Fingolimod for relapsing-remitting multiple sclerosis (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

T A B L E O F C O N T E N T S

HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 19
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Analysis 1.1. Comparison 1 Participants free from relapse, Outcome 1 At 6 months. . . . . . . . . . . . . 60
Analysis 1.2. Comparison 1 Participants free from relapse, Outcome 2 At 12 months. . . . . . . . . . . . 61
Analysis 1.3. Comparison 1 Participants free from relapse, Outcome 3 At 24 months. . . . . . . . . . . . 62
Analysis 2.1. Comparison 2 Participants free from disability worsening, Outcome 1 At 12 months. . . . . . . 63
Analysis 2.2. Comparison 2 Participants free from disability worsening, Outcome 2 At 24 months. . . . . . . 64
Analysis 3.1. Comparison 3 Number of withdrawals due to adverse events, Outcome 1 Withdrawals due to adverse events
over 6 months. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Analysis 3.2. Comparison 3 Number of withdrawals due to adverse events, Outcome 2 Withdrawals due to adverse events
over 12 months. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Analysis 3.3. Comparison 3 Number of withdrawals due to adverse events, Outcome 3 Withdrawals due to adverse events
over 24 months. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Analysis 3.4. Comparison 3 Number of withdrawals due to adverse events, Outcome 4 Withdrawals due to serious adverse events over 6 months. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Analysis 3.5. Comparison 3 Number of withdrawals due to adverse events, Outcome 5 Withdrawals due to serious adverse events over 12 months. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Analysis 3.6. Comparison 3 Number of withdrawals due to adverse events, Outcome 6 Withdrawals due to serious adverse events over 24 months. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Analysis 4.1. Comparison 4 Annualised relapse rate, Outcome 1 At 6 months. . . . . . . . . . . . . . . 71
Analysis 4.2. Comparison 4 Annualised relapse rate, Outcome 2 At 12 months. . . . . . . . . . . . . . 72
Analysis 4.3. Comparison 4 Annualised relapse rate, Outcome 3 At 24 months. . . . . . . . . . . . . . 73
Analysis 5.1. Comparison 5 Participants free from gadolinium-enhancing lesions, Outcome 1 At 6 months. . . . 74
Analysis 5.2. Comparison 5 Participants free from gadolinium-enhancing lesions, Outcome 2 At 12 months. . . . 75
Analysis 5.3. Comparison 5 Participants free from gadolinium-enhancing lesions, Outcome 3 At 24 months. . . . 76
Analysis 6.1. Comparison 6 Mean change of MRI T2-weighted lesion load, Outcome 1 At 12 months. . . . . . 77
Analysis 6.2. Comparison 6 Mean change of MRI T2-weighted lesion load, Outcome 2 At 24 months. . . . . . 78
Analysis 7.1. Comparison 7 Quality of life, Outcome 1 At 6 months. . . . . . . . . . . . . . . . . . 79
Analysis 7.2. Comparison 7 Quality of life, Outcome 2 At 24 months. . . . . . . . . . . . . . . . . 80
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 88

[Intervention Review]
Fingolimod for relapsing-remitting multiple sclerosis

Loredana La Mantia1, Irene Tramacere2, Belal Firwana3, Ilaria Pacchetti2, Roberto Palumbo4, Graziella Filippini5

1Unit of Neurorehabilitation – Multiple Sclerosis Center, I.R.C.C.S. Santa Maria Nascente – Fondazione Don Gnocchi, Milano, Italy. 2Neuroepidemiology Unit, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milano, Italy. 3Internal Medicine Department, University of Arkansas for Medical Sciences, Little Rock, AR, USA. 4U.O. Neurologia, Azienda Ospedaliera San Giovanni Addolorata, Roma, Italy. 5Scientific Direction, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milano, Italy
Contact address: Loredana La Mantia, Unit of Neurorehabilitation – Multiple Sclerosis Center, I.R.C.C.S. Santa Maria Nascente – Fondazione Don Gnocchi, Via Capecelatro, 66, Milano, 20148, Italy. [email protected].
Editorial group: Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group.
Publication status and date: New, published in Issue 4, 2016.
Review content assessed as up-to-date: 15 February 2016.

Citation: La Mantia L, Tramacere I, Firwana B, Pacchetti I, Palumbo R, Filippini G. Fingolimod for relapsing-remitting multiple sclerosis. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD009371. DOI: 10.1002/14651858.CD009371.pub2.

Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

A B S T R A C T
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.

P L A I N L A N G U A G E S U M M A R Y
Fingolimod for relapsing-remitting multiple sclerosis Background
Considering the autoimmune pathogenesis of multiple sclerosis (MS), most of the treatments have been based on the immunomodu- latory and immunosuppressive properties of drugs such as interferons, glatiramer, azathioprine, cyclophosphamide and mitoxantrone.
Fingolimod, was the first agent to gain approval as an oral treatment in 2010. It is efficiently absorbed, its absorption is unaffected by dietary intake and, as an oral therapy, it has aroused great interest in patients, having a more acceptable route of administration than injections.
Aim of the review
To assess the safety and the benefits of fingolimod in reducing disease activity in people with relapsing-remitting MS (RRMS). A number of safety concerns have already emerged, including serious infections and adverse cardiac effects.
Study characteristics

Six studies, published between 2006 and 2014, were included in this review, comprising a total of 5152 participants suffering from RRMS. The treatment duration was six months in three studies, 12 months in one study, and 24 months in two studies.
Key results and quality of evidence
The main conclusion of this review was that fingolimod, administered as monotherapy at the approved dose of 0.5 mg once-daily increases the probability of being relapse-free at 24 months compared to placebo. The benefit was confirmed with disease activity measures defined by magnetic resonance imaging (MRI) scans. However, there was no effect on preventing disability worsening; treatment was not associated with an increased risk of patient withdrawals due to adverse events.
Comparing the same dose of fingolimod to intramuscular interferon beta-1a, the drug at one year slightly increased the number of participants free from relapse or from inflammatory enhancing lesions and decreased the relapse rate. Again, we did not detect any advantage for preventing disability progression. We found a greater likelihood of discontinuation due to adverse events in the short- term (six months) for fingolimod as compared to immunomodulating drugs, and no significant difference compared to interferon beta at 12 months.
The duration of all studies was equal or inferior to 24 months, so that the efficacy (but mostly the safety) of fingolimod over 24 months remains uncertain. This is a key point for a lifetime disease with the probability of chronic treatments as in MS.
The risk of adverse events requires careful monitoring of patients over time and suggests the need for studies with longer follow-up, particularly considering the recent warning on the development of progressive multifocal leukoencephalopathy.
The six studies included in this review were sponsored by Novartis Pharma, and most co-authors of the published papers were affiliated to the pharmaceutical company; this is recognised as a potential source of bias.

S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Fingolimod 0.5 mg versus placebo for relapsing- remitting multiple sclerosis

Participants or population: people with relapsing-remitting multiple sclerosis
Settings: outpatients in multiple sclerosis centres
Intervention: f ingolimod 0.5 mg versus placebo
Outcomes at 24 months Illustrative comparative risks* (95% CI) Relative effect (95% CI) No. of Participants (studies) Quality of the evidence (GRADE)
Assumed risk Corresponding risk

Control (placebo)
Fingolimod 0.5 mg

Participants free from re- lapse
49 per 100
70 per 100
RR 1.44
1556 ⊕⊕⊕Ⓧ
(63 to 80) (1.28 to 1.63) (2 studies) moderatea

Participants free from dis- ability worsening
82 per 100
87 per 100
RR 1.07
1556 ⊕⊕ⓍⓍ
(83 to 91) (1.02 to 1.11) (2 studies) lowa,b

Withdrawals due to adverse events
9 per 100
13 per 100
RR 1.42
1556 ⊕ⓍⓍⓍ
(8 to 21) (0.89 to 2.25) (2 studies) very lowa,b,c
Annualised relapse rate - - Rate ratio 0.50
(0.40 to 0.62) 1556
(2 studies) ⊕⊕⊕Ⓧ
moderatea
Participants free from MRI gadolinium- enhancing le- sions 65 per 100 89 per 100 RR 1.36 1226 ⊕⊕ⓍⓍ
(83 to 94) (1.27 to 1.45) (2 studies) lowa,b

* For dichotomous outcomes, the corresponding risk with fingolimod 0.5 mg (and its 95% CI) is based on the assumed risk with the control group (i.e. the mean proportion of events in the control group across the two studies) and the relative effect of f ingolimod (and its 95% CI). For the annualised relapse rate, only the relative ef fect (i.e., the rate ratio) is given, because the assumed risk with the control group is not estimable.
CI: Confidence interval; RR: Risk ratio.

a Study limitations: significant dif ferences in reasons for incomplete outcome data between treatment and control groups.
b Imprecision: total number of events (i.e. the number of participants with disability worsening/ gadolinium-enhancing lesions) was less than 300 (the threshold rule-of-thumb value), and thus the available evidence did not meet the optimal information size criteria. Wide confidence intervals.
c Inconsistency: unexplained heterogeneity.

B A C K G R O U N D

Description of the condition
Multiple sclerosis (MS) is the most common nontraumatic cause of neurologic disability in young adults (Compston 2002; Noseworthy 2000). The overall incidence of MS is between 3.5 to 6.6 people per 100,000, while the prevalence rate is between 100 to 120 people per 100,000 (Alonso 2008; Richards 2002). A recent review showed an increase in the prevalence and inci- dence rate over time around the Mediterranean Basin, particularly in women (Elhami 2011). Western Europe and North America are high prevalence areas (Koch-Henriksen 2010). The social cost associated with MS is high because of its long duration, the early loss of productivity, the need for assistance in activities of daily living and the use of highly expensive immunotherapy and multi- disciplinary health care (Koutsouraki 2010). It is widely believed that MS is an immune-mediated disease whose clinical manifes- tations and course, as well as response to therapy, appear to be heterogeneous, as may be the underlying pathogenic mechanisms (Compston 2008).
Different clinical subtypes of MS are distinguishable. Approxi-
mately 80% of patients have an initial disease course characterised by relapses and remissions (relapsing-remitting MS (RRMS)). The remaining have primary or transitional progressive MS and ex- perience progressive decline in neurological function from onset. In patients with RRMS, disability can result from one or more of the following: incomplete recovery from relapses, development of secondary progressive MS (SPMS), or cognitive impairment. However, as many as 17% of patients with benign MS never de- velop a clinically important physical disability (Pittock 2004).
Considering the autoimmune pathogenesis of the disease, the mainstay of treatment has been based on immunomodulatory drugs, including interferon beta and glatiramer acetate, which are generally perceived as very safe drugs. However, they allow only a partial control of the disease. The available armamentarium has been expanding in recent years, with injectable and oral agents with more selective mechanisms of action and more efficacy (Oh J 2013).

Description of the intervention
Fingolimod is a sphingosine-1-phosphate (S1P)-receptor mod- ulator, 2-amino-2-(2-[4-octylphenyl]ethyl)-1, 3-propanediol ( Brinkmann 2002).
It is a prodrug, phosphorylated by sphingosine kinases to active phosphofingolimod. There are at least five S1P receptor subtypes, known as S1P subtypes 1-5 (S1P1-5), four of which bind fin- golimod-phosphate (Chun 2010). S1P1 is highly expressed on T and B lymphocytes. Fingolimod induces lymphocytes S1P1 down-

regulation, preventing the egress of cells from secondary lym- phoid tissues (Chun 2010; Pinschewer 2000). Therefore, lympho- cytes are retained away from the Central Nervous System (CNS) (Matloubian 2004; Pinschewer 2000). After oral administration, fingolimod is efficiently absorbed and its absorption is unaffected by dietary intake. After administration of one dose, blood concen- tration of fingolimod increases steadily over the first 12 hours and remains elevated during the 24-hour period until the next dose. It has a half-life of six to nine days. Steady-state blood concentra- tions are reached within one to two months following once-daily administration and steady-state levels are approximately 10-fold greater than with the initial dose (David 2012).
Other effects of fingolimod are the transient activation of S1P re- ceptors in atrial myocytes (associated with transient reduction of heart rate), the increase of lung hyperreactivity (associated with bronchospasm and airway constriction effects), mediated by S1P1 and S1P3 and a role in the regulation of endothelial permeabil- ity and vascular tone. Fingolimod has also been reported to be a competitive antagonist of cannabinoid receptors, and cannabinoid receptor activation has been shown to stimulate sphingomyelin catabolism (Paugh 2006).
Fingolimod can prevent renal graft rejections and suppress a variety of autoimmune disorders (Liu 2013).
Fingolimod marketed as Gilenya ® (Novartis Pharma) is provided as 0.5 mg hard gelatin capsules for oral use, once-daily. Each cap- sule contains 0.56 mg of fingolimod hydrochloride, equivalent to
0.5 mg of fingolimod.

How the intervention might work
Fingolimod has been shown to reduce disease activity and estab- lished neurologic deficits in animal models (Brinkmann 2002). Prophylactic administration of fingolimod to animals with exper- imental autoimmune encephalitis (EAE), a model of MS, com- pletely prevents development of EAE, whereas therapeutic admin- istration significantly reduces the clinical severity of EAE (Chun 2010). Phase II and phase III trials in RRMS patients showed sig- nificant reduction of the relapse rate and of the number of gadolin- ium-enhancing, and new and/or enlarging T2 lesions on magnetic resonance imaging (MRI), as compared with placebo and with interferon beta-1a (Oh J 2013). These effects have been related to sequestration of lymphocytes within lymph nodes, and a signifi- cant decrease in peripherally circulating lymphocytes, preventing autoaggressive lymphocytes from crossing the blood-brain barrier. Some studies have shown that fingolimod may promote neuro- protective and reparative processes within the CNS through mod- ulation of S1P receptors on glial and neural cells (Miron 2008; Paugh 2006; Pinschewer 2000).
Fingolimod was the first drug to gain approval as an oral treatment
in the United States on 21 September, 2010, by the US Food and Drug Administration (FDA), “for the treatment of patients with relapsing forms of MS to reduce the frequency of clinical

exacerbations and to delay the accumulation of physical disability.” Marketing authorisation was approved only for the 0.5 mg dose, due to a more favourable safety profile of this dosage compared to the 1.25 mg dose: “the higher dose, while exposing patients to more risk, did not expose patients to significantly increased efficacy,” and specific recommendations for monitoring patients and contraindications for use has been provided (FDA 2010).
The approval by the European Medicines Agency Committee for Medicinal Products for Human Use on 27 January, 2011 (EMA 2011), has been recently updated (EMA 2015). Gilenya® is indi- cated as single disease modifying therapy in highly active RRMS for the following adult patient groups.
1. Patients with high disease activity despite treatment with at least one disease modifying drug (DMD). These patients may be defined as those who have failed to respond to a full and adequate course (normally at least one year of treatment) of at least one DMD. Patients should have had at least one relapse in the previous year while on therapy, and have at least nine T2- hyperintense lesions in cranial MRI or at least one gadolinium- enhancing lesion. A “non-responder” could also be defined as a patient with an unchanged or increased relapse rate or ongoing severe relapses, as compared to the previous year.
2. Patients with rapidly evolving severe RRMS defined by two or more disabling relapses in one year, and with one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.

Why it is important to do this review
Oral therapies have aroused lively interest amongst stakehold- ers, suggesting a new era of MS therapies with improved efficacy and more acceptable routes of administration. After approval of the use of fingolimod for the treatment of RRMS, different de- scriptive reviews have been published confirming the effectiveness of fingolimod in people with MS (Del Santo 2011; Freedman 2013; Hillert 2012; Hutchinson 2014; Oh J 2013), but also rais- ing concerns about serious adverse events (Lu 2013; Parfenov 2013). A number of safety concerns emerged with post-market- ing surveillance, including serious infections and adverse cardiac effects (AIFA 2015; EMA 2015; Oh J 2013). The advantage of this therapy (as compared to other DMDs) has been questioned, suggesting need to reserve the use of fingolimod to patients who can be closely monitored.
No systematic review of trials evaluating the benefit and safety of
fingolimod has until now, been provided. By assessing and updat- ing its benefit-risk profile, the results of this review might clarify the use of fingolimod in clinical practice.

O B J E C T I V E S

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

M E T H O D S

Criteria for considering studies for this review

Types of studies
We considered randomised controlled trials (RCTs) that studied fingolimod versus placebo or other approved disease-modifying drugs (DMDs) in relapsing-remitting multiple sclerosis (RRMS), irrespective of publication status and language. We excluded cross- over studies.

Types of participants
We included participants of any age, gender and race affected by RRMS according to McDonald’s diagnostic criteria (Mc Donald 2001; Polman 2005; Polman 2011).

Types of interventions
1. Fingolimod, any dose and route of administration, versus placebo without restriction of treatment duration.
2. Fingolimod, any dose and route of administration, versus any other approved DMDs without restriction of treatment duration.

Types of outcome measures

Primary outcomes
1. Number of participants relapse-free at six,12 and 24 months after randomisation and at the end of follow-up.
2. Number of participants free from disability worsening at 12, 24 and 36 months after randomisation and at the end of follow- up. Disability worsening is defined as at least one point Expanded Disability Status Scale (EDSS) (Kurtzke 1983) increase, or a 0.5 point increase if the baseline EDSS was > 5.5, confirmed during two subsequent neurological examinations separated by at least 6 months’ interval free of relapses. We considered separately studies that reported disability worsening defined using different criteria.
3. Number of participants who withdrew from the study due to
a) adverse events;
b) serious adverse events, i.e. death, life-threatening, hospitalisa- tion, disability or permanent damage, congenital anomaly/birth defect (FDA 2013).

Secondary outcomes
4. Annualised relapse rate at six, 12 and 24 months after randomi- sation and at the end of follow-up.
5. Number of participants free from MRI gadolinium-enhancing lesions at six, 12 and 24 months after randomisation and at the end of follow-up.
6. Mean change of total MRI T2 weighted lesion load at 12 and 24 months after randomisation and at the end of follow-up.
7. Quality of life measured by validated questionnaires such as MSQOL-54 (Vickrey 1995).

Search methods for identification of studies
We did not apply any language restrictions.

Electronic searches
The Trials Search Co-ordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Specialised Trials Register, which contained trials identified from:
1. Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2).
2. MEDLINE (PubMed) (1966 to 15 February 2016).
3. EMBASE (Embase.com) (1974 to 15 February 2016).
4. Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCOhost) (1981 to 15 February 2016).
5. Latin American and Caribbean Health Science Information Database (LILACS) (Bireme) (1982 to 15 February 2016).
6. Clinical trial registries: clinicaltrials.gov.
7. World Health Organization (WHO) International Clinical Trials Registry Portal (apps.who.int/trialsearch/).
The keywords for this review are listed in (Appendix 1). Information on the Trial Register of the Review Group and details of search strategies used to identify trials can be found in the ’Spe- cialised Register’ section within the Cochrane Multiple Sclerosis and Rare Diseases of the CNS group module.

Searching other resources
1. Reference list of included studies and related reviews.
2. Abstract books of the main MS meetings (European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), European Neurological Society (ENS), American Academy of Neurology (AAN)) for the last eight years.
3. Contact with authors of primary studies, or drug manufacturers, or both.
4. FDA reports on fingolimod (www.fda.gov).
5. European Medicines Agency Committee for Medicinal Products for Human Use reports on fingolimod (EMA).

Data collection and analysis
We performed the review and meta-analyses following the recom- mendations of Cochrane (Higgins 2011a). We used Review Man- ager 5 to perform the analyses (RevMan 2015).

Selection of studies
Three review authors (LLM, IP, RP) independently identified tri- als and assessed titles and abstracts of the records retrieved by the search. We excluded irrelevant studies. We obtained the full text of the remaining studies to confirm inclusion. We resolved dis- agreements by discussion.

