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Link to original content: https://pubmed.ncbi.nlm.nih.gov/38174776
Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis - PubMed Skip to main page content
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Review
. 2024 Jan 4;1(1):CD011381.
doi: 10.1002/14651858.CD011381.pub3.

Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis

Marien Gonzalez-Lorenzo  1 , Ben Ridley  2 , Silvia Minozzi  3 , Cinzia Del Giovane  4   5 , Guy Peryer  6 , Thomas Piggott  7   8 , Matteo Foschi  9   10 , Graziella Filippini  11 , Irene Tramacere  12 , Elisa Baldin  2 , Francesco Nonino  2
Affiliations
Review

Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis

Marien Gonzalez-Lorenzo et al. Cochrane Database Syst Rev. .

Abstract

Background: Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biological agents. Although each one of these therapies reduces relapse frequency and slows disability accumulation compared to no treatment, their relative benefit remains unclear. This is an update of a Cochrane review published in 2015.

Objectives: To compare the efficacy and safety, through network meta-analysis, of interferon beta-1b, interferon beta-1a, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, immunoglobulins, cladribine, cyclophosphamide, diroximel fumarate, fludarabine, interferon beta 1-a and beta 1-b, leflunomide, methotrexate, minocycline, mycophenolate mofetil, ofatumumab, ozanimod, ponesimod, rituximab, siponimod and steroids for the treatment of people with RRMS.

Search methods: CENTRAL, MEDLINE, Embase, and two trials registers were searched on 21 September 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. A top-up search was conducted on 8 August 2022.

Selection criteria: Randomised controlled trials (RCTs) that studied one or more of the available immunomodulators and immunosuppressants as monotherapy in comparison to placebo or to another active agent, in adults with RRMS.

Data collection and analysis: Two authors independently selected studies and extracted data. We considered both direct and indirect evidence and performed data synthesis by pairwise and network meta-analysis. Certainty of the evidence was assessed by the GRADE approach.

Main results: We included 50 studies involving 36,541 participants (68.6% female and 31.4% male). Median treatment duration was 24 months, and 25 (50%) studies were placebo-controlled. Considering the risk of bias, the most frequent concern was related to the role of the sponsor in the authorship of the study report or in data management and analysis, for which we judged 68% of the studies were at high risk of other bias. The other frequent concerns were performance bias (34% judged as having high risk) and attrition bias (32% judged as having high risk). Placebo was used as the common comparator for network analysis. Relapses over 12 months: data were provided in 18 studies (9310 participants). Natalizumab results in a large reduction of people with relapses at 12 months (RR 0.52, 95% CI 0.43 to 0.63; high-certainty evidence). Fingolimod (RR 0.48, 95% CI 0.39 to 0.57; moderate-certainty evidence), daclizumab (RR 0.55, 95% CI 0.42 to 0.73; moderate-certainty evidence), and immunoglobulins (RR 0.60, 95% CI 0.47 to 0.79; moderate-certainty evidence) probably result in a large reduction of people with relapses at 12 months. Relapses over 24 months: data were reported in 28 studies (19,869 participants). Cladribine (RR 0.53, 95% CI 0.44 to 0.64; high-certainty evidence), alemtuzumab (RR 0.57, 95% CI 0.47 to 0.68; high-certainty evidence) and natalizumab (RR 0.56, 95% CI 0.48 to 0.65; high-certainty evidence) result in a large decrease of people with relapses at 24 months. Fingolimod (RR 0.54, 95% CI 0.48 to 0.60; moderate-certainty evidence), dimethyl fumarate (RR 0.62, 95% CI 0.55 to 0.70; moderate-certainty evidence), and ponesimod (RR 0.58, 95% CI 0.48 to 0.70; moderate-certainty evidence) probably result in a large decrease of people with relapses at 24 months. Glatiramer acetate (RR 0.84, 95%, CI 0.76 to 0.93; moderate-certainty evidence) and interferon beta-1a (Avonex, Rebif) (RR 0.84, 95% CI 0.78 to 0.91; moderate-certainty evidence) probably moderately decrease people with relapses at 24 months. Relapses over 36 months findings were available from five studies (3087 participants). None of the treatments assessed showed moderate- or high-certainty evidence compared to placebo. Disability worsening over 24 months was assessed in 31 studies (24,303 participants). Natalizumab probably results in a large reduction of disability worsening (RR 0.59, 95% CI 0.46 to 0.75; moderate-certainty evidence) at 24 months. Disability worsening over 36 months was assessed in three studies (2684 participants) but none of the studies used placebo as the comparator. Treatment discontinuation due to adverse events data were available from 43 studies (35,410 participants). Alemtuzumab probably results in a slight reduction of treatment discontinuation due to adverse events (OR 0.39, 95% CI 0.19 to 0.79; moderate-certainty evidence). Daclizumab (OR 2.55, 95% CI 1.40 to 4.63; moderate-certainty evidence), fingolimod (OR 1.84, 95% CI 1.31 to 2.57; moderate-certainty evidence), teriflunomide (OR 1.82, 95% CI 1.19 to 2.79; moderate-certainty evidence), interferon beta-1a (OR 1.48, 95% CI 0.99 to 2.20; moderate-certainty evidence), laquinimod (OR 1.49, 95 % CI 1.00 to 2.15; moderate-certainty evidence), natalizumab (OR 1.57, 95% CI 0.81 to 3.05), and glatiramer acetate (OR 1.48, 95% CI 1.01 to 2.14; moderate-certainty evidence) probably result in a slight increase in the number of people who discontinue treatment due to adverse events. Serious adverse events (SAEs) were reported in 35 studies (33,998 participants). There was probably a trivial reduction in SAEs amongst people with RRMS treated with interferon beta-1b as compared to placebo (OR 0.92, 95% CI 0.55 to 1.54; moderate-certainty evidence).

Authors' conclusions: We are highly confident that, compared to placebo, two-year treatment with natalizumab, cladribine, or alemtuzumab decreases relapses more than with other DMTs. We are moderately confident that a two-year treatment with natalizumab may slow disability progression. Compared to those on placebo, people with RRMS treated with most of the assessed DMTs showed a higher frequency of treatment discontinuation due to AEs: we are moderately confident that this could happen with fingolimod, teriflunomide, interferon beta-1a, laquinimod, natalizumab and daclizumab, while our certainty with other DMTs is lower. We are also moderately certain that treatment with alemtuzumab is associated with fewer discontinuations due to adverse events than placebo, and moderately certain that interferon beta-1b probably results in a slight reduction in people who experience serious adverse events, but our certainty with regard to other DMTs is lower. Insufficient evidence is available to evaluate the efficacy and safety of DMTs in a longer term than two years, and this is a relevant issue for a chronic condition like MS that develops over decades. More than half of the included studies were sponsored by pharmaceutical companies and this may have influenced their results. Further studies should focus on direct comparison between active agents, with follow-up of at least three years, and assess other patient-relevant outcomes, such as quality of life and cognitive status, with particular focus on the impact of sex/gender on treatment effects.

PubMed Disclaimer

Conflict of interest statement

MGL: none known.

GF: no relevant interests; Joint Co‐ordinating Editor of Cochrane Multiple Sclerosis and Rare Disease of the CNS (not involved in the editorial process of this review); involved with MAIN 2014 ‐ Azathioprine versus beta interferons for relapsing‐remitting multiple sclerosis: a multicentre randomized non‐inferiority trial. PLoS One 2014;9(11):e113371. Funding: AIFA (Italian Medicines Agency)). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Trial Registration: EudraCT 2006‐004937‐13. This study was approved by ethics committees in the co‐ordinating centre (Careggi University Hospital, Ethics Committee, Florence) and each of the participating centres (Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano; Clinica Neurologica, Novara; Universita ‘‘La Sapienza’’, Roma; Policlinico ‘‘G. Rodolico’’ Azienda Ospedaliero‐Universitaria, Catania; Clinica Neurologica 2, Genova; Azienda Ospedaliera Universitaria Integrata, Verona; Ospedale Clinicizzato ‘‘Colle Dall’Ara’’, Chieti; Universita` di Sassari, Sassari; Universita` di Napoli, Napoli; Ospedale S. Antonio, Padova; Ospedale Civile S. Agostino‐Estense, Modena; Ospedale Santa Maria, Reggio Emilia; Policlinico Universitario Mater Domini, Catanzaro; Ospedale S. Gerardo, Monza; Azienda Ospedaliero‐Universitaria S. Anna, Ferrara; Ospedali Riuniti, Ancona; Istituto S. Raffaele ‘‘G. Giglio’’, Cefalu; Azienda Ospedaliero San Giovanni Battista, Universita` di Torino, Torino; Ospedale Sacro Cuore, Negrar; Ospedale Santa Chiara, Trento; Ospedale Regionale, Bolzano; Azienda Ospedaliero‐Universitaria Senese, Policlinico ‘‘Le Scotte’’, Siena; Ospedale ‘‘Misericordia e Dolce’’, Prato; Universita degli Studi di Pisa, Pisa; Policlinico ‘‘G. Martino’’, Messina; Universita degli Studi di Palermo, Palermo; Universita Cattolica, Policlinico Gemelli, Roma; Dipartimento Neuroriabilitativo ASL CN1, Cuneo; Luigi Gonzaga Hospital, Orbassano Ethics Committees), adhered to Good Clinical Practice (GCP) guidelines and Declaration of Helsinki.

