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Link to original content: https://pubmed.ncbi.nlm.nih.gov/25900414/
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Review
. 2015 Apr 22;2015(4):CD011076.
doi: 10.1002/14651858.CD011076.pub2.

Dimethyl fumarate for multiple sclerosis

Zhu Xu  1 , Feng Zhang, FangLi Sun, KeFeng Gu, Shuai Dong, Dian He
Affiliations
Review

Dimethyl fumarate for multiple sclerosis

Zhu Xu et al. Cochrane Database Syst Rev. .

Abstract

Background: Multiple sclerosis (MS) often leads to severe neurological disability and a serious decline in quality of life. The ideal target of disease-modifying therapy for MS is to prevent disability worsening and improve quality of life. Dimethyl fumarate is considered to have an immunomodulatory activity and neuroprotective effect. It has been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency as a first-line therapy for adult patients with relapsing-remitting MS (RMSS).

Objectives: To assess the benefit and safety of dimethyl fumarate as monotherapy or combination therapy versus placebo or other approved disease-modifying drugs (interferon beta, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, alemtuzumab) for patients with MS.

Search methods: The Trials Search Co-ordinator searched the Trials Specialised Register of the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group (4 June 2014). We checked reference lists of published reviews and retrieved articles and searched reports (2004 to June 2014) from the MS societies in Europe and America. We also communicated with investigators participating in trials of dimethyl fumarate and the Biogen Idec Medical Information.

Selection criteria: We included randomised, controlled, parallel-group clinical trials (RCTs) with a length of follow-up equal to or greater than one year evaluating dimethyl fumarate, as monotherapy or combination therapy, versus placebo or other approved disease-modifying drugs for patients with MS without restrictions regarding dosage, administration frequency and duration of treatment.

Data collection and analysis: We used the standard methodological procedures of The Cochrane Collaboration. Two review authors independently assessed trial quality and extracted data. Disagreements were discussed and resolved by consensus among the review authors. We contacted the principal investigators of included studies for additional data or confirmation of data.

Main results: Two RCTs were included, involving 2667 adult patients with RRMS to evaluate the efficacy and safety of two dosages of dimethyl fumarate (240 mg orally three times daily or twice daily) by direct comparison with placebo for two years. Among them, a subsample of 1221 (45.8%) patients were selected to participate in MRI evaluations by each study site with MRI capabilities itself. No powered head-to-head study with an active treatment comparator has been found. Meta-analyses showed that dimethyl fumarate both three times daily and twice daily reduced the number of patients with a relapse (risk ratio (RR) 0.57, 95% confidence interval (CI) 0.50 to 0.66, P < 0.00001 and 0.64, 95% CI 0.54 to 0.77, P < 0.00001, respectively) or disability worsening (RR 0.70, 95% CI 0.57 to 0.87, P = 0.0009 and 0.65, 95% CI 0.53 to 0.81, P = 0.0001, respectively) over two years, compared to placebo. The treatment effects were decreased in the likely-case scenario analyses taking the effect of dropouts into consideration. Both dosages also reduced the annualised relapse rate. Data of active lesions on MRI scans were not combined because there was a high risk of selection bias for MRI outcomes and imprecision of MRI data in both studies, as well as an obvious heterogeneity between the studies. In terms of safety profile, both dosages increased the risk for adverse events and the risk for drug discontinuation due to adverse events. The most common adverse events included flushing and gastrointestinal events (upper abdominal pain, nausea and diarrhoea). Uncommon adverse events included lymphopenia and leukopenia, but they were more likely to happen with dimethyl fumarate than with placebo (high dosage: RR 5.25, 95% CI 2.20 to 12.51, P = 0.0002 and 5.23, 95% CI 2.47 to 11.07, P < 0.0001, respectively; low dosage: RR 5.69, 95% CI 2.40 to 13.46, P < 0.0001 and 6.53, 95% CI 3.13 to 13.64, P < 0.00001, respectively). Both studies had a high attrition bias resulting from the unbalanced reasons for dropouts among groups. Quality of evidence for relapse outcome was moderate, but for disability worsening was low.