Data extraction and management
Two review authors (LLM, IP) developed a data extraction form. Three review authors (LLM, IT, IP) extracted data on trial design, participants, interventions, and outcomes independently from each other. We resolved disagreements by discussion.

Assessment of risk of bias in included studies
Three review authors (LLM, IT, IP) independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We resolved any disagreement by discussion .
We followed Cochrane’s recommendations for assessing risk of bias for each included study (Higgins 2011a). We graded each potential source of bias as high, low or unclear (either lack of information or uncertainty over the potential for bias) and provided a quote for the study report together with a justification for our judgment in the “Risk of Bias” table. We assessed the risk of bias according the following domains:
1. Random sequence generation.
2. Allocation concealment.
3. Blinding of participants and personnel.
4. Blinding of outcome assessment.
5. Incomplete outcome data.
6. Selective outcome reporting.
7. Other bias.
Outcome data were judged as low risk of bias when numbers and causes of losses to follow up were balanced between arms and when the percentage of participants lost to follow-up was low (arbitrarily set at values lower than 15%).
In addition, we defined the following two specific criteria to assess adverse events.
1. Did the study provide a definition for severe adverse events?
2. Did the researchers actively monitor for adverse events (low risk of bias) or did they simply provide spontaneous reporting of adverse events that arose (high risk of bias)?

The preset outcomes involved dichotomous, continuous and count data. We used the risk ratio (RR) with 95% confidence in- tervals (CIs) for dichotomous data, the weighted mean difference with 95% CIs for continuous data, and the rate ratio with 95% CI for count data. The rate ratio compares the rate of events in two groups by dividing one by the other. In order to avoid the assumption that the variability between the studies was exclusively because of a random sampling variation around a fixed-effect, we used the random-effects model.

Unit of analysis issues
We performed a comparison with the parallel group maintaining the original randomisation of the study. In case of repeated ob- servations, we tried to analyse each predefined outcome to reflect short-term (six months), medium-term (one year) and long-term (> 2 years) follow-up.

Dealing with missing data
In order to assess the effect of missing outcome data, we analysed data according to a likely scenario, i.e. we assumed that the treat- ment and control group participants who contributed to the miss- ing data, both had experienced the outcome (relapse or disability).

Assessment of heterogeneity
We assessed between-study heterogeneity both by inspection of graphical presentations using forest plots (Egger 1997), and by calculating the I2 statistic (significant if more than 50%) and the Chi2 test (Higgins 2011a).

Assessment of reporting biases
We did not perform a funnel plot because less than ten trials were included (Egger 1997).

Data synthesis
We performed meta-analyses of primary and secondary outcomes using RevMan 5 (RevMan 2015).

Subgroup analysis and investigation of heterogeneity
Subgroup analyses were planned to answer specific questions, such as the effects about types of interventions (different dosages) or to investigate heterogeneous results (Deeks 2011).

In the case where there was evidence of trials results heterogeneity, we planned to perform a sensitivity analysis to determine the effect of excluding trials with a high risk of bias.

’Summary of findings’ table
We created two ’Summary of findings’ tables comparing fin- golimod at the approved dose of 0.5 mg daily; one versus placebo at 24 months after randomisation (Summary of findings for the main comparison), and one versus intramuscular interferon-beta 1a at 12 months (Summary of findings 2). In both ’Summary of findings’ tables, we included five outcomes: number of participants relapse-free; number of participants free from disability worsen- ing ; number of withdrawals due to adverse events; annualised relapse rate; and number of participants free from MRI gadolin- ium-enhancing lesions. We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence. We followed methods and recommendations described in Section
11.5 and Chapter 12 of the Cochrane Handbook for Systematic Re-
views of Interventions (Higgins 2011a).

R E S U L T S

Description of studies

Results of the search
Results of the search are described in a PRISMA flow chart (Figure 1; Moher 2009). We assessed for eligibility 81 out of
481 records; 19 studies did not satisfy the inclusion criteria (Characteristics of excluded studies). We included a total of six RCTs (Calabresi 2014; Cohen 2010; Fox 2014; Kappos 2006, Kappos 2010; Saida 2012). Fifty-six reports were ancillary to these primary studies. We found 10 ongoing trials; six are still ongoing (Characteristics of ongoing studies) and four have been completed and are awaiting classification (NCT01317004; NCT01333501; NCT01534182; NCT01623596) (Characteristics of studies awaiting classification).

Included studies

The six trials were as follows.
1. Calabresi 2014 (FREEDOMS II study) (phase III).
2. Cohen 2010 (TRANSFORMS study) (phase III).
3. Fox 2014 (EPOC study) (phase IV).
4. Kappos 2006 (phase II).
5. Kappos 2010 (FREEDOMS study) (phase III).
6. Saida 2012 (phase II).
These trials were published between 2006 and 2014. Four studies compared fingolimod to placebo (Calabresi 2014; Kappos 2006; Kappos 2010; Saida 2012), one to intramuscular interferon beta- 1a (Cohen 2010), and one to other DMDs (interferon beta-1a, interferon beta-1b, glatiramer acetate) (Fox 2014). Four studies used fingolimod at doses of 0.5 mg and 1.25 mg (Calabresi 2014; Cohen 2010; Kappos 2010; Saida 2012). One study used doses of
1.25 mg and 5.0 mg (Kappos 2006). One study evaluated only the dose of 0.5 mg (Fox 2014). Fingolimod was administered orally in all studies.
The primary outcome was annualised relapse rate in three studies (Calabresi 2014; Cohen 2010; Kappos 2010); MRI measures of activity in two studies: number of gadolinium-enhancing lesions (Kappos 2006) and percentage of participants free from gadolin- ium-enhancing lesions (Saida 2012); and treatment satisfaction in the other study (Fox 2014). Outcome measures and time points of assessment considered by each of the included trials are listed in Table 1.
Confirmed relapse was defined as the occurrence of new symp- toms, or worsening of previously stable or improving symptoms, and signs not associated with fever, lasting more than 24 hours. Symptoms had to appear at least 30 days after the onset of a preced- ing relapse (Cohen 2010; Saida 2012), and had to be accompanied by an increase of at least half a point in the EDSS score (Calabresi 2014; Cohen 2010; Kappos 2006; Kappos 2010) or one point in at least one of the functions in the Kurtzke Functional System score (excluding bowel-bladder and mental systems) (Kappos 2006) or one point in each of two functions in the Kurtzke Functional Sys- tems score, or two points in one of the functions in the Kurtzke Functional System score (excluding bowel-bladder or cerebral sys- tems) (Calabresi 2014; Cohen 2010; Kappos 2010; Saida 2012). Confirmed disability progression was defined as an increase of one point in the EDSS score (or 0.50 points if the baseline EDSS score
was > 5·0), that was
confirmed three months later in the absence of relapse (Calabresi
2014; Cohen 2010; Kappos 2010). Disability progression con- firmed at six months was available in two studies at 24 months (Calabresi 2014; Kappos 2010). Assessment of disability was performed using the Multiple Sclerosis Functional Composite (MSFC) score change in one study (Kappos 2006). Disability pro-

gression was not considered by Fox 2014 and Saida 2012.
The treatment duration was six months in three trials (Fox 2014; Kappos 2006; Saida 2012), 12 months in one trial (Cohen 2010), and 24 months in two trials (Calabresi 2014; Kappos 2010).
The Characteristics of included studies tables provide further de- tails.
All studies were sponsored by Novartis Pharma.

Description of participants
The overall population included in the six trials was 5152 par- ticipants with 3531 treated with fingolimod; 2061 with 0.5 mg daily, 1376 with 1.25 mg daily, and 94 with 5.0 mg daily. The comparison population included 1621 participants; 923 treated with placebo and 698 with intramuscular interferon beta-1a or other DMDs. Enrolled participants were Caucasian, except in Saida 2012, which included Japanese participants. Participants were affected by relapsing-remitting multiple sclerosis (RRMS) in all studies, and secondary progressive multiple sclerosis (SPMS) in a small percentage in two studies; 11% in Kappos 2006 and 2.3% in Saida 2012 (Table 2).
The inclusion criteria were similar among studies. Previous treat- ment with immunomodulating agents for at least six months were required in Fox 2014, and accepted in all other studies if the suspension occurred more than three months before trial onset (Calabresi 2014; Kappos 2006; Kappos 2010; Saida 2012), not specified in Cohen 2010.
Exclusion criteria were similar and included clinically signifi- cant systemic diseases, macular oedema (not specified for Kappos 2006), and diabetes (not specified for Kappos 2006 and Cohen 2010). Participants treated with immunosuppressants were ex- cluded (Kappos 2010; Fox 2014), they had to interrupt treatment in the six months prior to randomisation (Saida 2012), interrupt azathioprine or methotrexate within six months, cyclophospha- mide within 12 months, mitoxantrone or cladribine within 24 months (Kappos 2006), and natalizumab at least six months before randomisation (Calabresi 2014). Two studies specified as exclusion criteria the presence of cardiac abnormalities or leukopenia or lym- phopenia (Kappos 2006; Saida 2012). Participants with varicella zoster immunoglobulin G (IgG) antibody negative at screening were excluded in three studies (Calabresi 2014; Fox 2014; Saida 2012).
The baseline clinical characteristics were homogeneous in term
of age (ranging from 35.0 to 38.3 years), disability score (EDSS
1.8 to 2.7), disease duration (7.1 to 9.5 years), and mean relapse number in the year before randomisation (1.2 to 1.7). Percent- age of prestudy treatment-naive participants were different among studies, ranging from 0% to 60.4%. MRI enhancing lesions were detected in 31% to 49% of the participants, while the volume of

MRI T2-weighted lesions at baseline ranged from 4924 mm3 to 10,219 mm3 (Table 2).

Excluded studies
We excluded 18 studies because type of participants (three stud- ies), design (seven studies) or intervention (one study) did not meet our inclusion criteria, five studies were not original articles (reporting pooled data of trials), and two studies were overviews (Characteristics of excluded studies).

Risk of bias in included studies
We evaluated risk of bias separately for benefit estimate ( Characteristics of included studies), and adverse events monitor- ing (Table 3).

Allocation
We considered the method used to generate a random sequence and conceal allocation to be at low risk of bias in all trials except one; we judged Calabresi 2014 to be at unclear risk of bias.

Blinding
All included trials, except one open-label trial were described as double-blinded (Fox 2014). The drug in the treatment group was reported as identical in appearance to the drug in the control group. Assessors of clinical and radiological outcomes were reported as

unaware of participants’ assignment. We judged Fox 2014 to be at high risk of bias and the other trials to be at low risk of bias for blinding.

Incomplete outcome data
All trials provided a sufficient description of follow-up and with- drawals. We judged three trials to be at high risk of attrition bias be- cause significant differences in reasons of dropouts between treated and control groups were found (Calabresi 2014; Fox 2014; Kappos 2010).

Selective reporting
We judged all trials to be at low risk of bias apart from Calabresi 2014, which we judged to be at unclear risk of bias as it did not report on clinically relevant results.

Other potential sources of bias
All trials were sponsored by Novartis Pharma. We judged four trials to be at high risk of bias because the study sponsor participated in conducting the study, or data analysis and some study co-authors were affiliated to the pharmaceutical company (Calabresi 2014; Cohen 2010; Fox 2014; Kappos 2010) .
Further details are provided in relevant sections of the Characteristics of included studies tables and are presented as the ’Risk of bias’ summary and ’Risk of bias’ graph (Figure 2; Figure 3).

Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.

Figure 3. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.

Methods of adverse events monitoring
We judged the risk of bias regarding methods of adverse events monitoring to be low for all studies. We judged the risk of bias regarding methods of serious adverse events monitoring to be un- clear for the Calabresi 2014 and for the Fox 2014 studies and low for four others (Table 3).

Effects of interventions
See: Summary of findings for the main comparison Fingolimod
0.5 mg versus placebo for relapsing-remitting multiple sclerosis; Summary of findings 2 Fingolimod 0.5 mg versus interferon beta-1a for relapsing-remitting multiple sclerosis
We defined two main comparisons, one evaluating the effect of fingolimod versus placebo and one evaluating the effect of fin- golimod versus intramuscular IFN-beta 1a or other DMDs. For each comparison, we considered the effect of fingolimod separately for the approved dose (0.5 mg) and the other treatment schedules (1.25 mg and 5.0 mg).
We reported the main results concerning benefit and withdrawals due to adverse events of fingolimod at the approved dose of 0.5 mg compared to placebo at 24 months in Summary of findings for the main comparison and compared to intramuscular interferon beta-1a at 12 months in Summary of findings 2.

Fingolimod compared to placebo

Primary Outcomes
The number of participants who were free from relapses during treatment with fingolimod 0.5 mg compared to placebo were re- trieved from one trial (114 participants = 2.2%) at six months (Saida 2012), and two trials (1556 participants =30%) at 24 months (Calabresi 2014; Kappos 2010). At six months, there was a slight non-significant benefit (risk ratio (RR) 1.22, 95% confi- dence interval (CI) 0.96 to 1.54) (Analysis 1.1). At 24 months the overall results indicated a benefit of fingolimod (RR 1.44, 95% CI
1.28 to 1.63; moderate quality evidence) (Summary of findings for the main comparison; Analysis 1.3). The higher doses were effective at six months at 1.25 mg (RR 1.27, 95% CI 1.11 to 1.45) and 5 mg (RR 1.30, 95% CI 1.10 to 1.53) (Analysis 1.1), and at 24 months at 1.25 mg (RR 1.51, 95% CI 1.29 to 1.76) (Analysis 1.3).
Data from two trials were available to calculate the number of par- ticipants without disability worsening during the first 24 months of treatment with fingolimod compared to placebo (Calabresi 2014; Kappos 2010). The results indicated little or no difference of fingolimod at 0.5 mg (RR 1.07, 95% CI 1.02 to 1.11; low quality evidence) (Summary of findings for the main comparison). Similar results were found when fingolimod was used at 1.25 mg (RR 1.08, 95% CI 1.03 to 1.12) (Analysis 2.2).
The number of participants who withdrew from the study because of adverse events with 0.5 mg of fingolimod compared to placebo was retrieved from two trials during the first six months (RR 2.00,

95% CI 0.53 to 7.61) (Kappos 2006; Saida 2012: Analysis 3.1); and two trials during the first 24 months of treatment (RR 1.42, 95% CI 0.89 to 2.25; very low quality evidence) (Calabresi 2014; Kappos 2010; Summary of findings for the main comparison; Analysis 3.3). The risk of discontinuing 1.25 mg of fingolimod due to adverse events compared to placebo significantly increased at 24 months (RR 1.93, 95% CI 1.48 to 2,52) (Analysis 3.3).
Detailed descriptive data on the type of adverse events, as reported in the primary studies, are provided in Figure 4. It should be noted that infections, hypertension, and abnormal liver tests were more frequent in the fingolimod group than in the placebo group.

Figure 4. N, number of patients; n, number of events.Significant differences (based on Fisher exact test) are reported in red.

The number of participants who withdrew because of serious ad- verse events were available from two trials at six months (Kappos 2006; Saida 2012), and two trials at 24 months (Calabresi 2014; Kappos 2010). No difference was found between placebo and fingolimod administered at 0.5 mg and 1.25 mg (Analysis 3.4; Analysis 3.6). A significant increased risk of discontinuation was found for fingolimod 5.0 mg versus placebo at six months (RR 2.77, 95% CI 1.04 to 7.38) (Analysis 3.4).
Detailed descriptive data on the type of serious adverse events, as reported in the primary studies, are provided in Figure 5. It should be noted that infections, basal-cell carcinoma, and atrioventricular blocks were more frequent in the fingolimod group than in the placebo group.

Figure 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.

The results regarding data analysed according to a likely scenario did not add any additional information (data not reported).

Secondary outcomes
The annualised relapse rate was evaluated by two trials at six months (Kappos 2006; Saida 2012), and two trials at 24 months (Calabresi 2014; Kappos 2010): at these time points the results favoured fingolimod 0.5 mg compared to placebo at six months (rate ratio 0.51, 95% CI 0.26 to 0.99; Analysis 4.1) and 24 months
(rate ratio 0.50, 95% CI 0.40 to 0.62; moderate quality evidence) (Summary of findings for the main comparison; Analysis 4.3). Similar data were found for higher doses (Analysis 4.1, Analysis 4.3).
The number of participants free from MRI gadolinium-enhancing lesions was evaluated by four trials at six months (Calabresi 2014; Kappos 2006; Kappos 2010; Saida 2012; Analysis 5.1), two trials
at 12 months (Calabresi 2014; Kappos 2010; Analysis 5.2), and two trials at 24 months (Calabresi 2014; Kappos 2010; Analysis 5.3). We found better results for fingolimod doses compared to placebo at each time point: fingolimod 0.5 mg at six months (RR 1.42, 95% CI 1.33 to 1.51); 0.5 mg at 12 months (RR 1.39, 95%
CI 1.30 to 1.48); and 0.5 mg at 24 months (RR 1.36, 95% CI
1.27 to 1.45; low quality evidence) (Summary of findings for the main comparison).
The mean change of MRI T2-weighted lesion load was evaluated by one trial at 12 months (Kappos 2010): the results favoured fingolimod 0.5 mg compared to placebo (mean difference (MD)
-15.30, 95% CI -24.34 to -6.26); similar data were found when fingolimod was used at 1.25 mg for 12 months (Analysis 6.1). At 24 months the results also favoured fingolimod 0.5 mg compared to placebo (MD -20.43, 95% CI -34.03 to -6.83); similar data were found for fingolimod 1.25 mg (Analysis 6.2).
Quality of life was measured by the Hamburg Quality of Life Questionnarie in one trial at six months (Kappos 2006), and by the Euro quality of life scale (EQ-5D) in one trial at 24 months (Calabresi 2014). No differences were found between fingolimod and placebo in either study (Analysis 7.1; Analysis 7.2).

Fingolimod compared to intramuscular interferon beta-1a or other DMDs

Primary Outcomes
Data from one trial were available to evaluate the primary out- comes during the first 12 months of treatment with fingolimod 0.5 mg compared to intramuscular interferon beta-1a (Cohen 2010). The overall results (RR 1.18, 95% CI 1.09 to 1.27; moderate quality evidence) indicated a slight advantage for fingolimod 0.5 mg in favouring freedom from relapse (Summary of findings 2).

Similar results were found when fingolimod was used at 1.25 mg (RR 1.15, 95% CI 1.06 to 1.24) (Analysis 1.2).
The results indicated no difference in favouring freedom from disability worsening at 12 months between fingolimod 0.5 mg and intramuscular interferon beta-1a (RR 1.02, 95% CI 0.99 to 1.06; low quality evidence) (Summary of findings 2). Similar results were found when fingolimod was used at 1.25 mg (RR 1.01, 95% CI 0.98 to 1.05) (Analysis 2.1).
Compared to intramuscular interferon beta-1a, the number of participants who withdrew due to adverse events was higher, but not significant for fingolimod 0.5 mg (RR 1.51, 95% CI 0.81 to 2.80; moderate quality evidence) (Summary of findings 2). Significant risk was found when used at 1.25 mg (RR 2.69, 95% CI 1.54 to 4.72) (Analysis 3.2).
Compared to intramuscular interferon beta-1a, the number of par- ticipants who withdrew due to serious adverse events was higher, but not significant for fingolimod 0.5 mg (RR 1.21, 95% CI 0.72 to 2.02), and significantly higher for fingolimod 1.25 mg (RR 1.85, 95% CI 1.15 to 2.96) (Analysis 3.5).
Data from one trial were available to calculate the number of participants who withdrew due to adverse events during the first six months (Fox 2014): the RR was significantly higher for fingolimod
0.5 mg compared to other DMDs (RR 3.21, 95% CI 1.16 to 8.86) (Analysis 3.1).
Data from the same trial showed that the number of participants who withdrew due to serious adverse events were higher with fin- golimod 0.5 mg compared to other DMDs (Fox 2014), but the re- sult was not significant (RR 2.71, 95% CI 0.83 to 8.88) (Analysis
3.4).
Detailed descriptive data on the type of adverse and serious adverse events are provided in Figure 4 and Figure 5, respectively. The higher incidence of adverse events in fingolimod versus interferon beta-1a, suggests lower tolerability for fingolimod. It should be noted that hypertension was more frequent in participants taking fingolimod, and depression was more frequent in the interferon beta-1a group.

