Inmunomoduladores e inmunosupresores para la esclerosis múltiple recurrente remitente: un metanálisis de redes
Información
- DOI:
- https://doi.org/10.1002/14651858.CD011381.pub2Copiar DOI
- Base de datos:
-
- Cochrane Database of Systematic Reviews
- Versión publicada:
-
- 18 septiembre 2015see what's new
- Tipo:
-
- Intervention
- Etapa:
-
- Review
- Grupo Editorial Cochrane:
-
Grupo Cochrane de Esclerosis múltiple y enfermedades raras del sistema nervioso central
- Copyright:
-
- Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cifras del artículo
Altmetric:
Citado por:
Autores
Contributions of authors
Concept: GF, GS
Title registration: GF
Protocol draft: GF, IT, CDG, GS
Protocol editing: GF, IT, CDG, GS, RD
Title and abstract review: GF, IT
Data abstraction: IT, IP
Data entry: IT, IP
Data analysis: CDG, IT
Drafting the review: GF, IT
Editing and revising the review: GF, IT, CDG, GS, RD
Sources of support
Internal sources
-
Fondazione Istituto Neurologico Carlo Besta ‐ Milan, Italy.
External sources
-
Ministero della Salute, Italy.
Declarations of interest
GF: none
GS: none
CDG: none
IT: none
RD: none
Acknowledgements
We thank Andrea Fittipaldo for developing the search strategy methods for identification of studies, Ilaria Pacchetti for contributing to data collection, and Silvana Simi, Hwanhee Hong, and Chris Cameron for their useful comments during the preparation of the Cochrane review. We also express our gratitude for the assistance and guidance of Toby Lasserson and Nuala Livingstone for reviewing the review.
Version history
| Published | Title | Stage | Authors | Version |
| 2024 Jan 04 | Immunomodulators and immunosuppressants for relapsing‐remitting multiple sclerosis: a network meta‐analysis | Review | Marien Gonzalez-Lorenzo, Ben Ridley, Silvia Minozzi, Cinzia Del Giovane, Guy Peryer, Thomas Piggott, Matteo Foschi, Graziella Filippini, Irene Tramacere, Elisa Baldin, Francesco Nonino | |
| 2015 Sep 18 | Immunomodulators and immunosuppressants for relapsing‐remitting multiple sclerosis: a network meta‐analysis | Review | Irene Tramacere, Cinzia Del Giovane, Georgia Salanti, Roberto D'Amico, Graziella Filippini | |
| 2014 Nov 13 | Immunomodulators and immunosuppressants for relapsing‐remitting multiple sclerosis: a network meta‐analysis | Protocol | Irene Tramacere, Cinzia Del Giovane, Georgia Salanti, Roberto D'Amico, Ilaria Pacchetti, Graziella Filippini | |
Differences between protocol and review
We excluded the route of administration of treatments (oral, subcutaneous, intravenous) from the effect modifiers that were possible sources of inconsistency or heterogeneity, since it was not clinically expected.
Keywords
MeSH
Medical Subject Headings (MeSH) Keywords
Medical Subject Headings Check Words
Adult; Humans;
PICO
Study flow diagram.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Network plots of treatment comparisons for benefit and acceptability outcomes.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Contribution matrix: percentage contribution of each direct estimate to the NMA estimates versus placebo for relapses over 24 months outcome.
Contribution matrix: percentage contribution of each direct estimate to the NMA estimates versus placebo for disability worsening over 24 months outcome.
Comparison 1 Treatment benefit within pairwise comparisons, Outcome 1 Comparisons for relapses over 12 months.
Comparison 1 Treatment benefit within pairwise comparisons, Outcome 2 Comparisons for relapses over 24 months.
Comparison 1 Treatment benefit within pairwise comparisons, Outcome 3 Comparisons for disability worsening over 24 months.
Comparison 2 Treatment acceptability within pairwise comparisons, Outcome 1 Comparisons for treatment discontinuation due to AEs over 12 months.
Comparison 2 Treatment acceptability within pairwise comparisons, Outcome 2 Comparisons for treatment discontinuation due to AEs over 24 months.
Comparison 3 Treatment safety against placebo within pairwise comparisons, Outcome 1 Serious adverse events.
| Patient or population: patients with relapsing‐remitting multiple sclerosis (RRMS) Settings: secondary healthcare centres Intervention: any immunomodulators or immunosuppressants used for RRMS Comparison: placebo | |||||||
| Intervention | Illustrative comparative risks* | Relative effect | SUCRA | No of participants | Confidence in the evidence | Reasons for downgrading | |
| Assumed risk with placebo | Corresponding risk with intervention | ||||||
| CHANCE OF EXPERIENCING ONE OR MORE RELAPSES OVER 12 MONTHS | |||||||
| Alemtuzumab | Low | RR 0.40 (0.31 to 0.51) | 97% | — | Moderate | Downgraded one level due to risk of bias ‐ the majority of studies at high or unclear risk of bias in allocation concealment and/or blinding of outcome assessor domains | |
| 41 per 100 | 16 per 100 | ||||||
| High | |||||||
| 89 per 100 | 36 per 100 | ||||||
| Mitoxantrone | Low | RR 0.40 (0.20 to 0.76) | 93% | 51 | Low | Downgraded two levels due to risk of bias ‐ the singular study contributing to this estimate at high risk of bias in blinding of outcome assessor domain | |
| 41 per 100 | 16 per 100 | ||||||
| High | |||||||
| 89 per 100 | 36 per 100 | ||||||
| Natalizumab | Low | RR 0.56 (0.43 to 0.73) | 85% | 942 | High | — | |
| 41 per 100 | 23 per 100 | ||||||
| High | |||||||
| 89 per 100 | 50 per 100 | ||||||
| Fingolimod | Low | RR 0.63 (0.53 to 0.74) | 80% | 2355 | Low | Downgraded one level due to risk of bias and one level due to inconsistency ‐ the majority of studies at high or unclear risk of bias in allocation concealment and/or blinding of outcome assessor domains; I2 = 82% (P value = 0.02) | |
| 41 per 100 | 26 per 100 | ||||||
| High | |||||||
| 89 per 100 | 56 per 100 | ||||||
| Dimethyl fumarate | Low | RR 0.78 (0.65 to 0.93) | 55% | 2307 | Moderate | Downgraded one level due to inconsistency ‐ wide predictive interval | |
| 41 per 100 | 32 per 100 | ||||||
| High | |||||||
| 89 per 100 | 69 per 100 | ||||||
