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Link to original content: https://pubmed.ncbi.nlm.nih.gov/28440858
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Review
. 2017 Apr 25;4(4):CD012200.
doi: 10.1002/14651858.CD012200.pub2.

Treatment with disease-modifying drugs for people with a first clinical attack suggestive of multiple sclerosis

Graziella Filippini  1 , Cinzia Del Giovane  2 , Marinella Clerico  3 , Omid Beiki  4   5 , Miriam Mattoscio  6 , Federico Piazza  3 , Sten Fredrikson  4 , Irene Tramacere  1 , Antonio Scalfari  6 , Georgia Salanti  7
Affiliations
Review

Treatment with disease-modifying drugs for people with a first clinical attack suggestive of multiple sclerosis

Graziella Filippini et al. Cochrane Database Syst Rev. .

Abstract

Background: The treatment of multiple sclerosis has changed over the last 20 years. The advent of disease-modifying drugs in the mid-1990s heralded a period of rapid progress in the understanding and management of multiple sclerosis. With the support of magnetic resonance imaging early diagnosis is possible, enabling treatment initiation at the time of the first clinical attack. As most of the disease-modifying drugs are associated with adverse events, patients and clinicians need to weigh the benefit and safety of the various early treatment options before taking informed decisions.

Objectives: 1. to estimate the benefit and safety of disease-modifying drugs that have been evaluated in all studies (randomised or non-randomised) for the treatment of a first clinical attack suggestive of MS compared either with placebo or no treatment;2. to assess the relative efficacy and safety of disease-modifying drugs according to their benefit and safety;3. to estimate the benefit and safety of disease-modifying drugs that have been evaluated in all studies (randomised or non-randomised) for treatment started after a first attack ('early treatment') compared with treatment started after a second attack or at another later time point ('delayed treatment').

Search methods: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register, MEDLINE, Embase, CINAHL, LILACS, clinicaltrials.gov, the WHO trials registry, and US Food and Drug Administration (FDA) reports, and searched for unpublished studies (until December 2016).

Selection criteria: We included randomised and observational studies that evaluated one or more drugs as monotherapy in adult participants with a first clinical attack suggestive of MS. We considered evidence on alemtuzumab, azathioprine, cladribine, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, immunoglobulins, interferon beta-1b, interferon beta-1a (Rebif®, Avonex®), laquinimod, mitoxantrone, natalizumab, ocrelizumab, pegylated interferon beta-1a, rituximab and teriflunomide.

Data collection and analysis: Two teams of three authors each independently selected studies and extracted data. The primary outcomes were disability-worsening, relapses, occurrence of at least one serious adverse event (AE) and withdrawing from the study or discontinuing the drug because of AEs. Time to conversion to clinically definite MS (CDMS) defined by Poser diagnostic criteria, and probability to discontinue the treatment or dropout for any reason were recorded as secondary outcomes. We synthesized study data using random-effects meta-analyses and performed indirect comparisons between drugs. We calculated odds ratios (OR) and hazard ratios (HR) along with relative 95% confidence intervals (CI) for all outcomes. We estimated the absolute effects only for primary outcomes. We evaluated the credibility of the evidence using the GRADE system.

