Annualized relapse rate of first-line treatments for multiple sclerosis: a meta-analysis, including indirect comparisons versus fingolimod

Abstract

Objectives:

Previous systematic reviews and meta-analyses of treatments in relapsing–remitting multiple sclerosis (RRMS) derived their findings from either placebo-controlled studies only or separately from head-to-head and comparative studies. The purpose of this study is to compare annualized relapse rates (ARR) of fingolimod versus all of the commonly used first-line treatments in RRMS using evidence from both placebo-controlled and head-to-head studies. In absence of the head-to-head data between fingolimod and the other treatments, these comparisons were formed using meta-analysis techniques for indirect treatment comparisons.

Methods:

A systematic literature review was conducted by searching MEDLINE, EMBASE, and the Cochrane Library with no limitations applied on publication language or dates. Included studies were randomized controlled trials evaluating one or more of fingolimod, interferon beta-1a, interferon beta-1b, or glatiramer acetate in RRMS populations. Primary outcome was ARR. Data extraction included author, year, treatment, dosage, mean age, percentage females, duration of disease, Expanded Disability Status Scale (EDSS) score at baseline, relapses in 2 years prior to baseline, trial duration, relapse-related outcome, and definition of relapse. The indirect treatment comparisons were performed using a mixed-treatment comparison framework. ARR was analyzed as a Poisson outcome.

Results:

The relative ARRs, for each treatment versus fingolimod, estimated from our meta-analyses were 1.43 (glatiramer acetate 20 mg), 1.51 (interferon beta-1b 250 mcg), 1.55 (interferon beta-1a 44 mcg), 1.67 (interferon beta-1a 22 mcg), 1.93 (interferon beta-1a 30 mcg), and 2.32 (placebo). None of the 95% confidence intervals for these estimates overlapped unity, implying statistical significance of these findings.

Limitations:

The key limitations of this study are the persisting heterogeneity even after adjusting for covariates and the variability in outcome definition across the included trials.

Conclusions:

Our study demonstrated that fingolimod significantly reduces relapse frequency in patients with RRMS compared with current first-line disease-modifying therapies.

Keywords::

• Annualized relapse rate
• Fingolimod
• Indirect comparison
• Meta-analysis
• Multiple sclerosis

Transparency

Declaration of funding

This study was funded by Novartis Pharmaceuticals US (Novartis). Novartis is developing fingolimod for patients with multiple sclerosis. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors, and are fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development.

Declaration of financial/other relationships

N.S.R., E.A.Z. and C.E.R. have disclosed that they are employees of RTI Health Solutions, a company that received funding from Novartis to conduct this study. B.J.E. and D.A.T. have disclosed that they are employees of Novartis.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgments

The authors thank Dr Jianmin Wang, RTI Health Solutions, for his help developing the MTC statistical methodology, and Dr Miny Samuel, RTI Health Solutions, for her contributions regarding the design and conduct of the literature searches.

Notes

*Copaxone is a registered trade name of Teva Pharmaceutical Industries Ltd, Israel.

†Avonex is a registered trade name of Biogen Idec MA Inc., USA.

‡Rebif is a registered trade name of Ares Trading SA, Switzerland.

§Extavia is a registered trade name of Novartis AG, Switzerland.

*Betaseron is a registered trade name of Bayer Schering Pharma, Germany.

†Tysabri is a registered trade name of Elan Pharmaceuticals Inc., USA.

‡Gilenya is a registered trade name of Novartis AG, Switzerland.