Secondary outcomes
The annualised relapse rate was evaluated by one trial at 12 months (Cohen 2010). A significant benefit for fingolimod 0.5 mg (RR 0.48, 95% CI 0.34 to 0.70) and fingolimod 1.25 mg (RR 0.61, 95% CI 0.47 to 0.78) doses compared to intramuscular interferon beta-1a was observed (Analysis 4.2).
The number of participants free from MRI gadolinium-enhancing lesions at 12 months was evaluated by the same trial (Cohen 2010); a slight advantage for fingolimod 0.5 mg (RR 1.12, 95% CI 1.05
to 1.19) and fingolimod 1.25 mg (RR 1.13, 95% CI 1.06 to 1.20) compared to intramuscular interferon beta-1a was observed

(Analysis 5.2).
The mean change of MRI T2-weighted lesion load at 12 months was evaluated by the same trial (Cohen 2010); we found no sig- nificant reduction for fingolimod 0.5 mg (MD -0.50, 95% CI
-6.32 to 5.32) and fingolimod 1.25 mg (MD -3.70, 95% CI -
9.18 to 1.78) doses compared to intramuscular interferon beta-1a (Analysis 6.1).
Quality of life was measured at six months by the FS36 question- naire in participants treated with fingolimod 0.5 mg compared to DMDs (Fox 2014). The results favoured fingolimod (Analysis 7.1).

A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]

Fingolimod 0.5 mg versus intramuscular interferon beta- 1a for relapsing- remitting multiple sclerosis

Participants or population: people with relapsing-remitting multiple sclerosis
Settings: outpatients in multiple sclerosis centres
Intervention: f ingolimod 0.5 mg versus intramuscular interferon beta-1a
Outcomes at 12 months Illustrative comparative risks* (95% CI) Relative effect (95% CI) No. of Participants (studies) Quality of the evidence (GRADE)
Assumed risk Corresponding risk

Control (interferon beta- 1a)
Fingolimod 0.5 mg

Participants free from re- lapse
70 per 100
83 per 100
RR 1.18
860 ⊕⊕⊕Ⓧ
(76 to 89) (1.09 to 1.27) (1 study) moderatea
Participants free from dis- ability worsening 92 per 100 94 per 100 RR 1.02 860 ⊕⊕ⓍⓍ
(91 to 98) (0.99 to 1.06) (1 study) lowa,b
Withdrawals due to adverse events 4 per 100 6 per 100 RR 1.51 860 ⊕⊕⊕Ⓧ
(3 to 10) (0.81 to 2.80) (1 study) moderatea
Annualised relapse rate - - Rate ratio 0.48
(0.34 to 0.70) 860
(1 study) ⊕⊕⊕Ⓧ
moderatea
Participants free from MRI gadolinium- enhancing le- sions 81 per 100 90 per 100 RR 1.12 728 ⊕⊕⊕Ⓧ
(85 to 96) (1.05 to 1.19) (1 study) moderatea

* For dichotomous outcomes, the corresponding risk with the intervention (and its 95% CI) is based on the assumed risk with the control (i.e. the mean proportion of events in the control group across studies) and the relative effect of the intervention (and its 95% CI). For the annualised relapse rate, only the relative ef fect (i.e., the rate ratio) is given. CI: Confidence interval; RR: Risk ratio.

a Imprecision: total number of events (i.e. the number of participants with disability worsening/ gadolinium-enhancing lesions) was less than 300 (the threshold rule-of-thumb value), and thus the available evidence did not meet the optimal information size criteria.
b Indirectness: surrogate outcome (progression confirmed at three months of follow-up).

D I S C U S S I O N

Summary of main results
Six RCTscontributed to this review. The overall population in- cluded 5152 participants; 3531 were randomly assigned to fin- golimod (2061 of them treated with the approved dose of 0.5 mg daily) and 1621 controls, 923 treated with placebo and 698 with intramuscular interferon beta-1a or other DMDs. The treat- ment duration was six months in three trials (Fox 2014; Kappos 2006; Saida 2012),12 months in one trial (Cohen 2010a), and 24 months in two trials (Calabresi 2014; Kappos 2010). All studies were sponsored by Novartis Pharma.
Fingolimod administered at the approved dose of 0.5 mg orally once-daily is effective in increasing the number of people free from relapse (moderate quality of evidence) and from MRI gadolin- ium-enhancing lesions (low quality of evidence), and in reduc- ing the annualised relapse rate (moderate quality of evidence) at 24 months compared to placebo. A benefit on prevention of disability worsening was not observed (low quality of evidence). The risk of withdrawal due to adverse events was not significant (very low quality of evidence) (Summary of findings for the main comparison). Furthermore, MRI T2-weighted lesion load changes at 12 and 24 months favour fingolimod versus placebo.
A slight advantage of fingolimod at a dose of 0.5 mg compared to intramuscular interferon beta-1a in increasing freedom from relapse and from gadolinium-enhancing lesions at 12 months was observed (moderate quality of evidence). A benefit was found for other measures of clinical activity (relapse rate: moderate qual- ity of evidence). No difference between the two active treatments was found regarding prevention of disability worsening at 12 months (low quality of evidence). The risk of withdrawal due to adverse events was not significant (moderate quality of evidence) (Summary of findings 2) despite a worst tolerability due to the higher incidence of adverse events. Furthermore, no difference was observed regarding the mean change of MRI T2-weighted lesion load at 12 months.

Overall completeness and applicability of evidence
All studies assessed the clinical and MRI outcomes selected for this review, except Fox 2014 who included only patient-oriented out- comes. Participants were adults with relapsing-remitting multiple sclerosis (RRMS), a high prestudy relapse frequency, low disability and disease duration over five years (Table 2).
The following four points, relevant for clinical practice, should be highlighted:
1. Measures of treatment response.
2. Worsening of disability.
3. Comparison with other active treatments.
4. Impact on quality of life.

1. The assessment of disease activity has been recently incorporated to redefine MS disease phenotypes (Lublin 2014). On the other hand, treatment expectations have evolved to include potential remission from MS symptoms to freedom from disease activity. We have chosen the number of participants without clinical (relapse and worsening of disability) and MRI (gadolinium-enhancing lesions) events, as separate outcome measures. This is to underline the possible benefit from treatment. We have included a further MRI endpoint (total volume of abnormal T2-hyperintensity) as a marker of disease severity (Lavery 2014). We have not included composite measures, such as, ’no evidence of disease activity’ (NEDA), as they are not yet accepted as a primary outcome, and are of uncertain prognostic value (Giovannoni 2015; Rotstein 2015). Only post-hoc analysis concerning NEDA on pooled fingolimod trial populations has been published (Kappos 2015b; Nixon 2014), and useful data in the primary studies were lacking.
2. We did not find substantial evidence that fingolimod
modified the risk of disability worsening, in spite of efficacy for inflammatory disease activity. We considered disability worsening as confirmed at six months follow-up. Using less stringent criteria (three months), Calabresi 2014 and Kappos 2010 found that fingolimod was effective over the 24-month period; however, this result may be related to reversible relapse- related disability accrual. Dissociation between relapse and disability worsening is well documented during the natural course of the disease (Scalfari 2010; Scalfari 2013). On the other hand, meaningful changes might be difficult to detect using the outcomes currently approved to measure clinical disability, mainly in the early stages of the disease, and after a short treatment period (Cohen 2012; Lavery 2014). A divergent effect might also occur when different pathogenetic mechanisms occur (degenerative and inflammatory). In fact, no effect on progressive MS has been reported (Lublin 2016; Novartis 2016).
3. We only included one comparison concerning clinical and
MRI outcomes in this review, i.e. fingolimod versus intramuscular interferon beta-1a. We will evaluate ongoing trials of fingolimod compared to other approved DMDs in future updates of the review.
4. We did not find any benefit for fingolimod for quality of life in people with RRMS over two years of therapy, in comparison to placebo (Analysis 7.2). This result is relevant considering the expectation of oral therapy after the era of injectable drugs; following the introduction of fingolimod, patients with RRMS have switched to this drug rather than any other therapies, and they did so for convenience (Warrender-Sparkes 2015). Type of scales and assessment methods used to measure quality of life in the included studies might have influenced the estimated effect of fingolimod for this outcome (Table 1).
The following limitations of the review need to be highlighted: .
1. The duration of the included trials was equal to or less than 24 months. Extension studies have been reported, but in most of

them placebo-treated participants switched to the fingolimod group. We excluded open-label extension studies in this review.
2. The influence of patients’ baseline characteristics on the effect of fingolimod was not explored due to lack of useful data in the included trials. Contradictory data are available in the literature. For example, one article reported that response to fingolimod was associated with patients’ baseline high relapse frequency (Oh J 2013). A post-hoc subgroup analysis of the FREEDOM study (Kappos 2010), reported lack of benefit of fingolimod on the relapse rate for people with MS older than 40 years and on disability worsening for those with baseline expanded disability status scale (EDSS) less than 3.5 score (Devonshire 2012). Fingolimod was found to be superior to intramuscular interferon beta-1a in all subgroups defined by demographic factors or baseline disease characteristics (Cohen 2013). Another study reported that fingolimod demonstrated similar efficacy in patients with RRMS regardless of prior treatment history (Kremenchutzky 2014).
3. People with systemic disorders were excluded in all included
trials, while in the real world comorbidity is frequent. Precautions and new recommendations need to be followed before and after starting treatment, or when restarting treatment with fingolimod (EMA 2011; EMA 2015).
4. We did not plan to explore safety outcomes beyond the duration of primary RCTs. The Food and Drug Administration (FDA) required planning of two studies (FDA 2010):
i) A post-marketing observational prospective, parallel cohort study in relapsing multiple sclerosis patients to assess the potentially serious risk of: eye toxicity, cardiac and vascular toxicity, pulmonary toxicity, seizures, serious and opportunistic infections, malignancies, liver toxicity and atypical multiple sclerosis relapse. Specific outcomes examined should include, but not be limited to, macular oedema, symptomatic bradycardia, second and third degree atrioventricular block, and lymphoma. Final Report Submission: 15 December, 2020.
ii) Develop and maintain a prospective, observational pregnancy exposure registry study conducted in the United States. Final Report Submission: 31 October, 2017.
At 31 October, 2011, 89 pregnancies were reported in completed or ongoing clinical studies, with 74 pregnancies in fingolimod treatment arms. Of 66 pregnancies with in utero exposure to fin- golimod, there were 28 live births, nine spontaneous abortions, 24 elective abortions (one case each of tetralogy of Fallot, spon- taneous intrauterine death, and failure of fetal development), two infants were born with malformations (one with congenital uni- lateral posteromedial bowing of the tibia and one with acrania). There were five cases (7.6%) of abnormal fetal development in the 66 pregnancies. Considering also the known risk of teratogenicity in animals, women of childbearing potential should use effective contraception during fingolimod therapy and for two months af- ter treatment discontinuation (Karlsson 2014).

Quality of the evidence
We downgraded the quality of the evidence for all included out- comes at 24 months due to significant differences in reasons of incomplete outcome data between fingolimod 0.5 mg and placebo groups. We further downgraded the quality of evidence for dis- ability worsening, withdrawals due to adverse events, and MRI gadolinium-enhancing lesions due to insufficient information size and wide confidence intervals. We further downgraded the qual- ity of evidence for withdrawals due to inconsistency. Overall we gave a GRADE rating of moderate for relapses, low for disability progression, very low for withdrawals due to adverse events, and low for MRI gadolinium-enhancing lesions .
We downgraded the quality of the evidence for all included out- comes at 12 months due to insufficient information size be- tween the fingolimod 0.5 mg and intramuscular interferon beta- 1a groups in Cohen 2010, resulting in moderate quality evidence. We further downgraded the quality of evidence for disability wors- ening because this study required only three months’ follow-up to confirm sustained disability worsening. Although we had to accept the definition given in the original paper, we assessed this defini- tion as unreliable in capturing unremitting disability worsening.

Potential biases in the review process
The search strategy for the trials, and contacts initiated with the main investigators, suggest the likelihood that we identified all relevant studies and obtained all relevant data.

Agreements and disagreements with other studies or reviews
Previous reviews on fingolimod as compared with placebo or other approved DMDs in RRMS have been published, but only descrip- tive data have been reported (Ali 2013; Doggrell 2010; Fox 2012; Gajofatto 2015; Gold 2011; Oh J 2013).
Other reviews have used a structured methodology, including net- work meta-analysis, but they have considered a low number of RCTs, with different and limited endpoints. A systematic non- Cochrane review assessed the efficacy and safety of fingolimod at different doses (Bao 2012); it was based on three RCTs published up to 2010. The results showed that fingolimod was safe and effec- tive in treating RRMS, considering clinical and MRI (incidence rate of so-called “intense lesion” on T2-weighted) endpoints.
One review evaluated the comparative effects of fingolimod versus other DMDs using network meta-analysis. It included ten studies, two of them assessing the effects of fingolimod (Del Santo 2011). The endpoint was limited to the relapse-free rate at 12 months. The results suggested that fingolimod was superior to interferon beta-1a (direct comparison) and glatiramer (indirect comparison) in terms of prevention of relapse at 12 months follow-up.

The results of a Cochrane review evaluating the effect of im- munomodulators and immunosuppressants in people with RRMS using network meta-analysis, demonstrated that alemtuzumab, natalizumab, and fingolimod are the best choices against the re- currence of relapses, but the evidence was limited to the first 24 months of follow-up (Tramacere 2015).

A U T H O R S ’ C O N C L U S I O N S

Implications for practice
The results of this review showed that fingolimod is a useful treat- ment of people with RRMS, because of its efficacy in the preven- tion of disease activity compared to placebo, although the benefit in terms of preventing disability worsening remains unclear. The direct comparison with other approved first-line DMDs, in par- ticular intramuscular interferon beta-1a, indicates a higher benefit of fingolimod in terms of relapse prevention, but a significant risk of discontinuation in the first months of treatment. A higher in- cidence of adverse events was found, suggesting lower tolerability for fingolimod versus interferon beta-1a, requiring careful moni- toring over time.
However, the data were inadequate, for the low number of head- to-head RCTs and types of comparisons, with short follow-up duration.

Implications for research
There is a need to further explore the long-term benefit and safety profile of fingolimod considering the risk of progressive multifocal leukoencephalopathy (FDA 2015), and basal cell carcinoma po- tentially associated with fingolimod therapy (EMA 2015). Head- to-head trials comparing fingolimod with other DMDs, and the evaluation of drug effects using other outcome measures, including disease activity freedom (Giovannoni 2015), are useful to guide clinicians to personalise patient treatment. The ongoing, and as yet unpublished trials, will possibly satisfy these issues.

A C K N O W L E D G E M E N T S

We wish to thank: Dr. Anas Shaneh Saz, Rim Hasan and Suleiman Kojan for their contribution in writing the review protocol.
We also thank Andrea Fittipaldo, Trials Search Co-ordinator, for support provided in paper retrieval, and Sara Nuzzo for helping with data extraction of primary studies.
We are grateful to Liliana Coco for valuable and helpful technical assistance provided, as well as for support in writing the review.
We are grateful to Prof. Bianca Weinstock-Guttman for valuable and helpful comments.

References to studies included in this review

Calabresi 2014 {published data only}
Calabresi P, Radue EW, Goodin D, Jeffery D, Kottil R,

R E F E R E N C E S

2014;13:545-56.
Coyle P, Cree B, Cabre P, Inglese M, Perumal J, Meng X, et al. Fingolimod efficacy and safety in an African-American patient subgroup from freedoms II. Abstract meeting of the

Reder A, et al. Efficacy and safety of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS): results from an additional 24-month double-blind, placebo- controlled study (freedoms II study). Abstract meeting of the 64th American Academy of Neurology Annual Meeting, 2012, New Orleans, United States. Neurology. 2012.
Calabresi PA, Goodin D, Jeffery D, Kappos L, Lublin FD, Rammohan K, et al. Efficacy and safety of fingolimod versus placebo: Primary outcomes from the phase 3 FREEDOMS II study in patients with relapsing-remitting multiple sclerosis. Abstract meeting of the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, 2012, Lyon, France. Multiple Sclerosis. 2012; Vol. 18.
∗ Calabresi PA, Radue EW, Goodin D, Jeffery D,
Rammohan KW, Reder AT, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. The Lancet Neurology

66th American Academy of Neurology Annual Meeting,
AAN 2014, Philadelphia, United States. Neurology. 2014; Vol. 82.
Goodin D, Jeffery D, Kappos L, Lublin F, Radue EW, Rammohan K, et al. Fingolimod reduces annualized relapse rate in patients with relapsing-remitting multiple sclerosis: Freedoms II study subgroup analysis. Abstract meeting of the 65th American Academy of Neurology Annual Meeting, 2013, San Diego, United States. Neurology. 2013; Vol. 80. Khan O, Cree B, Cabre P, Inglese M, Perumal J, Meng X, et al. The efficacy and safety of fingolimod in an African- American patient subgroup from FREEDOMS II. Abtract meeting of The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); 2013 October 2-5; Copenhagen, Denmark. Multiple Sclerosis. 2013.
Radue E, Goodin D, Jeffery D, Kappos L, Lublin F, Rammohan K, et al. Fingolimod reduces magnetic resonance imaging inflammatory lesion activity versus placebo in patients with relapsing-remitting multiple

sclerosis: results from the phase 3. Multiple Sclerosis 2012;
18(4):322–3.
Reder A, Jeffery D, Goodin D, Kappos L, Lublin F, Radue E, et al. Long-term efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis: results from the phase 3 FREEDOMS II extension study. Multiple Sclerosis 2013; 19:510–1.
Vollmer T, Goodin D, Jeffery D, Kappos L, Radue E, Rammohan K, et al. Effect of fingolimod on severe relapses, healthcare utilisation and relapse recovery in patients with relapsing-remitting multiple sclerosis: results from the phase 3 FREEDOMS II study. Multiple Sclerosis 2012;18:438–9. Vollmer T, Jeffery D, Goodin D, Kappos L, Lublin F, Radue EW, et al. Long-term safety of fingolimod in patients with relapsing-remitting multiple sclerosis: results from phase 3 freedoms II extension study. Neurology. 2013; Vol. 80.
Winges KM, Werner JS, Harvey DJ, Cello KE, Durbin MK, Balcer LJ, et al. Baseline retinal nerve fiber layer thickness and macular volume quantified by OCT in the North American phase 3 fingolimod trial for relapsing-remitting multiple sclerosis. Journal of Neuro-Ophthalmology 2013; 33:322-9.

