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. 2015 Sep 18;2015(9):CD011381.
doi: 10.1002/14651858.CD011381.pub2.

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

Irene Tramacere  1 , Cinzia Del Giovane, Georgia Salanti, Roberto D'Amico, Graziella Filippini
Affiliations

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

Irene Tramacere et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biologics. Although there is consensus that these therapies reduce the frequency of relapses, their relative benefit in delaying new relapses or disability worsening remains unclear due to the limited number of direct comparison trials.

Objectives: To compare the benefit and acceptability of interferon beta-1b, interferon beta-1a (Avonex, Rebif), glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine and immunoglobulins for the treatment of people with RRMS and to provide a ranking of these treatments according to their benefit and acceptability, defined as the proportion of participants who withdrew due to any adverse event.

Search methods: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register, which contains trials from CENTRAL (2014, Issue 9), MEDLINE (1966 to 2014), EMBASE (1974 to 2014), CINAHL (1981 to 2014), LILACS (1982 to 2014), clinicaltrials.gov and the WHO trials registry, and US Food and Drug Administration (FDA) reports. We ran the most recent search in September 2014.

Selection criteria: Randomised controlled trials (RCTs) that studied one or more of the 15 treatments as monotherapy, compared to placebo or to another active agent, for use in adults with RRMS.

Data collection and analysis: Two authors independently identified studies from the search results and performed data extraction. We performed data synthesis by pairwise meta-analysis and network meta-analysis. We assessed the quality of the body of evidence for outcomes within the network meta-analysis according to GRADE, as very low, low, moderate or high.

Main results: We included 39 studies in this review, in which 25,113 participants were randomised. The majority of the included trials were short-term studies, with a median duration of 24 months. Twenty-four (60%) were placebo-controlled and 15 (40%) were head-to-head studies.Network meta-analysis showed that, in terms of a protective effect against the recurrence of relapses in RRMS during the first 24 months of treatment, alemtuzumab, mitoxantrone, natalizumab, and fingolimod outperformed other drugs. The most effective drug was alemtuzumab (risk ratio (RR) versus placebo 0.46, 95% confidence interval (CI) 0.38 to 0.55; surface under the cumulative ranking curve (SUCRA) 96%; moderate quality evidence), followed by mitoxantrone (RR 0.47, 95% CI 0.27 to 0.81; SUCRA 92%; very low quality evidence), natalizumab (RR 0.56, 95% CI 0.47 to 0.66; SUCRA 88%; high quality evidence), and fingolimod (RR 0.72, 95% CI 0.64 to 0.81; SUCRA 71%; moderate quality evidence).Disability worsening was based on a surrogate marker, defined as irreversible worsening confirmed at three-month follow-up, measured during the first 24 months in the majority of included studies. Both direct and indirect comparisons revealed that the most effective treatments were mitoxantrone (RR versus placebo 0.20, 95% CI 0.05 to 0.84; SUCRA 96%; low quality evidence), alemtuzumab (RR 0.35, 95% CI 0.26 to 0.48; SUCRA 94%; low quality evidence), and natalizumab (RR 0.64, 95% CI 0.49 to 0.85; SUCRA 74%; moderate quality evidence).Almost all of the agents included in this review were associated with a higher proportion of participants who withdrew due to any adverse event compared to placebo. Based on the network meta-analysis methodology, the corresponding RR estimates versus placebo over the first 24 months of follow-up were: mitoxantrone 9.92 (95% CI 0.54 to 168.84), fingolimod 1.69 (95% CI 1.32 to 2.17), natalizumab 1.53 (95% CI 0.93 to 2.53), and alemtuzumab 0.72 (95% CI 0.32 to 1.61).Information on serious adverse events (SAEs) was scanty, characterised by heterogeneous results and based on a very low number of events observed during the short-term duration of the trials included in this review.

Authors' conclusions: Conservative interpretation of these results is warranted, since most of the included treatments have been evaluated in few trials. The GRADE approach recommends providing implications for practice based on moderate to high quality evidence. Our review shows that alemtuzumab, natalizumab, and fingolimod are the best choices for preventing clinical relapses in people with RRMS, but this evidence is limited to the first 24 months of follow-up. For the prevention of disability worsening in the short term (24 months), only natalizumab shows a beneficial effect on the basis of moderate quality evidence (all of the other estimates were based on low to very low quality evidence). Currently, therefore, insufficient evidence is available to evaluate treatments for the prevention of irreversible disability worsening.There are two additional major concerns that have to be considered. First, the benefit of all of these treatments beyond two years is uncertain and this is a relevant issue for a disease with a duration of 30 to 40 years. Second, short-term trials provide scanty and poorly reported safety data and do not provide useful evidence in order to obtain a reliable risk profile of treatments. In order to provide long-term information on the safety of the treatments included in this review, it will be necessary also to evaluate non-randomised studies and post-marketing reports released from the regulatory agencies. Finally, more than 70% of the studies included in this review were sponsored by pharmaceutical companies and this may have influenced the results.There are three needs that the research agenda should address. First, randomised trials of direct comparisons between active agents would be useful, avoiding further placebo-controlled studies. Second, follow-up of the original trial cohorts should be mandatory. Third, more studies are needed to assess the medium and long-term benefit and safety of immunotherapies and the comparative safety of different agents.