| Immunoglobulins | Low | RR 0.78 (0.61 to 1.00) | 53% | 219 | Very low | Downgraded one level due to risk of bias, two levels due to inconsistency, and one level due to imprecision ‐ the majority of studies at unclear risk of bias in allocation concealment and/or blinding of outcome assessor domains; I2 = 83% (P value = 0.003) and differences between pairwise and common τ2 (0.18 versus 0.01); wide CIs | |
| 41 per 100 | 32 per 100 | ||||||
| High | |||||||
| 89 per 100 | 69 per 100 | ||||||
| Glatiramer acetate | Low | RR 0.80 (0.68 to 0.93) | 52% | 2416 | Moderate | Downgraded one level due to inconsistency ‐ wide predictive interval | |
| 41 per 100 | 33 per 100 | ||||||
| High | |||||||
| 89 per 100 | 71 per 100 | ||||||
| Daclizumab | Low | RR 0.79 (0.61 to 1.02) | 52% | 621 | Moderate | Downgraded one level due to imprecision ‐ wide CIs | |
| 41 per 100 | 32 per 100 | ||||||
| High | |||||||
| 89 per 100 | 70 per 100 | ||||||
| Teriflunomide | Low | RR 0.84 (0.72 to 0.99) | 42% | 2257 | Low | Downgraded one level due to risk of bias and one level due to inconsistency ‐ the majority of studies at unclear risk of bias in allocation concealment and/or blinding of outcome assessor domains; wide predictive interval | |
| 41 per 100 | 34 per 100 | ||||||
| High | |||||||
| 89 per 100 | 75 per 100 | ||||||
| Azathioprine | Low | RR 0.87 (0.58 to 1.31) | 39% | 59 | Very low | Downgraded one level due to risk of bias, one level due to indirectness, and two levels due to imprecision ‐ the singular study contributing to this estimate at unclear risk of bias in allocation concealment domain; indirectness of population (one monocentric study); wide CIs | |
| 41 per 100 | 36 per 100 | ||||||
| High | |||||||
| 89 per 100 | 77 per 100 | ||||||
| Interferon beta‐1a (Rebif) | Low | RR 0.87 (0.76 to 1.01) | 36% | 853 | Low | Downgraded one level due to risk of bias and one level due to inconsistency ‐ the majority of studies at high or unclear risk of bias in allocation concealment and/or blinding of outcome assessor domains; I2 = 88% (P value = 0.004) | |
| 41 per 100 | 36 per 100 | ||||||
| High | |||||||
| 89 per 100 | 77 per 100 | ||||||
| Pegylated interferon beta‐1a | Low | RR 0.89 (0.70 to 1.13) | 33% | 1512 | Low | Downgraded one level due to risk of bias and one level due to imprecision ‐ the singular study contributing to this estimate at unclear risk of bias in blinding of outcome assessor domain; wide CIs | |
| 41 per 100 | 36 per 100 | ||||||
| High | |||||||
| 89 per 100 | 79 per 100 | ||||||
| Interferon beta‐1b (Betaseron) | Low | RR 0.98 (0.54 to 1.75) | 27% | — | Very low | Downgraded one level due to risk of bias and two levels due to imprecision ‐ the majority of studies at unclear risk of bias in allocation concealment and/or blinding of outcome assessor domains; wide CIs | |
| 41 per 100 | 40 per 100 | ||||||
| High | |||||||
| 89 per 100 | 87 per 100 | ||||||
| Interferon beta‐1a (Avonex) | Low | RR 0.93 (0.78 to 1.10) | 25% | 301 | Moderate | Downgraded one level due to risk of bias ‐ the majority of studies at high or unclear risk of bias in allocation concealment and/or blinding of outcome assessor domains | |
| 41 per 100 | 38 per 100 | ||||||
| High | |||||||
| 89 per 100 | 83 per 100 | ||||||
| Interferons beta (Avonex, Rebif or Betaseron) | Low | RR 1.05 (0.61 to 1.79) | 20% | — | Very low | Downgraded one level due to risk of bias, one level due to indirectness, and two levels due to imprecision ‐ the majority of studies at high or unclear risk of bias in allocation concealment and/or blinding of outcome assessor domains; indirectness of population (one monocentric study contributing 50% to this estimate); wide CIs | |
| 41 per 100 | 43 per 100 | ||||||
| High | |||||||
| 89 per 100 | 93 per 100 | ||||||
| CHANCE OF EXPERIENCING ONE OR MORE RELAPSES OVER 24 MONTHS | |||||||
| Alemtuzumab | Low | RR 0.46 (0.38 to 0.55) | 96% | — | Moderate | Downgraded one level due to risk of bias ‐ the majority of studies at high or unclear risk of bias in allocation concealment and/or blinding of outcome assessor domains | |
| 57 per 100 | 26 per 100 | ||||||
| High | |||||||
| 85 per 100 | 39 per 100 | ||||||
| Mitoxantrone | Low | RR 0.47 (0.27 to 0.81) | 92% | 51 | Very low | Downgraded two levels due to risk of bias and one level due to inconsistency ‐ the singular study contributing to this estimate at high risk of bias in blinding of outcome assessor domain; wide predictive interval | |
| 57 per 100 | 27 per 100 | ||||||
| High | |||||||
| 85 per 100 | 40 per 100 | ||||||
| Natalizumab | Low | RR 0.56 (0.47 to 0.66) | 88% | 942 | High | — | |
| 57 per 100 | 32 per 100 | ||||||
| High | |||||||
| 85 per 100 | 48 per 100 | ||||||
| Fingolimod | Low | RR 0.72 (0.64 to 0.81) | 71% | 2355 | Moderate | Downgraded one level due to risk of bias ‐ studies at unclear risk of bias in allocation concealment domain | |
| 57 per 100 | 41 per 100 | ||||||
| High | |||||||
| 85 per 100 | 61 per 100 | ||||||
| Immunoglobulins | Low | RR 0.74 (0.60 to 0.91) | 66% | 190 | Moderate | Downgraded one level due to inconsistency ‐ wide predictive interval | |
| 57 per 100 | 42 per 100 | ||||||
| High | |||||||
| 85 per 100 | 63 per 100 | ||||||
| Azathioprine | Low | RR 0.77 (0.55 to 1.07) | 57% | 59 | Very low | Downgraded one level due to risk of bias, one level due to indirectness, and one level due to imprecision ‐ the singular study contributing to this estimate at unclear risk of bias in allocation concealment domain; indirectness of population (one monocentric study); wide CIs | |
| 57 per 100 | 44 per 100 | ||||||
| High | |||||||
| 85 per 100 | 65 per 100 | ||||||
| Glatiramer acetate | Low | RR 0.83 (0.75 to 0.91) | 48% | 1024 | Moderate | Downgraded one level due to inconsistency ‐ wide predictive interval | |
| 57 per 100 | 47 per 100 | ||||||
| High | |||||||
| 85 per 100 | 71 per 100 | ||||||
| Interferon beta‐1b (Betaseron) | Low | RR 0.85 (0.77 to 0.94) | 42% | 372 | Very low | Downgraded one level due to risk of bias and two levels due to inconsistency ‐ the majority of studies at high or unclear risk of bias in allocation concealment and/or blinding of outcome assessor domains; wide predictive interval and inconsistent loops of evidence | |