Cohen 2010 {published data only}
Barkhof F, Cohen J, Montalban X, Comi G, Auberson L, Holdbrook F, et al. Fingolimod (FTY720) reduces brain volume loss over 12 months compared with intramuscular interferon beta-1a: subgroup analyses of TRANSFORMS data based on inflammatory disease activity. Abstract meeting of the 5th Joint Triennal Congress of the European and Americas Committees for the treatment and research in Multiple Sclerosis; 2011 Oct 19-22, Amsterdam, The Netherlands. Multiple Sclerosis. 2011; Vol. 17.
Barkhof F, de Jong R, Sfikas N, de Vera A, Francis G, Cohen J, TRANSFORMS study group. The influence of patient demographics, disease characteristics and treatment on brain volume loss in Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS), a phase 3 study of fingolimod in multiple sclerosis. Multiple Sclerosis 2014;20(13):1704–13.
∗ Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO,
Montalban X, et al. Oral Fingolimod or intramuscular interferon for relapsing multiple sclerosis. New England Journal of Medicine 2010;362(5):402–15.
Cohen JA, Barkhof F, Comi G, Izquierdo G, Khatri B, Montalban X, et al. Fingolimod versus intramuscular interferon in patient subgroups from TRANSFORMS. Journal of Neurology 2013;260(8):2023–32.
Hartung H, Barkhof F, Comi G, Kappos L, Khatri B, Montalban X, et al. Relationship between early disease activity and long-term clinical outcome: results from the phase 3 TRANSFORMS study extension at 4.5 years in relapsing-remitting multiple sclerosis. Abstract meeting of the twenty-third meeting of the ENS; 2013 June 8-11; Barcelona, Spain. Journal of Neurology. 2013; Vol. 260. Khatri B, Barkhof F, Comi G, Hartung H, Kappos L, Montalban X, et al. Long-term efficacy data from the extension of the phase III TRANSFORMS study of

fingolimod versus Interferon beta-1a in relapsing-remitting multiple sclerosis: 4.5 year follow-up. Journal of Neurology 2012;259(1):S21.
Khatri B, Barkhof F, Comi G, Hartung HP, Kappos L, Montalban X, et al. Comparison of fingolimod with Interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. The Lancet Neurology 2011;10(6):520–9.
Khatri B, Barkhof F, Comi G, Jin J, Francis G, Cohen J. Fingolimod treatment increases the proportion of patients who are free from disease activity in multiple sclerosis compared to IFN-B1A: results from a phase 3, active- controlled study (TRANSFORMS). Abstract meeting of the 64th American Academy of Neurology Annual Meeting, 2012, New Orleans, United States. Neurology. 2012; Vol. 78:1.
Meng X, Cutter G, Chin P, Hashmonay R, Islam MZ. Effect of switching from intramuscular Interferon B-1a to fingolimod on time to relapse in patients with relapsing- remitting multiple sclerosis enrolled in a 1-year extension of transforms. Abstract meeting of the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, 2013, Lyon, France. Neurology. 2013; Vol. 80.
Montalban X, Barkhof F, Comi G, Hartung HP, Kappos L, Khatri B, et al. Long term efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis previously treated with interferon beta-1a or disease modifying therapies: A post hoc analysis of the TRANSFORMS 4.5 year extension study. Journal of Neurology 2013;260:S124–5.

Fox 2014 {published data only}
Barbato L, Schofield L, McCague K, Pestreich L, Tobias K, Malhotra M. Randomized, open-label study to evaluate patient-reported outcomes (PRO) with fingolimod after changing from prior disease-modifying therapy (DMT) for relapsing multiple sclerosis (MS): EPOC study rationale and design. Abstract meeting of the 136th Annual Meeting of the American Neurological Association; 2011 Sept 25- 27; San Diego, United States. Annals of Neurology. 2011. Calkwood J, Cree B, Crayton H, Kantor D, Brian Steingo B, Barbato L, et al. Impact of a switch to fingolimod versus staying on glatiramer acetate or beta interferons on patient- and physician-reported outcomes in relapsing multiple sclerosis: post hoc analyses of the EPOC trial. BMC Neurology 2014;14(220):1–11.
Cascione M, Wynn D, Agashivala N, McCague K, Pestreich L, Schofield L, et al. Summary scores for patient-reported outcome measures in multiple sclerosis. Baseline data from the trial to Evaluate Patient OutComes, safety and tolerability of fingolimod (EPOC). Multiple Sclerosis 2012; 18:488–9.
Cascione M, Wynn D, Barbato LM, Pestreich L, Schofield L, McCague K. Randomized, open-label study to evaluate patient-reported outcomes with fingolimod after changing from prior disease-modifying therapy for relapsing multiple sclerosis: EPOC study rationale and design. Journal of

Medical Economics 2013;16(7):859-65.
Crayton H, Hunter S, Huffman C, Agashivala N, Schofield L, McCague K, et al. Improved quality of life after therapy change to fingolimod. Journal of Neurology 2013;260:S127. Cree B, Kantor D, Steingo M, Agashivala N, Li S, McCague K, et al. Patient and physician reported outcomes after therapy switch from glatiramer acetate to fingolimod versus staying on glatiramer acetate. Multiple Sclerosis 2013;19: 464–5.
DiBernardo A, Agashivala N, Meng X, Hashmonay R, Barbato M, Chin P. Effect of fingolimod on two sub domains of the Beck depression inventory-II In patients with relapsing multiple sclerosis. Abstract meeting of the 18th Annual Conference of Rehabilitation in MS; 2013 Oct 2-5; Copenhagen, Denmark. Multiple Sclerosis. 2013. Edwards K, Crayton H, Calkwood J, Agashivala N, Li S, Chin P, et al. Patient-and physician-reported outcomes after therapy switch from interferon (beta) to fingolimod versus staying on interferon (beta) therapy. Abstract meeting of the 29th Congress of European Committee for Treatment and Research in MS; 2013 Oct 2-5; Copenhagen, Denmark. Multiple Sclerosis. 2013; Vol. 19:231–2.
∗ Fox E, Edwards K, Burch JG, Wynn DR, LaGanke C,
Crayton H, et al. Outcomes of switching directly to oral fingolimod from injectable therapies: results of the Evaluate Patient OutComes (EPOC) study in relapsing multiple sclerosis. Multiple Sclerosis and Related Disorders 2014;3(5): 607-19.
Gudesblatt M, Agashivala N, Randhaw S, Li S, Barbato L, Singer B. Outcomes of a switch to fingolimod to treat relapsing multiple sclerosis: A patient subgroup post hoc
analysis. Journal of Multiple Sclerosis 2014; Vol. 2, issue 1: Open Access.
Hughes B, Cascione M, Freedman M, Agius M, Kantor D, Gudesblatt M, et al. First-dose effects of fingolimod after switching from injectable therapies in the randomized, open-label, multicenter, Evaluate Patient OutComes (EPOC) study in relapsing multiple sclerosis. Multiple Sclerosis 2014;3(5):620–8.
Singer B, Gudesblatt M, Agashivala N, Li S, Randhawa S, McCague K, et al. Patient-reported outcomes after therapy switch to fingolimod: post-hoc subgroup analysis of the EPOC study. Abstract meeting of the 66th American Academy of Neurology Annual Meeting, April 26-May 3, 2014, Philadelphia, United States. Neurology. 2014; Vol. 82.

Kappos 2006 {published data only}
Antel J, Montalban X, O’Connor P, de Vera A, Cremer M, Sfikas N, et al. Long-term (7-year) data from a phase 2 extension study of fingolimod in relapsing multiple sclerosis. Abstract meeting of The American Academy of Neurology, 64th AAN Annual Meeting; April 21 – 28, 2012; New Orleans, United States. Neurology. 2012; Vol. 78.
Cohen JA, Khatri B, Barkhof F, Comi G, Hartung HP, Montalban X, et al. Long-term (up to 4.5 years) treatment with fingolimod in multiple sclerosis: results from the extension of the randomised TRANSFORMS study.

Journal of Neurology, Neurosurgery, and Psychiatry 2015 June 25 [Epub ahead of print].
Comi G, O’Connor P, Montalban X, Antel J, Radue EW, Karlsson G, et al. Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results. Multiple Sclerosis 2009;16:197–207.
Izquierdo G, O’Connor P, Montalban X, von Rosenstiel P, Cremer M, de Vera A, et al. Five-year results from a phase 2 study of oral fingolimod in relapsing multiple sclerosis. Multiple Sclerosis 2014;20(7):877–81.
∗ Kappos L, Antel J, Comi G, Montalban X, O’Connor P,
Polman CH, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. New England Journal of Medicine 2006; 355(11):1124–40.
Montalban X, Comi G, Antel J, O’Connor P, de Vera A, Cremer M, et al. Long-term (>7-year) efficacy and safety data from a phase II extension study of fingolimod in relapsing multiple sclerosis. Journal of Neurology 2012;259 (1):S69–70.
Montalban X, Comi G, O’Connor P, Gold S, de Vera A, Eckert B, et al. Oral fingolimod (FTY720) in relapsing multiple sclerosis: impact on health-related quality of life in a phase II study. Multiple Sclerosis 2011;17(11):1341–50. Montalban X, O’Connor P, Antel J. Oral fingolimod (FTY720) shows sustained low rates of clinical and MRI disease activity in patients with relapsing multiple sclerosis: four-year results from a phase II extension. Neurology.
2009; Vol. 72:A313.
Montalban X, O’Connor P, Izquierdo G, Von Rosenstiel P, Cremer M, Prut L, et al. Long-term fingolimod (FTY720) in relapsing MS: 5-year results from an extension of a phase II, multicentre study show a sustained low level of disease activity. Multiple Sclerosis 2011;17(10):S442–3.
O’Connor P, Comi G, Montalban X, Antel J, Radue EW, de Vera A, et al. Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study. Neurology 2009;72(1):73–9.

Kappos 2010 {published data only}
Bergvall N, Sfikas N, Alsop J, Chin P, Von Rosensteil P, Kappos L. Consequences of different definitions of
confirmed disability progression across randomised trials of MS therapies. Multiple Sclerosis 2012;18(4):473–4.
Camu W, Thouvenot E, Meinel M, Sfikas N, Chin P, Piani-Meier D, et al. Influence of baseline clinical and demographic characteristics on disease evolution in the phase 3 FREEDOMS study in patients with relapsing- remitting multiple sclerosis. Abtract meetings of the ECTRIMS 18th Annual Conference on Rehabilitation, 2013, Copenhagen, Denmark. Multiple Sclerosis. 2013;
Vol. 19.
Chin P, Von Rosenstiel P, Haering D, Francis G, Kappos
L. Fingolimod leads to early clinical and MRI benefits in relapsing-remitting multiple sclerosis. Abstract meeting of the twenty-third ENS, 2013, Spain. Journal of Neurology. 2013.
Cutter G, Chin P, Francis G, Meng X, Hashmonay R, Lublin F. Relapse is associated with residual deficits in

relapsing-remitting multiple sclerosis: Analysis of freedoms data. Abstract meeting, The American Academy of Neurology’s 65th AAN Annual Meeting, 2013, San Diego, United States. Neurology. 2013; Vol. 80.
Devonshire V, Havrdova E, Radue EW, O’Connor P, Zhang-Auberson L, Agoropoulou C, et al. Relapse and disability outcomes in patients with multiple sclerosis treated with Fingolimod: subgroup analyses of the double- blind, randomised, placebo-controlled FREEDOMS study. The Lancet Neurology 2012;11:420-8.
Hohlfeld R, Calabresi PA, O’Connor P. Oral fingolimod (FTY720) reduces relapse rate in patients previously treated with disease-modifying therapies for multiple sclerosis and in patients who are treatment naive: subgroup analysis of data from a 24-month phase III study (FREEDOMS).
Journal of Neurology. 2010; Vol. 257.
Kappos L, De SN, Freedman MS, Cree BA, Radue EW, Sprenger T, et al. Inclusion of brain volume loss in a revised measure of ’no evidence of disease activity’ (NEDA-4) in relapsing-remitting multiple sclerosis. Multiple Sclerosis 2015 Nov 19 [Epub ahead of print].
Kappos L, O’Connor P, Radue E, Polman C, Hohlfeld R, Selmaj K, et al. Long-term effects of fingolimod in multiple sclerosis: The randomized FREEDOMS extension trial.
Neurology 2015;84(15):1582–91.
∗ Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, et al. A placebo-controlled trial of oral
fingolimod in relapsing multiple sclerosis. New England Journal of Medicine 2010;362(5):387–401.
Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, et al. Long-term efficacy and safety of fingolimod (FTY720) in relapsing-remitting multiple sclerosis (RRMS): Results from the extension of the phase III FREEDOMS study. Neurology. 2012; Vol. 78:1.
Kremenchutzky M, O’Connor P, Hohlfeld R, Zhang- Auberson L, Von Rosenstiel P, Meng X, et al. Impact of prior treatment status and reasons for discontinuation on the efficacy and safety of fingolimod: Subgroup analyses of the Fingolimod Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study. Multiple Sclerosis and Related Disorders 2013;3:341-9.
O’Connor P, Polman C, Hohlfeld R, Selmaj K, Olsson T, Agoropoulou C, et al. Phase III FREEDOMS study extension: Long-term safety of fingolimod (FTY720) in relapsing-remitting multiple sclerosis. Multiple Sclerosis 2012;18(4):223.
Radue E, Kappos L, O’Connor P, Polman C, Hohlfeld R, Calabresi P, et al. Fingolimod significantly reduced brain volume loss in patients with relapsing-remitting multiple sclerosis: 4-year data from FREEDOMS extension study. Journal of Neurology. 2012; Vol. 259, issue 1:S21–2.
Radue E, Sprenger T, de Vera A, Francis G, Rochotte E, Tomic D, et al. Effect of fingolimod on evolution of baseline enhancing MRI lesions into persistent T1
hypointense lesions: Post hoc analysis of the FREEDOMS study. Multiple Sclerosis 2014;20:112–3.
Radue EW, O’Connor P, Polman CH, Hohlfeld R,

Calabresi P, Selmaj K, et al. Impact of fingolimod therapy on magnetic resonance imaging outcomes in patients with multiple sclerosis. Archives of Neurology 2012;69(10): 1259–69.
Saida 2012 {published data only}
Kira J, Itoyama Y, Kikuchi S, Hao Q, Kurosawa T, Nagato K, et al. Fingolimod (FTY720) therapy in Japanese patients with relapsing multiple sclerosis over 12 months: results of a phase 2 observational extension. BMC Neurology 2014; 14:1–23.
Kira J, Itoyama Y, Kikuchi S, Hao Q, Kurosawa T, Nagato K, et al. Oral fingolimod (FTY720) in Japanese patients with relapsing multiple sclerosis: Results of a 12-month, phase 2 extension study. Multiple Sclerosis 2011;17(10): S193.
∗ Saida T, Kikuchi S, Itoyama Y, Hao Q, Kurosawa
T, Nagato K, et al. A randomized, controlled trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis. Multiple Sclerosis 2012;18:1269-77. [PUBMED: 22354739]
Saida T, Kikuchi S, Itoyama Y, Hao Q, Kurosawa T, Nagato K, et al. Oral fingolimod (FTY720) in Japanese patients with relapsing multiple sclerosis: Results of a 6-month, randomised, double-blind, placebo-controlled, phase 2 study. Multiple Sclerosis 2011;17:S418–9.
References to studies excluded from this review

Boulton 2013 {published data only}
Boulton C, David OJ, Meiser K, Schmouder R. Tolerability and pulmonary pharmacodynamic effects during treatment initiation of once-daily oral fingolimod in subjects
with moderate asthma. Clinical Pharmacology in Drug Development 2013;2(1):2–10.
Chinea 2014 {published data only}
Chinea A, Alvarenga R, Tomic D, DiBernardo A, Meng X, Hawker K. Efficacy and safety of fingolimod in hispanic patients: Pooled data from three phase 3 clinical trials.
Neurology 2014;82:10.
Comi 2013 {published data only}
Comi G, Gold R, Kappos L, Von Rosenstiel P, Sinha A, Tomic D. Relapse and safety outcomes in patients who transitioned from glatiramer acetate or interferon (beta) to fingolimod in the open-label FIRST study. Multiple Sclerosis 2013;19:205.
Francis 2014 {published data only}
Francis G, Kappos L, O’Connor P, Collins W, Tang D, Mercier F, et al. Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy. Multiple Sclerosis 2014;20(4):471-80.
Gold 2014 {published data only}
Gold R, Comi G, Palace J, Siever A, Gottschalk R, Bijarnia M, et al. Assessment of cardiac safety during fingolimod treatment initiation in a real-world relapsing multiple sclerosis population: a phase 3b, open-label study. Journal of Neurology 2014;261(2):267–76.

Green 2013 {published data only}
Green A, Sergott R, Bennett L, Hamilton S, Costello F, Dahlke F, et al. Fingolimod for the treatment of acute optic neuritis: design of a phase 2 study. Multiple Sclerosis 2013; 19:238–9.
Havla 2013 {published data only}
Havla J, Tackenberg B, Hellwig K, Meinl I, Krumbholz M, Seitz F, et al. Fingolimod reduces recurrence of disease activity after natalizumab withdrawal in multiple sclerosis. Journal of Neurology 2013;260(5):1382–7.
Kappos 2014 {published data only}
Kappos L, Zhang L, Francis AG, Cohen J. Fingolimod in relapsing multiple sclerosis: An integrated analysis of safety findings. Multiple Sclerosis and Related Disorders 2014;3: 494-504.
Kappos 2014a {published data only}
Kappos L, Radue E, Karlsson G, Zheng H, Rosenstiel P, Jeffery D. Efficacy benefits of fingolimod 0.5 mg once daily in patients previously treated with glatiramer acetate: Pooled analysis of phase 3 FREEDOMS and FREEDOMS II studies. Neurology 2014;82(10 Suppl):193.
Kappos 2015 {published data only}
Kappos L, Mehling M, Arroyo R, Izquierdo G, Selmaj K, Curovic-Perisic V, et al. Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis.
Neurology 2015;84(9):872–9.
Kappos 2015a {published data only}
Kappos L, Radue EW, Comi G, Montalban X, Butzkueven H, Wiendl H, et al. Switching from natalizumab to fingolimod. A randomized, placebo-controlled study in RRMS. Neurology 2015;85(1):29-39.
Karlsson 2014 {published data only}
Karlsson G, Francis G, Koren G, Heining P, Zhang X, Cohen J, et al. Pregnancy outcomes in the clinical
development program of fingolimod in multiple sclerosis.
Neurology 2014;82:674-80.
laroni 2013 {published data only}
Laroni A, Brogi D, Morra V, Guidi L, Pozzilli C, Comi G, et al. Safety of the first dose of fingolimod for multiple sclerosis: Results of an open-label clinical trial. BMC Neurology 2014;14(65):1–9.
Limmorth 2013 {published data only}
Limmroth V, Hoyer S, Schuh K, Lang M, Hoffmann O, Ziemssen T. Good cardiac safety profile after fingolimod (Gilenya registered trademark) treatment initiation in patients with relapsing remitting multiple sclerosis: First interim analysis of the START study. Multiple Sclerosis. 2013; Vol. 19.
Lublin 2016 {published data only}
Lublin F, Miller DH, Freedman MS, Cree BA, Wolinsky JS, Weiner H, et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 2016 Jan 27 [Epub ahead of print].

