Comparative effectiveness using a matching-adjusted indirect comparison between delayed-release dimethyl fumarate and fingolimod for the treatment of multiple sclerosis

Abstract

Objective: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) and fingolimod are approved oral disease-modifying treatments for relapsing–remitting multiple sclerosis. In phase 3 trials, DMF (DEFINE/CONFIRM) and fingolimod (FREEDOMS/FREEDOMS II) resulted in significant reductions in clinical and magnetic resonance imaging activity, with acceptable safety profiles. Direct comparisons of these treatments are not possible due to a lack of head-to-head trials. We compared 2 year efficacy of DMF versus fingolimod at the approved dosage using a matching-adjusted indirect approach.

Research design and methods: Individual patient data from DEFINE and CONFIRM, and aggregate data from FREEDOMS and FREEDOMS II, were pooled and compared using the matching-adjusted in-direct method. To account for cross-trial differences, data from trials with available individual patient data were adjusted to match aggregate data (i.e. average patient characteristics) from trials without patient-level data. Data from DMF-treated patients were weighted such that average baseline characteristics matched those of fingolimod-treated patients. After matching, weighted treatment outcomes for DMF-treated patients (240 mg twice daily) were compared with summary outcomes for fingolimod-treated patients (0.5 mg once daily). All comparison results of DMF versus fingolimod used fingolimod as the reference.

Results: After matching, baseline characteristics were balanced between DMF and fingolimod. At year 2, the efficacy of DMF was similar to that of fingolimod for annualized relapse rate (rate ratio [95% confidence interval (CI)]: 1.11 [0.88, 1.40]), 12 week confirmed disability progression (hazard ratio [95% CI]: 0.90 [0.63, 1.29]), and Multiple Sclerosis Functional Composite (mean difference [95% CI]: 0.04 [−0.05, 0.13]). For patient-reported outcomes (EuroQoL 5-Dimensions questionnaire), the mean differences (95% CI) were 0.05 (0.01, 0.08) for utility score and 3.22 (0.58, 5.86) for visual analog scale score, significantly favoring DMF. There was no significant difference in the percentage of patients with no evidence of disease activity (NEDA) for DMF versus fingolimod among matching-adjusted patients with complete NEDA data: rate ratio (95% CI): 0.92 (0.51, 1.64).

Conclusions: Using the matching-adjusted indirect comparison approach, the efficacy of DMF and fingolimod were similar on all clinical outcomes, while patient-reported outcomes showed greater benefit with DMF. Study limitations include possible confounding from unobserved/unknown differences between trials, and trial length may have been insufficient to detect significant differences on disability progression.

Clinical trial registration: NCT00420212 (DEFINE); NCT00451451 (CONFIRM); NCT00289978 (FREEDOMS); NCT00355134 (FREEDOMS II).

Keywords:

• Delayed-release dimethyl fumarate
• fingolimod
• indirect comparison
• multiple sclerosis

Transparency

Declaration of funding

This study was supported by Biogen (Cambridge, MA, USA).

Author contributions: All authors contributed to study conception and design, acquisition of data, analysis and interpretation of data, and drafting and review of the manuscript.

Declaration of financial/other relationships

R.J.F. has disclosed that he has received consulting fees from Actelion, Biogen, MedDay, Novartis, Mallinckrodt, Teva, and Xenoport; been on advisory committees for Biogen and Novartis; and received research grant funding from Novartis. A.C. has disclosed that he has received personal compensation for activities from Almirall Hermal, Bayer HealthCare, Biogen, Genzyme, Merck Serono, Novartis, Roche, Sanofi-Aventis, and Teva Neuroscience; and research support from Biogen, Genzyme, and Novartis. A.Z., J.X., D.L., J.B.L., and M.R.E. have disclosed that they are employees of and hold stock/stock options in Biogen. J.L.M. has disclosed that she performed the majority of the work while an employee of, and holds stock in, Biogen, Cambridge, MA, USA; her current affiliation is with Alexion Pharmaceuticals, New Haven, CT, USA.

CMRO peer reviewer 1 has disclosed that he has been a consultant to Avita Medical Ltd, Bayer plc, Daiichi-Sankyo Europe, EUSA Pharma, GlaxoSmithKline, Ipsen Pharma, Janssen EMEA, Janssen UK, Menarini Pharma UK and Norgine Ltd. Peer reviewers 2 and 3 have no relevant financial or other relationships to disclose.

Acknowledgments

Biogen provided funding for medical writing support in the development of this paper; Gina Rocco PhD from Complete Medical Communications wrote the first draft of the manuscript based on input from authors. Ana Antaloae PhD from Excel Scientific Solutions incorporated feedback from authors, and Elizabeth Cassell from Excel Scientific Solutions copyedited and styled the manuscript per journal requirements. Dr. G. Cutter provided valuable feedback during the manuscript development. Biogen reviewed and provided feedback on the paper. The authors had full editorial control of the paper, and provided their final approval of all content.

Previous presentation: previously presented as a poster at: 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis, Barcelona, Spain, 7–10 October 2015; 18th European Congress of the International Society for Pharmacoeconomics and Outcomes Research, Milan, Italy, 7–11 November 2015.