CDG: Multiple Sclerosis International Federation (grant/contract).

BR: no relevant interests; Managing Editor of Cochrane Multiple Sclerosis and Rare Diseases of the CNS (not involved in the editorial process of this review).

FN: no relevant interests; epidemiologist and neurologist within the public Italian Health Service (at the IRCCS Istituto delle Scienze Neurologiche di Bologna); Co‐ordinating Editor of Cochrane Multiple Sclerosis and Rare Disease of the CNS (not involved in the editorial process of this review).

SM: no relevant interests; Joint Co‐ordinating Editor and Methods Editor of Cochrane Drugs and Alcohol.

GP: Bristol‐Myers Squibb (consultation); Multiple Sclerosis International Federation (patient representative and consultant); Multiple Sclerosis Society (patient representative and consultant); National Institute for Health Research (patient representative); published 'Celani MG, Nonino F, Mahan K, Orso M, Ridley B, Baldin E, et al. Identifying unanswered questions and setting the agenda for future systematic research in Multiple Sclerosis. A worldwide, multi‐stakeholder Priority Setting project. Mult Scler Relat Disord. 2022;60:103688'; 'Li V, Leurent B, Barkhof F, Braisher M, Cafferty F, Ciccarelli O, et al. Designing Multi‐arm Multistage Adaptive Trials for Neuroprotection in Progressive Multiple Sclerosis. Neurology. 2022;98(18):754‐764' and 'Alexander S, Peryer G, Gray E, Barkhof F, Chataway J. Wearable technologies to measure clinical outcomes in multiple sclerosis: A scoping review. Mult Scler. 2021;27(11):1643‐1656'; volunteered for the UK MS Society; acted as a peer reviewer for Cochrane.

TP: Multiple Sclerosis International Federation (grant/contract).

MF: Novartis, Merck, (travel); published an opinion paper on dalfampridine ‐ see Foschi M, Lugaresi A. Evaluating dalfampridine for the treatment of relapsing‐remitting multiple sclerosis: does it add to the treatment armamentarium? Expert Opinion on Pharmacotherapy, 2019 Jun; Consultant Neurologist at S. Maria delle Croci Hospital of Ravenna, AUSL Romagna, Ravenna, Italy.

EB: no relevant interests; author of a manuscript on ponesimod for the treatment of relapsing multiple sclerosis; Neurologist IRCCS Istituto delle Scienze Neurologiche di Bologna; Affiliated Researcher of Cochrane Multiple Sclerosis and Rare Disease of the CNS (not involved in the editorial process of this review).