Nolan 2013 {published data only}
Nolan R, Gelfand JM, Green AJ. Fingolimod treatment in multiple sclerosis leads to increased macular volume. Neurology 2013;80:139–44.
Van Lokven 2013 {published data only}
Van Lokven T, Ortler S, Moser S, Vollmar P, Ziemssen T. Comparison of therapy efficacy and satisfaction of German relapsing remitting multiple sclerosis (RRMS) patients on baseline therapy with fingolimod-treated patients; results of an interim analysis of two non-interventional studies (PANGAEA and PEARL). Multiple Sclerosis. 2013; Vol. 19:252.
Vollmer 2013 a {published data only}
Vollmer T, Radue E, Vermersch P, Von Rosenstiel P, Putzki N, Meinel M, et al. Clinical and magnetic resonance imaging (MRI) disease activity after fingolimod discontinuation. Multiple Sclerosis 2013;19:227–8.
Zarbin 2013 {published data only}
Zarbin M, Jampol L, Jager R, Reder A, Francis G, Collins W, et al. Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis. Ophthalmology 2013;120(7):1432–9.
References to studies awaiting assessment

NCT01317004 {published data only}
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NCT01633112. A 12-month, randomized, rater- and dose-blinded study to compare the efficacy and safety of fingolimod 0.25 mg and 0.5 mg administered orally once daily with glatiramer acetate 20 mg administered subcutaneously once daily in patients with relapsing-
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NCT01892722 {published data only}
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NCT02141022 {published data only}
NCT02141022. A pilot study of plasticity-based and adaptive cognitive remediation in adults with multiple sclerosis treated with Gilenya. https://clinicaltrials.gov/ct2/ show/study/NCT02141022?term=NCT02141022&rank= 1 (accessed 26 June 2015).
NCT02307838 {published data only}
NCT02307838. Long-term follow-up at 10 years of patients enrolled in the fingolimod phase ii program in relapsing multiple sclerosis. https://clinicaltrials.gov/ct2/ show/NCT02307838?term=NCT02307838&rank=1 (accessed 10 December 2015).
NCT02342704 {published data only}
NCT02342704. A multicenter, randomized, open-label study to assess the impact of Natalizumab versus fingolimod on central nervous system tissue damage and recovery in active relapsing-remitting multiple sclerosis subjects. https:
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References to other published versions of this review

Shaneh 2011
Shaneh Saz A, Firwana BM, Hasan R, Kojan S, La Mantia L, Filippini G. Fingolimod for relapsing remitting multiple sclerosis. Cochrane Database of Systematic Reviews 2011, Issue 10. [DOI: 10.1002/14651858.CD009371]
∗ Indicates the major publication for the study

C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Calabresi 2014

Methods
Randomised, double-blind, placebo-controlled parallel groups, phase III trial Multicentre (117 centres) performed across eight countries, predominantly in USA (101)
, 1 centre in Australia, 1 centre in Austria, 2 centres in Canada, 3 centres in Poland, 3 centres in Romania, 5 centres in Turkey, 1 centre in United Kingdom
Duration: 24 months
Enrollment: from June 2006 to March 2009 Acronym: FREEDOMS II

Participants
1083 participants with RRMS Inclusion criteria:
1. 18 to 55 years of age
2. Diagnosis of RRMS according to the 2005 revised McDonald criteria (Polman 2005)
3. One or more confirmed relapses during the preceding year (or two or more confirmed relapses during the previous two years)
4. EDSS score between 0 to 5.5 points (Kurtzke 1983)
5. No relapse or steroid treatment within 30 days before randomisation
6. Both treatment-naive and previously treated people
7. Previously treated participants were eligible if interferon beta or glatiramer acetate therapy was stopped at least three months before randomisation and natalizumab treat- ment at least six months before randomisation
Exclusion criteria:
1. Clinically significant systemic disease
2. Immune suppression (drug-induced or disease induced)
3. Active infection or macular oedema, diabetes mellitus
4. History of malignancy (apart from successfully treated basal or squamous-cell skin carcinoma)
5. Participants with specific cardiac, pulmonary, or hepatic disorders
6. Varicella ZV IgG antibody negative (Calabresi 2014, Supplementary web appendix)

Interventions
Participants were randomly allocated to one of the three groups:
1. Fingolimod 0.5 mg orally once-daily (358 participants)
2. Fingolimod 1.25 mg orally once-daily (370 participants)
3. Placebo orally once-daily (355 participants)
After review of data from the FREEDOMS and TRANSFORMS studies, on Nov 12, 2009, participants treated with the 1.25 mg dose, owing to the absence of clear added benefits and a higher risk for safety events such as infections and macular oedema ( Calabresi 2014, Supplementary web appendix), were subsequently switched to the 0.5 mg dose in a blinded manner

Outcomes
Primary endpoint was the annualised relapse rate (defined as the number of confirmed relapses) at 24 month period
A relapse was confirmed when it was accompanied by an increase of at least half a point on EDSS score, an increase of 1-point in 2 different functional systems, or 2-points in 1 functional system (excluding bowel, bladder, or cerebral functional systems)

The clinical secondary objectives were as follows.
1. Time to disability progression confirmed at 3 months
2. Time to disability progression confirmed at 6 months
Progression was defined as 1-point EDSS change or 0.5-point if baseline EDSS was > 5. 0
3. Safety and tolerability
4. Time to first relapse
5. Proportion of relapse-free patients
6. Change from baseline to the end of study on the MSFC score
7. Quality of life using the EQ-5D and Patient Reported Indices in Multiple Sclerosis (PRIMUS)
8. Fatigue using the Modified Fatigue Impact Scale (MFIS) The MRI secondary objectives were:
1. Percent brain-volume change from baseline at 24 months
2. Number and volume of gadolinium-enhancing T1 lesions
3. Number of new or newly enlarged T2 lesions
4. Proportion of participants free of gadolinium-enhancing T1 lesions
5. Proportion of participants free of new or newly enlarged T2 lesions
6. Proportion of participants free of new inflammatory activity (no gadolinium-enhanc- ing T1 lesions and no new or newly enlarged T2 lesions)
7. Percentage change from baseline in volume of gadolinium-enhancing T1 lesions
8. Percentage change from baseline in volume of new or newly enlarged T2 lesions
9. Percentage change from baseline in brain volume

Notes
The trial was registered with clinicaltrials.gov, number NCT00355134 The study was sponsored by Novartis Pharma
Risk of bias

Bias
Authors’ judgement
Support for judgement

Random sequence generation (selection bias)
Low risk
“randomlyallocated patients (1:1:1; stratified by study centre). The randomisation sequence was generated with an automated system” pg 546

Allocation concealment (selection bias)
Unclear risk
“the randomisation sequence was generated with an automated system” under the super- vision of the Novartis Drug Supply Manage- ment team“ pg 546

Blinding of participants and personnel (performance bias)
All outcomes
Low risk
”both Fingolimod and placebo were dispensed in hard gelatin capsules of identical colour and size and packed in identical bottles“ pg 546

Blinding of outcome assessment (detection bias)
All outcomes
Low risk
”The efficacy assessments (i.e., confirmation of relapses, scheduled EDSS, and Multiple Sclerosis Functional Composite [MSFC] were

done by an independent, specially trained, andcertified assessor not otherwise involved in the treatment of patient“.”In order to main- tain the blind, efficacy assessments (i.e., sched- uled EDSS and confirmation of relapses) were performed by an independent evaluat- ing physician, not involved with any other aspects of subject care and management. Pa- tients were instructed not to discuss adverse events with the independentevaluating physi- cian“ (Supplementary web appendix)
All MRI scans were centrally reviewed by an independent radiologist (E-WR) unaware of treatment allocation”

Incomplete outcome data (attrition bias) All outcomes
High risk
Overall, 28.2% (305/1083) discontinued the study [32.2% (119/370) in fingolimod
1.25 mg, 24.0% (86/358) in fingolimod 0. 5 mg, and 28.2% (100/ 355) in placebo], with some significant differences in rea- sons: unsatisfactory therapeutic effect (2. 7% in fingolimod 1.25 mg, 1.7% in fin- golimod 0.5 mg, and 4.8% in placebo) and adverse events or abnormal laboratory val- ues (12.7% in fingolimod 1.25 mg, 10. 1% in fingolimod 0.5 mg, and 5.1% in placebo)

Selective reporting (reporting bias)
Unclear risk
Differences between study design described in the article (protocol not available) and reported findings were not found. After 9 months from enrolment conclusion, par- ticipants treated with 1.25 mg were shifted to 0.5 mg. The number of participants shifted to 0.5 mg and the treatment dura- tion were unknown

Other bias
High risk
The study was sponsored by Novartis Pharma, “The study sponsor participated in the design of the study, conduct of the study, data collection, datamanagement, data anal- ysis and interpretation, and preparation, re- view, and approval of the paper” pg 550, and four co-authors of the published paper were affiliated to the pharmaceutical company

Methods
Randomised, double-blind, 3 parallel group phase III trial
Multicentre (172 centres) performed in 18 countries (Argentina, Australia, Austria, Bel- gium, Brazil, Canada, Egypt, France, Germany, Greece, Hungary, Italy, Republic of Ko- rea, Portugal, Spain, Switzerland, UK, USA)
Duration: 12 months
Enrollment: from May 2006 to September 2007 Acronym: TRANSFORMS

Participants
1292 participants with RRMS Inclusion criteria:
1. 18 to 55 years of age
2. Relapsing-remitting course
3. At least 1 documented relapse in the previous year or at least 2 documented relapses in the previous 2 years
4. EDSS score between 0 to 5.5 Exclusion criteria:
1. A documented relapse or corticosteroid treatment within 30 days before randomisation
2. Active infection
3. Macular edema
4. Immune-suppression (either drug- or disease-induced)
5. Clinically significant coexisting systemic disease
Previous disease-modifying therapy was not considered an exclusion criteria. The per- centage of previously treated participants was 56.7%, in details 56.3% in interferon beta- 1a group, 55.2% in fingolimod 0.5 mg and 58.5% in fingolimod 1.25 mg. Most of them were treated with any interferon beta. Glatiramer acetate was previously administered in 15.7%, 13.1% and 15.4%, and natalizumab in 0.2%, 0.9% and 0.7% respectively

Interventions
Participants were randomly allocated to one of the three groups:
1. Fingolimod 1.25 mg orally once-daily (426 participants)
2. Fingolimod 0.5 mg orally once-daily (431 participants)
3. Interferon beta-1a 30 ug intramuscularly once a week (435 participants)

Outcomes
Primary endpoint was the annualised relapse rate (defined as the number of confirmed relapses) at 12-month period
Relapse was defined as new, worsening, or recurrent neurologic symptoms that occurred at least 30 days after the onset of a preceding relapse, that lasted at least 24 hours without fever or infection, and that were accompanied by an increase of at least half a point on EDSS or an increase of at least 1-point in 2 functional systems scores or of at least 2- points in 1 functional system score (excluding changes in bowel or bladder function and cognition)
Secondary endpoints:
1. Number of new or enlarged lesions on T2-weighted MRI scans at 12 months
2. Time to confirmed disability progression
Progression of disability was defined as a 1-point increase in EDSS score (or a half point increase for participants with a baseline score 5.5) that was confirmed 3 months later in the absence of relapse

Notes
The trial was registered with clinicaltrials.gov, number: NCT00340834 The study was sponsored by Novartis Pharma

Risk of bias

Bias
Authors’ judgement
Support for judgement

Random sequence generation (selection bias)
Low risk
“Randomisation was performed in blocks of six within each site and was stratified accord- ing to site” pg 403

Allocation concealment (selection bias)
Low risk
“Randomisation was performed centrally” and “Study-group assignments were per- formed with the use of an interactive voice- response system” pg 403

Blinding of participants and personnel (performance bias)
All outcomes
Low risk
“During the trial, patients, study personnel, steering-committee members, and the study statistician were unaware of study-group as- signments and leukocyte counts. Capsules, sy- ringes, and packaging materials for active and placebo treatments were indistinguish- able” pg 404

Blinding of outcome assessment (detection bias)
All outcomes
Low risk
“At each site, a treating neurologist super- vised medical management”, “Patients were instructed to cover injection sites at visits, to not to discuss adverse events with clinical eval- uators”, and “Potential relapses triggered an unscheduled visit and were confirmed by the treating neurologist on the basis of blinded ex- amination by the examining neurologist” pg 403-404
The treating neurologist was possibly not blinded. Moreover, it is not clear how and when the examining neurologist evaluated the potential relapse
MRI evaluators were unaware of study group assignment and leukocyte counts. An independent data and safety monitor- ing board evaluated overall safety in the fin- golimod phase 3 program

Incomplete outcome data (attrition bias) All outcomes
Low risk
Overall, 10.8% (139/1292) discontinued the study [13.4% (57/426) in fingolimod
1.25 mg, 7.7% (33/43) in fingolimod 0. 5 mg, and 11.3% (49/435) in interferon beta-1a)], with some non-significant differ- ences in reasons: unsatisfactory therapeutic effect (0.7% in fingolimod 1.25 mg, 0.7% in fingolimod 0.5 mg, and 1.6% in inter-

feron beta-1a) adverse events (6.1% in fin- golimod 1.25 mg, 2.1% in fingolimod 0. 5 mg, and 2.1% in interferon beta-1a) and abnormal laboratory values (0.9% in fin- golimod 1.25 mg, 1.4% in fingolimod 0.5 mg, and 0.2% in interferon beta-1a)

Selective reporting (reporting bias)
Low risk
Additional MRI data from the key end- points were reported (protocol not avail- able)

Other bias
High risk
The study was sponsored by Novartis Pharma, “data were analysed by the spon- sor” pg 403, and five co-authors of the pub- lished paper were affiliated to the pharma- ceutical company

Fox 2014

Methods
Randomised active comparator, parallel group, open-label, phase IV trial Multicentre study (157), 152 centres in the USA and 6 centres in Canada Duration: 6 months
Enrollment: between August 2010 and August 2012. Acronymus: EPOC

Participants
1053 participants with RRMS Inclusion criteria
1. 18 to 65 years of age
2. Diagnosis of relapsing MS in accordance with the 2005 McDonald criteria (Polman 2005)
3. EDSS score between 0 to 5.5
4. Treated with an injectable (DMD for at least 6 months before screening
5. Participants must be candidates for a change in therapy as determined by the treating physician
6. Treatment-naïve to fingolimod Exclusion criteria
1. History of chronic disease of the immune system (except for MS)
2. Immunodeficiency
3. Malignancy other than localized basal cell carcinoma within the past 5 years
4. Cardiac arrest, myocardial infarction, ischaemic heart disease, or coronary spasm within 6 months
5. Mobitz type II second-degree heart block, third-degree atrioventricular block, or an increased QTc interval (4470 ms)
6. Uncontrolled diabetes mellitus (glycated haemoglobin > 7%)
7. Bone marrow transplant
8. Alcohol abuse within the past 5 years
9. Macular edema present at screening
10. Negative test for varicella zoster immunoglobulin G antibodies

11. Positive tests for hepatitis B, hepatitis C, or HIV
12. Active systemic bacterial, viral or fungal infections, tuberculosis
13. Pregnancy
14. Uncontrolled or poorly controlled cardiovascular and pulmonary disorders (hyper- tension or asthma; cardiac failure; severe respiratory disease or pulmonary fibrosis)
15. Chronic liver or biliary disease
16. Previous treatment with immunosuppressants, immunoglobulins, or monoclonal antibodies within 6 months before screening; any live or live attenuated vaccines within 1 month before screening; cladribine, cyclophosphamide, or mitoxantrone at any time; and class Ia or class III antiarrhythmic drugs at time of screening
Participants randomly assigned to treatment with fingolimod changed from their pre- randomisation DMD with no washout
period. Participants randomised to the DMD group chose to either remain on the same therapy or, following a consultation with a physician, switch immediately to another approved DMD

Interventions
Participants were randomly allocated to one of the two groups:
1. Fingolimod 0.5 mg orally once-daily (790 participants)
2. DMD (263 participants): interferon beta 1-b (Extavia® or Betaseron®) 0.25 mg injected subcutaneously every other day (46 participants); interferon beta 1-a (Avonex®) 30 µg intramuscular injected once a week (60 participants); interferon beta-1a (Rebif®) 22 µg or 44 µg injected subcutaneously three times a week (65 participants); or glatiramer acetate (Copaxone®) 20 mg injected subcutaneously once-daily (92 participants)

Outcomes
Primary endpoint was to evaluate differences in satisfaction as measured by the Global Satisfaction subscale score on the Treatment Satisfaction Questionnaire for Medication (Atkinson 2004)
Secondary objectives were 1, Effectiveness
2. Side effects
3. Fatigue
4. Depression
5. Activities of daily living
6. Health-related QOL measured using the 36-item Short-Form Health Survey v2 (SF- 36 v2) (Jenkinson 1999)

Notes
The trial was registered with clinicaltrials.gov, number: NCT01216072
Four co-authors of the published paper were affiliated to the pharmaceutical company (Novartis)
Risk of bias

Bias
Authors’ judgement
Support for judgement

Random sequence generation (selection bias)
Low risk
“Patients were randomised using an interac- tive voice response system (IVRS) to either the once-daily fingolimod (FTY720; Gileny- aTM, Novartis Pharma AG, Basel, Switzer- land) 0.5 mg arm or the injectable DMT

arm, in a 3:1 ratio. A patient randomisation list was produced by an interactive voice re- sponse system using a validated system that automated the random assignment of patient numbers to the different treatment arms” pg 5

Allocation concealment (selection bias)
Low risk
“A patient randomisation list was produced by the IVRS using a validated system that automated the random assignment of patient numbers to the different treatment arms”

Blinding of participants and personnel (performance bias)
All outcomes
High risk
“Fingolimod capsules (0.5 mg) were supplied, packaged, and labelled in accordance with the US Code of Federal Regulations governingthe handling of investigational treatments. The capsules were dispensed by the study physician and supplied by Novartis Drug Supply Man- agement. Patients randomised to the DMT group could choose to either remain on the same therapy”

Blinding of outcome assessment (detection bias)
All outcomes
High risk
The study was open- label

Incomplete outcome data (attrition bias) All outcomes
High risk
Overall, 10.4% (110/1053) discontinued the study (9.6% – 76/790 – in fingolimod 0.5 mg, and 12.9% – 34/263 – in DMD)
, with some significant differences in rea- sons: unsatisfactory therapeutic effect (0. 4% in fingolimod 0.5 mg, and 1.5% in DMD), adverse events (5.3% in fin- golimod 0.5 mg, and 1.5% in DMD group)

Selective reporting (reporting bias)
Low risk
Inclusion and exclusion criteria were de- tailed in the protocol Cascione 2013 and summarised in the published primary study (Fox 2014). Missing data (SD of QOL values) request to the Authors (12 March 2015) were not provided

Other bias
High risk
The study was sponsored by Novartis Pharma, and 4 co-authors of the published paper were affiliated to the pharmaceutical company. The criteria for changing treat- ment were undefined “ Participants must be candidates for a change in therapy as de-

termined by the treating physician. Partici- pants randomised to the DMD group could have choose to either remain on the same ther- apy or, following a consultation with a physi- cian, switch immediately to another approved DMD ”

Kappos 2006

Methods
Randomised, double-blind, 3 parallel groups double-dummy phase II (proof of concept) trial
Multicentre (32 centres) performed in Canada and in 10 European countries (Denmark, Finland, France, Germany, Italy, Poland, Portugal, Spain, Switzerland, UK
Duration: 6 months
Enrollment: from May 2003 to April 2004 Acronym: FTY720 D2201

Participants
281 patients with MS, 246 with RRMS and 31 with SPMS Inclusion criteria:
1. Age 18-60 years
2. Diagnosis of relapsing multiple sclerosis (Mc Donald 2001)
3. At least one of the following: two or more documented relapses during the previous 2 years, one or more documented relapses in the year before enrolment, and one or more gadolinium-enhancing lesions detected on magnetic resonance imaging (MRI) at screening
4. EDSS score between 0 to 6
5. Neurologically stable condition, with no evidence of relapse for at least 30 days before screening and during the screening and baseline phases
Exclusion criteria:
1. Use of corticosteroids (within the previous 30 days)
2. Immunomodulatory therapy (within the previous 3 months)
3. Immunosuppressive treatment (azathioprine or methotrexate within 6 months, cyclo- phosphamide within 12 months, or mitoxantrone or cladribine within 24 months)
4. History of cardiac conditions that might increase the risk of a decrease in heart rate
5. White-cell count less than 3500 per cubic millimetre
6. Lymphocyte count of less than 800 per cubic millimetre

Interventions
Participants were randomly allocated to one of the three groups:
1. Fingolimod 5.0 mg orally once- daily (94 patients)
2. Fingolimod 1.25 mg orally once- daily (94 patients)
3. Placebo orally once- daily (93 patients)