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Conflict of interest statement

GF: none

GS: none

CDG: none

IT: none

RD: none

Figures

1
1
Study flow diagram.
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 benefit and acceptability outcomes.
5
5
Network meta‐analysis (NMA) estimates of treatment benefit against placebo: relapses over 12 and 24 months, and disability worsening over 24 months. CI: confidence interval; RR: risk ratio.
6
6
Network meta‐analysis (NMA) estimates of treatment acceptability against placebo: treatment discontinuation due to AEs over 12 and 24 months. AEs: adverse events; CI: confidence interval; RR: risk ratio.
7
7
Network meta‐analysis (NMA) estimates of treatment benefit (lower triangle) and acceptability (upper triangle) over 12 months for each comparison: relapses and treatment discontinuation due to adverse events (AEs) over 12 months. Drugs are reported in order of primary benefit ranking. Comparisons should be read from left to right. The estimate (risk ratio, RR) is located at the intersection of the column‐defining treatment and the row‐defining treatment. A RR value below 1 favours the column‐defining treatment for lower triangle, and the row‐defining treatment for upper triangle. To obtain RRs for comparisons in the opposing direction, reciprocals should be taken. Significant results are bolded and underscored. Alemtuz: alemtuzumab; Avonex: interferon beta‐1a (Avonex); Aza: azathioprine; Betaseron: interferon beta‐1b (Betaseron); Dacliz: daclizumab; Dimethyl: dimethyl fumarate; Fingolim: fingolimod; Glatir: glatiramer acetate; IFNß: interferons beta; Immunogl: immunoglobulins; Mitoxan: mitoxantrone; Nataliz: natalizumab; PegIFNß: pegylated interferon beta‐1a; Rebif: interferon beta‐1a (Rebif); Terifl: teriflunomide.
8
8
Network meta‐analysis (NMA) estimates of treatment benefit (lower triangle) and acceptability (upper triangle) over 24 months for each comparison: relapses and treatment discontinuation due to adverse events (AEs) over 24 months. Drugs are reported in order of primary benefit ranking. Comparisons should be read from left to right. The estimate (risk ratio, RR) is located at the intersection of the column‐defining treatment and the row‐defining treatment. A RR value below 1 favours the column‐defining treatment for lower triangle, and the row‐defining treatment for upper triangle. To obtain RRs for comparisons in the opposing direction, reciprocals should be taken. Significant results are bolded and underscored. Alemtuz: alemtuzumab; Avonex: interferon beta‐1a (Avonex); Aza: azathioprine; Betaseron: interferon beta‐1b (Betaseron); Dimethyl: dimethyl fumarate; Fingolim: fingolimod; Glatir: glatiramer acetate; IFNß: interferons beta; Immunogl: immunoglobulins; Laquin: laquinimod; Mitoxan: mitoxantrone; Nataliz: natalizumab; Rebif: interferon beta‐1a (Rebif); Terifl: teriflunomide.
9
9
Clustered ranking plot based on cluster analysis of surface under the cumulative ranking curve (SUCRA) values for benefit (relapses) and acceptability (treatment discontinuation due to AEs) over 24 months. Each colour represents a group of treatments that belong to the same cluster. Treatments lying in the upper right corner are more effective and acceptable than the other treatments.
10
10
Network meta‐analysis (NMA) estimates of treatment benefit (lower triangle) and acceptability (upper triangle) over 24 months for each comparison: disability worsening and treatment discontinuation due to adverse events (AEs) over 24 months. Drugs are reported in order of primary benefit ranking. Comparisons should be read from left to right. The estimate is located at the intersection of the column‐defining treatment and the row‐defining treatment. A RR value below 1 favours the column‐defining treatment for lower triangle, and the row‐defining treatment for upper triangle. To obtain RRs for comparisons in the opposing direction, reciprocals should be taken. Significant results are bolded and underscored. Alemtuz: alemtuzumab; Avonex: interferon beta‐1a (Avonex); Aza: azathioprine; Betaseron: interferon beta‐1b (Betaseron); Dimethyl: dimethyl fumarate; Fingolim: fingolimod; Glatir: glatiramer acetate; IFNß: interferons beta; Immunogl: immunoglobulins; Laquin: laquinimod; Mitoxan: mitoxantrone; Nataliz: natalizumab; Rebif: interferon beta‐1a (Rebif); Terifl: teriflunomide.
11
11
Clustered ranking plot based on cluster analysis of surface under the cumulative ranking curve (SUCRA) values for benefit (disability worsening) and acceptability (treatment discontinuation due to AEs) over 24 months. Each colour represents a group of treatments that belong to the same cluster. Treatments lying in the upper right corner are more effective and acceptable than the other treatments.
12
12
Inconsistency plots for relapses over 12 and 24 months and disability worsening over 24 months assuming loop‐specific heterogeneity estimates. RRR is calculated as the risk ratio for direct evidence over the risk ratio for indirect evidence in the loop and it is reported together with its 95% confidence interval (CI). RRR values close to one indicate the absence of evidence for disagreement between direct and indirect evidence.