IT: none known

Figures

1
1
PRISMA flow chart * Several of the studies were reported in the same reports: ASCLEPIOS I 2020; ASCLEPIOS II 2020 (reported in Hauser 2020); CARE‐MS I 2012; CARE‐MS II 2012 (reported in Arroyo 2017); OPERA I 2017; OPERA II 2017 (reported in the same four reports); CONFIRM 2012; DEFINE 2012 (reported in Fernandez 2017 and Havrdova 2017); FREEDOMS 2010; FREEDOMS II 2014 (reported in Vermersch 2017); DECIDE 2015; SELECT 2013 (reported in Giovannoni 2016 and Rose 2017).
2
2
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
4
4
Network plots of treatment comparisons for primary efficacy and safety outcomes (Primary outcomes). The width of the lines is proportional to the precision of each pair of treatments, and the size of every circle is proportional to the number of trials comparing every pair of treatments. AE, adverse effects; SAE, serious adverse events.
5
5
Network plots of treatment comparisons for secondary efficacy and safety outcomes (Secondary outcomes). The width of the lines is proportional to the precision of each pair of treatments, and the size of every circle is proportional to the number of trials comparing every pair of treatments. Gd, gadolinium; MRI, magnetic resonance imaging; w, weighted.
6
6
Network plots of treatment comparisons for cognitive decline and quality of life*. The width of the lines is proportional to the precision of each pair of treatments, and the size of every circle is proportional to the number of trials comparing every pair of treatments. * Please refer to Effects of interventions for further details on the quality‐of‐life scales used. Abbreviations: MH,; MSQOL,: PH,; SF‐36,.
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Network meta‐analysis (NMA) estimates of primary efficacy and safety outcomes in comparisons against placebo. AE, adverse effects; CI, confidence interval; RR, risk ratio; SAE, serious adverse events.
1.1
1.1. Analysis
Comparison 1: Treatment efficacy (primary outcomes): pairwise comparisons, Outcome 1: Comparisons for relapse (12 months)
1.2
1.2. Analysis
Comparison 1: Treatment efficacy (primary outcomes): pairwise comparisons, Outcome 2: Comparisons for relapse (24 months)
1.3
1.3. Analysis
Comparison 1: Treatment efficacy (primary outcomes): pairwise comparisons, Outcome 3: Comparisons for relapse (36 months)
1.4
1.4. Analysis
Comparison 1: Treatment efficacy (primary outcomes): pairwise comparisons, Outcome 4: Comparisons for disability worsening (24 months)
1.5
1.5. Analysis
Comparison 1: Treatment efficacy (primary outcomes): pairwise comparisons, Outcome 5: Comparisons for disability worsening (36 months)
2.1
2.1. Analysis
Comparison 2: Treatment safety (primary outcomes): pairwise comparisons, Outcome 1: Number of patients who discontinued treatment due to adverse effects
2.2
2.2. Analysis
Comparison 2: Treatment safety (primary outcomes): pairwise comparisons, Outcome 2: Number of patients with any serious adverse effect
3.1
3.1. Analysis
Comparison 3: Treatment efficacy and safety (secondary outcomes): pairwise comparisons, Outcome 1: Comparisons for new gadolinium‐enhancing positive T1‐weighted MRI lesions (12 months)
3.2
3.2. Analysis
Comparison 3: Treatment efficacy and safety (secondary outcomes): pairwise comparisons, Outcome 2: Comparisons for new gadolinium‐enhancing positive T1‐weighted MRI lesions (24 months)
3.3
3.3. Analysis
Comparison 3: Treatment efficacy and safety (secondary outcomes): pairwise comparisons, Outcome 3: Comparisons for new or enlarging T2‐weighted MRI lesions (12 months)
3.4
3.4. Analysis
Comparison 3: Treatment efficacy and safety (secondary outcomes): pairwise comparisons, Outcome 4: Comparisons for new or enlarging T2‐weighted MRI lesions (24 months)
3.5
3.5. Analysis
Comparison 3: Treatment efficacy and safety (secondary outcomes): pairwise comparisons, Outcome 5: Comparisons for quality of life total (non‐MS related: EQ‐5D VAS)
3.6
3.6. Analysis
Comparison 3: Treatment efficacy and safety (secondary outcomes): pairwise comparisons, Outcome 6: Comparisons for quality of life total (non‐MS related) (INDEX)
3.7
3.7. Analysis
Comparison 3: Treatment efficacy and safety (secondary outcomes): pairwise comparisons, Outcome 7: Comparisons for quality of life ‐ physical (non‐MS related: SF‐36)
3.8
3.8. Analysis
Comparison 3: Treatment efficacy and safety (secondary outcomes): pairwise comparisons, Outcome 8: Comparisons for quality of life ‐ physical (MS related: MSQOL‐54 PH; MSQoL‐54; MSIS29 Psychological)
3.9
3.9. Analysis
Comparison 3: Treatment efficacy and safety (secondary outcomes): pairwise comparisons, Outcome 9: Comparisons for quality of life ‐ mental (Non‐MS related: SF‐36)
3.10
3.10. Analysis
Comparison 3: Treatment efficacy and safety (secondary outcomes): pairwise comparisons, Outcome 10: Comparisons for quality of life ‐ mental (MS related: MSQOL‐54 PH; MSQoL‐54; MSIS29 Psychological)
3.11
3.11. Analysis
Comparison 3: Treatment efficacy and safety (secondary outcomes): pairwise comparisons, Outcome 11: Mortality
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CONFIRM 2012 {published data only}
    1. Fernández Ó, Giovannoni G, Fox RJ, Gold R, Phillips JT, Potts J, et al. Efficacy and Safety of Delayed-release Dimethyl Fumarate for Relapsing-remitting Multiple Sclerosis in Prior Interferon Users: An Integrated Analysis of DEFINE and CONFIRM. Clin Ther 2017;39(8):1671-1679. [DOI: 10.1016/j.clinthera.2017.06.012] - DOI - PubMed
    1. Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. New England Journal of Medicine 2012;367(12):1087-97. - PubMed
    1. Havrdova E, Giovannoni G, Gold R, Fox RJ, Kappos L, Phillips JT, et al. Effect of delayed-release dimethyl fumarate on no evidence of disease activity in relapsing-remitting multiple sclerosis: integrated analysis of the phase III DEFINE and CONFIRM studies. Eur J Neurol 2017;24(5):726-733. [DOI: 10.1111/ene.13272] - DOI - PMC - PubMed
    1. Hutchinson M, Fox RJ, Miller DH, Phillips JT, Kita M, Havrdova E, et al. Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the CONFIRM study. J Neurol 2013;260(9):2286-96. [DOI: 10.1007/s00415-013-6968-1] [PMID: ] - DOI - PubMed
    1. Kita M, Fox RJ, Phillips JT, Hutchinson M, Havrdova E, Sarda SP, et al. Effects of BG-12 (dimethyl fumarate) on health-related quality of life in patients with relapsing-remitting multiple sclerosis: findings from the CONFIRM study. Mult Scler 2014;20(2):253-7. [DOI: 10.1177/1352458513507818] [PMID: ] - DOI - PubMed
DECIDE 2015 {published data only}
    1. Benedict RH, Cohan S, Lynch SG, Riester K, Wang P, Castro-Borrero W, et al. Improved cognitive outcomes in patients with relapsing-remitting multiple sclerosis treated with daclizumab beta: Results from the DECIDE study. Mult Scler 2018 ;24(6):795-804. [DOI: ] - PMC - PubMed
    1. Kappos L, Havrdova E, Giovannoni G, Khatri BO, Gauthier SA, Greenberg SJ, et al. No evidence of disease activity in patients receiving daclizumab versus intramuscular interferon beta-1a for relapsing-remitting multiple sclerosis in the DECIDE study. Mult Scler 2017;23(13):1736-1747. [DOI: 10.1177/1352458516683266] - DOI - PubMed
    1. Kappos L, Wiendl H, Selmaj K, Arnold DL, Havrdova E, Boyko A, et al. Daclizumab HYP versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med 2015;373(15):1418-28. [DOI: 10.1056/NEJMoa1501481] - DOI - PubMed
    1. Krueger JG, Kircik L, Hougeir F, Friedman A, You X, Lucas N, et al. Cutaneous Adverse Events in the Randomized, Double-Blind, Active-Comparator DECIDE Study of Daclizumab High-Yield Process Versus Intramuscular Interferon Beta-1a in Relapsing-Remitting Multiple Sclerosis. Adv Ther 2016;33(7):231-45. [DOI: 10.1007/s12325-016-0353-2] - DOI - PMC - PubMed
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DEFINE 2012 {published data only}
    1. Arnold DL, Gold R, Kappos L, Bar-Or A, Giovannoni G, Selmaj K, et al. Effects of delayed-release dimethyl fumarate on MRI measures in the Phase 3 DEFINE study. J Neurol 2014;261(9):1794-802. [DOI: 10.1007/s00415-014-7412-x] [PMID: ] - DOI - PMC - PubMed
    1. Arnold DL, Gold R, Kappos L, Bar-Or A, Giovannoni G, Selmaj K, et al. Magnetization transfer ratio in the delayed-release dimethyl fumarate DEFINE study. J Neurol 2014;261(12):2429-37. [DOI: 10.1007/s00415-014-7504-7] [PMID: ] - DOI - PMC - PubMed
    1. Bar-Or A, Gold R, Kappos L, Arnold DL, Giovannoni G, Selmaj K, et al. Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the DEFINE study. J Neurol 2013 ;260(9):2297-305. [DOI: 10.1007/s00415-013-6954-7] [PMID: ] - DOI - PubMed
    1. Fernández Ó, Giovannoni G, Fox RJ, Gold R, Phillips JT, Potts J, et al. Efficacy and Safety of Delayed-release Dimethyl Fumarate for Relapsing-remitting Multiple Sclerosis in Prior Interferon Users: An Integrated Analysis of DEFINE and CONFIRM. Clin Ther 2017;39(8):1671-1679. [DOI: 10.1016/j.clinthera.2017.06.012] [PMID: ] - DOI - PubMed