Outcomes
Primary endpoint was the total number of gadolinium-enhancing lesions per patient recorded on T1-weighted MRI at monthly intervals for 6 months
The clinical secondary objectives were:
1. Number of participants remaining free of relapse
2. Annualised relapse rate
3. Time to the first relapse
Confirmed relapse was defined as the occurrence of new symptoms or worsening of

previously stable or improving symptoms and signs not associated with fever, lasting more than 24 hours and accompanied by an increase of at least half a point in EDSS score or 1-point in the score for at least 1 of the functional system (excluding the bowel and bladder and mental systems)
The MRI secondary objectives were:
1. Total volume of gadolinium-enhancing lesions per patient
2. Proportion of participants with gadolinium-enhancing lesions
3. Total number of new lesion per patient on T-weighted images
4. Changes in lesion volume on T2-weighted images
5. Brain volume from baseline to month 6

Notes
The study was sponsored by Novartis Pharma
The trial was registered with clinicaltrials.gov,numbers: NCT00333138 (for core study) and NCT00235430 (for the extension)
After the core study, participants could continue in the extension study; participants who had received active treatment in the core study continued with the same dose, and those who had received placebo were randomly assigned to receive 1.25 or 5.0 mg of fingolimod. The results have been reported for 227 out of 281 (81%) at 1 year (Kappos 2006), for 189 (67%) at 2 (O’Connor 2009), for 173 (62%) at 3 (Comi 2010), for 140
(49.8%) at 5 (Izquierdo 2013; Montalban 2011b,) for 122 (43.4%) at 7 years (Antel
2012; Montalban 2012)
Risk of bias

Bias
Authors’ judgement
Support for judgement

Random sequence generation (selection bias)
Low risk
“In the core study, patients were randomly as- signed, in a 1:1:1 ratio, to 1.25 mg of fin- golimod, 5.0 mg of fingolimod, or a matching placebo once daily” pg 1125

Allocation concealment (selection bias)
Low risk
“Randomisation was stratified according to disease course (relapsing-remitting or sec- ondary progressive) with the use of a cen- tralized automated system that provided ran- domised packages of the study drug to each centre” pg 1125

Blinding of participants and personnel (performance bias)
All outcomes
Low risk
“All drugs were given as identical capsules” and “The medication was prepackaged on the basis of a block size of 3; this information was not disclosed to investigators and monitors” pg 1125 and “ Laboratory values that might have revealed the treatment assignment (e.g., lymphocyte counts) were not disclosed to treat- ing physicians unless they exceeded prespeci- fied safety limits” pg 1126

Blinding of outcome assessment (detection bias)
All outcomes
Low risk
Information about participants assign- ments was not disclosed to investigators and monitors, “Relapses were confirmed by the treating physician on the basis of an exam- ination by the EDSS rater who was not oth- erwise involved in patient care. When war- ranted, relapses were managed by the treating physician according to a standardized scheme” and “Neurologic assessments were performed by specially trained, independent neurologists who were unaware of the treatment assign- ments, were not involved in the everyday care of the patients, andhadnoaccess to their med- ical records” pg 1126

Incomplete outcome data (attrition bias) All outcomes
Low risk
Overall, 1.4% (4/281) discontinued the study [2.1% (2/94) in fingolimod 5.0 mg, 1.1% (1/94) in fingolimod 1.25 mg, and 1.1% (1/93) in placebo] pg 1128
Reasons for lost-to follow up were not re- ported

Selective reporting (reporting bias)
Low risk
Quality of life assessment was not registered either among the study endpoints of the published RCT or in the study registration at the clinicaltrials.gov. The data have been published Montalban 2011a

Other bias
Low risk
The study was supported by Novartis Pharma, Basel, Switzerland. There are no potential risks for other biases. The steer- ing-committee members and the sponsors designed the study. The authors had access to all data. An independent external data and safety monitoring board evaluated ad- verse events and other safety data as well as clinical and MRI efficacy data

Methods
Randomised, double-blind, 3 parallel group placebo controlled phase III trial Multicentre (138 centres) performed in 22 countries (Australia, Belgium, Canada, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Israel, Nether- lands, Poland, Romania, Russia, Slovakia, South Africa, Sweden, Switzerland, Turkey, UK)
Duration: 2 years
Enrollment: from January 2006 to August 2007 Acronym: FREEDOMS

Participants
1272 participants with RRMS Inclusion criteria:
1. 18 to 55 years of age
2. Diagnosis of multiple sclerosis, according to the revised McDonald criteria (Polman 2005)
3. Relapsing-remitting course
4. One or more documented relapses in the previous year or two or more in the previous 2 years
5. EDSS score between 0 to 5.5 Exclusion criteria:
1. Relapse or corticosteroid treatment within 30 days before randomisation
2. Active infection
3. Macular edema
4. Diabetes mellitus
5. Immune suppression (drug- or disease-induced)
6. Clinically significant systemic disease
7. Interferon beta or glatiramer acetate therapy within 3 months

Interventions
Participants were randomly allocated to one of the three groups:
1. Fingolimod 0.5 mg orally once-daily (425)
2. Fingolimod 1.25 mg orally once-daily (429)
3. Placebo orally once-daily (418)

Outcomes
Primary endpoint was the annualised relapse rate (defined as the number of confirmed relapses per year)
To constitute a confirmed relapse, the symptoms must have been accompanied by an increase of at least half a point in the EDSS score, of 1 point in each of 2 EDSS functional system scores, or of 2 points in 1 EDSS functional-system score (excluding scores for the bowel-bladder or cerebral functional systems)
The clinical secondary objectives were:
1. Time to the first relapse
2. Time to confirmed disability progression confirmed at 3 months
3. Time to confirmed disability progression confirmed at 6 months
Time to confirmed disability progression was defined as an increase of 1-point in the EDSS score (or half a point if the baseline EDSS score was equal to 5.5), confirmed after 3 months, with an absence of relapse at the time of assessment and with all EDSS scores measured during that time
4. Changes in the EDSS score and MSFC z score between baseline and 24 months
5. Safety and tolerability
The MRI secondary objectives were:

1. Number of gadolinium-enhancing lesions
2. Proportion of participants free from gadolinium-enhancing lesions
3. Number of new or enlarged lesions on T2-weighted MRI scans
4. Proportion of participants free from new or enlarged lesions on T2-weighted scans
5. Volume of hyperintense lesions on T2-weighted scans
6. Volume of hypointense lesions on T1-weighted scans
7. Change in brain volume between baseline and 24 months

Notes
The trial was registered with clinicaltrials.gov number: NCT00289978 The study was sponsored by Novartis Pharma
Risk of bias

Bias
Authors’ judgement
Support for judgement

Random sequence generation (selection bias)
Low risk
”Randomization was performed centrally with the use of stratification according to site, with a block size of six within each site“ pg 388

Allocation concealment (selection bias)
Low risk
” Patients were randomly assigned, in a 1: 1:1 ratio, to receive oral fingolimod capsules in a dose of 0.5 mg or 1.25 mg or matching placebo. Randomisation was performed cen- trally, with the use of a validated system and stratification according to site, with a block size of six within each site“ pg 388

Blinding of participants and personnel (performance bias)
All outcomes
Low risk
”Double blind“ (pg 388) procedure and methods ”to ensure that all assessments re- mained unbiased regarding the study-group assignments (i.e., unaffected by awareness of them) were adopted pg 388

Blinding of outcome assessment (detection bias)
All outcomes
Low risk
“To ensure that all assessments remained un- biased regarding the study-group assignments (i.e., unaffected by awareness of them), an in- dependent examining neurologist determined all the EDSS scores , this examining neurolo- gist or a trained technician administered the Multiple Sclerosis Functional Composite pg
388. Another independent physician moni- tored patients for 6 or more hours after ad- ministration of the first dose of the study drug pg 389. Relapses were verified by the examin- ing neurologist within 7 days after the onset of symptoms”
MRI scans were analysed at a central MRI

evaluation centre by radiologists who were unaware of the study group assignments and an independent data and safety moni- toring board evaluated the safety and over- all benefit-risk profiles

Incomplete outcome data (attrition bias) All outcomes
High risk
Overall, 18.7% (238/1272) discontinued the study [22.4% (96/429) in fingolimod
1.25 mg, 13.2% (56/425) in fingolimod 0.5 mg, and 20.6% (86/418) in placebo], with some significant differences in rea- sons: unsatisfactory therapeutic effect (3. 0% in fingolimod 1.25 mg, 1.4% in fin- golimod 0.5 mg, and 6.0% in placebo) and abnormal laboratory values (4.7% in fin- golimod 1.25 mg, 2.1% in fingolimod 0.5 mg, and 0.2% in placebo)

Selective reporting (reporting bias)
Low risk
Differences between study design described in the article (protocol not available) and reported findings were not found

Other bias
High risk
The study was sponsored by Novartis Pharma, “data were analysed by the sponsor” pg 388, and 4 co-authors of the published paper were affiliated to the pharmaceutical company

Saida 2012

Methods
Randomised, double-blind, parallel group phase II trial Multicentre (43 centres) performed in Japan
Duration: 6 months
Enrollment: from October 2007 to February 2010 Acronym: none

Participants
171 Japanese participants with MS, 167 with RRMS and 4 with SPMS Inclusion criteria:
1. 18-60 years of age
2. Diagnosis of MS according to the revised McDonald criteria (Polman 2005)
3. Relapsing course of the disease (relapsing-remitting or secondary progressive)
4. One or more relapses in the previous year or 2 or more relapses in the previous two years or at least one gadolinium enhanced T1-weighted brain lesion within the 30 days prior to study commencement
5. EDSS score between 0 to 6
6. At least one T2-weighted brain lesion Exclusion criteria
1. Long cord lesions of at least three vertebral segments on spinal MRI

2. Primary progressive MS
3. Relapse or corticosteroid treatment within 30 days before randomisation
4. Malignancy
5. Macular oedema
6. Diabetes mellitus
7. Active infection
8. Clinically significant systemic disease
9. Pregnancy
10. Received cladribine, cyclophosphamide, mitoxantrone, or other immunosuppressive or immunoglobulin medication in the six months prior to randomisation, or who had had plasmapheresis immunoadsorption or interferon beta therapy in the three months prior to randomisation
11. History of cardiac disorder including arrhythmia
12. Pulmonary condition including asthma
13. Leukopenia less than 3500 cell/mm3 or lymphocyte count of less than 800
14. Abnormal liver enzyme
15. Negative for varicella zoster at screening
16. Received any live or live attenuated vaccines

Interventions
Participants were randomly allocated to one of the three groups:
1. Fingolimod 0.5 mg orally once-daily (57)
2. Fingolimod 1.25 mg orally once-daily (57)
3. Placebo orally once-daily (57)
Relapses were treated with methylprednisolone up to 1000 mg/day for 3-5 days without an oral taper

Outcomes
Primary endpoint was the percentage of participants free from gadolinium-enhancing lesions at 3 and 6 months
Secondary endpoints were
1. Percentage of participants free from relapses over six months
2. Safety measures
Confirmed relapse was defined as new, worsening, or recurrent neurological symptoms that occurred at least 30 days after the onset of a preceding relapse, lasted at least 24 hours without fever or infection and were accompanied by an increase of at least half a point in EDSS score or an increase of at least 1-point in 2 functional systems scores or of at least 2-points in 1 functional system (excluding changes in bowel-bladder function and cognition)

Notes
The trial was registered with clinicaltrials.gov number: NCT00537082
The work was supported by Novartis Pharma KK and Mitsubishi Tanabe Pharma Corp.
, Tokyo, Japan
Risk of bias

Bias
Authors’ judgement
Support for judgement

Random sequence generation (selection bias)
Low risk
“Patients were randomly assigned, in a 1:1:
1 ratio, to receive once-daily fingolimod cap- sules, 0.5 mgor 1.25 mg, or matching placebo

for six months” pg 2

Allocation concealment (selection bias)
Low risk
Randomisation was performed by a central centre (Bellsystem 24 Inc., Tokyo), with the use of a validated system that assigned ran- domisation numbers to participants and automated the dynamic allocation of treat- ment arms to randomisation numbers

Blinding of participants and personnel (performance bias)
All outcomes
Low risk
The identity of treatments was concealed by the use of study drugs that were identi- cal in appearance, packaging, labelling and schedule of administration. “Patients, inves- tigators, site personnel, first-dose administra- tors remained blinded during the six-month core study” pg 2

Blinding of outcome assessment (detection bias)
All outcomes
Low risk
“MRI evaluators and data analysts remained blinded during the six-month core study” pg 2

Incomplete outcome data (attrition bias) All outcomes
Low risk
Overall, 14.0% (24/171) discontinued the study [15.8% (9/57) in fingolimod 1.25 mg, 15.8% (9/57) in fingolimod 0.5 mg, and 10.5% (6/57) in placebo] with some non-significant differences in reasons: ad- verse events (10.5% in fingolimod 1.25 mg, 10.5% in fingolimod 0.5 mg, and 5.3% in placebo) unsatisfactory therapeutic ef- fect (0% in fingolimod 1.25 mg, 0% in fin- golimod 0.5 mg, and 3.5% in placebo)

Selective reporting (reporting bias)
Low risk
All relevant study endpoints were reported. Protocol was not available

Other bias
Low risk
The study was sponsored by Novartis Pharma, and 3 co-authors of the published paper were affiliated to the pharmaceutical company
The inclusion criteria of participants are unclear (number at least one T2-weighted brain lesion and diagnosis according to Polman 2005)

DMD: disease-modifying drug; EDSS: Expanded Disability Status Scale; EQ-5D; Euro quality of life scale; IgG: immunoglobulin G; MRI: magnetic resonance imaging; MS: multiple sclerosis; MSFC: Multiple Sclerosis Functional Composite; RRMS: relapsing- remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis

Characteristics of excluded studies [ordered by study ID]

Study
Reason for exclusion

Boulton 2013
Type of participants: RCT evaluating the effect of fingolimod on pulmonary function in otherwise healthy people with moderate asthma

Chinea 2014
Pooled data of RCTs: subgroup analysis on Hispanic population

Comi 2013
Design: not randomised study (FIRST study)

Francis 2014
Pooled data of RCTs on safety: relationship between lymphocyte counts and infections

Gold 2014
Design: not randomised study on cardiac safety

Green 2013
Type of participants: RCT evaluating acute optic neuritis

Havla 2013
Design: not randomised study on people with relapsing-remitting MS during the first year after switching from natalizumab to fingolimod

Kappos 2014
Pooled data of RCTs on safety

Kappos 2014a
Pooled data of RCTs: subgroup analysis on participants previously treated with glatiramer acetate

Kappos 2015
Type of intervention: RCT evaluating immune response to influenza vaccine administered to people with MS treated with fingolimod or placebo

Kappos 2015a
Design: cross-over study evaluating the optimal timing for initiating fingolimod therapy following natalizumab discontinuation in RRMS. After baseline infusion of Natalizumab, patients were subsequently randomised to one of three treatment groups:
a) 8-week washout (8 weeks no treatment) followed by 24 weeks of treatment with fingolimod, b) 12-week washout (8 weeks no treatment and 4 weeks placebo) followed by 20 weeks of treatment with fingolimod, or c) 16-week washout (8 weeks no treatment and 8 weeks placebo) followed by 16 weeks of treatment with fingolimod

Karlsson 2014
Overview of studies reporting outcomes of pregnancies that occurred during fingolimod treatment

laroni 2013
Design: not randomised study on safety of the first dose of fingolimod in people with MS

Limmorth 2013
Design: not randomised study of the cardiac safety profile of the initiation of fingolimod treatment (START study)

Lublin 2016
Type of participants: primary progressive MS (INFORMS study)

Nolan 2013
Design: not randomised study on ophthalmic findings (macular volume) in people with MS

Van Lokven 2013
Design: not randomised study

Vollmer 2013 a
Pooled data of RCTs on disease outcome after fingolimod discontinuation

(Continued)

Zarbin 2013
Overview reporting ophthalmic outcomes of people with MS receiving fingolimod

MS: multiple sclerosis; RCT: randomised controlled trial

Characteristics of studies awaiting assessment [ordered by study ID]

NCT01317004

Methods
Randomised study evaluating the change in patient-reported treatment satisfaction after 6 months of treatment with fingolimod 0.5 mg/day versus DMD standard of care, using the global satisfaction subscale of the Treatment Satisfaction Questionnaire for Medication (TSQM-9)

Participants
RRMS

Interventions
Experimental: fingolimod
Active comparator: standard therapy

Outcomes
Primary outcome measure: change in patient-reported treatment satisfaction

Notes
This study has been completed (June 2014). Partial results on 61 patients of the EPOC study have been reported in the site clinicaltrials.gov (accessed 22 February 2016)

NCT01333501

Methods
An 18-month, open-label, rater-blinded, randomised, multicentre, 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 to RRMS and to assess possible relationship of these effects to regional brain atrophy

Participants
RRMS

Interventions
Experimental: fingolimod
Active comparator: interferon beta-1b

Outcomes
Cognitive dysfunction progression

Notes
The study has been completed (September 2015) (accessed 22 February 2016)

Methods
Phase IV, 6-month, randomised, active comparator, open-label, multicentre study to evaluate patient outcomes, safety and tolerability of fingolimod 0.5 mg/day in patients with relapsing-remitting multiple sclerosis who are candidates for MS therapy change from previous DMD

Participants
RRMS

Interventions
Experimental: fingolimod
Active comparator: standard DMD

Outcomes
Primary outcome measure: change in patient-reported treatment satisfaction

Notes
This study has been completed (June 2013) and partial results on 298 participants of the EPOC study comparing fingolimod versus Interferon beta-1a and glatiramer acetate have been reported in the site clinicaltrials.gov (accessed 22 February 2016)

NCT01623596

Methods
Evaluation of patient retention of fingolimod versus currently approved DMD in patients with RRMS (PREFERMS)
. A 12-month study where 1000 participants with RRMS will be randomised 1:1 to fingolimod or approved DMD. Participants will be in early stages of the disease and be treatment-naive or have only been treated with one class of DMD (Interferon beta or glatiramer acetate) for no more than 5 years total exposure

Participants
RRMS

Interventions
Experimental: fingolimod
Active comparator: disease modifying therapy

Outcomes
Primary outcome measures: retention on treatment

Notes
The study has been completed (August 2015) (accessed 22 February 2016)

DMD: disease-modifying drugs; MS: multiple sclerosis; RRMS: relapsing-remitting multiple sclerosis;

Characteristics of ongoing studies [ordered by study ID]

EUCTR2013-004622-29-IT

Trial name or title
A multicenter, randomised, open-label study to assess the impact of natalizumab versus fingolimod on central nervous system tissue damage and recovery in active relapsing-remitting multiple sclerosis subjects

Methods
Multicentre, randomised, open-label study

Participants
Relapsing-Remitting multiple sclerosis (RRMS)

Interventions
Experimental: fingolimod Active comparator: natalizumab

Outcomes
The effect of natalizumab compared to fingolimod on the evolution of
new on-treatment T1-gadolinium-enhancing lesions to persistent black holes over 52 weeks

Starting date
10 November 2014

Contact information
[email protected]

Notes
Authorised-recruitment may be ongoing or finished (EUCTR) (access 6 August 2015)

NCT01633112

Trial name or title
MS study evaluating safety and efficacy of two doses of fingolimod versus Copaxone

Methods
12-month, randomised, rater- and dose-blinded study to compare the efficacy and safety of fingolimod 0.25 mg and 0.5 mg administered orally once-daily with glatiramer acetate 20 mg administered subcutaneously once-daily in patients with RRMS

Participants
RRMS

Interventions
Experimental: fingolimod
Active comparator: glatiramer acetate

Outcomes
Primary outcome measure annualised relapse rate up to 12 months

Starting date
August 2012

Contact information
Novartis Pharmaceuticals

Notes
This study is currently recruiting participants

NCT01892722

Trial name or title
Two-year, double-blind, randomised multicenter, active-controlled study to evaluate safety and efficacy of oral fingolimod versus intramuscular Interferon beta-1a in paediatric patients with multiple sclerosis

