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Review
. 2016 Apr 19;4(4):CD009371.
doi: 10.1002/14651858.CD009371.pub2.

Fingolimod for relapsing-remitting multiple sclerosis

Loredana La Mantia  1 , Irene Tramacere, Belal Firwana, Ilaria Pacchetti, Roberto Palumbo, Graziella Filippini
Affiliations
Review

Fingolimod for relapsing-remitting multiple sclerosis

Loredana La Mantia et al. Cochrane Database Syst Rev. .

Abstract

Background: Fingolimod was approved in 2010 for the treatment of patients with the relapsing-remitting (RR) form of multiple sclerosis (MS). It was designed to reduce the frequency of exacerbations and to delay disability worsening. Issues on its safety and efficacy, mainly as compared to other disease modifying drugs (DMDs), have been raised.

Objectives: To assess the safety and benefit of fingolimod versus placebo, or other disease-modifying drugs (DMDs), in reducing disease activity in people with relapsing-remitting multiple sclerosis (RRMS).

Search methods: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System (CNS) Group's Specialised Trials Register and US Food and Drug Administration reports (15 February 2016).

Selection criteria: Randomised controlled trials (RCTs) assessing the beneficial and harmful effects of fingolimod versus placebo or other approved DMDs in people with RRMS.

Data collection and analysis: We used standard methodological procedures as expected by Cochrane.

Main results: Six RCTs met our selection criteria. The overall population included 5152 participants; 1621 controls and 3531 treated with fingolimod at different doses; 2061 with 0.5 mg, 1376 with 1.25 mg, and 94 with 5.0 mg daily. Among the controls, 923 participants were treated with placebo and 698 with others DMDs. The treatment duration was six months in three, 12 months in one, and 24 months in two trials. One study was at high risk of bias for blinding, three studies were at high risk of bias for incomplete outcome reporting, and four studies were at high risk of bias for other reasons (co-authors were affiliated with the pharmaceutical company). We retrieved 10 ongoing trials; four of them have been completed.Comparing fingolimod administered at the approved dose of 0.5 mg to placebo, we found that the drug at 24 months increased the probability of being relapse-free (risk ratio (RR) 1.44, 95% confidence interval (CI) (1.28 to 1.63); moderate quality of evidence), but it might lead to little or no difference in preventing disability progression (RR 1.07, 95% CI 1.02 to 1.11; primary clinical endpoints; low quality evidence). Benefit was observed for other measures of inflammatory disease activity including clinical (annualised relapse rate): rate ratio 0.50, 95% CI 0.40 to 0.62; moderate quality evidence; and magnetic resonance imaging (MRI) activity (gadolinium-enhancing lesions): RR of being free from (MRI) gadolinium-enhancing lesions: 1.36, 95% CI 1.27 to 1.45; low quality evidence.The mean change of MRI T2-weighted lesion load favoured fingolimod at 12 and 24 months.No significant increased risk of discontinuation due to adverse events was observed for fingolimod 0.5 mg compared to placebo at six and 24 months. The risk of fingolimod discontinuation was significantly higher compared to placebo for the dose 1.25 mg at 24 months (RR 1.93, 95% CI 1.48 to 2.52).No significant increased risk of discontinuation due to serious adverse events was observed for fingolimod 0.5 mg compared to placebo at six and 24 months. A significant increased risk of discontinuation due to serious adverse events was found for fingolimod 5.0 mg (RR 2.77, 95% CI 1.04 to 7.38) compared to placebo at six months.Comparing fingolimod 0.5 mg to intramuscular interferon beta-1a, we found moderate quality evidence that the drug at one year slightly increased the number of participants free from relapse (RR 1.18, 95% CI 1.09 to 1.27) or from gadolinium-enhancing lesions (RR 1.12, 95% CI 1.05 to 1.19), and decreased the relapse rate (rate ratio 0.48, 95% CI 0.34 to 0.70). We did not detect any advantage for preventing disability progression (RR 1.02, 95% CI 0.99 to 1.06; low quality evidence). We did not detect any significant difference for MRI T2-weighted lesion load change.We found a greater likelihood of participants discontinuing fingolimod, as compared to other DMDs, due to adverse events in the short-term (six months) (RR 3.21, 95% CI 1.16 to 8.86), but there was no significant difference versus interferon beta-1a at 12 months (RR 1.51, 95% CI 0.81 to 2.80; moderate quality evidence). A higher incidence of adverse events was suggestive of the lower tolerability rate of fingolimod compared to interferon-beta 1a.Quality of life was improved in participants after switching from a different DMD to fingolimod at six months, but this effect was not found compared to placebo at 24 months.All studies were sponsored by Novartis Pharma.

