guttman  8 , Amit Bar-Or  9 , Susanne Mientus  10 , Daniel Sienkiewicz  11 , Ying Zhang  11 , Rajesh Karan  10 , Nadia Tenenbaum  11 ; ASSESS Trial Investigators
Affiliations

Efficacy and Safety of 2 Fingolimod Doses vs Glatiramer Acetate for the Treatment of Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial

Bruce A C Cree et al. JAMA Neurol. .

Abstract

Importance: Doses of fingolimod lower than 0.5 mg per day were not investigated during the fingolimod clinical development program. Whether lower doses of fingolimod might retain efficacy with fewer safety risks remains unknown.

Objective: To evaluate the efficacy and safety of fingolimod, 0.5 mg, and fingolimod, 0.25 mg, compared with glatiramer acetate and to assess whether these doses of fingolimod show superior efficacy to glatiramer acetate in adult patients with relapsing-remitting multiple sclerosis.

Interventions: Fingolimod, 0.5 mg, or fingolimod, 0.25 mg, orally once per day or glatiramer acetate, 20 mg, subcutaneously once per day.

Design, setting, and participants: The Multiple Sclerosis Study Evaluating Safety and Efficacy of Two Doses of Fingolimod Versus Copaxone (ASSESS) was a phase 3b multicenter randomized rater-blinded and dose-blinded 12-month clinical trial conducted between August 9, 2012, and April 30, 2018 (including the time required to recruit participants). A total of 1461 patients aged 18 to 65 years with relapsing-remitting multiple sclerosis were screened, and 1064 participants were randomized. These participants had at least 1 documented relapse during the previous year or 2 documented relapses during the previous 2 years and an Expanded Disability Status Scale score of 0 to 6 at screening. Data were analyzed between September and November 2018.

Main outcomes and measures: The superiority of the fingolimod doses was tested hierarchically, with fingolimod, 0.5 mg, vs glatiramer acetate, 20 mg, tested first, followed by fingolimod, 0.25 mg, vs glatiramer acetate, 20 mg. The primary end point was the reduction in annualized relapse rate (ARR). Magnetic resonance imaging parameters, safety, and tolerability were also assessed.

Results: Of 1461 adult patients screened, 1064 participants (72.8%) were randomized (mean [SD] age, 39.6 [11.0] years; 792 women [74.4%]) to 3 treatment groups: 352 participants received fingolimod, 0.5 mg, 370 participants received fingolimod, 0.25 mg, and 342 participants received glatiramer acetate, 20 mg. In total, 859 participants (80.7%) completed the study. Treatment with fingolimod, 0.5 mg, was superior to treatment with glatiramer acetate, 20 mg, in reducing ARR (40.7% relative reduction); the relative reduction with fingolimod, 0.25 mg, was 14.6%, which was not statistically significant (for fingolimod, 0.5 mg, ARR, 0.15; 95% CI, 0.11-0.21; for fingolimod, 0.25 mg, ARR, 0.22; 95% CI, 0.17-0.29; for glatiramer acetate, 20 mg, ARR, 0.26; 95% CI, 0.20-0.34). Treatment with both fingolimod doses (0.5 mg and 0.25 mg) significantly reduced new or newly enlarging T2 and gadolinium-enhancing T1 lesions compared with treatment with glatiramer acetate. Adverse events were reported in similar proportions across treatment groups (312 participants [90.4%] in the fingolimod, 0.5 mg, group, 323 participants [88.3%] in the fingolimod, 0.25 mg, group, and 283 participants [87.3%] in the glatiramer acetate group).

Conclusions and relevance: Fingolimod, 0.5 mg, demonstrated superior clinical efficacy compared with glatiramer acetate, 20 mg, and had a superior benefit-risk profile compared with fingolimod, 0.25 mg, in adult participants with relapsing-remitting multiple sclerosis.

Trial registration: ClinicalTrials.gov Identifier: NCT01633112.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cree reported receiving personal fees from Akili Interactive Labs, Alexion Pharmaceuticals, Atara Biotherapeutics, Biogen, EMD Serono, Novartis, and TG Therapeutics outside the submitted work. Dr Goldman reported receiving grants from Novartis during the conduct of the study and personal fees from Adamas, Biogen, Celgene, EMD Serono, Novartis, Sanofi Genzyme, and Teva Neuroscience outside the submitted work. Dr Corboy reported receiving grants from Novartis during the conduct of the study, consulting fees from Mylan, and speaking honorarium from PRIME Education during the conduct of the study and grants from MedDay Pharmaceuticals, the National Multiple Sclerosis Society, and the Patient-Centered Outcomes Research Institute outside the submitted work. Dr Singer reported receiving grants and personal fees from Novartis during the conduct of the study; grants from AbbVie, Acorda Therapeutics, Alkermes, Biogen, MedImmune, Roche, and Sanofi Genzyme outside the submitted work; and personal fees from AbbVie, Alexion Pharmaceuticals, Bayer, Biogen, Bristol-Myers Squibb, EMD Serono, Genentech, Roche, Sanofi Genzyme, Teva Neuroscience, and TG Therapeutics outside the submitted work. Dr Fox reported receiving personal fees from Alexion, Biogen, Bristol-Myers Squibb, Chugai, EMD Serono, Genentech Roche, MedDay, Novartis, Sanofi-Genzyme, and TG Therapeutics outside the submitted work. Dr Arnold reported receiving personal fees from Novartis during the conduct of the study; grants from Biogen, Immunotec, and Novartis outside the submitted work; and personal fees from the LEO Albert Charitable Trust (Florida, US), Biogen, Celgene, Frequency Therapeutics, GeNeuro, MedDay Pharmaceuticals, Merck Serono, NeuroRx, Novartis, Sanofi Aventis, and Wave Life Sciences outside the submitted work. Dr Ford reported receiving grants from Novartis during the conduct of the study and grants from Actelion, Adamas, Alkermes, Biogen, Genentech, Mallinckrodt Pharmaceuticals, MedDay Pharmaceuticals, Novartis, Roche, Sanofi Aventis, Sanofi Genzyme, Teva Neuroscience, and TG Therapeutics outside the submitted work. Dr Weinstock-Guttman reported receiving grants from Biogen, EMD Serono, Genentech, and Novartis and personal fees from AbbVie, Biogen, Celgene, EMD Serono, Genentech, Mallinckrodt Pharmaceuticals, and Novartis outside the submitted work. Dr Bar-Or reported receiving grants from Biogen, EMD Serono, Genentech, and Novartis and personal fees from Actelion, Atara Biotherapeutics, Biogen, Celgene, EMD Serono, Genentech, Novartis, and Sanofi Genzyme outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
A total of 2 participants from a closed site discontinued the study early, and 4 participants did not enter the treatment phase according to the screening log case report form. These 6 participants were not considered to be discontinued from the study because they were missing study completion case report forms. Off study drug indicates participants who completed the study but discontinued treatment with the study drug prematurely. On study drug indicates participants who received treatment with the study drug until study completion.
Figure 2.
Figure 2.. Time to First Confirmed Relapse Through Month 12 for Full Analysis Set
See this image and copyright information in PMC

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