Methods
Randomised controlled study

Participants
Paediatric patients with MS

Interventions
Oral fingolimod versus intramuscular Interferon beta-1a

Outcomes
Primary outcome measure: frequency of relapses in patients treated for up to 24 months

Starting date
July 2013

Contact information
Contact: Novartis Pharmaceuticals

Notes
This study is currently recruiting participants

NCT02141022

Trial name or title
Computerised exercise training for cognitive remediation in adults with multiple sclerosis treated with Gilenya

Methods
RCT investigating the efficacy of computer-based cognitive exercises as a means of cognitive remediation in patients with MS who are beginning Gileyna

Participants
MS

Interventions
Experimental: PACR program: plasticity based, adaptive cognitive remediation Active Comparator: Ordinary Computer Games

Outcomes
Primary outcome measure: change from baseline in neuropsychological test results at 12 weeks

Starting date
August 2013

Contact information
Lauren Krupp, Stony Brook University

Notes
This study is ongoing, but not recruiting participants

NCT02307838

Trial name or title
Long-term follow-up at 10 years of patients enrolled in the fingolimod phase II program in relapsing multiple sclerosis

Methods
Observational: to collect follow-up data on patients who were randomised and received one dose of study drug (fingolimod)

Participants
RRMS

Interventions
None

Outcomes
Change from baseline in Expanded Disability Status Scale at 10 years

Starting date
June 2014

Contact information
Novartis Pharmaceuticals

Notes
This study is currently recruiting participants

Trial name or title
The impact of natalizumab versus fingolimod on central nervous system tissue damage and recovery in active RRMS subjects (REVEAL)

Methods
To assess the effect of natalizumab compared to fingolimod on the evolution of new on-treatment T1- gadolinium-enhancing (Gd+) lesions to persistent black holes over 52 weeks

Participants
RRMS

Interventions
Experimental: natalizumab Active Comparator: fingolimod

Outcomes Cumulative number of ≥ 6-months confirmed T1-hypointense lesions arising from new on-treatment T1 Gd+

Starting date
November 2014

Contact information
Contact: Biogen Idec

Notes
This study is currently recruiting participants

MS: multiple sclerosis; RCT: randomised controlled trial; RRMS: relapsing-remitting multiple sclerosis;

Comparison 1. Participants free from relapse

Outcome or subgroup title

No. of studies

No. of
participants Statistical method Effect size

1 At 6 months 2 Risk Ratio (M-H, Random, 95% CI) Subtotals only

1.1 Fingolimod 0.5 mg versus
placebo 1 114 Risk Ratio (M-H, Random, 95% CI) 1.22 [0.96, 1.54]
1.2 Fingolimod 1.25 mg
versus placebo 2 299 Risk Ratio (M-H, Random, 95% CI) 1.27 [1.11, 1.45]
1.3 Fingolimod 5.0 mg versus placebo
2 At 12 months 1

1 184 Risk Ratio (M-H, Random, 95% CI)

Risk Ratio (M-H, Random, 95% CI) 1.30 [1.10, 1.53]

Subtotals only
2.1 Fingolimod 0.5 mg versus
interferon beta-1a 1 860 Risk Ratio (M-H, Random, 95% CI) 1.18 [1.09, 1.27]
2.2 Fingolimod 1.25 mg versus interferon beta-1a
3 At 24 months 1

2 851 Risk Ratio (M-H, Random, 95% CI)

Risk Ratio (M-H, Random, 95% CI) 1.15 [1.06, 1.24]

Subtotals only
3.1 Fingolimod 0.5 mg versus
placebo 2 1556 Risk Ratio (M-H, Random, 95% CI) 1.44 [1.28, 1.63]
3.2 Fingolimod 1.25 mg
versus placebo 2 1572 Risk Ratio (M-H, Random, 95% CI) 1.51 [1.29, 1.76]

Comparison 2. Participants free from disability worsening

Outcome or subgroup title

No. of studies

No. of
participants Statistical method Effect size

1 At 12 months 1 Risk Ratio (M-H, Random, 95% CI) Subtotals only

1.1 Fingolimod 0.5 mg versus
interferon beta-1a 1 860 Risk Ratio (M-H, Random, 95% CI) 1.02 [0.99, 1.06]
1.2 Fingolimod 1.25 mg versus interferon beta-1a
2 At 24 months 1

2 851 Risk Ratio (M-H, Random, 95% CI)

Risk Ratio (M-H, Random, 95% CI) 1.01 [0.98, 1.05]

Subtotals only
2.1 Fingolimod 0.5 mg versus
placebo 2 1556 Risk Ratio (M-H, Random, 95% CI) 1.07 [1.02, 1.11]
2.2 Fingolimod 1.25 mg
versus placebo 2 1572 Risk Ratio (M-H, Random, 95% CI) 1.08 [1.03, 1.12]

No. of Outcome or subgroup title studies No. of
participants Statistical method Effect size
1 Withdrawals due to adverse 3
events over 6 months Risk Ratio (M-H, Random, 95% CI) Subtotals only
1.1 Fingolimod 0.5 mg versus 1
placebo 114 Risk Ratio (M-H, Random, 95% CI) 2.0 [0.53, 7.61]
1.2 Fingolimod 0.5 mg versus 1
DMDs 1028 Risk Ratio (M-H, Random, 95% CI) 3.21 [1.16, 8.86]
1.3 Fingolimod 1.25 mg 2
versus placebo 298 Risk Ratio (M-H, Random, 95% CI) 1.60 [0.63, 4.03]
1.4 Fingolimod 5.0 mg versus 1
placebo 187 Risk Ratio (M-H, Random, 95% CI) 1.98 [0.62, 6.35]
2 Withdrawals due to adverse 1
events over 12 months Risk Ratio (M-H, Random, 95% CI) Subtotals only
2.1 Fingolimod 0.5 mg versus 1
interferon beta-1a 860 Risk Ratio (M-H, Random, 95% CI) 1.51 [0.81, 2.80]
2.2 Fingolimod 1.25 mg 1
versus interferon beta-1a 851 Risk Ratio (M-H, Random, 95% CI) 2.69 [1.54, 4.72]
3 Withdrawals due to adverse 2
events over 24 months Risk Ratio (M-H, Random, 95% CI) Subtotals only
3.1 Fingolimod 0.5 mg versus 2
placebo 1556 Risk Ratio (M-H, Random, 95% CI) 1.42 [0.89, 2.25]
3.2 Fingolimod 1.25 mg 2
versus placebo 1572 Risk Ratio (M-H, Random, 95% CI) 1.93 [1.48, 2.52]
4 Withdrawals due to serious 3
adverse events over 6 months Risk Ratio (M-H, Random, 95% CI) Subtotals only
4.1 Fingolimod 0.5 mg versus 1
placebo 114 Risk Ratio (M-H, Random, 95% CI) 1.67 [0.42, 6.65]
4.2 Fingolimod 0.5 mg versus 1
DMDs 1028 Risk Ratio (M-H, Random, 95% CI) 2.71 [0.83, 8.88]
4.3 Fingolimod 1.25 mg 2
versus placebo 298 Risk Ratio (M-H, Random, 95% CI) 2.36 [0.99, 5.66]
4.4 Fingolimod 5.0 mg versus 1
placebo 187 Risk Ratio (M-H, Random, 95% CI) 2.77 [1.04, 7.38]
5 Withdrawals due to serious 1
adverse events over 12 months Risk Ratio (M-H, Random, 95% CI) Subtotals only
5.1 Fingolimod 0.5 mg versus 1
interferon beta-1a 860 Risk Ratio (M-H, Random, 95% CI) 1.21 [0.72, 2.02]
5.2 Fingolimod 1.25 mg 1
versus interferon beta-1a 851 Risk Ratio (M-H, Random, 95% CI) 1.85 [1.15, 2.96]
6 Withdrawals due to serious 2
adverse events over 24 months Risk Ratio (M-H, Random, 95% CI) Subtotals only
6.1 Fingolimod 0.5 mg versus 2
placebo 1556 Risk Ratio (M-H, Random, 95% CI) 0.91 [0.55, 1.50]
6.2 Fingolimod 1.25 mg 2 1572 Risk Ratio (M-H, Random, 95% CI) 0.98 [0.74, 1.29]
versus placebo

Outcome or subgroup title

No. of studies

No. of
participants Statistical method Effect size

1 At 6 months 2 Rate Ratio (Random, 95% CI) Subtotals only

1.1 Fingolimod 0.5 mg versus
placebo 1 Rate Ratio (Random, 95% CI) 0.51 [0.26, 0.99]
1.2 Fingolimod 1.25 mg
versus placebo 2 Rate Ratio (Random, 95% CI) 0.44 [0.28, 0.70]
1.3 Fingolimod 5.0 mg versus 1 Rate Ratio (Random, 95% CI) 0.47 [0.26, 0.83]
placebo
2 At 12 months
1
Rate Ratio (Random, 95% CI)
0.56 [0.46, 0.69]
2.1 Fingolimod 0.5 mg versus
interferon beta-1a 1 Rate Ratio (Random, 95% CI) 0.48 [0.34, 0.70]
2.2 Fingolimod 1.25 versus 1 Rate Ratio (Random, 95% CI) 0.61 [0.47, 0.78]
interferon beta-1a
3 At 24 months
2
Rate Ratio (Random, 95% CI)
Subtotals only
3.1 Fingolimod 0.5 mg versus
placebo 2 Rate Ratio (Random, 95% CI) 0.50 [0.40, 0.62]
3.2 Fingolimod 1.25 mg
versus placebo 2 Rate Ratio (Random, 95% CI) 0.47 [0.38, 0.59]

Comparison 5. Participants free from gadolinium-enhancing lesions

Outcome or subgroup title

No. of studies

No. of
participants Statistical method Effect size

1 At 6 months 4 Risk Ratio (M-H, Random, 95% CI) Subtotals only

1.1 Fingolimod 0.5 mg versus
placebo 3 1519 Risk Ratio (M-H, Random, 95% CI) 1.42 [1.33, 1.51]
1.2 Fingolimod 1.25 mg
versus placebo 4 1674 Risk Ratio (M-H, Random, 95% CI) 1.43 [1.34, 1.53]
1.3 Fingolimod 5 mg versus placebo
2 At 12 months 1

3 158 Risk Ratio (M-H, Random, 95% CI)

Risk Ratio (M-H, Random, 95% CI) 1.74 [1.35, 2.25]

Subtotals only
2.1 Fingolimod 0.5 mg versus
placebo 2 1343 Risk Ratio (M-H, Random, 95% CI) 1.39 [1.30, 1.48]
2.2 Fingolimod 1.25 mg
versus placebo 2 1319 Risk Ratio (M-H, Random, 95% CI) 1.39 [1.30, 1.48]
2.3 Fingolimod 0.5 mg versus
interferon beta-1a 1 728 Risk Ratio (M-H, Random, 95% CI) 1.12 [1.05, 1.19]
2.4 Fingolimod 1.25 mg versus interferon beta-1a
3 At 24 months 1

2 706 Risk Ratio (M-H, Random, 95% CI)

Risk Ratio (M-H, Random, 95% CI) 1.13 [1.06, 1.20]

Subtotals only
3.1 Fingolimod 0.5 mg versus
placebo 2 1226 Risk Ratio (M-H, Random, 95% CI) 1.36 [1.27, 1.45]

3.2 Fingolimod 1.25 mg 2 1182 Risk Ratio (M-H, Random, 95% CI) 1.43 [1.33, 1.52]
versus placebo

Comparison 6. Mean change of MRI T2-weighted lesion load

Outcome or subgroup title

No. of studies

No. of
participants Statistical method Effect size

1 At 12 months 2 Mean Difference (IV, Random, 95% CI) Subtotals only

1.1 Fingolimod 0.5 mg versus 1 733 Mean Difference (IV, Random, 95% CI) -15.30 [-24.34, -6.
placebo 26]
1.2 Fingolimod 1.25 mg
versus placebo 1 706 Mean Difference (IV, Random, 95% CI) -16.0 [-25.23, -6.77]
1.3 Fingolimod 0.5 mg versus
interferon beta-1a 1 733 Mean Difference (IV, Random, 95% CI) -0.5 [-6.32, 5.32]
1.4 Fingolimod 1.25 mg versus interferon beta-1a
2 At 24 months 1

2 711 Mean Difference (IV, Random, 95% CI)

Mean Difference (IV, Random, 95% CI) -3.7 [-9.18, 1.78]

Subtotals only
2.1 Fingolimod 0.5 mg versus 2 1216 Mean Difference (IV, Random, 95% CI) -20.43 [-34.03, -6.
placebo 83]
2.2 Fingolimod 1.25 mg 2 1171 Mean Difference (IV, Random, 95% CI) -32.51 [-40.39, -24.
versus placebo 62]

Comparison 7. Quality of life

Outcome or subgroup title

No. of studies

No. of
participants Statistical method Effect size

1 At 6 months 2 Mean Difference (Random, 95% CI) Subtotals only

1.1 Fingolimod 1.25 mg
versus placebo (Hamburg Quality of Life Questionnaire) 1 Mean Difference (Random, 95% CI) -0.14 [-9.13, 8.85]
1.2 Fingolimod 0.5 mg versus DMDs (Change in FS36
Mental component summary) 1 Mean Difference (Random, 95% CI) 1.8 [0.42, 3.18]
1.3 Fingolimod 0.5 mg versus DMDs (Change in FS36 Physical component summary)
2 At 24 months 1

1 Mean Difference (Random, 95% CI)

Mean Difference (IV, Random, 95% CI) 1.30 [0.30, 2.30]

Subtotals only
2.1 Fingolimod 0.5 mg versus placebo (Euro quality of life
scale) 1 713 Mean Difference (IV, Random, 95% CI) -0.01 [-0.04, 0.02]

Outcome: 1 At 6 months

Study or subgroup Fingolimod Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M-
H,Random,95%
CI

M-
H,Random,95%
CI

1 Fingolimod 0.5 mg versus placebo

Saida 2012 45/57 37/57 100.0 % 1.22 [ 0.96, 1.54 ]
Subtotal (95% CI) 57
Total events: 45 (Fingolimod), 37 (Placebo) 57 100.0 % 1.22 [ 0.96, 1.54 ]
Heterogeneity: not applicable
Test for overall effect: Z = 1.64 (P = 0.10)
2 Fingolimod 1.25 mg versus placebo
Kappos 2006 80/93 61/92 66.1 % 1.30 [ 1.10, 1.53 ]
Saida 2012 45/57 37/57 33.9 % 1.22 [ 0.96, 1.54 ]
Subtotal (95% CI) 150 149 100.0 % 1.27 [ 1.11, 1.45 ]
Total events: 125 (Fingolimod), 98 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.20, df = 1 (P = 0.66); I2 =0.0% Test for overall effect: Z = 3.44 (P = 0.00058)
3 Fingolimod 5.0 mg versus placebo
Kappos 2006 79/92 61/92
Subtotal (95% CI) 92 92
Total events: 79 (Fingolimod), 61 (Placebo) Heterogeneity: not applicable
Test for overall effect: Z = 3.02 (P = 0.0025)

100.0 %

100.0 %

1.30 [ 1.10, 1.53 ]

1.30 [ 1.10, 1.53 ]

0.5 0.7 1 1.5 2
Favours placebo Favours fingolimod

Study or subgroup Fingolimod Placebo Risk Ratio Weight Risk Ratio

n/N
n/N M-
H,Random,95%
CI M-
H,Random,95%
CI

1 Fingolimod 0.5 mg versus
interferon beta-1a
Cohen 2010 (1) 354/429 302/431
100.0 % 1.18 [ 1.09, 1.27 ]
Subtotal (95% CI) 429 431

100.0 % 1.18 [ 1.09, 1.27 ]
Total events: 354 (Fingolimod), 302 (Placebo) Heterogeneity: not applicable
Test for overall effect: Z = 4.24 (P = 0.000022) 2 Fingolimod 1.25 mg versus interferon beta-1a
Cohen 2010 (2) 338/420 302/431 100.0 % 1.15 [ 1.06, 1.24 ]
Subtotal (95% CI) 420 431 100.0 % 1.15 [ 1.06, 1.24 ]
Total events: 338 (Fingolimod), 302 (Placebo) Heterogeneity: not applicable
Test for overall effect: Z = 3.50 (P = 0.00047)
Test for subgroup differences: Chi2 = 0.21, df = 1 (P = 0.65), I2 =0.0%

0.5 0.7 1 1.5 2
Favours placebo Favours fingolimod

(1) Placebo = interfern beta 1 a

(2) Palcebo = interferon beta 1 a

Study or subgroup Fingolimd Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M-
H,Random,95%
CI

M-
H,Random,95%
CI

1 Fingolimod 0.5 mg versus placebo
Calabresi 2014 (1) 256/358 187/355 50.6 % 1.36 [ 1.21, 1.53 ]
Kappos 2010 (2) 299/425 191/418 49.4 % 1.54 [ 1.36, 1.74 ]
Subtotal (95% CI) 783 773 100.0 % 1.44 [ 1.28, 1.63 ]
Total events: 555 (Fingolimd), 378 (Placebo)
Heterogeneity: Tau2 = 0.00; Chi2 = 2.13, df = 1 (P = 0.14); I2 =53% Test for overall effect: Z = 5.83 (P < 0.00001)
2 Fingolimod 1.25 mg versus placebo
Calabresi 2014 (3) 271/370 187/355 50.2 % 1.39 [ 1.24, 1.56 ]
Kappos 2010 (4) 320/429 191/418 49.8 % 1.63 [ 1.45, 1.84 ]
Subtotal (95% CI) 799 773 100.0 % 1.51 [ 1.29, 1.76 ]
Total events: 591 (Fingolimd), 378 (Placebo)
Heterogeneity: Tau2 = 0.01; Chi2 = 3.61, df = 1 (P = 0.06); I2 =72% Test for overall effect: Z = 5.09 (P < 0.00001)
Test for subgroup differences: Chi2 = 0.17, df = 1 (P = 0.68), I2 =0.0%

0.5 0.7 1 1.5 2
Favours placebo Favours fingolimod

(1) Estimated by Kaplan-Meier as reported in the primary study (Page 549)

(2) Estimated by Kaplan-Meier as reported in the primary study (Page 393)

(3) Estimated by Kaplan-Meier as reported in the primary study (Page 549)

(4) Estimated by Kaplan-Meier as reported in the primary study (Page 393)

Study or subgroup Fingolimod Placebo Risk Ratio Weight Risk Ratio

n/N
n/N M-
H,Random,95%
CI M-
H,Random,95%
CI

1 Fingolimod 0.5 mg versus
interferon beta-1a
Cohen 2010 (1) 404/429 397/431 100.0 % 1.02 [ 0.99, 1.06 ]
Subtotal (95% CI) 429 431 100.0 % 1.02 [ 0.99, 1.06 ]
Total events: 404 (Fingolimod), 397 (Placebo) Heterogeneity: not applicable
Test for overall effect: Z = 1.19 (P = 0.23)
2 Fingolimod 1.25 mg versus interferon beta-1a
Cohen 2010 (2) 392/420 397/431 100.0 % 1.01 [ 0.98, 1.05 ]
Subtotal (95% CI) 420 431 100.0 % 1.01 [ 0.98, 1.05 ]
Total events: 392 (Fingolimod), 397 (Placebo) Heterogeneity: not applicable
Test for overall effect: Z = 0.69 (P = 0.49)
Test for subgroup differences: Chi2 = 0.11, df = 1 (P = 0.74), I2 =0.0%

0.5 0.7 1 1.5 2
Favours placebo Favours fingolimod

(1) progression confirmed at 3 months (table 2 page 409)

(2) progression confirmed at 3 months (table 2 page 409)

Study or subgroup Fingolimod Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M-
H,Random,95%
CI