| 57 per 100 | 48 per 100 | ||||||
| High | |||||||
| 85 per 100 | 72 per 100 | ||||||
| Interferon beta‐1a (Rebif) | Low | RR 0.86 (0.77 to 0.95) | 39% | 560 | Low | Downgraded one level due to risk of bias and one level due to inconsistency ‐ the majority of studies at high or unclear risk of bias in allocation concealment and/or blinding of outcome assessor domains; wide predictive interval | |
| 57 per 100 | 49 per 100 | ||||||
| High | |||||||
| 85 per 100 | 73 per 100 | ||||||
| Interferons beta (Avonex, Rebif or Betaseron) | Low | RR 0.89 (0.56 to 1.42) | 33% | — | Very low | Downgraded one level due to risk of bias, one level due to indirectness, and one level due to imprecision ‐ the majority of studies at high or unclear risk of bias in allocation concealment and/or blinding of outcome assessor domains; indirectness of population (one monocentric study contributing for 50% to this estimate); wide CIs | |
| 57 per 100 | 51 per 100 | ||||||
| High | |||||||
| 85 per 100 | 76 per 100 | ||||||
| Teriflunomide | Low | RR 0.88 (0.75 to 1.03) | 32% | 1088 | Very low | Downgraded two levels due to risk of bias and one level due to imprecision ‐ the singular study contributing to this estimate at high risk of bias in blinding of outcome assessor domain; wide CIs | |
| 57 per 100 | 50 per 100 | ||||||
| High | |||||||
| 85 per 100 | 75 per 100 | ||||||
| Laquinimod | Low | RR 0.88 (0.79 to 0.99) | 31% | 1990 | Very low | Downgraded one level due to risk of bias and two levels due to inconsistency ‐ the majority of studies at high or unclear risk of bias in allocation concealment and/or blinding of outcome assessor domains; I2 = 66% (P value = 0.09), wide predictive interval and inconsistent loops of evidence | |
| 57 per 100 | 50 per 100 | ||||||
| High | |||||||
| 85 per 100 | 75 per 100 | ||||||
| Dimethyl fumarate | Low | RR 0.89 (0.81 to 0.98) | 30% | 2307 | Moderate | Downgraded one level due to inconsistency ‐ wide predictive interval | |
| 57 per 100 | 51 per 100 | ||||||
| High | |||||||
| 85 per 100 | 76 per 100 | ||||||
| Interferon beta‐1a (Avonex) | Low | RR 0.91 (0.82 to 1.02) | 22% | 1198 | Low | Downgraded one level due to risk of bias and one level due to inconsistency ‐ the majority of studies at high or unclear risk of bias in allocation concealment and/or blinding of outcome assessor domains; inconsistent loops of evidence | |
| 57 per 100 | 52 per 100 | ||||||
| High | |||||||
| 85 per 100 | 77 per 100 | ||||||
| CHANCE OF DISABILITY GETTING WORSE OVER 24 MONTHS | |||||||
| Mitoxantrone | Low | RR 0.20 (0.05 to 0.84) | 96% | 51 | Low | Downgraded one level due to indirectness and one level due to inconsistency ‐ surrogate outcome unclear; wide predictive interval | |
| 25 per 100 | 5 per 100 | ||||||
| High | |||||||
| 52 per 100 | 10 per 100 | ||||||
| Alemtuzumab | Low | RR 0.35 (0.26 to 0.48) | 94% | — | Low | Downgraded one level due to risk of bias and one level due to indirectness ‐ the majority of studies at high or unclear risk of bias in allocation concealment and/or blinding of outcome assessor domains; surrogate outcome in the majority of studies contributing to this estimate | |
| 25 per 100 | 9 per 100 | ||||||
| High | |||||||
| 52 per 100 | 18 per 100 | ||||||
| Natalizumab | Low | RR 0.64 (0.49 to 0.85) | 74% | 942 | Moderate | Downgraded one level due to indirectness ‐ surrogate outcome | |
| 25 per 100 | 16 per 100 | ||||||
| High | |||||||
| 52 per 100 | 33 per 100 | ||||||
| Azathioprine | Low | RR 0.64 (0.30 to 1.37) | 64% | 59 | Very low | Downgraded one level due to risk of bias, two levels due to indirectness, and two levels due to imprecision ‐ the singular study contributing to this estimate at unclear risk of bias in allocation concealment domain; indirectness of population (one monocentric study) and surrogate outcome unclear; wide CIs | |
| 25 per 100 | 16 per 100 | ||||||
| High | |||||||
| 52 per 100 | 33 per 100 | ||||||
| Glatiramer acetate | Low | RR 0.77 (0.64 to 0.92) | 58% | 1024 | Very low | Downgraded one level due to indirectness and two levels due to inconsistency ‐ surrogate outcome in the majority of studies contributing to this estimate; wide predictive interval and inconsistent loops of evidence | |
| 25 per 100 | 19 per 100 | ||||||
| High | |||||||
| 52 per 100 | 40 per 100 | ||||||
| Immunoglobulins | Low | RR 0.70 (0.39 to 1.27) | 56% | 190 | Very low | Downgraded one level due to indirectness, one level due to inconsistency, and two levels due to imprecision ‐ surrogate outcome in the majority of studies contributing to this estimate; wide predictive interval; wide CIs | |
| 25 per 100 | 18 per 100 | ||||||
| High | |||||||
| 52 per 100 | 36 per 100 | ||||||
| Interferon beta‐1b (Betaseron) | Low | RR 0.79 (0.65 to 0.97) | 51% | 372 | Very low | Downgraded one level due to risk of bias, one level due to indirectness, and two levels due to inconsistency ‐ the majority of studies at high or unclear risk of bias in allocation concealment and/or blinding of outcome assessor domains; surrogate outcome in the majority of studies contributing to this estimate; wide predictive interval and inconsistent loops of evidence | |
| 25 per 100 | 20 per 100 | ||||||
| High | |||||||
| 52 per 100 | 41 per 100 | ||||||
| Dimethyl fumarate | Low | RR 0.80 (0.67 to 0.94) | 50% | 2307 | Low | Downgraded one level due to indirectness and one level due to inconsistency ‐ surrogate outcome in the majority of studies contributing to this estimate; wide predictive interval | |
| 25 per 100 | 20 per 100 | ||||||
| High | |||||||
| 52 per 100 | 42 per 100 | ||||||
| Interferons beta (Avonex, Rebif or Betaseron) | Low | RR 0.83 (0.34 to 2.07) | 40% | — | Very low | Downgraded one level due to indirectness, one level due to inconsistency, and two levels due to imprecision ‐ indirectness of population and surrogate outcome unclear (one study contributing for 50% to this estimate); wide predictive interval; wide CIs | |