    1. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. New England Journal of Medicine 2012;367(12):1098-107. - PubMed
Etemadifar 2006 {published data only}
    1. Etemadifar M, Janghorbani M, Shaygannejad V. Comparison of Betaferon, Avonex, and Rebif in treatment of relapsing-remitting multiple sclerosis. Acta Neurologica Scandinavica 2006;113(5):283-7. - PubMed
Etemadifar 2007 {published data only}
    1. Etemadifar M, Janghorbani M, Shaygannejad V. Comparison of interferon beta products and azathioprine in the treatment of relapsing-remitting multiple sclerosis. Journal of Neurology 2007;254(12):1723-8. - PubMed
Fazekas 1997 {published data only}
    1. Fazekas F, Deisenhammer F, Strasser-Fuchs S, Nahler G, Mamoli B. Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet 1997;349(9052):589-93. - PubMed
FREEDOMS 2010 {published data only}
    1. Devonshire V, Havrdova E, Radue EW, O'Connor P, Zhang-Auberson L, Agoropoulou C, et al, FREEDOMS study group. Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study. Lancet Neurol 2012;11(5):420-8. [DOI: 10.1016/S1474-4422(12)70056-X] [PMID: ] - DOI - PubMed
    1. Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, Calabresi P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. New England Journal of Medicine 2010;362(5):387-401. - PubMed
    1. Kremenchutzky M, O'Connor P, Hohlfeld R, Zhang-Auberson L, Rosenstiel P, Meng X, et al. Impact of prior treatment status and reasons for discontinuation on the efficacy and safety of fingolimod: Subgroup analyses of the Fingolimod Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study. Mult Scler Relat Disord 2014;3(3):341-9. [DOI: 10.1016/j.msard.2013.10.006] [PMID: ] - DOI - PubMed
    1. Radue EW, O'Connor P, Polman CH, Hohlfeld R, Calabresi P, Selmaj K, Mueller-Lenke N, Agoropoulou C, Holdbrook F, Vera A, Zhang-Auberson L, Francis G, Burtin P, Kappos L, FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) Study Group. Impact of fingolimod therapy on magnetic resonance imaging outcomes in patients with multiple sclerosis. Arch Neurol 2012;69(10):1259-69. [PMID: 10.1001/archneurol.2012.1051] [PMID: ] - DOI - PubMed
    1. Sormani MP, De Stefano N, Francis G, Sprenger T, Chin P, Radue EW, Kappos L Fingolimod effect on brain volume loss independently contributes to its effect on disability. Mult Scler. 2015 21;7:916-24. [DOI: 10.1177/1352458515569099] [PMID: ] - DOI - PubMed
FREEDOMS II 2014 {published data only}
    1. Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurology 2014;13(6):545-56. - PubMed
    1. Vermersch P, Radue EW, Putzki N, Ritter S, Merschhemke M, Freedman MS A comparison of multiple sclerosis disease activity after discontinuation of fingolimod and placebo. Mult Scler J Exp Transl Clin. 2017 3;3:2055217317730096. [DOI: 10.1177/2055217317730096] [PMID: ] - DOI - PMC - PubMed
GALA 2013 {published data only}
    1. Davis MD, Ashtamker N, Steinerman JR, Knappertz V. Time course of glatiramer acetate efficacy in patients with RRMS in the GALA study. 2017 Neurol Neuroimmunol Neuroinflamm;4(2):e327. [DOI: 10.1212/NXI.0000000000000327] [PMID: ] - DOI - PMC - PubMed
    1. Khan O, Rieckmann P, Boyko A, Selmaj K, Zivadinov R, GALA Study Group. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Annals of Neurology 2013;73(6):705-13. - PubMed
    1. Zivadinov R, Dwyer M, Barkay H, Steinerman JR, Knappertz V, Khan O. Effect of glatiramer acetate three-times weekly on the evolution of new, active multiple sclerosis lesions into T1-hypointense "black holes": a post hoc magnetic resonance imaging analysis. J Neurol 2015;262(3):648-53. [DOI: 10.1007/s00415-014-7616-0] [PMID: ] - DOI - PubMed
    1. Zivadinov R, Dwyer MG, Ramasamy DP, Davis MD, Steinerman JR, Khan O. The Effect of Three Times a Week Glatiramer Acetate on Cerebral T1 Hypointense Lesions in Relapsing-Remitting Multiple Sclerosis. J Neuroimaging 2015;25(6):989-95. [DOI: 10.1111/jon.12293] [PMID: ] - DOI - PMC - PubMed
Gobbi 2013 {published data only}
    1. Gobbi C, Meier DS, Cotton F, Sintzel M, Leppert D, Guttmann CR, Zecca C. Interferon beta 1b following natalizumab discontinuation: one year, randomized, prospective, pilot trial. BMC Neurol 2013;13:101. [DOI: 10.1186/1471-2377-13-101] [PMID: ] - DOI - PMC - PubMed
    1. Zecca C, Riccitelli GC, Calabrese P, Pravatà E, Candrian U, Guttmann CR, Gobbi C. Treatment satisfaction, adherence and behavioral assessment in patients de-escalating from natalizumab to interferon β. BMC Neurol 2014;14:38. [DOI: 10.1186/1471-2377-14-38] [PMID: ] - DOI - PMC - PubMed
GOLDEN 2017 {published data only}
    1. Comi G, Patti F, Rocca MA, Mattioli FC, Amato MP, Gallo P, Centonze D, Pozzilli C, Saccà F, Bergh FT, Bartezaghi M, Turrini R, Filippi M, Golden Study Group. Efficacy of fingolimod and interferon beta-1b on cognitive, MRI, and clinical outcomes in relapsing-remitting multiple sclerosis: an 18-month, open-label, rater-blinded, randomised, multicentre study (the GOLDEN study). J Neurol 2017;264(12):2436-2449. [DOI: 10.1007/s00415-017-8642-5] [PMID: ] - DOI - PMC - PubMed
Goodkin 1991 {published data only}
    1. Goodkin D, Bailly R, Teetzen M, Hertsgaard D, Beatty W. The efficacy of azathioprine in relapsing-remitting multiple sclerosis. Neurology 1991;41:20-5. - PubMed
IFNB MS Group 1993 {published data only}
    1. IFNB MSG. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology 1993;43(4):655-61. - PubMed
INCOMIN 2002 {published data only}
    1. Durelli L, Verdun E, Barbero P, Bergui M, Versino E, Ghezzi A, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet 2002;359:1453-60. - PubMed
Johnson 1995 {published data only}
    1. Johnson K, Brooks B, Cohen J, Ford C, Goldstein J, Lisak R, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995;45(7):1268-76. - PubMed
Knobler 1993 {published data only}
    1. Knobler RL, Greenstein JI, Johnson KP, Lublin FD, Panitch HS, Conway K, et al. Systemic recombinant human interferon-beta treatment of relapsing-remitting multiple sclerosis: pilot study analysis and six-year follow-up. Journal of Interferon Research 1993;13(5):333-40. - PubMed
Koch‐Henriksen 2006 {published data only}
    1. Koch-Henriksen N, Sørensen P, Christensen T, Frederiksen J, Ravnborg M, Jensen K, et al. A randomised study of two interferon-beta treatments in relapsing-remitting multiple sclerosis. Neurology 2006;66(7):1056-60. - PubMed
Lewanska 2002 {published data only}
    1. Lewanska M, Siger-Zajdel M, Selmaj K. No difference in efficacy of two different doses of intravenous immunoglobulins in MS: clinical and MRI assessment. European Journal of Neurology 2002;9(6):565-72. - PubMed
MAIN 2014 {published data only}
    1. Massacesi L, Tramacere I, Amoroso S, Battaglia MA, Benedetti MD, Filippini G, et al. Azathioprine versus beta interferons for relapsing-remitting multiple sclerosis: a multicentre randomized non-inferiority trial. PLoS One 2014;9(11):e113371. - PMC - PubMed
Millefiorini 1997 {published data only}
    1. Millefiorini E, Gasperini C, Pozzilli C, D'Andrea F, Bastianello S, Trojano M, et al. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome. Journal of Neurology 1997;244(3):153-9. - PubMed
Mokhber 2014 {published data only}
    1. Mokhber N, Azarpazhooh A, Orouji E, Khorram B, Modares Gharavi M, Kakhi S, Khallaghi H, Azarpazhooh MR. Therapeutic effect of Avonex, Rebif and Betaferon on quality of life in multiple sclerosis. Psychiatry Clin Neurosci. 2015;69(10):649-57. [DOI: 10.1111/pcn.12308] [PMID: ] - DOI - PubMed
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MSCRG 1996 {published data only}
    1. Jacobs L, Cookfair D, Rudick R, Herndon R, Richert J, Salazar A, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Annals of Neurology 1996;39:285-94. - PubMed
OPERA I 2017 {published data only}
    1. A randomized, double-blind, double-dummy, parallel-group study to evaluate the efficacy and safety of Ocrelizumab in comparison to interferon beta-1a (Rebif®) in patients with relapsing multiple sclerosis. https://clinicaltrials.gov/ct2/show/study/NCT01247324 (accessed 30 September 2014).
    1. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, et al, OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med 2017;376(3):221-234. [DOI: 10.1056/NEJMoa1601277] [PMID: ] - DOI - PubMed
    1. Mayer L, Kappos L, Racke MK, Rammohan K, Traboulsee A, Hauser SL, Julian L, Köndgen H, Li C, Napieralski J, Zheng H, Wolinsky JS. Ocrelizumab infusion experience in patients with relapsing and primary progressive multiple sclerosis: Results from the phase 3 randomized OPERA I, OPERA II, and ORATORIO studies.. Mult Scler Relat Disord 2019;30:236-243. [DOI: 10.1016/j.msard.2019.01.044] [PMID: ] - DOI - PubMed
    1. Turner B, Cree BAC, Kappos L, Montalban X, Papeix C, Wolinsky JS, Buffels R, Fiore D, Garren H, Han J, Hauser SL. Ocrelizumab efficacy in subgroups of patients with relapsing multiple sclerosis. J Neurol 2019;266(5):1182-1193. [DOI: 10.1007/s00415-019-09248-6] [PMID: ] - DOI - PMC - PubMed