Authors' conclusions: Treatment with fingolimod compared to placebo in RRMS patients is effective in reducing inflammatory disease activity, but it may lead to little or no difference in preventing disability worsening. The risk of withdrawals due to adverse events requires careful monitoring of patients over time. The evidence on the risk/benefit profile of fingolimod compared with intramuscular interferon beta-1a was uncertain, based on a low number of head-to-head RCTs with short follow-up duration. The ongoing trial results will possibly satisfy these issues.

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Conflict of interest statement

Loredana La Mantia: none. Belal Firwana: none. Irene Tramacere: none. Ilaria Pacchetti: none. Roberto Palumbo: none. Graziella Filippini: none. As Co‐ordinating Editor, Dr. Filippini was excluded from the editorial process to ensure separation of the author and the editorial process. This includes all editorial decisions and related activities (e.g. Sign‐off for publication).

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
N, number of patients; n, number of events. Significant differences (based on Fisher exact test) are reported in red.
5
5
N, number of patients; n, number of events. * One case of basal‐cell carcinoma was not reported as a serious adverse event by the site investigator (Calabresi 2014). Significant differences (based on Fisher exact test) are reported in red.
1.1
1.1. Analysis
Comparison 1 Participants free from relapse, Outcome 1 At 6 months.
1.2
1.2. Analysis
Comparison 1 Participants free from relapse, Outcome 2 At 12 months.
1.3
1.3. Analysis
Comparison 1 Participants free from relapse, Outcome 3 At 24 months.
2.1
2.1. Analysis
Comparison 2 Participants free from disability worsening, Outcome 1 At 12 months.
2.2
2.2. Analysis
Comparison 2 Participants free from disability worsening, Outcome 2 At 24 months.
3.1
3.1. Analysis
Comparison 3 Number of withdrawals due to adverse events, Outcome 1 Withdrawals due to adverse events over 6 months.
3.2
3.2. Analysis
Comparison 3 Number of withdrawals due to adverse events, Outcome 2 Withdrawals due to adverse events over 12 months.
3.3
3.3. Analysis
Comparison 3 Number of withdrawals due to adverse events, Outcome 3 Withdrawals due to adverse events over 24 months.
3.4
3.4. Analysis
Comparison 3 Number of withdrawals due to adverse events, Outcome 4 Withdrawals due to serious adverse events over 6 months.
3.5
3.5. Analysis
Comparison 3 Number of withdrawals due to adverse events, Outcome 5 Withdrawals due to serious adverse events over 12 months.
3.6
3.6. Analysis
Comparison 3 Number of withdrawals due to adverse events, Outcome 6 Withdrawals due to serious adverse events over 24 months.
4.1
4.1. Analysis
Comparison 4 Annualised relapse rate, Outcome 1 At 6 months.
4.2
4.2. Analysis
Comparison 4 Annualised relapse rate, Outcome 2 At 12 months.
4.3
4.3. Analysis
Comparison 4 Annualised relapse rate, Outcome 3 At 24 months.
5.1
5.1. Analysis
Comparison 5 Participants free from gadolinium‐enhancing lesions, Outcome 1 At 6 months.
5.2
5.2. Analysis
Comparison 5 Participants free from gadolinium‐enhancing lesions, Outcome 2 At 12 months.
5.3
5.3. Analysis
Comparison 5 Participants free from gadolinium‐enhancing lesions, Outcome 3 At 24 months.
6.1
6.1. Analysis
Comparison 6 Mean change of MRI T2‐weighted lesion load, Outcome 1 At 12 months.
6.2
6.2. Analysis
Comparison 6 Mean change of MRI T2‐weighted lesion load, Outcome 2 At 24 months.
7.1
7.1. Analysis
Comparison 7 Quality of life, Outcome 1 At 6 months.
7.2
7.2. Analysis
Comparison 7 Quality of life, Outcome 2 At 24 months.
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References

References to studies included in this review

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References to studies awaiting assessment

NCT01317004 {published data only}
    1. NCT01317004. A 6‐month, randomized, active comparator, open‐label, multi‐center study to evaluate patient outcomes, safety and tolerability of fingolimod (FTY720) 0.5 mg/day in patients with relapsing remitting multiple sclerosis who are candidates for ms therapy change from previous disease modifying therapy (EPOC). clinicaltrials.gov/ct2/show/NCT01317004?term=NCT01317004&rank=1 (accessed 22 February 2016).
NCT01333501 {published data only}
    1. NCT01333501. An 18‐month, open‐label, Rater‐blinded, randomized, multi‐center, active‐controlled, parallel‐group pilot study to assess efficacy and safety of fingolimod in comparison to interferon beta 1b in treating the cognitive symptoms associated with relapsing‐remitting multiple sclerosis and to assess possible relationship of these effects to regional brain atrophy. clinicaltrials.gov/ct2/show/study/NCT01333501?term=NCT01333501&rank=1 (accessed 22 February 2016).
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References to ongoing studies

EUCTR2013‐004622‐29‐IT {published data only}
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NCT02342704 {published data only}
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