| 25 per 100 | 21 per 100 | ||||||
| High | |||||||
| 52 per 100 | 43 per 100 | ||||||
| Interferon beta‐1a (Rebif) | Low | RR 0.86 (0.69 to 1.06) | 36% | 560 | Very low | Downgraded one level due to risk of bias, one level due to indirectness, one level due to inconsistency, and one level due to imprecision ‐ the majority of studies at high or unclear risk of bias in allocation concealment and/or blinding of outcome assessor domains; surrogate outcome in the majority of studies contributing to this estimate; inconsistent loops of evidence; wide CIs | |
| 25 per 100 | 22 per 100 | ||||||
| High | |||||||
| 52 per 100 | 45 per 100 | ||||||
| Fingolimod | Low | RR 0.86 (0.73 to 1.03) | 34% | 2355 | Very low | Downgraded one level due to risk of bias, one level due to indirectness, and one level due to imprecision ‐ studies at unclear risk of bias in allocation concealment domain; surrogate outcome; wide CIs | |
| 25 per 100 | 22 per 100 | ||||||
| High | |||||||
| 52 per 100 | 45 per 100 | ||||||
| Laquinimod | Low | RR 0.87 (0.72 to 1.04) | 34% | 1990 | Low | Downgraded one level due to indirectness and one level due to imprecision ‐ surrogate outcome in the majority of studies contributing to this estimate; wide CIs | |
| 25 per 100 | 22 per 100 | ||||||
| High | |||||||
| 52 per 100 | 45 per 100 | ||||||
| Teriflunomide | Low | RR 0.87 (0.69 to 1.10) | 34% | 1088 | Low | Downgraded one level due to indirectness and one level due to imprecision ‐ surrogate outcome; wide CIs | |
| 25 per 100 | 22 per 100 | ||||||
| High | |||||||
| 52 per 100 | 45 per 100 | ||||||
| Interferon beta‐1a (Avonex) | Low | RR 0.93 (0.77 to 1.13) | 21% | 1198 | Very low | Downgraded one level due to risk of bias, one level due to indirectness, and two levels due to inconsistency ‐ the majority of studies at high or unclear risk of bias in allocation concealment and/or blinding of outcome assessor domains; surrogate outcome in the majority of studies contributing to this estimate; I2 = 57% (P value = 0.13), and inconsistent loops of evidence | |
| 25 per 100 | 23 per 100 | ||||||
| High | |||||||
| 52 per 100 | 48 per 100 | ||||||
| *The corresponding risk with intervention (and its 95% confidence interval) is based on the assumed risk with placebo and the relative effect of the intervention (and its 95% CI). Two values were chosen for the assumed risk with placebo, i.e. the second highest and second lowest placebo group risks in the included studies, defined as low and high assumed risk. #No of Participants (studies) is not available when the nature of the evidence is indirect. °We did not downgrade for reasons of reporting bias as insufficient studies contributed to network treatment estimates to draw meaningful conclusions. | |||||||
| GRADE Working Group grades of evidence | |||||||
| Study | Risk of bias | Did the researchers actively monitor for adverse events (AEs) or did they simply provide spontaneous reporting of AEs that arose? | Risk of bias | Did the authors define serious AEs (SAEs) according to an accepted international classification and report the number of SAEs? |
| Unclear | Not reported | High | SAEs not reported | |
| Unclear | Not reported | Low | Categorisation of SAEs conformed to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) | |
| Low | "Treating neurologists were responsible for all aspects of patient care, including the management of adverse events". Participants"visited the clinic every 12 weeks for ... blood chemical and hematologic analyses, evaluation of adverse events..." (Page 901) | Unclear | Insufficient information on SAEs definition | |
| Low | "Safety assessments were performed at screening, at baseline, and every 3 months until month 24" (Page 1002) | Low | Categorisation of SAEs conformed to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) | |
| Low | "After the initial interim analysis failed to raise any safety concerns with the use of monthly triple dose gadolinium, all patients still in the study were offered the option of obtaining additional monthly MRI scans for a second year of treatment" (Page 1977) | High | SAEs not reported | |
| Low | "Clinic visits were scheduled every 3 months to assess ... safety, and tolerability. The occurrence of new neurological symptoms and adverse events was assessed by telephone, 6 weeks after each visit" (Page 891) | Low | Categorisation of SAEs conformed to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) | |
| High | "Self‐evaluation reported to a clinical assistant" (Page 409) | High | SAEs not reported | |
| Low | "Patients were evaluated at 12 scheduled visits: months ‐1 (screening), 0 (baseline), 1, 2, 3, 6, 9, 12, 15, 18, 21, and 24. Safety assessments (laboratory measures, vital signs) were performed at all visits, and electrocardiograms (ECGs) were performed at months ‐1, 0, 1, 2, 3, 6, 12, 18, and 24/early termination" (Page 775) | Unclear | Insufficient information on SAEs definition | |
| Low | "Safety was assessed quarterly by the treating neurologist, who was aware of study‐group assignment" (Page 1787), "Thyroid function and levels of antithyrotropinreceptor antibodies and lymphocyte subpopulations were measured quarterly at a central laboratory", and "All adverse events with an onset up to 36 months are reported. In addition, all serious adverse events and autoimmune‐associated disorders occurring before March 1, 2008, are listed" (Page 1788) | Low | Categorisation of SAEs conformed to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) | |
| Low | "To assess safety, we undertook monthly questionnaire follow‐up of patients, and did complete blood counts, serum creatinine, urinalysis, and microscopy monthly (every three months in patients in the interferon beta 1a group), and thyroid function tests every 3 months", "Circulating lymphocyte subsets were assessed every 3 months in all patients and 1 month after alemtuzumab administration. We screened for antialemtuzumab antibodies with a bridging ELISA before and at 1 month, 3 months, and 12 months after each dosing", and "We measured interferon beta 1a‐neutralising antibodies at baseline and at 24 months with a cytopathic effect inhibition assay" (Page 1821) | Low | Categorisation of SAEs conformed to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use). | |