OPERA II 2017 {published data only}
    1. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, et al, OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med 2017;376(3):221-234. [DOI: 10.1056/NEJMoa1601277] [PMID: ] - DOI - PubMed
    1. Mayer L, Kappos L, Racke MK, Rammohan K, Traboulsee A, Hauser SL, et al. Ocrelizumab infusion experience in patients with relapsing and primary progressive multiple sclerosis: Results from the phase 3 randomized OPERA I, OPERA II, and ORATORIO studies. Mult Scler Relat Disord 2019;30:236-243. [DOI: 10.1016/j.msard.2019.01.044] [PMID: ] - DOI - PubMed
    1. NCT01412333. A randomized, double-blind, double-dummy, parallel-group study to evaluate the efficacy and safety of Ocrelizumab in comparison to Interferon Beta-1a (Rebif®) in patients with relapsing multiple sclerosis. https://clinicaltrials.gov/ct2/show/study/NCT01412333 (accessed 30 September 2014).
    1. Turner B, Cree BAC, Kappos L, Montalban X, Papeix C, Wolinsky JS, et al. Ocrelizumab efficacy in subgroups of patients with relapsing multiple sclerosis. J Neurol 2019;266(5):1182-1193. [DOI: 10.1007/s00415-019-09248-6] [PMID: ] - DOI - PMC - PubMed
OPTIMUM 2021 {published data only}
    1. Kappos L, Fox RJ, Burcklen M, Freedman MS, Havrdová EK, Hennessy B, et al. Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study: A Randomized Clinical Trial. JAMA Neurol 2021 May 1;;78(5):558-567. [DOI: 10.1001/jamaneurol.2021.0405] [PMID: ] - DOI - PMC - PubMed
PRISMS 1998 {published data only}
    1. Ebers GC. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet 1998;352(9139):1498-1504. [DOI: 10.1016/S0140-6736(98)03334-0] - DOI - PubMed
    1. Traboulsee A, Li DKB, Cascione M, Fang J, Dangond F, Miller A. Effect of interferon beta-1a subcutaneously three times weekly on clinical and radiological measures and no evidence of disease activity status in patients with relapsing-remitting multiple sclerosis at year 1. BMC Neurol 2018;18(1):143. [DOI: 10.1186/s12883-018-1145-x] [PMID: ] - DOI - PMC - PubMed
RADIANCE 2019 {published data only}
    1. Cohen JA, Comi G, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, et al, RADIANCE Trial Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol 2019;18(11):1021-1033. [DOI: 10.1016/S1474-4422(19)30238-8] [PMID: ] - DOI - PubMed
    1. NCT01628393. Efficacy and Safety Study of RPC1063 in Relapsing Multiple Sclerosis Patients (Radiance Study). https://clinicaltrials.gov/show/NCT01628393 2012.
REGARD 2008 {published data only}
    1. Mikol D, Barkhof F, Chang P, Coyle P, Jeffery D, Schwid S, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurology 2008;7(10):903-14. - PubMed
SELECT 2013 {published data only}
    1. Giovannoni G, Kappos L, Gold R, Khatri BO, Selmaj K, Umans K, et al. Safety and tolerability profile of daclizumab in patients with relapsing-remitting multiple sclerosis: An integrated analysis of clinical studies. Mult Scler Relat Disord 2016 ;9:36-46. [DOI: 10.1016/j.msard.2016.05.010] - DOI - PubMed
    1. Giovannoni G, Radue EW, Havrdova E, Riester K, Greenberg S, Mehta L, et al. Effect of daclizumab high-yield process in patients with highly active relapsing-remitting multiple sclerosis. J Neurol 2014;261(2):316-23. [DOI: 10.1007/s00415-013-7196-4] - DOI - PMC - PubMed
    1. Gold R, Giovannoni G, Selmaj K, Havrdova E, Montalban X, Radue EW, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet 2013;381(9884):2167-75. - PubMed
    1. Havrdova E, Giovannoni G, Stefoski D, Forster S, Umans K, Mehta L, et al. Disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with daclizumab high-yield process in the SELECT study. Mult Scler 2014;20(4):464-70. [DOI: 10.1177/1352458513502113] - DOI - PubMed
    1. Phillips G, Guo S, Bender R, Havrdová E, Proskorovsky I, Vollmer T. Assessing the impact of multiple sclerosis disease activity and daclizumab HYP treatment on patient-reported outcomes: Results from the SELECT trial. Mult Scler Relat Disord 2016 ;6:66-72. [DOI: 10.1016/j.msard.2016.02.001] - DOI - PubMed
SUNBEAM 2019 {published data only}
    1. Comi G, Kappos L, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, et al, SUNBEAM Study Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurology 2019 ;18(11):1009-1020. [DOI: 10.1016/S1474-4422(19)30239-X] - DOI - PubMed
    1. DeLuca J, Schippling S, Montalban X, Kappos L, Cree BAC, Comi G, et al. Effect of Ozanimod on Symbol Digit Modalities Test Performance in Relapsing MS. Mult Scler Relat Disord 2021;48:102673. [DOI: 10.1016/j.msard.2020.102673] - DOI - PubMed
    1. NCT02294058. Study of Ozanimod (RPC1063) in Relapsing Multiple Sclerosis (MS). https://ClinicalTrials.gov/show/NCT02294058 2014.
TEMSO 2011 {published data only}
    1. Miller AE, O'Connor P, Wolinsky JS, Confavreux C, Kappos L, Olsson TP, et al, Teriflunomide Multiple Sclerosis Trial Group. Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. Mult Scler 2012;18(11):1625-32. [DOI: 10.1177/1352458512450354] [PMID: ] - DOI - PMC - PubMed
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    1. O'Connor PW, Lublin FD, Wolinsky JS, Confavreux C, Comi G, Freedman MS, et al. Teriflunomide reduces relapse-related neurological sequelae, hospitalizations and steroid use. J Neurol 2013;260(10):2472-80. [DOI: 10.1007/s00415-013-6979-y] [PMID: ] - DOI - PMC - PubMed
    1. Radue EW, Sprenger T, Gaetano L, Mueller-Lenke N, Cavalier S, Thangavelu K, et al. Teriflunomide slows BVL in relapsing MS: A reanalysis of the TEMSO MRI data set using SIENA. Neurol Neuroimmunol Neuroinflamm 2017;4(5):e390. [DOI: 10.1212/NXI.0000000000000390] [PMID: ] - DOI - PMC - PubMed
    1. Wolinsky JS, Narayana PA, Nelson F, Datta S, O'Connor P, Confavreux C, et al, Teriflunomide Multiple Sclerosis Oral (TEMSO) Trial Group. Magnetic resonance imaging outcomes from a phase III trial of teriflunomide. Mult Scler 2013 ;19(10):1310-9. [DOI: 10.1177/1352458513475723] [PMID: ] - DOI - PubMed
TOWER 2014 {published data only}
    1. Confavreux C, O'Connor P, Comi G, Freedman MS, Miller AE, Olsson TP, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurology 2014;13(3):247-56. - PubMed
    1. Freedman MS, Morawski J, Thangavelu K. Clinical efficacy of teriflunomide over a fixed 2-year duration in the TOWER study. Mult Scler J Exp Transl Clin 2018;4(2):2055217318775236. [DOI: 10.1177/2055217318775236] [PMID: ] - DOI - PMC - PubMed
    1. Miller AE, Macdonell R, Comi G, Freedman MS, Kappos L, Mäurer M, et al. Teriflunomide reduces relapses with sequelae and relapses leading to hospitalizations: results from the TOWER study. J Neurol 2014;261(9):1781-8. [DOI: 10.1007/s00415-014-7395-7] [PMID: ] - DOI - PMC - PubMed
    1. Miller AE, Xu X, Macdonell R, Vucic S, Truffinet P, Benamor M, et al. Efficacy and safety of teriflunomide in Asian patients with relapsing forms of multiple sclerosis: A subgroup analysis of the phase 3 TOWER study. J Clin Neurosci 2019;59:229-231. [DOI: 10.1016/j.jocn.2018.09.012] [PMID: ] - DOI - PubMed
    1. Qiu W, Huang DH, Hou SF, Zhang MN, Jin T, Dong HQ, et al, TOWER Trial Chinese Group. Efficacy and Safety of Teriflunomide in Chinese Patients with Relapsing Forms of Multiple Sclerosis: A Subgroup Analysis of the Phase 3 TOWER Study. Chin Med J (Engl) 2018;131(23):2776-2784. [DOI: 10.4103/0366-6999.246067] [PMID: ] - DOI - PMC - PubMed
TRANSFORMS 2010 {published data only}
    1. Barkhof F, Jong R, Sfikas N, Vera A, Francis G, Cohen J, TRANSFORMS study group. The influence of patient demographics, disease characteristics and treatment on brain volume loss in Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS), a phase 3 study of fingolimod in multiple sclerosis. Mult Scler 2014;20(13):1704-13. [DOI: 10.1177/1352458514532317] [PMID: ] - DOI - PubMed
    1. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. New England Journal of Medicine 2010;362(5):402-15. - PubMed
    1. Cohen JA, Barkhof F, Comi G, Izquierdo G, Khatri B, Montalban X, et al. Fingolimod versus intramuscular interferon in patient subgroups from TRANSFORMS. J Neurol 2013;260(8):2023-32. [DOI: 10.1007/s00415-013-6932-0] [PMID: ] - DOI - PMC - PubMed
    1. Khatri BO, Pelletier J, Kappos L, Hartung HP, Comi G, Barkhof F, et al, TRANSFORMS Study Group. Effect of prior treatment status and reasons for discontinuation on the efficacy and safety of fingolimod vs. interferon β-1a intramuscular: Subgroup analyses of the Trial Assessing Injectable Interferon vs. Fingolimod Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). Mult Scler Relat Disord 2014;3(3):355-63. [DOI: 10.1016/j.msard.2013.11.006] [PMID: ] - DOI - PubMed
    1. Meng X, Chin PS, Hashmonay R, Zahur Islam M, Cutter G. Effect of switching from intramuscular interferon β-1a to oral fingolimod on time to relapse in patients with relapsing-remitting multiple sclerosis enrolled in a 1-year extension of TRANSFORMS. Contemp Clin Trials 2015;41:69-74. [DOI: 10.1016/j.cct.2014.12.011] [PMID: ] - DOI - PubMed

