Abstract
Objectives
Oral drugs for relapsing–remitting multiple sclerosis (RRMS) have been recently investigated and, one of these, fingolimod, is already available in several countries. In this framework, an analysis of the data in terms of the comparative effectiveness for all treatments thus far approved for RRMS can be useful to reappraise their place in therapy.
Methods
After a MEDLINE search, we selected all randomised trials studying the effectiveness of drugs for RRMS and included in our analysis those randomised trials in which interferon, glatiramer, natalizumab or fingolimod were studied. The end-point was the relapse-free rate at 12 months, which was compared between the various treatments. Direct comparisons, based on actual randomised trials, were handled by calculating the trial-specific hazard ratio (HR) or the meta-analytic value of HR (when at least 2 trials were available). Indirect comparisons for which data from actual trials were missing were instead managed through a network meta-analysis.
Results
Ten randomised trials met the criteria set for our analysis. All active treatments were found to be significantly more effective than placebo (direct comparisons) in terms of freedom from relapse at the 12-month follow-up assessments; the values of HR ranged from 1.28 for glatiramer to 1.53 for interferon beta. The comparisons between active agents revealed that fingolimod was superior to interferon (HR = 1.18; direct comparison) and glatiramer (HR = 1.23; indirect comparison), while the other four head-to-head comparisons of treatments revealed no significant difference.
Conclusions
On the basis of the effectiveness data presently available, fingolimod seems to offer the advantage of oral administration together with the most favorable profile in terms of relapse-free rate at the 1-year follow-up assessment.
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Appendix 1
Appendix 1
This Appendix contains four sections: Section 1, which presents the bibliographic details for the clinical studies included in our analysis; Section 2, which presents details on the studies that met some but not all of our inclusion criteria and were therefore excluded from our analysis; Section 3, which presents details on the traditional meta-analysis carried out in our study as well as those resulting from the analysis of a single trial; Section 4, which presents detailed information on the sources of the trial-specific raw data on event rate.
Section 1: Bibliographic details for the studies included in the analysis
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Bornstein MB, Miller A, Slagle S, Weitzman M, Crystal H, Drexler E et al (1987) A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N Eng J Med 317(7):408–414
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Cadavid D, Wolansky LJ, Skurnick J, Lincoln J, Cheriyan J, Szczepanowski K, Kamin SS, Pachner AR, Halper J, Cook SD (2009) Efficacy of treatment of MS with IFNbeta-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology 72(23):1976–1983
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Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, Tiel-Wilck K, de Vera A, Jin J, Stites T, Wu S, Aradhye S, Kappos L, TRANSFORMS Study Group (2010) Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 362(5):402–415
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Comi G, Filippi M, Wolinsky JS, the European/Canadian Glatiramer Acetate Study Group (2001) 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-remitting multiple sclerosis. Ann Neurol 149(3):290–297
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Filippi M, Rocca MA, Camesasca F, Cook S, O'Connor P, Arnason BG, Kappos L, Goodin D, Jeffery D, Hartung HP, Comi G, Wolinsky JS, Bogumil T, Pohl C, Beckmann K, Sandbrink R, Croze E, Brown C, Desimone TM, Arnold DL, Cutter G, Knappertz V (2011) Interferon β-1b and glatiramer acetate effects on permanent black hole evolution. Neurology 76(14):1222–1228
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IFNB Multiple Sclerosis Study Group (1993) Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43(4):655–661
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Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, Fischer JS, Goodkin DE, Granger CV, Simon JH, Alam JJ, Bartoszak DM, Bourdette DN, Braiman J, Brownscheidle CM, Coats ME, Cohan SL, Dougherty DS, Kinkel RP, Mass MK, Munschauer FE 3rd, Priore RL, Pullicino PM, Scherokman BJ, Whitham RH et al (1996) Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 39(3):285–294