| Low | "To assess safety, we undertook monthly questionnaire follow‐up of patients, and did complete blood counts, serum creatinine, and urinalysis with microscopy monthly (every 3 months in patients in the interferon beta 1a group), and thyroid function tests every 3 months", "We assessed circulating lymphocyte subsets every 3 months in all patients and 1 month after every course of alemtuzumab. We screened for anti‐alemtuzumab antibodies with ELISA before and at 1 month, 3 months and 12 months after each dosing", and "We measured interferon beta 1a‐neutralising antibodies at baseline and at 24 months with a cytopathic effect inhibition assay" (Page 1832) | Low | Categorisation of SAEs conformed to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) | |
| Low | "Safety was assessed by recording all adverse events, serious and nonserious" (Page 329) | Unclear | No information on SAE definition | |
| Unclear | "The treating physician monitored safety..." (Page 291) | Unclear | Insufficient information on SAEs definition | |
| Low | "Throughout the course of the study, every effort was made to remain alert to possible adverse events (AEs)" and "Any AE or SAE experienced by the subject was recorded on the CRF, regardless of the severity of the event or its relationship to study treatment" (Pages 66‐7 of Protocol) | Low | Categorisation of SAEs conformed to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) | |
| Low | "Study visits were scheduled every 4 weeks for safety assessments, including the monitoring of laboratory values" (Page 1100) | Low | Categorisation of SAEs conformed to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) | |
| Low | "Adverse events, vital signs and blood tests were monitored monthly" (Page 1724) | High | SAEs not reported | |
| High | "Adverse events were determined by spontaneous reporting and monthly laboratory testing during the comparative phase" (Page 2031) | Unclear | Insufficient information on SAEs definition | |
| Low | Participants "asked about safety monthly..." (Page 590) | High | SAEs not reported | |
| Unclear | Not reported | Unclear | Insufficient information on SAEs definition | |
| Low | "An independent data and safety monitoring board evaluated the safety" and "Study visits, including safety assessments, were scheduled at 2 weeks and 1, 2, 3, 6, 9, 12, 15, 18, 21, and 24 months after randomization" (Page 389) | Low | Categorisation of SAEs conformed to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) | |
| Low | "...safety assessments, were scheduled at 2 weeks and 1, 2, 3, 6, 9, 12, 15, 18, 21, and 24 months after randomization" (Appendix, Page 2) | Low | Categorisation of SAEs conformed to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) | |
| Low | "Safety assessments included adverse events (AEs), standard clinical laboratory tests, vital signs, and electrocardiographic (ECG) measurements" (Page 707) | Unclear | No information on SAE definition | |
| High | "Side effect were reported to the treating neurologist every 6 months" (Page 21) | High | SAEs not reported | |
| Low | "Treating neurologist reviewed side effects, laboratory findings for toxicity ..." (Page 656) | High | SAEs not reported | |
| Low | "Safety assessments included adverse events, vital signs, physical examination, and concomitant medications. Patients underwent haematology and biochemical tests, including liver‐function tests, every 2 weeks for the first 8 weeks, and then every 3 months" (Page 1455) | High | SAEs not reported | |
| Low | "The evaluating physician monitored safety every 3 month..." (Page 1270) | Unclear | Insufficient information on SAEs definition | |
| Low | "Patients were interviewed about side effects and had routine blood tests including hematology and liver function tests every 3 months and thyroid tests and neutralizing antibodies every 6 months" (Page 1057) | High | SAEs not reported | |
| Unclear | "Laboratory safety examinations were made at the beginning and at the end of the study period" (Page 566) | Unclear | Insufficient information on SAEs definition | |
| Low | "At scheduled (quarterly) and unscheduled (i.e., at the onset of new symptoms or complications) follow‐up visits the treating neurologist recorded symptoms, blood test results, clinical AEs and their management" | Low | Categorisation of SAEs conformed to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) | |
| Low | "The safety of the treatment was assessed on the basis of adverse events volunteered by the patient either spontaneously or on questioning and monitoring of the main laboratory parameters" (Page 155) | Unclear | Insufficient information on SAEs definition | |
| Low | "Study visits were scheduled at baseline and every 6 months. Treating physicians reviewed toxicity test results, examined patients, and made all medical decision" (Page 286) | Unclear | Insufficient information on SAEs definition | |
| Unclear | "The treating physician recorded and treated AEs..." (Page 680) | Unclear | Insufficient information on SAEs definition | |
| Unclear | "A “treating” neurologist was responsible for overall medical management of the patient, including treatment of any side‐effects" (Page 1499) | Unclear | Insufficient information on SAEs definition | |
| Unclear | "Adverse events (including pregnancy), withdrawals owing to adverse events, serious adverse events, and laboratory results were obtained for safety comparisons" (Page 905) | Unclear | Insufficient information on SAEs definition | |
| Low | "Safety parameters were assessed at all visits" (Page 2168) | Unclear | No information on SAE definition | |