References to studies excluded from this review

ACT 2009 {published data only}
    1. Cohen JA, Imrey PB, Calabresi PA, Edwards KR, Eickenhorst T, Felton WL 3rd, et al. Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS. Neurology 2009;72(6):535-41. - PubMed
Agius 2014 {published data only}
    1. Agius M, Meng X, Chin P, Grinspan A, Hashmonay R. Fingolimod therapy in early multiple sclerosis: an efficacy analysis of the TRANSFORMS and FREEDOMS studies by time since first symptom.. CNS Neurosci Ther 2014;20(5):446-51. [DOI: 10.1111/cns.12235] [PMID: ] - DOI - PMC - PubMed
Ashtari 2011 {published data only}
    1. Ashtari F, Savoj MR. Effects of low dose methotrexate on relapsing-remitting multiple sclerosis in comparison to Interferon β-1α: a randomized controlled trial. Journal of Research in Medical Sciences 2011;16(4):457-62. - PMC - PubMed
ATAMS 2014 {published data only}
    1. Kappos L, Hartung HP, Freedman MS, Boyko A, Radü EW, Mikol DD, et al. Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Neurology 2014;13(4):353-63. - PubMed
Bar‐Or 2017 {published data only}
    1. Bar-Or A, Grove RA, Austin DJ, Tolson JM, VanMeter SA, Lewis EW, Derosier FJ, Lopez MC, Kavanagh ST, Miller AE, Sorensen PS. Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study.. Neurology. 2018 ;90(20):e1805-e1814. [DOI: 10.1212/WNL.0000000000005516] - DOI - PMC - PubMed
Boiko 2018 {published data only}
    1. Boiko AN, Bosenko LP, Vasilovskii VV, Volkova LI, Zakharova MN, Kotov SV, Lekomtseva EV, Negrich TI, Parshina EV, Patrusheva OP, Prokopenko SV, Sazonov DV, Timchenko PV, Trinitatskii YV, Khabirov FA, Khavunka MY, Chichanovskaya LV, Sherman MA, Lin'kova YN, Zinkina‐Orikhan AV, Tursunova KB. A Comparative Placebo-Controlled Clinical Trial of the Efficacy and Safety of Interferon β-1a Formulations for S.C. Administration in Patients with Remitting Multiple Sclerosis: first-Year Results. Neuroscience and behavioral physiology 2018;48(7):883‐889.
Boyko 2016 {published data only}
    1. Boyko AN, Lashch NY, Sharanova SN, Zakharova MN, Trifonova OV, Simaniv TO, Lysogorskaya EV, Guryanova OE, Kotov SV, Iakushina TI, Lizhdvoy VY, Belova YA, Khabirov FA, Babicheva NN, Khaibullin TI, Granatov EV, Averyanova LA, Sazonov DV, Odinak MM, Trinitatsky YV, Tsukurova LA, Sergeeva AI, Ivanov RA, Shustova MS. [Comparative, placebo-controlled clinical study of efficacy and safety of glatiramer acetate 20 mg in patients with relapsing-remitting multiple sclerosis: results of the first year of the study] [Sravnitel'noe platsebo-kontroliruemoe klinicheskoe issledovanie effektivnosti i bezopasnosti preparatov glatiramera atsetata 20 mg u patsientov s remittiruyushchim rasseyannym sklerozom: rezul'taty pervogo goda nablyudeniya]. Zh Nevrol Psikhiatr Im S S Korsakova. 2016;116(10 Pt 2):61-67. [DOI: 10.17116/jnevro201611610261-67] - DOI - PubMed
British and Dutch 1988 {published data only}
    1. The British, Dutch MSATG. Double-masked trial of azathioprine in multiple sclerosis. Lancet 1988;Vol. 2(8604):179–83. - PubMed
Calabrese 2012 {published data only}
    1. Calabrese M, Bernardi V, Atzori M, Mattisi I, Favaretto A, Rinaldi F, et al. Effect of disease-modifying drugs on cortical lesions and atrophy in relapsing-remitting multiple sclerosis. Multiple Sclerosis (Houndmills, Basingstoke, England) 2012;18(4):418-24. - PubMed
Cascione 2018 {published data only}
    1. Cascione M, Tenenbaum N, Wendt J, Meng X, Schofield L, Cree BAC, PREFERMS investigators. Treatment retention on fingolimod compared with injectable multiple sclerosis therapies in African-American patients: A subgroup analysis of a randomized phase 4 study.. Mult Scler Relat Disord. 2018 ;25:50-56. [DOI: 10.1016/j.msard.2018.07.014] - DOI - PubMed
CHOICE 2010 {published data only}
    1. Wynn D, Kaufman M, Montalban X, Vollmer T, Simon J, Elkins J, et al. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurology 2010;9(4):381-90. - PubMed
Cohen 2015 {published data only}
    1. Cohen J, Belova A, Selmaj K, Wolf C, Sormani MP, Oberyé J, den Tweel E, Mulder R, Koper N, Voortman G, Barkhof F, Glatiramer Acetate Clinical Trial to Assess Equivalence With Copaxone (GATE) Study Group. Equivalence of Generic Glatiramer Acetate in Multiple Sclerosis: A Randomized Clinical Trial.. JAMA Neurol 2015;72(12):1433-41. [DOI: 10.1001/jamaneurol.2015.2154] - DOI - PubMed
Cohen 2016 {published data only}
    1. Cohen JA, Arnold DL, Comi G, Bar-Or A, Gujrathi S, Hartung JP, Cravets M, Olson A, Frohna PA, Selmaj KW, RADIANCE Study Group. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial.. Lancet Neurol. 2016 ;15(4):373-81. [DOI: 10.1016/S1474-4422(16)00018-1] - DOI - PubMed
Comi 2001 {published data only}
    1. Comi G, Filippi M, Wolinsky JS. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging--measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Annals of Neurology 2001;49(3):290-7. [PMID: ] - PubMed
Coyle 2017 {published data only}
    1. Patricia K Coyle, Anthony T Reder, Mark S Freedman, Juanzhi Fang, Fernando Dangond. Early MRI results and odds of attaining ‘no evidence of disease activity’ status in MS patients treated with interferon β-1a in the EVIDENCE study. Journal of the Neurological Sciences 2017;379:151-156. [DOI: 10.1016/j.jns.2017.05.052] - DOI - PubMed
Cree 2018 {published data only}
    1. Cree BAC, Arnold DL, Cascione M, Fox EJ, Williams IM, Meng X, Schofield L, Tenenbaum N. Phase IV study of retention on fingolimod versus injectable multiple sclerosis therapies: a randomized clinical trial.. Ther Adv Neurol Disord. 2018;11:756286418774338. [DOI: 10.1177/1756286418774338] - DOI - PMC - PubMed
EVIDENCE 2007 {published data only}
    1. Schwid S, Panitch H. Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis. Clinical Therapeutics 2007;29(9):2031-48. - PubMed
Fazekas 2008 {published data only}
    1. Fazekas F, Lublin F, Li D, Freedman M, Hartung H, Rieckmann P, et al. Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: a dose-finding trial. Neurology 2008;71(4):265-71. - PubMed
FORTE 2011 {published data only}
    1. Comi G, Cohen JA, Arnold DL, Wynn D, Filippi M, FORTE Study Group. Phase III dose-comparison study of glatiramer acetate for multiple sclerosis. Annals of Neurology 2011;69(1):75-82. - PubMed
Fox 2014 {published data only}
    1. Fox E, Edwards K, Burch G, Wynn DR, LaGanke C, Crayton H, Hunter SF, Huffman C, Kim E, Pestreich L, McCague K, Barbato L, EPOC study investigators. Outcomes of switching directly to oral fingolimod from injectable therapies: results of the randomized, open-label, multicenter, Evaluate Patient OutComes (EPOC) study in relapsing multiple sclerosis. Multiple sclerosis and related disorders 2014;3(5):607‐619. - PubMed