Main results: We included 10 randomised trials, eight open-label extension studies (OLEs) and four cohort studies published between 2010 and 2016. The overall risk of bias was high and the reporting of AEs was scarce. The quality of the evidence associated with the results ranges from low to very low. Early treatment versus placebo during the first 24 months' follow-upThere was a small, non-significant advantage of early treatment compared with placebo in disability-worsening (6.4% fewer (13.9 fewer to 3 more) participants with disability-worsening with interferon beta-1a (Rebif®) or teriflunomide) and in relapses (10% fewer (20.3 fewer to 2.8 more) participants with relapses with teriflunomide). Early treatment was associated with 1.6% fewer participants with at least one serious AE (3 fewer to 0.2 more). Participants on early treatment were on average 4.6% times (0.3 fewer to 15.4 more) more likely to withdraw from the study due to AEs. This result was mostly driven by studies on interferon beta 1-b, glatiramer acetate and cladribine that were associated with significantly more withdrawals for AEs. Early treatment decreased the hazard of conversion to CDMS (HR 0.53, 95% CI 0.47 to 0.60). Comparing active interventions during the first 24 months' follow-upIndirect comparison of interferon beta-1a (Rebif®) with teriflunomide did not show any difference on reducing disability-worsening (OR 0.84, 95% CI 0.43 to 1.66). We found no differences between the included drugs with respect to the hazard of conversion to CDMS. Interferon beta-1a (Rebif®) and teriflunomide were associated with fewer dropouts because of AEs compared with interferon beta-1b, cladribine and glatiramer acetate (ORs range between 0.03 and 0.29, with substantial uncertainty). Early versus delayed treatmentWe did not find evidence of differences between early and delayed treatments for disability-worsening at a maximum of five years' follow-up (3% fewer participants with early treatment (15 fewer to 11.1 more)). There was important variability across interventions; early treatment with interferon beta-1b considerably reduced the odds of participants with disability-worsening during three and five years' follow-up (OR 0.52, 95% CI 0.32 to 0.84 and OR 0.57, 95% CI 0.36 to 0.89). The early treatment group had 19.6% fewer participants with relapses (26.7 fewer to 12.7 fewer) compared to late treatment at a maximum of five years' follow-up and early treatment decreased the hazard of conversion to CDMS at any follow-up up to 10 years (i.e. over five years' follow-up HR 0.62, 95% CI 0.53 to 0.73). We did not draw any conclusions on long-term serious AEs or discontinuation due to AEs because of inadequacies in the available data both in the included OLEs and cohort studies.

Authors' conclusions: Very low-quality evidence suggests a small and uncertain benefit with early treatment compared with placebo in reducing disability-worsening and relapses. The advantage of early treatment compared with delayed on disability-worsening was heterogeneous depending on the actual drug used and based on very low-quality evidence. Low-quality evidence suggests that the chances of relapse are less with early treatment compared with delayed. Early treatment reduced the hazard of conversion to CDMS compared either with placebo, no treatment or delayed treatment, both in short- and long-term follow-up. Low-quality evidence suggests that early treatment is associated with fewer participants with at least one serious AE compared with placebo. Very low-quality evidence suggests that, compared with placebo, early treatment leads to more withdrawals or treatment discontinuation due to AEs. Difference between drugs on short-term benefit and safety was uncertain because few studies and only indirect comparisons were available. Long-term safety of early treatment is uncertain because of inadequately reported or unavailable data.

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Conflict of interest statement

GF ‐ none. As Co‐ordinating Editor, Dr. Filippini was excluded from the editorial process to ensure separation of the review author from the editorial process. This included all editorial decisions and related activities (e.g. sign‐off for publication). CDG ‐ received financial support for conducting the review process from a grant financed by Swiss MS Register. This had no bearing on, and did not influence, what has been written in the submitted work. MC ‐ received personal compensation from Merck, Biogen, Novartis and Sanofi‐Genzyme for serving on advisory boards and for providing expert testimony as well as for travel/ accommodation/meeting expenses. Dr. Clerico's institution received some grants for research projects from Merck. OB ‐ received salary from Cognizant Technology Solutions for epidemiological consultation for Pharma companies. MM ‐ speaker honoraria from Merck Serono and Novartis; received financial support for travel/accommodation/meeting expenses from Biogen Idec, Novartis, Genzyme and Teva. This had no bearing on, and did not influence, what has been written in the submitted work. FP ‐ none SF ‐ received honoraria for consultancy, educational activities and/or lectures from Allergan, Bayer, Biogen, Genzyme, Merck, Novartis, Sanofi and Teva. IT ‐ none AS ‐ none GS ‐ none