| Low | "A treating neurologist at each site was responsible for recording and managing adverse events and monitoring safety assessments" and "Safety was evaluated on the basis of adverse events reported by study participants or investigators. Laboratory tests were performed at the time of screening, at baseline, every 2 weeks for the first 24 weeks, and then every 6 weeks until study completion. Physical and neurologic examinations were performed at week 12 and then every 24 weeks. An abdominal ultrasonographic examination to asses for pancreatic abnormalities was performed before the study and then every 24 weeks, because of previous infrequent reports of pancreatitis associated with leflunomide use" (Pages 1294‐5) | Low | Categorisation of SAEs conformed to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) | |
| Low | "Safety and tolerability were assessed using AE reporting, vital signs and laboratory assessments. Adverse event reports were collected at randomisation, Weeks 2, 6, 12, 18, 24, 36 and every 12 weeks thereafter. Vital signs were documented at screening, randomisation and every 12 weeks thereafter; clinical laboratory results were assessed throughout the study. Adverse events and vital signs were also recorded during unscheduled relapse visits" (Page 707) | Low | Categorisation of SAEs conformed to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) [information provided on request by Genzyme] | |
| Low | "Safety was assessed through adverse event reporting (upon occurrence), clinical laboratory tests (every 2 weeks until week 24, then every 6 weeks while still on treatment), vital signs (at weeks 2 and 6, then every 6 weeks until week 24, then every 12 weeks while still on treatment), abdominal ultrasonography (at week 24, then every 24 weeks), and electrocardiography (at baseline and end of treatment)" (Page 248) | Low | Categorisation of SAEs conformed to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) | |
| Low | "An independent data and safety monitoring board evaluated overall safety in the fingolimod phase 3 program" and "Safety assessments were conducted during screening, at baseline, and at months 1, 2, 3, 6, 9, and 12" (Page 404) | Low | Categorisation of SAEs conformed to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) |
| Intervention | Subgroup analysis by | |||||||
| Diagnostic criteria | Previous treatments RR (95% CI) | Definition of relapse RR (95% CI) | Pre‐trial relapse rate RR (95% CI) | |||||
| Poser criteria | McDonald criteria | No | Yes | 24‐hour definition | 48‐hour definition | ≥ 1 during the year before randomisation | ≥ 2 during the 2/3 years before randomisation | |
| Alemtuzumab | — | 0.48 (0.33 to 0.68) | 0.46 (0.28 to 0.76) | 0.47 (0.27 to 0.79) | — | 0.46 (0.27 to 0.78) | 0.63 (0.48 to 0.81) | 0.28 (0.16 to 0.49) |
| Natalizumab | — | 0.56 (0.45 to 0.69) | — | 0.70 (0.56 to 0.88) | 0.63 (0.52 to 0.77) | — | 0.68 (0.54 to 0.85) | — |
| Fingolimod | — | 0.72 (0.63 to 0.83) | — | 0.72 (0.65 to 0.80) | 0.81 (0.67 to 0.97) | — | — | 0.72 (0.60 to 0.87) |
| CI: confidence interval; NMA: network meta‐analysis; RR: risk ratio. | ||||||||
| Intervention | Sensitivity analysis | ||
| Including only trials of low risk of bias | Excluding studies that did not provide complete and clear reporting of dropout data RR (95% CI) | Excluding trials with a total sample size of fewer than 50 randomised participants RR (95% CI) | |
| Alemtuzumab | — | 0.47 (0.35 to 0.63) | 0.46 (0.39 to 0.56) |
| Natalizumab | 0.66 (0.54 to 0.81) | — | 0.56 (0.47 to 0.66) |
| Fingolimod | — | 0.72 (0.65 to 0.80) | 0.72 (0.64 to 0.81) |
| CI: confidence interval; NMA: network meta‐analysis; RR: risk ratio. | |||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Comparisons for relapses over 12 months Show forest plot | 29 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 Interferon beta‐1a (Avonex) versus placebo | 1 | 301 | Risk Ratio (M‐H, Random, 95% CI) | 0.88 [0.73, 1.05] |
| 1.2 Interferon beta‐1a (Rebif) versus placebo | 2 | 853 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.66, 1.19] |
| 1.3 Glatiramer acetate versus placebo | 4 | 2416 | Risk Ratio (M‐H, Random, 95% CI) | 0.79 [0.66, 0.95] |
| 1.4 Natalizumab versus placebo | 1 | 942 | Risk Ratio (M‐H, Random, 95% CI) | 0.56 [0.47, 0.66] |
| 1.5 Mitoxantrone versus placebo | 1 | 51 | Risk Ratio (M‐H, Random, 95% CI) | 0.40 [0.21, 0.74] |
| 1.6 Fingolimod versus placebo | 2 | 2355 | Risk Ratio (M‐H, Random, 95% CI) | 0.63 [0.48, 0.82] |
| 1.7 Teriflunomide versus placebo | 2 | 2257 | Risk Ratio (M‐H, Random, 95% CI) | 0.86 [0.78, 0.95] |
| 1.8 Dimethyl fumarate versus placebo | 2 | 2307 | Risk Ratio (M‐H, Random, 95% CI) | 0.79 [0.71, 0.88] |
| 1.9 Pegylated interferon beta‐1a versus placebo | 1 | 1512 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.78, 1.01] |
| 1.10 Daclizumab versus placebo | 1 | 621 | Risk Ratio (M‐H, Random, 95% CI) | 0.79 [0.68, 0.92] |
| 1.11 Azathioprine versus placebo | 1 | 59 | Risk Ratio (M‐H, Random, 95% CI) | 0.87 [0.61, 1.24] |
| 1.12 Immunoglobulins versus placebo | 3 | 219 | Risk Ratio (M‐H, Random, 95% CI) | 0.80 [0.47, 1.36] |
| 1.13 Interferon beta‐1a (Rebif) versus interferon beta‐1a (Avonex) | 1 | 677 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.80, 1.03] |
| 1.14 Glatiramer acetate versus interferon beta‐1b (Betaseron) | 1 | 75 | Risk Ratio (M‐H, Random, 95% CI) | 0.81 [0.48, 1.38] |
| 1.15 Azathioprine versus interferons beta (Avonex, Rebif or Betaseron) | 2 | 244 | Risk Ratio (M‐H, Random, 95% CI) | 0.81 [0.49, 1.33] |
| 1.16 Fingolimod versus interferon beta‐1a (Avonex) | 1 | 1292 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.57, 0.79] |
| 1.17 Teriflunomide versus interferon beta‐1a (Rebif) | 1 | 324 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.69, 1.18] |
| 1.18 Dimethyl fumarate versus glatiramer acetate | 1 | 1067 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.80, 1.14] |
| 1.19 Alemtuzumab versus interferon beta‐1a (Rebif) | 3 | 1582 | Risk Ratio (M‐H, Random, 95% CI) | 0.46 [0.39, 0.55] |