Authors' conclusions: There is moderate-quality evidence to support that dimethyl fumarate at a dose of 240 mg orally three times daily or twice daily reduces both the number of patients with a relapse and the annualised relapse rate over two years of treatment in comparison with placebo. However, the quality of the evidence to support the benefit in reducing the number of patients with disability worsening is low. There is no high-quality data available to evaluate the benefit on MRI outcomes. The common adverse effects such as flushing and gastrointestinal events are mild-to-moderate for most patients. Lymphopenia and leukopenia are uncommon adverse events but significantly associated with dimethyl fumarate. Both dosages of dimethyl fumarate have similar benefit and safety profile, which supports the option of low-dose administration. New studies of high quality and long-term follow-up are needed to evaluate the benefit of dimethyl fumarate on prevention of disability worsening and to observe the long-term adverse effects including progressive multifocal leukoencephalopathy.

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Conflict of interest statement

HD ‐ none

XZ ‐ none

ZF ‐ none

SFL ‐ none

GKF‐ none

DS ‐ 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.
1.1
1.1. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 1 The proportion of patients with at least one relapse at two years.
1.2
1.2. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 2 The proportion of patients with at least one relapse at two years (the likely‐case scenario).
1.3
1.3. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 3 The annualised relapse rate at two years.
1.4
1.4. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 4 The proportion of patients with disability worsening at two years.
1.5
1.5. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 5 The proportion of patients with disability worsening at two years (the likely‐case scenario).
1.6
1.6. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 6 The mean change in SF‐36 Physical Component Summary scores from baseline to two years.
1.7
1.7. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 7 The mean change in SF‐36 Mental Component Summary scores from baseline to two years.
1.8
1.8. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 8 The number of patients with adverse events excluding relapses at two years.
1.9
1.9. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 9 The number of patients with serious adverse events excluding relapses at two years.
1.10
1.10. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 10 The number of patients who discontinued study drug because of adverse events excluding relapses at two years.
1.11
1.11. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 11 The number of patients with flushing at two years.
1.12
1.12. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 12 The number of patients with upper abdominal pain at two years.
1.13
1.13. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 13 The number of patients with nausea at two years.
1.14
1.14. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 14 The number of patients with diarrhoea at two years.
1.15
1.15. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 15 The number of patients with proteinuria at two years.
1.16
1.16. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 16 The number of patients with a decreased lymphocyte count of less than 0.5×109 per litre at two years.
1.17
1.17. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 17 The number of patients with a decreased white‐cell count of less than 3.0×109 per litre at two years.
1.18
1.18. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 18 The number of patients with an increased alanine aminotransferase level at least three times the upper limit of the normal range at two years.
1.19
1.19. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 19 The number of patients with gastrointestinal events at two years.
1.20
1.20. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 20 The number of patients with infections at two years.
1.21
1.21. Analysis
Comparison 1 High‐dose (240 mg orally three times daily) dimethyl fumarate versus placebo, Outcome 21 The number of patients with serious infections at two years.
2.1
2.1. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 1 The proportion of patients with at least one relapse at two years.
2.2
2.2. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 2 The proportion of patients with at least one relapse at two years (the likely‐case scenario).
2.3
2.3. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 3 The annualised relapse rate at two years.
2.4
2.4. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 4 The proportion of patients with disability worsening at two years.
2.5
2.5. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 5 The proportion of patients with disability worsening at two years (the likely‐case scenario).
2.6
2.6. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 6 The mean change in SF‐36 Physical Component Summary scores from baseline to two years.
2.7
2.7. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 7 The mean change in SF‐36 Mental Component Summary scores from baseline to two years.
2.8
2.8. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 8 The number of patients with adverse events excluding relapses at two years.
2.9
2.9. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 9 The number of patients with serious adverse events excluding relapses at two years.
2.10
2.10. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 10 The number of patients who discontinued study drug because of adverse events excluding relapses at two years.
2.11
2.11. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 11 The number of patients with flushing at two years.
2.12
2.12. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 12 The number of patients with upper abdominal pain at two years.
2.13
2.13. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 13 The number of patients with nausea at two years.
2.14
2.14. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 14 The number of patients with diarrhoea at two years.
2.15
2.15. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 15 The number of patients with proteinuria at two years.
2.16
2.16. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 16 The number of patients with a decreased lymphocyte count of less than 0.5×109 per litre at two years.
2.17
2.17. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 17 The number of patients with a decreased white‐cell count of less than 3.0×109 per litre at two years.
2.18
2.18. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 18 The number of patients with an increased alanine aminotransferase level at least three times the upper limit of the normal range at two years.
2.19
2.19. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 19 The number of patients with gastrointestinal events at two years.
2.20
2.20. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 20 The number of patients with infections at two years.
2.21
2.21. Analysis
Comparison 2 Low‐dose (240 mg orally twice daily) dimethyl fumarate versus placebo, Outcome 21 The number of patients with serious infections at two years.
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