Freedman 2012 {published data only}
    1. Freedman MS, Wolinsky JS, Wamil B, Confavreux C, Comi G, Kappos L, et al. Teriflunomide added to interferon-β in relapsing multiple sclerosis: a randomized phase II trial. Neurology 2012;78(23):1877-85. - PubMed
Ghezzi 1989 {published data only}
    1. Ghezzi A, Di Falco M, Locatelli C In: Consette RE, Delmotte P editor(s). Clinical controlled randomized trial of azathioprine in multiple sclerosis. Elsevier 1989.
Havrdova 2009 {published data only}
    1. Havrdova E, Zivadinov R, Krasensky J, Dwyer MG, Novakova I, Dolezal O, et al. Randomized study of interferon beta-1a, low-dose azathioprine, and low-dose corticosteroids in multiple sclerosis. Multiple Sclerosis (Houndmills, Basingstoke, England) 2009;15(8):965-76. - PubMed
IMPROVE 2010 {published data only}
    1. De Stefano N, Curtin F, Stubinski B, et al. Rapid benefits of a new formulation of subcutaneous interferon beta-1a in relapsing—remitting multiple sclerosis.. Multiple Sclerosis Journal. 2010;16(7):888-892. [DOI: 10.1177/1352458510362442] - DOI - PubMed
    1. De Stefano N, Sormani MP, Stubinski B, Blevins G, Drulovic JS, Issard D, Shotekov P, Gasperini C. Efficacy and safety of subcutaneous interferon β-1a in relapsing-remitting multiple sclerosis: further outcomes from the IMPROVE study.. J Neurol Sci. 2012;312((1-2)):97-101. [DOI: 10.1016/j.jns.2011.08.013] [PMID: ] - DOI - PubMed
    1. Giorgio A, Battaglini M, Gentile G, Stromillo ML, Gasperini C, Visconti A, Paolillo A and De Stefano N. Mapping the ProgressiveTreatment-Related Reduction ofActive MRI Lesions in MultipleSclerosis.. Front. Neurol 2020;11:585296. [DOI: 10.3389/fneur.2020.585296] - DOI - PMC - PubMed
Kappos 2006 {published data only}
    1. Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. New Egyptian Journal of Medicine 2006;355(11):1124-40. - PubMed
Kappos 2008 {published data only}
    1. Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, et al. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 2008;372(9648):1463-72. - PubMed
Kappos 2011 {published data only}
    1. Kappos L, Li D, Calabresi PA, O'Connor P, Bar-Or A, Barkhof F, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 2011;378(9805):1779-87. - PubMed
Khoury 2010 {published data only}
    1. Khoury SJ, Healy BC, Kivisäkk P, Viglietta V, Egorova S, Guttmann CR, et al. A randomized controlled double-masked trial of albuterol add-on therapy in patients with multiple sclerosis. Archives of Neurology 2010;67(9):1055-61. - PMC - PubMed
Lampl 2013 {published data only}
    1. Lampl C, Nagl S, Arnason B, Comi G, O Connor P, Cook S, Jeffery D, Kappos L, Filippi M, Beckmann K, Bogumil T, Pohl C, Sandbrink R, Hartung HP. Efficacy and safety of interferon beta-1b sc in older RRMS patients--a posthoc analysis of the BEYOND study. J Neurol 2013;260(7):1838-45. [DOI: 10.1007/s00415-013-6888-0] - DOI - PubMed
Le Page 2015 {published data only}
    1. Le Page E, Veillard D, Laplaud DA, Hamonic S, Wardi R, Lebrun C, Zagnoli F, Wiertlewski S, Deburghgraeve V, Coustans M, Edan G, COPOUSEP investigators, West Network for Excellence in Neuroscience. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial.. Lancet. 2015;386(9997):974-81. [DOI: 10.1016/S0140-6736(15)61137-0] - DOI - PubMed
Milanese 1993 {published data only}
    1. Milanese C, La Mantia L, Salmaggi A, Eoli M. A double blind study on azathioprine efficacy in multiple sclerosis: final report.. Journal of Neurology 1993;240(5):295–8. - PubMed
Newsome  2015 {published data only}
    1. Newsome SD, Guo S, Altincatal A, Proskorovsky I, Kinter E, Phillips G, You X, Sabatella G. Impact of peginterferon beta-1a and disease factors on quality of life in multiple sclerosis. Mult Scler Relat Disord. 2015;4(4):446-51. [DOI: 10.1111/cns.12235] - DOI - PubMed
Ochi 2018 {published data only}
    1. Ochi H, Niino M, Onizuka Y, Hiramatsu K, Hase M, Yun J, Matta A, Torii S. 72-Week Safety and Tolerability of Dimethyl Fumarate in Japanese Patients with Relapsing-remitting Multiple Sclerosis: Analysis of the Randomised, Double Blind, Placebo-Controlled, Phase III APEX Study and its Open-Label Extension.. Adv Ther. 2018 ;35(10):1598-1611. [DOI: 10.1007/s12325-018-0788-8] - DOI - PMC - PubMed
OWIMS 1999 {published data only}
    1. OWIMS. Evidence of interferon beta-1a dose response in relapsing-remitting MS: the OWIMS Study. The Once Weekly Interferon for MS Study Group. Neurology 1999;53(4):679-86. - PubMed
Saida 2012 {published data only}
    1. Saida T, Kikuchi S, Itoyama Y, Hao Q, Kurosawa T, Nagato K, et al. A randomized, controlled trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis. Multiple Sclerosis (Houndmills, Basingstoke, England) 2012;18(9):1269-77. - PubMed
Saida  2017 {published data only}
    1. Saida T, Kira JI, Kishida S, Yamamura T, Ohtsuka N, Dong Q, Tibung JT. Natalizumab for Achieving Relapse-Free, T1 Gadolinium-Enhancing-Lesion-Free, and T2 Lesion-Free Status in Japanese Multiple Sclerosis Patients: A Phase 2 Trial Subanalysis.. Neurol Ther. 2017;6(1):153-159. [DOI: 10.1007/s40120-016-0062-4] - DOI - PMC - PubMed
SENTINEL 2006 {published data only}
    1. Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. New England Journal of Medicine 2006;354(9):911-23. - PubMed
Simaniv 2019 {published data only}
    1. Simaniv, T O, Zakharova, M N, Boyko, A N, Lashch, NYu, Kotov, S V, Khabirov, F A, Khaibullin, T I, Sazonov, D V, Yarmoschuk, A V, Babenko, L A, et al. SAFETY ASPECTS WITHOUT LOSS OF EFFECTIVENESS IN THE SWITCH OF PATIENTS WITH MULTIPLE SCLEROSIS FROM THE ORIGINAL DRUG GLATIRAMER ACETATE COPAXONE-TEVA ON THE BIOSIMILAR TIMEXON. Russian neurological Journal 2019;0(4):44-51. [DOI: ]
Sorensen 2014 {published data only}
    1. Sorensen PS, Lisby S, Grove R, Derosier F, Shackelford S, Havrdova E, et al. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study. Neurology 2014;82(7):573-81. - PubMed
TENERE 2014 {published data only}
    1. Vermersch P, Czlonkowska A, Grimaldi LM, Confavreux C, Comi G, Kappos L, et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Multiple Sclerosis (Houndmills, Basingstoke, England) 2014;20(6):705-16. - PubMed
Ziemssen 2017 {published data only}
    1. Ziemssen T, Tumani H, Sehr T, Thomas K, Paul F, Richter N, Samara E, Spiegelstein O, Sorani E, Bar-Ilan O, Mimrod D, Hayardeny L. Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS. J Neuroinflammation. 2017 ;31(14(1)):172. [DOI: 10.1186/s12974-017-0945-z] - DOI - PMC - PubMed