| 2 Comparisons for relapses over 24 months Show forest plot | 26 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.1 Interferon beta‐1b (Betaseron) versus placebo | 1 | 372 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.81, 0.99] |
| 2.2 Interferon beta‐1a (Avonex) versus placebo | 2 | 1198 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.76, 1.04] |
| 2.3 Interferon beta‐1a (Rebif) versus placebo | 1 | 560 | Risk Ratio (M‐H, Random, 95% CI) | 0.85 [0.77, 0.92] |
| 2.4 Glatiramer acetate versus placebo | 3 | 1024 | Risk Ratio (M‐H, Random, 95% CI) | 0.86 [0.75, 0.98] |
| 2.5 Natalizumab versus placebo | 1 | 942 | Risk Ratio (M‐H, Random, 95% CI) | 0.56 [0.49, 0.64] |
| 2.6 Mitoxantrone versus placebo | 1 | 51 | Risk Ratio (M‐H, Random, 95% CI) | 0.47 [0.27, 0.80] |
| 2.7 Fingolimod versus placebo | 2 | 2355 | Risk Ratio (M‐H, Random, 95% CI) | 0.72 [0.67, 0.78] |
| 2.8 Teriflunomide versus placebo | 1 | 1088 | Risk Ratio (M‐H, Random, 95% CI) | 0.88 [0.79, 0.98] |
| 2.9 Dimethyl fumarate versus placebo | 2 | 2307 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.81, 0.97] |
| 2.10 Laquinimod versus placebo | 2 | 1990 | Risk Ratio (M‐H, Random, 95% CI) | 0.86 [0.75, 0.99] |
| 2.11 Azathioprine versus placebo | 1 | 59 | Risk Ratio (M‐H, Random, 95% CI) | 0.77 [0.56, 1.05] |
| 2.12 Immunoglobulins versus placebo | 2 | 190 | Risk Ratio (M‐H, Random, 95% CI) | 0.74 [0.61, 0.90] |
| 2.13 Interferon beta‐1a (Avonex) versus interferon beta‐1b (Betaseron) | 1 | 188 | Risk Ratio (M‐H, Random, 95% CI) | 1.34 [1.06, 1.71] |
| 2.14 Interferon beta‐1a (Rebif) versus interferon beta‐1b (Betaseron) | 1 | 301 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.89, 1.11] |
| 2.15 Glatiramer acetate versus interferon beta‐1b (Betaseron) | 2 | 2319 | Risk Ratio (M‐H, Random, 95% CI) | 0.80 [0.47, 1.38] |
| 2.16 Glatiramer acetate versus interferon beta‐1a (Rebif) | 1 | 764 | Risk Ratio (M‐H, Random, 95% CI) | 0.92 [0.78, 1.09] |
| 2.17 Dimethyl fumarate versus glatiramer acetate | 1 | 1067 | Risk Ratio (M‐H, Random, 95% CI) | 1.09 [0.98, 1.21] |
| 2.18 Alemtuzumab versus interferon beta‐1a (Rebif) | 3 | 1582 | Risk Ratio (M‐H, Random, 95% CI) | 0.50 [0.39, 0.65] |
| 2.19 Laquinimod versus interferon beta‐1a (Avonex) | 1 | 881 | Risk Ratio (M‐H, Random, 95% CI) | 1.13 [0.97, 1.32] |
| 2.20 Azathioprine versus interferons beta (Avonex, Rebif or Betaseron) | 1 | 150 | Risk Ratio (M‐H, Random, 95% CI) | 0.86 [0.64, 1.16] |
| 3 Comparisons for disability worsening over 24 months Show forest plot | 26 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 3.1 Interferon beta‐1b (Betaseron) versus placebo | 1 | 372 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.72, 1.32] |
| 3.2 Interferon beta‐1a (Avonex) versus placebo | 2 | 1198 | Risk Ratio (M‐H, Random, 95% CI) | 0.87 [0.70, 1.09] |
| 3.3 Interferon beta‐1a (Rebif) versus placebo | 1 | 560 | Risk Ratio (M‐H, Random, 95% CI) | 0.77 [0.61, 0.96] |
| 3.4 Glatiramer acetate versus placebo | 3 | 1024 | Risk Ratio (M‐H, Random, 95% CI) | 0.81 [0.61, 1.09] |
| 3.5 Natalizumab versus placebo | 1 | 942 | Risk Ratio (M‐H, Random, 95% CI) | 0.64 [0.52, 0.80] |
| 3.6 Mitoxantrone versus placebo | 1 | 51 | Risk Ratio (M‐H, Random, 95% CI) | 0.20 [0.05, 0.83] |
| 3.7 Fingolimod versus placebo | 2 | 2355 | Risk Ratio (M‐H, Random, 95% CI) | 0.87 [0.76, 0.99] |
| 3.8 Teriflunomide versus placebo | 1 | 1088 | Risk Ratio (M‐H, Random, 95% CI) | 0.87 [0.75, 1.01] |
| 3.9 Dimethyl fumarate versus placebo | 2 | 2307 | Risk Ratio (M‐H, Random, 95% CI) | 0.80 [0.72, 0.90] |
| 3.10 Laquinimod versus placebo | 2 | 1990 | Risk Ratio (M‐H, Random, 95% CI) | 0.83 [0.73, 0.95] |
| 3.11 Azathioprine versus placebo | 1 | 59 | Risk Ratio (M‐H, Random, 95% CI) | 0.64 [0.31, 1.34] |
| 3.12 Immunoglobulins versus placebo | 2 | 190 | Risk Ratio (M‐H, Random, 95% CI) | 0.70 [0.39, 1.24] |
| 3.13 Interferon beta‐1a (Avonex) versus interferon beta‐1b (Betaseron) | 1 | 188 | Risk Ratio (M‐H, Random, 95% CI) | 2.23 [1.29, 3.83] |
| 3.14 Interferon beta‐1a (Rebif) versus interferon beta‐1b (Betaseron) | 1 | 301 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.78, 1.25] |
| 3.15 Glatiramer acetate versus interferon beta‐1b (Betaseron) | 2 | 2319 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.86, 1.13] |
| 3.16 Glatiramer acetate versus interferon beta‐1a (Rebif) | 1 | 764 | Risk Ratio (M‐H, Random, 95% CI) | 0.58 [0.39, 0.85] |
| 3.17 Dimethyl fumarate versus glatiramer acetate | 1 | 1067 | Risk Ratio (M‐H, Random, 95% CI) | 1.01 [0.83, 1.22] |
| 3.18 Alemtuzumab versus interferon beta‐1a (Rebif) | 3 | 1582 | Risk Ratio (M‐H, Random, 95% CI) | 0.41 [0.32, 0.54] |
| 3.19 Laquinimod versus interferon beta‐1a (Avonex) | 1 | 881 | Risk Ratio (M‐H, Random, 95% CI) | 1.07 [0.85, 1.33] |
| 3.20 Azathioprine versus interferons beta (Avonex, Rebif or Betaseron) | 1 | 150 | Risk Ratio (M‐H, Random, 95% CI) | 0.77 [0.49, 1.23] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Comparisons for treatment discontinuation due to AEs over 12 months Show forest plot | 13 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 Interferon beta‐1a (Avonex) 30 µg versus placebo | 1 | 301 | Risk Ratio (M‐H, Random, 95% CI) | 3.17 [0.67, 15.00] |
| 1.2 Interferon beta‐1a (Rebif) 22 µg versus placebo | 1 | 195 | Risk Ratio (M‐H, Random, 95% CI) | 3.16 [0.13, 76.54] |
| 1.3 Interferon beta‐1a (Rebif) 44 µg versus placebo | 1 | 198 | Risk Ratio (M‐H, Random, 95% CI) | 11.22 [0.63, 200.27] |
| 1.4 Glatiramer acetate 20 mg daily versus placebo | 1 | 239 | Risk Ratio (M‐H, Random, 95% CI) | 1.51 [0.26, 8.89] |
| 1.5 Glatiramer 40 mg three times per week versus placebo | 1 | 1404 | Risk Ratio (M‐H, Random, 95% CI) | 2.36 [0.99, 5.65] |
| 1.6 Teriflunomide 7 mg versus placebo | 1 | 797 | Risk Ratio (M‐H, Random, 95% CI) | 2.06 [1.31, 3.24] |
| 1.7 Teriflunomide 14 mg versus placebo | 1 | 761 | Risk Ratio (M‐H, Random, 95% CI) | 2.51 [1.61, 3.91] |
| 1.8 Pegylated interferon beta‐1a every 4 weeks versus placebo | 1 | 1000 | Risk Ratio (M‐H, Random, 95% CI) | 2.78 [1.31, 5.89] |