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Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P, FREEDOMS Study Group (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362:387–401
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O'Connor P, Filippi M, Arnason B, Comi G, Cook S, Goodin D, Hartung HP, Jeffery D, Kappos L, Boateng F, Filippov V, Groth M, Knappertz V, Kraus C, Sandbrink R, Pohl C, Bogumil T, BEYOND Study Group, O'Connor P, Filippi M, Arnason B, Cook S, Goodin D, Harung HP, Kappos L, Jeffery D, Comi G (2009) 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol 8(10):889–897
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Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW, AFFIRM Investigators (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354(9):899–910
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PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group (1998) Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 352(9139):1498–504
Section 2: Medline search
Using the keywords “multiple sclerosis” AND “relapsing remitting” AND interferon OR glatiramer OR natalizumab OR fingolimod combined with the limitation “randomised controlled trial”, a MEDLINE search was run on 25 July 2011, which retrieved a total of 197 studies. Ten studies met our inclusion criteria (see Table 1). For the comparison between interferon and glatiramer, the BEYOND trial, which has been described in two separate papers (Filippi et al. 2011; O’Connor et al. 2009—see Section 1 of Appendix), could not be included in our analysis for the following reasons: (1) the paper by O’Connor et al. (2009) presented the relapse-free rate at 2 years (520/897, i.e. 58% in the interferon group vs. 262/448, i.e. 59% in the glatiramer group), but not at 1 year, while the paper by Filippi et al. (2011) was based exclusively on the assessment of new lesions evolving into permanent black holes and did not report any information on the relapse-free rates. However, even if the BEYOND trial was excluded from our analysis, the two trials studying interferon versus glatiramer that were included instead (Cadavid et al. 2009; Mikol et al. 2000—see Section 1 of Appendix) gave nearly identical results to those found in the BEYOND trial.
Section 3: Traditional meta-analysis of the direct comparisons based on two or more clinical trials and analysis of data sets based on a single trial
Traditional meta-analysis
According to our study design, the three placebo-controlled trials available for the two types of interferon were pooled into a single therapeutic modality, and a meta-analysis was carried out accordingly. Other direct comparisons based on two or more trials and requiring a traditional meta-analysis were glatiramer versus placebo and interferon versus glatiramer, respectively. Figure 2 shows the results generated by the REVMAN software (including the information on heterogeneity).
Analysis of data sets based on a single-trial
There were three such data sets (namely, natalizumab vs, placebo, fingolimod vs. placebo, and fingolimod vs, interferon). Despite the fact that these analyses were not a meta-analysis, the REVMAN software was used to determine the trial-specific statistical indexes. Figure 3 shows the results generated by the REVMAN software (including the information on heterogeneity).
Section 4: Detailed information on the sources of the trial-specific raw data of event ratea
First author(a) | Data source for the relapse-free rates |
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Jacobs et al. (1996) | These results are reported by Freedman et al. (2008), page 5, Fig. 1, panel b |
PRISMS Study Group (1998) | Table 2, page 1501 |
The IFNB Multiple Sclerosis Study Group (1993) | Fig. 2, page 658b |
Bornstein et al. (1987) | Fig. 5, page 17 of the paper by La Mantia et al. (2010) |
Comi et al. (2001) | Fig. 5, page 17 of the paper by La Mantia et al. (2010) |
Cadavid et al. (2009) | Table 3, page 1981 |
Mikol et al. (2000) | Fig. 3, page 907b |
Polman et al. (2006) | Page 903 |
Cohen et al. (2010) | Table 2, page 408 |
Kappos et al. (2010) | Fig. 2A, page 396b |
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Del Santo, F., Maratea, D., Fadda, V. et al. Treatments for relapsing–remitting multiple sclerosis: summarising current information by network meta-analysis. Eur J Clin Pharmacol 68, 441–448 (2012). https://doi.org/10.1007/s00228-011-1141-1
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DOI: https://doi.org/10.1007/s00228-011-1141-1