References to studies awaiting assessment

ACTRN12621001502820 {published data only}
    1. Reducing the frequency of Autoimmune adverse events in the treatment of Multiple sclerosis with alemtuzumab using B-celL dEpletion (RAMBLE): a phase II, randomised, placebo-controlled clinical trial. https://trialsearch.who.int/Trial2.aspx?TrialID=ACTRN12621001502820.
Boyko 2022 {published data only}
    1. Boyko AN, Boyko OV, Bakhtiyarova KZ, Gusev EI, Dudin VA, Zaslavsky LG, Malkova NA, Parshina YV, Poverennova IY, Siverceva SA, Totolyan NA, Shchur SG, Fedulov AS, Khabirov FA, Bolsun DD, Zinkina-Orikhan AV, Linkova YN, Chernovskaya TV. Efficacy and safety of sampeginterferon β-1a in the treatment of relapsing remitting multiple sclerosis: results of 52 weeks of therapy in a randomized, double-blind clinical trial [Effektivnost' i bezopasnost' sampeginterferona β-1a dlya lecheniya remittiruyushchego rasseyannogo skleroza: rezul'taty 52-nedel'nogo randomizirovannogo dvoinogo slepogo klinicheskogo issledovaniya]. Zh Nevrol Psikhiatr Im S S Korsakova 2022;122(1):62-71. [DOI: 10.17116/jnevro202212201162] [PMID: ] - DOI - PubMed
CLARITY {published data only}
    1. De Stefano N, Sormani MP, Giovannoni G, Rammohan K, Leist T, Coyle PK, Dangond F, Keller B, Alexandri N, Galazka A. Analysis of frequency and severity of relapses in multiple sclerosis patients treated with cladribine tablets or placebo: The CLARITY and CLARITY Extension studies. Mult Scler 2022;28(1):111-120. [DOI: 10.1177/13524585211010294] [PMID: ] - DOI - PMC - PubMed
    1. Vermersch P, Galazka A, Dangond F, Damian D, Wong SL, Jack D, Harty G. Efficacy of cladribine tablets in high disease activity patients with relapsing multiple sclerosis: post hoc analysis of subgroups with and without prior disease-modifying drug treatment. Curr Med Res Opin 2021 ;37(3):459-464. [DOI: 10.1080/03007995.2020.1865888] [PMID: ] - DOI - PubMed
CombiRx {published data only}
    1. Koch MW, Mostert J, Repovic P, Bowen JD, Wolinsky JS, Lublin FD, Strijbis E, Cutter G. Early first-line treatment response and subsequent disability worsening in relapsing-remitting multiple sclerosis. Eur J Neurol 2022 ;29(4):1106-1116. [DOI: 10.1111/ene.15220] [PMID: ] - DOI - PubMed
    1. Koch MW, Mostert J, Zhang Y, Wolinsky JS, Lublin FD, Strijbis E, Cutter G. Association of Age With Contrast-Enhancing Lesions Across the Multiple Sclerosis Disease Spectrum. Neurology 2021;97(13):e1334-e1342. [DOI: 10.1212/WNL.0000000000012603] [PMID: ] - DOI - PMC - PubMed
EUCTR2017‐000559‐26‐IT {published data only}
    1. A multicentric, international study in order to compare the effectiveness of fingolimod versus dimethyl-fumarate on patients with Multiple Sclerosis. https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2017-000559-26-IT.
EUCTR2020‐001205‐23‐SE {published data only}
    1. Ocrelizumab VErsus Rituximab off-Label at the Onset of Relapsing MS Disease. https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2020-001205-23-SE.
EUCTR2020‐004505‐32‐FR {published data only}
    1. Study of efficacy and tolerability of ofatumumab vs. First Line disease modifying treatment (DMT) - physician’s choice in the treatment of newly diagnosed relapsing multiple sclerosis (RMS) patients. https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2020-004505-32-FR.
EVOLVE‐MS‐1 Study {published data only}
    1. Wray S, Then Bergh F, Wundes A, Arnold DL, Drulovic J, Jasinska E, Bowen JD, Negroski D, Naismith RT, Hunter SF, Gudesblatt M, Chen H, Lyons J, Shankar SL, Kapadia S, Mendoza JP, Singer BA. Efficacy and Safety Outcomes with Diroximel Fumarate After Switching from Prior Therapies or Continuing on DRF: Results from the Phase 3 EVOLVE-MS-1 Study. Adv Ther 2022;39(4):1810-1831. [DOI: 10.1007/s12325-022-02068-7] [PMID: ] - DOI - PMC - PubMed
Masjedi 2021 {published data only}
    1. Masjedi SS, Etemadifar M, Zadeh NM, Afzali M. Assessment of fingolimod versus dimethyl fumarate for the treatment of multiple sclerosis; a 24-month follow-up study. Am J Clin Exp Immunol 2021 ;10(3):86-92. [PMID: ] - PMC - PubMed
NCT04695080 {published data only}
    1. ChariotMS - Cladribine to Halt Deterioration in People With Advanced Multiple Sclerosis (ChariotMS). https://clinicaltrials.gov/show/NCT04695080.
OPTIMUM {published data only}
    1. Diener, H C. The randomized phase III OPTIMUM study. Ponesimod compared with teriflunomide in patients with relapsing-remitting multiple sclerosis. Arzneimitteltherapie 2021;39(9):309‐310. [CENTRAL: CN-02343138]
RIFUND‐MS {published data only}
    1. Svenningsson A, Frisell T, Burman J, Salzer J, Fink K, Hallberg S, Hambraeus J, Axelsson M, Nimer FA, Sundström P, Gunnarsson M, Johansson R, Mellergård J, Rosenstein I, Ayad A, Sjöblom I, Risedal A, Flon P, Gilland E, Lindeberg J, Shawket F, Piehl F, Lycke J. Safety and efficacy of rituximab versus dimethyl fumarate in patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome in Sweden: a rater-blinded, phase 3, randomised controlled trial. Lancet Neurol 2022;21(8):693-703. [DOI: 10.1016/S1474-4422(22)00209-5] [PMID: ] - DOI - PubMed
SUNBEAM/RADIANCE {published data only}
    1. Harris S, Comi G, Cree BAC, Arnold DL, Steinman L, Sheffield JK, Southworth H, Kappos L, Cohen JA, Ozanimod Study Investigators. Plasma neurofilament light chain concentrations as a biomarker of clinical and radiologic outcomes in relapsing multiple sclerosis: Post hoc analysis of Phase 3 ozanimod trials. Eur J Neurol 2021;28(11):3722-3730. [DOI: 10.1111/ene.15009] [PMID: ] - DOI - PMC - PubMed

References to ongoing studies

EUCTR2012‐000540‐10‐PL {published data only}
    1. Euctr P L. International clinical trial to compare ponesimod and teriflunomide in relapsing multiple sclerosis. http://www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2012-000540-10-PL 2015.
EUCTR2012‐003647‐30‐SK {published data only}
    1. Euctr S K. A clinical study in subjects with relapsing-remitting multiple sclerosis (RRMS) consisting of two parts: first part is to assess the efficacy, safety and tolerability of two oral doses of laquinimod either of 0.6 mg/day or 1.2mg/day (experimental drug) as compared placebo. Second part (all subjects receiving active treatment) is to evaluate the efficacy, safety and tolerability of two oral doses of laquinimod 0.6 mg/day or 1.2 mg/day (experimental drug). http://www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2012-003647-30-SK 2014.
EUCTR2013‐002082‐19‐SE {published data only}
    1. Euctr S E. A clinical study in subjects with relapsing-remitting multiple sclerosis (RRMS) to assess the efficacy, safety and tolerability of two oral doses of laquinimod either of 0.6 mg/day or 1.2mg/day (experimental drug) as compared to Interferon ß-1a (Avonex, authorised drug) administered once weekly. http://www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2013-002082-19-SE 2013.
EUCTR2013‐003884‐71‐BE {published data only}
    1. EUCTR2013-003884-71-BE, Genzyme Corporation Yes. Phase IIIB-IV long term follow-up study for patients who participated in CAMMS03409. https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2013-003884-71-BE 2014.
EUCTR2014‐001012‐19‐NL {published data only}
    1. EUCTR2014-001012-19-NL, Yes V U University Medical Center. Effects of fingolimod on advanced brain measures and clinical measures in multiple sclerosis. https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2014-001012-19-NL 2014.
EUCTR2018‐000284‐93‐BG {published data only}
    1. EUCTR2018-000284-93-BG, Mapi Pharma Ltd Yes. A multinational, multicenter, randomized, Phase III, double blind, parallel group, placebo controlled study in subjects with Relapsing forms of Multiple Sclerosis (RMS) to assess the efficacy, safety and tolerability of GA Depot, a long acting IM injection of glatiramer acetate, administered once every four weeks. https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_nu... 2019.
EUCTR2018‐005038‐39‐GB {published data only}
    1. Euctr G B. A phase 2b study of Cladribine to halt deterioration in people with advanced multiple sclerosis. http://www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2018-005038-39-GB 2020.
EUCTR2019‐001505‐24‐NO {published data only}
    1. Euctr N O. A Clinical Study Comparing Rituximab and Cladribine for Relapsing Multiple Sclerosis. http://www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2019-001505-24-NO 2019.
EUCTR2020‐002981‐15‐DK {published data only}
    1. Euctr D K. Non-inferiority study of ocrelizumab and rituximab in active multiple sclerosis. http://www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2020-002981-15-DK 2020.
IRCT20130812014333N {published data only}
    1. Irct20130812014333N. Comparison of effectiveness and complication of rituximab and fingolimod in improvement disability motion. http://www.who.int/trialsearch/Trial2.aspx?TrialID=IRCT20130812014333N125 2019.
IRCT201404195280N {published data only}
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