| 1.9 Pegylated interferon beta‐1a every 2 weeks versus placebo | 1 | 1012 | Risk Ratio (M‐H, Random, 95% CI) | 2.82 [1.34, 5.96] |
| 1.10 Daclizumab 150 mg versus placebo | 1 | 412 | Risk Ratio (M‐H, Random, 95% CI) | 3.43 [0.72, 16.33] |
| 1.11 Daclizumab 300 mg versus placebo | 1 | 413 | Risk Ratio (M‐H, Random, 95% CI) | 4.39 [0.96, 20.08] |
| 1.12 Immunoglobulins 0.2 g versus placebo | 2 | 163 | Risk Ratio (M‐H, Random, 95% CI) | 2.14 [0.23, 19.96] |
| 1.13 Immunoglobulins 0.4 g versus placebo | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 3.35 [0.15, 76.93] |
| 1.14 Interferon beta‐1a (Rebif) 44 µg versus interferon beta‐1a (Avonex) 30 µg | 1 | 677 | Risk Ratio (M‐H, Random, 95% CI) | 1.05 [0.56, 1.97] |
| 1.15 Fingolimod 0.5 mg versus interferon beta‐1a (Avonex) 30 µg | 1 | 866 | Risk Ratio (M‐H, Random, 95% CI) | 1.43 [0.81, 2.54] |
| 1.16 Fingolimod 1.25 mg versus interferon beta‐1a (Avonex) 30 µg | 1 | 861 | Risk Ratio (M‐H, Random, 95% CI) | 2.36 [1.40, 3.98] |
| 1.17 Teriflunomide 7 mg versus interferon beta‐1a (Rebif) 44 µg | 1 | 213 | Risk Ratio (M‐H, Random, 95% CI) | 0.39 [0.19, 0.81] |
| 1.18 Teriflunomide 14 mg versus interferon beta‐1a (Rebif) 44 µg | 1 | 215 | Risk Ratio (M‐H, Random, 95% CI) | 0.51 [0.27, 0.98] |
| 1.19 Azathioprine versus interferons beta (Avonex, Rebif or Betaseron) | 1 | 94 | Risk Ratio (M‐H, Random, 95% CI) | 1.0 [0.21, 4.70] |
| 2 Comparisons for treatment discontinuation due to AEs over 24 months Show forest plot | 23 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.1 Interferon beta‐1b (Betaseron) 50 µg versus placebo | 1 | 248 | Risk Ratio (M‐H, Random, 95% CI) | 4.92 [0.58, 41.51] |
| 2.2 Interferon beta‐1b (Betaseron) 250 µg versus placebo | 1 | 247 | Risk Ratio (M‐H, Random, 95% CI) | 9.92 [1.29, 76.32] |
| 2.3 Interferon beta‐1a (Avonex) 30 µg versus placebo | 1 | 897 | Risk Ratio (M‐H, Random, 95% CI) | 1.43 [0.81, 2.54] |
| 2.4 Interferon beta‐1a (Rebif) 22 µg versus placebo | 1 | 376 | Risk Ratio (M‐H, Random, 95% CI) | 2.31 [0.61, 8.79] |
| 2.5 Interferon beta‐1a (Rebif) 44 µg versus placebo | 1 | 371 | Risk Ratio (M‐H, Random, 95% CI) | 3.05 [0.84, 11.08] |
| 2.6 Glatiramer acetate 20 mg daily versus placebo | 3 | 1024 | Risk Ratio (M‐H, Random, 95% CI) | 1.74 [0.49, 6.13] |
| 2.7 Natalizumab versus placebo | 1 | 942 | Risk Ratio (M‐H, Random, 95% CI) | 1.53 [0.93, 2.53] |
| 2.8 Mitoxantrone versus placebo | 1 | 51 | Risk Ratio (M‐H, Random, 95% CI) | 9.82 [0.57, 168.84] |
| 2.9 Fingolimod 0.5 mg versus placebo | 2 | 1556 | Risk Ratio (M‐H, Random, 95% CI) | 1.42 [0.89, 2.25] |
| 2.10 Fingolimod 1.25 mg versus placebo | 2 | 1572 | Risk Ratio (M‐H, Random, 95% CI) | 1.93 [1.48, 2.52] |
| 2.11 Teriflunomide 7 mg versus placebo | 1 | 729 | Risk Ratio (M‐H, Random, 95% CI) | 1.23 [0.77, 1.96] |
| 2.12 Teriflunomide 14 mg versus placebo | 1 | 722 | Risk Ratio (M‐H, Random, 95% CI) | 1.36 [0.86, 2.15] |
| 2.13 Dimethyl fumarate 480 mg versus placebo | 2 | 1546 | Risk Ratio (M‐H, Random, 95% CI) | 1.17 [0.91, 1.51] |
| 2.14 Dimethyl fumarate 720 mg versus placebo | 2 | 1534 | Risk Ratio (M‐H, Random, 95% CI) | 1.20 [0.93, 1.54] |
| 2.15 Laquinimod versus placebo | 2 | 1990 | Risk Ratio (M‐H, Random, 95% CI) | 1.39 [0.96, 2.00] |
| 2.16 Azathioprine versus placebo | 1 | 59 | Risk Ratio (M‐H, Random, 95% CI) | 5.8 [0.74, 45.26] |
| 2.17 Immunoglobulins 0.15 to 0.20 g versus placebo | 1 | 150 | Risk Ratio (M‐H, Random, 95% CI) | 3.0 [0.32, 28.19] |
| 2.18 Interferon beta‐1a (Avonex) 30 µg versus interferon beta‐1b (Betaseron) 250 µg | 1 | 188 | Risk Ratio (M‐H, Random, 95% CI) | 0.21 [0.02, 1.75] |
| 2.19 Glatiramer acetate 20 mg daily versus interferon beta‐1b (Betaseron) 250 μg | 2 | 1420 | Risk Ratio (M‐H, Random, 95% CI) | 1.19 [0.56, 2.53] |
| 2.20 Glatiramer acetate 20 mg daily versus interferon beta‐1b (Betaseron) 500 μg | 1 | 1347 | Risk Ratio (M‐H, Random, 95% CI) | 0.79 [0.37, 1.68] |
| 2.21 Glatiramer acetate 20 mg daily versus interferon beta‐1a (Rebif) 44 µg | 1 | 764 | Risk Ratio (M‐H, Random, 95% CI) | 0.84 [0.47, 1.52] |
| 2.22 Dimethyl fumarate 480 mg versus glatiramer acetate 20 mg daily | 1 | 722 | Risk Ratio (M‐H, Random, 95% CI) | 1.22 [0.80, 1.84] |
| 2.23 Dimethyl fumarate 720 mg versus glatiramer acetate 20 mg daily | 1 | 705 | Risk Ratio (M‐H, Random, 95% CI) | 1.22 [0.80, 1.85] |
| 2.24 Alemtuzumab 12 mg versus interferon beta‐1a (Rebif) 44 µg | 3 | 1472 | Risk Ratio (M‐H, Random, 95% CI) | 0.38 [0.22, 0.68] |
| 2.25 Alemtuzumab 24 mg versus interferon beta‐1a (Rebif) 44 µg | 2 | 625 | Risk Ratio (M‐H, Random, 95% CI) | 0.33 [0.10, 1.09] |
| 2.26 Laquinimod versus interferon beta‐1a (Avonex) 30 µg | 1 | 881 | Risk Ratio (M‐H, Random, 95% CI) | 0.84 [0.49, 1.45] |
| 2.27 Azathioprine versus interferons beta (Avonex, Rebif or Betaseron) | 1 | 150 | Risk Ratio (M‐H, Random, 95% CI) | 2.21 [0.90, 5.45] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Serious adverse events Show forest plot | 16 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 Interferons beta (Avonex, Rebif or Betaseron) versus placebo | 3 | 870 | Risk Ratio (M‐H, Random, 95% CI) | 1.26 [0.67, 2.37] |
| 1.2 Glatiramer acetate versus placebo | 2 | 490 | Risk Ratio (M‐H, Random, 95% CI) | 1.87 [0.73, 4.74] |
| 1.3 Natalizumab versus placebo | 1 | 939 | Risk Ratio (M‐H, Random, 95% CI) | 1.19 [0.81, 1.73] |
| 1.4 Fingolimod versus placebo | 2 | 1572 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.72, 1.30] |
| 1.5 Teriflunomide versus placebo | 1 | 718 | Risk Ratio (M‐H, Random, 95% CI) | 1.26 [0.87, 1.83] |
| 1.6 Dimethyl fumarate versus placebo | 2 | 1531 | Risk Ratio (M‐H, Random, 95% CI) | 1.09 [0.76, 1.55] |
| 1.7 Pegylated interferon beta‐1a versus placebo | 1 | 1012 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.57, 1.68] |
| 1.8 Daclizumab versus placebo | 1 | 413 | Risk Ratio (M‐H, Random, 95% CI) | 1.55 [0.77, 3.10] |
| 1.9 Laquinimod versus placebo | 2 | 1988 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.67, 1.41] |
| 1.10 Immunoglobulins versus placebo | 1 | 83 | Risk Ratio (M‐H, Random, 95% CI) | 0.65 [0.11, 3.70] |
