Treatments for relapsing–remitting multiple sclerosis: summarising current information by network meta-analysis

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.

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

• 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

• 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

• 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

• 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

• 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

• Freedman MS, Hughes B, Mikol DD, Bennett R, Cuffel B, Divan V, LaVallee N, Al-Sabbagh A (2008) Efficacy of disease-modifying therapies in relapsing remitting multiple sclerosis: a systematic comparison. Eur Neurol 60(1):1–11

• 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

• 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

• 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

• La Mantia L, Munari LM, Lovati R (2010) Glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev May 12;(5):CD004678

• Messori A, Trippoli G, Vaiani M, Cattel F (2000) Survival meta-analysis of individual patient data and survival meta-analysis of published (aggregate) data. Clin Drug Invest 20:309–316

• Mikol DD, Barkhof F, Chang P, Coyle PK, Jeffery DR, Schwid SR, Stubinski B, Uitdehaag BM, REGARD Study Group (2008) 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 Neurol 7(10):903–914

• 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

• 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

• 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).

Fig. 2

Forest plots for the direct comparisons including two or more clinical trials. Three separate “traditional” meta-analyses were carried out. In each case, the REVMAN software was used to determine the pooled value of the risk ratio (with 95% CI) between the intervention group and the control group; the end-point was freedom from relapse at 1 year. The three graphs generated by this software are shown along with the study-specific event rates extracted from each trial. Superiority in the intervention arm was found in the first two analyses (interferon vs. placebo and glatiramer vs. placebo, respectively), while the third (interferon vs. glatiramer) showed no significant difference. Depending on the “direction” of the comparison being considered, the values of risk ratio were incorporated into our network meta-analysis either without any change or after conversion into their reciprocal

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).

Fig. 3

Event-rate analysis for the direct comparisons based on a single clinical trial. Three separate analyses were carried out. For each of these three direct comparisons, the REVMAN software was used to determine the trial-specific value of the risk ratio (with 95% CI) between the intervention group and the control group. The graphs generated through these analyses are shown below along with the study-specific event rates extracted from each trial. All of these three comparisons showed superiority for the intervention group in comparison with the control group (namely, superiority of natalizumab vs. placebo, of fingolimod vs. placebo, and of fingolimod vs. interferon, respectively). Depending on the “direction” of the comparison being considered, the values of risk ratio resulting from these analyses were incorporated into our network meta-analysis either without any change or after conversion into their reciprocal

Section 4: Detailed information on the sources of the trial-specific raw data of event rate^a

First author(a)	Data source for the relapse-free rates
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

1. ^aSee Section 1 of the Appendix for a full description of the references
2. ^bWhile the relapse-free rates at 2 years were reported by these authors in numerical form, this information at 1 year was available only in graphical form; the event rate at 1 year expressed in numerical form was therefore estimated from the Kaplan–Meier curve published in the referenced figure according to the procedure described by Messori et al. (2000)