Figures

1
1
Study flow diagram.
 DMD: disease‐modifying drugs; OLEs: open label extension studies; RCTs: randomised controlled trials
2
2
Review authors' judgements about each risk of bias item presented as percentages across all included studies and review authors' judgements about each risk of bias item for each included study
3
3
Forest plot of comparison: treatment with disease‐modifying drugs compared with placebo. Random‐effects meta‐analysis results of proportion of participants with disability‐worsening over 24 months in RCT studies. We assumed in both groups that the odds of disability‐worsening in missing participants were 5.95 times the odds in the observed participants with 95% CI from 3 to 7
4
4
Network plot of comparisons and network meta‐analysis estimates for the proportion of participants who withdrew from the study because of adverse events in RCT studies. The estimate is located at the intersection of the column‐defining treatment and the row‐defining treatment. In the lower triangle the comparisons should be read from left to right, a OR value less than 1 favours the column‐defining treatment. In the upper triangle the comparisons should be read from right to left, a OR value larger 1 favours the row‐defining treatment. Significant results are in italic
5
5
Network plot of comparisons and network meta‐analysis estimates for the time to conversion to CDMS in RCT studies over 24 months. The estimate is located at the intersection of the column‐defining treatment and the row‐defining treatment. In the lower triangle the comparisons should be read from left to right, a HR value less than 1 favours the column‐defining treatment. In the upper triangle the comparisons should be read from right to left, a HR value larger than 1 favours the row‐defining treatment. Significant results are in italic
6
6
Network plot of comparisons and network meta‐analysis estimates for the proportion of participants who discontinued treatment and were followed up to the end of the study or who were lost to follow‐up for any reason in RCT studies. The estimate is located at the intersection of the column‐defining treatment and the row‐defining treatment. In the lower triangle the comparisons should be read from left to right, a HR value less than 1 favours the column‐defining treatment. In the upper triangle the comparisons should be read from right to left, a HR value larger 1 favours the row‐defining treatment
7
7
Forest plot of comparison: early treatment compared with delayed treatment with disease‐modifying drugs. Random‐effects meta‐analysis results of proportions of participants with disability‐worsening at a maximum of 3 years, 5 years and 10 years of follow‐up in open‐label extension studies. We assumed in both groups that the odds of disability‐worsening in missing participants were 5.95 times the odds in the observed participants with 95% CI from 3 to 7
8
8
Forest plot of comparison: Early treatment compared with delayed treatment with disease‐modifying drugs. Random‐effects meta‐analysis results for proportion of participants with relapse over 5 years follow‐up in OLE studies. We assumed in both groups that the odds of relapses in missing participants were 5.95 times the odds in the observed participants with 95% CI from 3 to 7
1.1
1.1. Analysis
Comparison 1 Active intervention versus placebo, Outcome 1 Occurrence of at least one serious adverse event over 24 months.
1.2
1.2. Analysis
Comparison 1 Active intervention versus placebo, Outcome 2 Occurrence of at least one serious adverse event over 36 months.
1.3
1.3. Analysis
Comparison 1 Active intervention versus placebo, Outcome 3 Withdrawing from the study or discontinuing the drug due to adverse events over 24 months.
1.4
1.4. Analysis
Comparison 1 Active intervention versus placebo, Outcome 4 Withdrawing from the study or discontinuing the drug due to adverse events over 12 months.
1.5
1.5. Analysis
Comparison 1 Active intervention versus placebo, Outcome 5 Time to conversion to CDMS over 24 months.
1.6
1.6. Analysis
Comparison 1 Active intervention versus placebo, Outcome 6 Time to conversion to CDMS over 12 months.
1.7
1.7. Analysis
Comparison 1 Active intervention versus placebo, Outcome 7 Withdrawing from the study or discontinuing the drug for any reason over 24 months.
1.8
1.8. Analysis
Comparison 1 Active intervention versus placebo, Outcome 8 Withdrawing from the study or discontinuing the drug for any reason over 12 months.
2.1
2.1. Analysis
Comparison 2 Early versus delayed treatment, Outcome 1 Time to conversion to CDMS at different follow‐up years.
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References

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References to ongoing studies

NCT01013350 {unpublished data only}
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NCT01371071 {published and unpublished data}
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