13
13
Inconsistency plots for acceptability over 12 and 24 months assuming loop‐specific heterogeneity estimates. RRR is calculated as the risk ratio for direct evidence over the risk ratio for indirect evidence in the loop and it is reported together with its 95% confidence interval (CI). RRR values close to one indicate the absence of evidence for disagreement between direct and indirect evidence.
14
14
Study limitations distribution for each network estimate for pairwise comparisons versus placebo on relapses over 12 and 24 months and disability worsening over 24 months outcomes. Calculations are based on the contributions of direct evidence to the network estimates and the overall risks of bias considering our predefined criteria (allocation concealment, blinding of outcome assessor, and incomplete outcome data) within studies contributing to the direct evidence. The colours represent risk (green, low; yellow, moderate; red, high). The direct comparisons against placebo are described in the vertical axis.
15
15
Contribution matrix: percentage contribution of each direct estimate to the NMA estimates versus placebo for relapses over 12 months outcome. Rows correspond to NMA risk ratios of each treatment versus placebo (separated for mixed and indirect evidence) and the columns correspond to direct meta‐analysis risk ratios. The last row shows the number of included direct comparisons. The names of the treatment comparisons are shown in the first column. For example, for relapses over 12 months, information for the network estimate of interferon beta 1a (Avonex) versus placebo is derived from both direct and indirect evidence (generating a mixed estimate). Of this mixed network estimate, trials directly comparing interferon beta 1a (Avonex) versus placebo contribute 31.2% of the information to the network estimate of effect and trials directly comparing interferon beta 1a (Rebif) versus interferon beta 1a (Avonex) contribute 18.8% of the network estimated effect, etc. The contribution matrix shows how much each direct comparison in the network contributes to each network (mixed or indirect) estimate and to the entire network.
16
16
Contribution matrix: percentage contribution of each direct estimate to the NMA estimates versus placebo for relapses over 24 months outcome.
17
17
Contribution matrix: percentage contribution of each direct estimate to the NMA estimates versus placebo for disability worsening over 24 months outcome.
1.1
1.1. Analysis
Comparison 1 Treatment benefit within pairwise comparisons, Outcome 1 Comparisons for relapses over 12 months.
1.2
1.2. Analysis
Comparison 1 Treatment benefit within pairwise comparisons, Outcome 2 Comparisons for relapses over 24 months.
1.3
1.3. Analysis
Comparison 1 Treatment benefit within pairwise comparisons, Outcome 3 Comparisons for disability worsening over 24 months.
2.1
2.1. Analysis
Comparison 2 Treatment acceptability within pairwise comparisons, Outcome 1 Comparisons for treatment discontinuation due to AEs over 12 months.
2.2
2.2. Analysis
Comparison 2 Treatment acceptability within pairwise comparisons, Outcome 2 Comparisons for treatment discontinuation due to AEs over 24 months.
3.1
3.1. Analysis
Comparison 3 Treatment safety against placebo within pairwise comparisons, Outcome 1 Serious adverse events.
See this image and copyright information in PMC

References

References to studies included in this review

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INCOMIN 2002 {published data only}
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MAIN TRIAL {published data only}
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REGARD 2008 {published data only}
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SELECT 2013 {published data only}
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TEMSO 2011 {published data only}
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TENERE 2014 {published data only}
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References to studies excluded from this review

ACT 2009 {published data only}
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ATAMS 2014 {published data only}
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CHOICE 2010 {published data only}
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Etemadifar 2006 {published data only}
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FORTE 2011 {published data only}
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Freedman 2012 {published data only}
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Havrdova 2009 {published data only}
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Kappos 2006 {published data only}
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Kappos 2008 {published data only}
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References to other published versions of this review

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