M-
H,Random,95%
CI

Calabresi 2014 (1) 309/358 292/355 45.9 % 1.05 [ 0.98, 1.12 ]
Kappos 2010 (2) 372/425 339/418 54.1 % 1.08 [ 1.02, 1.14 ]
Subtotal (95% CI) 783 773 100.0 % 1.07 [ 1.02, 1.11 ]

Calabresi 2014 (3) 322/370 292/355 45.9 % 1.06 [ 0.99, 1.13 ]
Kappos 2010 (4) 380/429 339/418 54.1 % 1.09 [ 1.03, 1.16 ]
Subtotal (95% CI) 799 773 100.0 % 1.08 [ 1.03, 1.12 ]

0.5 0.7 1 1.5 2
Favours placebo Favours fingolimod

(1) Estimated by Kaplan-Meier as reported in the primary study (Page 549)

(2) Estimated by Kaplan-Meier as reported in the primary study (Page 393)

(3) Estimated by Kaplan-Meier as reported in the primary study (Page 549)

(4) Estimated by Kaplan-Meier as reported in the primary study (Page 393)

Outcome: 1 Withdrawals due to adverse events over 6 months

Study or subgroup Fingolimod Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M-
H,Random,95%
CI

M-
H,Random,95%
CI

1 Fingolimod 0.5 mg versus placebo
Saida 2012 6/57 3/57
Subtotal (95% CI) 57 57
Total events: 6 (Fingolimod), 3 (Placebo) Heterogeneity: not applicable
Test for overall effect: Z = 1.02 (P = 0.31) 2 Fingolimod 0.5 mg versus DMDs
Fox 2014 41/783 4/245

Subtotal (95% CI) 783 245
Total events: 41 (Fingolimod), 4 (Placebo) Heterogeneity: not applicable
Test for overall effect: Z = 2.25 (P = 0.025) 3 Fingolimod 1.25 mg versus placebo
Kappos 2006 5/94 4/93

100.0 % 2.00 [ 0.53, 7.61 ]

100.0 % 2.00 [ 0.53, 7.61 ]

100.0 % 3.21 [ 1.16, 8.86 ]

100.0 % 3.21 [ 1.16, 8.86 ]

52.0 % 1.24 [ 0.34, 4.46 ]

Saida 2012 6/54 3/57
Subtotal (95% CI) 148 150
Total events: 11 (Fingolimod), 7 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.32, df = 1 (P = 0.57); I2 =0.0% Test for overall effect: Z = 0.99 (P = 0.32)
4 Fingolimod 5.0 mg versus placebo
Kappos 2006 8/94 4/93

Subtotal (95% CI) 94 93
Total events: 8 (Fingolimod), 4 (Placebo) Heterogeneity: not applicable
Test for overall effect: Z = 1.15 (P = 0.25)

48.0 % 2.11 [ 0.56, 8.02 ]

100.0 % 1.60 [ 0.63, 4.03 ]

100.0 % 1.98 [ 0.62, 6.35 ]

100.0 % 1.98 [ 0.62, 6.35 ]

0.01 0.1 1 10 100
Favours fingolimod Favours placebo

Study or subgroup Fingolimod Control Risk Ratio Weight Risk Ratio

n/N
n/N M-
H,Random,95%
CI M-
H,Random,95%
CI

1 Fingolimod 0.5 mg versus
interferon beta-1a

Cohen 2010 24/429 16/431 100.0 % 1.51 [ 0.81, 2.80 ]
Subtotal (95% CI) 429 431 100.0 % 1.51 [ 0.81, 2.80 ]
Total events: 24 (Fingolimod), 16 (Control) Heterogeneity: not applicable
Test for overall effect: Z = 1.30 (P = 0.19)
2 Fingolimod 1.25 mg versus interferon beta-1a
Cohen 2010 42/420 16/431
Subtotal (95% CI) 420 431
Total events: 42 (Fingolimod), 16 (Control) Heterogeneity: not applicable
Test for overall effect: Z = 3.47 (P = 0.00052)

100.0 %

100.0 %

2.69 [ 1.54, 4.72 ]

2.69 [ 1.54, 4.72 ]

0.1 0.2 0.5 1 2 5 10
Favours fingolimod Favours int beta-1

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio

n/N n/N

M-
H,Random,95%
CI

M-
H,Random,95%
CI

1 Fingolimod 0.5 mg versus placebo
Calabresi 2014 (1) 66/358 37/355 53.2 % 1.77 [ 1.22, 2.57 ]
Kappos 2010 (2) 38/425 34/418 46.8 % 1.10 [ 0.71, 1.71 ]
Subtotal (95% CI) 783 773 100.0 % 1.42 [ 0.89, 2.25 ]
Total events: 104 (Experimental), 71 (Control)
Heterogeneity: Tau2 = 0.07; Chi2 = 2.58, df = 1 (P = 0.11); I2 =61% Test for overall effect: Z = 1.46 (P = 0.14)
2 Fingolimod 1.25 mg versus placebo
Calabresi 2014 72/370 37/355 52.4 % 1.87 [ 1.29, 2.70 ]
Kappos 2010 (3) 70/429 34/418 47.6 % 2.01 [ 1.36, 2.95 ]
Subtotal (95% CI) 799 773 100.0 % 1.93 [ 1.48, 2.52 ]
Total events: 142 (Experimental), 71 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.07, df = 1 (P = 0.79); I2 =0.0% Test for overall effect: Z = 4.84 (P < 0.00001)
Test for subgroup differences: Chi2 = 1.29, df = 1 (P = 0.26), I2 =23%

0.1 0.2 0.5 1 2 5 10
Favours fingolimod Favours placebo

(1) table 3 page 552

(2) see Figure 1 page 391

(3) see Figure 1 page 391

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio

n/N n/N

M-
H,Random,95%
CI

M-
H,Random,95%
CI

1 Fingolimod 0.5 mg versus placebo
Saida 2012 5/57 3/57
Subtotal (95% CI) 57 57
Total events: 5 (Experimental), 3 (Control) Heterogeneity: not applicable
Test for overall effect: Z = 0.72 (P = 0.47) 2 Fingolimod 0.5 mg versus DMDs
Fox 2014 26/783 3/245

Subtotal (95% CI) 783 245
Total events: 26 (Experimental), 3 (Control) Heterogeneity: not applicable
Test for overall effect: Z = 1.65 (P = 0.099) 3 Fingolimod 1.25 mg versus placebo
Kappos 2006 (1) 8/94 5/93

100.0 % 1.67 [ 0.42, 6.65 ]

100.0 % 1.67 [ 0.42, 6.65 ]

100.0 % 2.71 [ 0.83, 8.88 ]

100.0 % 2.71 [ 0.83, 8.88 ]

55.3 % 1.58 [ 0.54, 4.66 ]

Saida 2012 11/54 3/57
Subtotal (95% CI) 148 150
Total events: 19 (Experimental), 8 (Control)
Heterogeneity: Tau2 = 0.06; Chi2 = 1.16, df = 1 (P = 0.28); I2 =14% Test for overall effect: Z = 1.93 (P = 0.054)
4 Fingolimod 5.0 mg versus placebo
Kappos 2006 (2) 14/94 5/93

Subtotal (95% CI) 94 93
Total events: 14 (Experimental), 5 (Control) Heterogeneity: not applicable
Test for overall effect: Z = 2.04 (P = 0.042)

44.7 % 3.87 [ 1.14, 13.12 ]

100.0 % 2.36 [ 0.99, 5.66 ]

100.0 % 2.77 [ 1.04, 7.38 ]

100.0 % 2.77 [ 1.04, 7.38 ]

0.01 0.1 1 10 100
Favours fingolimod Favours placebo

(1) see table 4 page 1135

(2) see table 4 page 1135

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio

n/N n/N

M-
H,Random,95%
CI

M-
H,Random,95%
CI

1 Fingolimod 0.5 mg versus interferon beta-1a
Cohen 2010 30/429 25/431
Subtotal (95% CI) 429 431
Total events: 30 (Experimental), 25 (Control) Heterogeneity: not applicable
Test for overall effect: Z = 0.71 (P = 0.48)
2 Fingolimod 1.25 mg versus interferon beta-1a
Cohen 2010 45/420 25/431

Subtotal (95% CI) 420 431
Total events: 45 (Experimental), 25 (Control) Heterogeneity: not applicable
Test for overall effect: Z = 2.56 (P = 0.011)
Test for subgroup differences: Chi2 = 1.44, df = 1 (P = 0.23), I2 =31%

100.0 % 1.21 [ 0.72, 2.02 ]

100.0 % 1.21 [ 0.72, 2.02 ]

100.0 % 1.85 [ 1.15, 2.96 ]

100.0 % 1.85 [ 1.15, 2.96 ]

0.1 0.2 0.5 1 2 5 10
Favours fingolimod Favours placebo

Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio

n/N n/N

M-
H,Random,95%
CI

M-
H,Random,95%
CI

Calabresi 2014 53/358 45/355 50.7 % 1.17 [ 0.81, 1.69 ]
Kappos 2010 (1) 39/425 55/418 49.3 % 0.70 [ 0.47, 1.03 ]
Subtotal (95% CI) 783 773 100.0 % 0.91 [ 0.55, 1.50 ]

Calabresi 2014 53/370 45/355 49.2 % 1.13 [ 0.78, 1.64 ]
Kappos 2010 (2) 48/429 55/418 50.8 % 0.85 [ 0.59, 1.22 ]
Subtotal (95% CI) 799 773 100.0 % 0.98 [ 0.74, 1.29 ]
Total events: 101 (Experimental), 100 (Control)
Heterogeneity: Tau2 = 0.01; Chi2 = 1.16, df = 1 (P = 0.28); I2 =14% Test for overall effect: Z = 0.16 (P = 0.88)

0.1 0.2 0.5 1 2 5 10
Favours fingolimod Favours placebo

(1) See table 3 page 398, excluding relapses

(2) See table 3 page 398, excluding relapses

Outcome: 1 At 6 months

Study or subgroup log [Rate Ratio] Rate Ratio Weight Rate Ratio
(SE) IV,Random,95% CI IV,Random,95% CI

1 Fingolimod 0.5 mg versus placebo
Saida 2012 -0.68309685 (0.34390413)

Subtotal (95% CI)
Heterogeneity: not applicable
Test for overall effect: Z = 1.99 (P = 0.047) 2 Fingolimod 1.25 mg versus placebo
Kappos 2006 -0.78845736 (0.30185338)

100.0 % 0.51 [ 0.26, 0.99 ]

100.0 % 0.51 [ 0.26, 0.99 ]

61.2 % 0.45 [ 0.25, 0.82 ]

Saida 2012 -0.88154778 (0.37894065)

Subtotal (95% CI)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.04, df = 1 (P = 0.85); I2 =0.0% Test for overall effect: Z = 3.49 (P = 0.00048)
3 Fingolimod 5.0 mg versus placebo
Kappos 2006 -0.76028648 (0.29516183)

Subtotal (95% CI)
Heterogeneity: not applicable
Test for overall effect: Z = 2.58 (P = 0.010)
Test for subgroup differences: Chi2 = 0.12, df = 2 (P = 0.94), I2 =0.0%

38.8 % 0.41 [ 0.20, 0.87 ]

100.0 % 0.44 [ 0.28, 0.70 ]

100.0 % 0.47 [ 0.26, 0.83 ]

100.0 % 0.47 [ 0.26, 0.83 ]

0.01 0.1 1 10 100
Favours fingolimod Favours placebo

Study or subgroup log [Rate Ratio] Rate Ratio Weight Rate Ratio
(SE) IV,Random,95% CI IV,Random,95% CI

1 Fingolimod 0.5 mg versus interferon beta-1a
Cohen 2010 -0.72391884 (0.18606908)

Subtotal (95% CI)
Heterogeneity: not applicable
Test for overall effect: Z = 3.89 (P = 0.00010) 2 Fingolimod 1.25 versus interferon beta-1a
Cohen 2010 -0.50077529 (0.12871442)

Subtotal (95% CI)
Heterogeneity: not applicable
Test for overall effect: Z = 3.89 (P = 0.00010)
Total (95% CI)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.97, df = 1 (P = 0.32); I2 =0.0% Test for overall effect: Z = 5.41 (P < 0.00001)
Test for subgroup differences: Chi2 = 0.97, df = 1 (P = 0.32), I2 =0.0%

32.4 % 0.48 [ 0.34, 0.70 ]

32.4 % 0.48 [ 0.34, 0.70 ]

67.6 % 0.61 [ 0.47, 0.78 ]

67.6 % 0.61 [ 0.47, 0.78 ]

100.0 % 0.56 [ 0.46, 0.69 ]

0.01 0.1 1 10 100
Favours fingolimod Favours placebo

Study or subgroup log [Rate Ratio] Rate Ratio Weight Rate Ratio
(SE) IV,Random,95% CI IV,Random,95% CI

1 Fingolimod 0.5 mg versus placebo
Calabresi 2014 -0.65392647 (0.1277488)

72.1 % 0.52 [ 0.40, 0.67 ]

Kappos 2010 -0.7985077 (0.20524067)

Subtotal (95% CI)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.36, df = 1 (P = 0.55); I2 =0.0% Test for overall effect: Z = 6.40 (P < 0.00001)
2 Fingolimod 1.25 mg versus placebo
Calabresi 2014 -0.69314718 (0.13031266)

27.9 % 0.45 [ 0.30, 0.67 ]

100.0 % 0.50 [ 0.40, 0.62 ]

76.6 % 0.50 [ 0.39, 0.65 ]

Kappos 2010 -0.91629073 (0.23551448)

Subtotal (95% CI)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.69, df = 1 (P = 0.41); I2 =0.0% Test for overall effect: Z = 6.54 (P < 0.00001)
Test for subgroup differences: Chi2 = 0.11, df = 1 (P = 0.75), I2 =0.0%

23.4 % 0.40 [ 0.25, 0.63 ]

100.0 % 0.47 [ 0.38, 0.59 ]

0.01 0.1 1 10 100
Favours fingolimod Favours placebo

Study or subgroup Fingolimod Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M-
H,Random,95%
CI

M-
H,Random,95%
CI

1 Fingolimod 0.5 mg versus placebo
Calabresi 2014 (1) 283/323 206/325 43.9 % 1.38 [ 1.26, 1.52 ]
Kappos 2010 361/403 232/373 50.7 % 1.44 [ 1.32, 1.57 ]
Saida 2012 39/45 29/50 5.4 % 1.49 [ 1.15, 1.94 ]
Subtotal (95% CI) 771 748 100.0 % 1.42 [ 1.33, 1.51 ]
Total events: 683 (Fingolimod), 467 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.57, df = 2 (P = 0.75); I2 =0.0% Test for overall effect: Z = 11.19 (P < 0.00001)
2 Fingolimod 1.25 mg versus placebo
Calabresi 2014 (2) 288/326 206/325 41.5 % 1.39 [ 1.27, 1.53 ]
Kappos 2006 64/83 38/81 6.8 % 1.64 [ 1.27, 2.13 ]
Kappos 2010 337/388 232/373 43.8 % 1.40 [ 1.28, 1.53 ]
Saida 2012 47/48 29/50 7.9 % 1.69 [ 1.33, 2.14 ]
Subtotal (95% CI) 845 829 100.0 % 1.43 [ 1.34, 1.53 ]
Total events: 736 (Fingolimod), 505 (Placebo)
Heterogeneity: Tau2 = 0.00; Chi2 = 3.53, df = 3 (P = 0.32); I2 =15% Test for overall effect: Z = 10.17 (P < 0.00001)
3 Fingolimod 5 mg versus placebo
Kappos 2006 63/77 38/81 100.0 % 1.74 [ 1.35, 2.25 ]
Subtotal (95% CI) 77
Total events: 63 (Fingolimod), 38 (Placebo) 81 100.0 % 1.74 [ 1.35, 2.25 ]
Heterogeneity: not applicable
Test for overall effect: Z = 4.28 (P = 0.000018)
Test for subgroup differences: Chi2 = 2.41, df = 2 (P = 0.30), I2 =17%

0.5 0.7 1 1.5 2
Favours placebo Favours fingolimod

(1) Data were retrieved from Supplementary webappendix (Page 10). The analysis inivolved 89% of partecipants.

(2) Data were retrieved from Supplementary webappendix (Page 10). The analysis inivolved 89% of partecipants.

Study or subgroup Fingolimod Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M-
H,Random,95%
CI

M-
H,Random,95%
CI

1 Fingolimod 0.5 mg versus placebo
Calabresi 2014 (1) 269/301 185/292 44.1 % 1.41 [ 1.28, 1.55 ]
Kappos 2010 348/394 230/356 55.9 % 1.37 [ 1.26, 1.49 ]
Subtotal (95% CI) 695 648 100.0 % 1.39 [ 1.30, 1.48 ]
Total events: 617 (Fingolimod), 415 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.23, df = 1 (P = 0.63); I2 =0.0% Test for overall effect: Z = 10.09 (P < 0.00001)
2 Fingolimod 1.25 mg versus placebo
Calabresi 2014 (2) 267/295 185/292 45.0 % 1.43 [ 1.30, 1.57 ]
Kappos 2010 330/376 230/356 55.0 % 1.36 [ 1.25, 1.48 ]
Subtotal (95% CI) 671 648 100.0 % 1.39 [ 1.30, 1.48 ]

Total events: 597 (Fingolimod), 415 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.60, df = 1 (P = 0.44); I2 =0.0% Test for overall effect: Z = 10.15 (P < 0.00001)
3 Fingolimod 0.5 mg versus interferon beta-1a
Cohen 2010 337/374 286/354
Subtotal (95% CI) 374 354
Total events: 337 (Fingolimod), 286 (Placebo) Heterogeneity: not applicable
Test for overall effect: Z = 3.51 (P = 0.00044) 4 Fingolimod 1.25 mg versus interferon beta-1a
Cohen 2010 321/352 286/354

Subtotal (95% CI) 352 354
Total events: 321 (Fingolimod), 286 (Placebo) Heterogeneity: not applicable
Test for overall effect: Z = 3.94 (P = 0.000082)
Test for subgroup differences: Chi2 = 45.15, df = 3 (P = 0.00), I2 =93%

100.0 % 1.12 [ 1.05, 1.19 ]

100.0 % 1.12 [ 1.05, 1.19 ]

100.0 % 1.13 [ 1.06, 1.20 ]

100.0 % 1.13 [ 1.06, 1.20 ]

0.5 0.7 1 1.5 2
Favours placebo Favours fingolimod

(1) Data were retrieved from Supplementary webappendix (Page 10). The analysis involved 82% of participants.

(2) Data were retrieved from Supplementary webappendix (Page 10). The analysis involved 82% of participants.

Study or subgroup Fingolimod Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M-
H,Random,95%
CI

M-
H,Random,95%
CI

1 Fingolimod 0.5 mg versus placebo
Calabresi 2014 (1) 234/269 167/256

42.2 % 1.33 [ 1.21, 1.47 ]

Kappos 2010 (2) 331/369 216/332
Subtotal (95% CI) 638 588
Total events: 565 (Fingolimod), 383 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.24, df = 1 (P = 0.62); I2 =0.0% Test for overall effect: Z = 9.20 (P < 0.00001)
2 Fingolimod 1.25 mg versus placebo
Calabresi 2014 (3) 242/251 167/256

57.8 % 1.38 [ 1.27, 1.50 ]

100.0 % 1.36 [ 1.27, 1.45 ]

47.0 % 1.48 [ 1.35, 1.62 ]

Kappos 2010 308/343 216/332
Subtotal (95% CI) 594 588
Total events: 550 (Fingolimod), 383 (Placebo)
Heterogeneity: Tau2 = 0.00; Chi2 = 1.12, df = 1 (P = 0.29); I2 =11% Test for overall effect: Z = 10.36 (P < 0.00001)
Test for subgroup differences: Chi2 = 0.98, df = 1 (P = 0.32), I2 =0.0%

53.0 % 1.38 [ 1.27, 1.50 ]

100.0 % 1.43 [ 1.33, 1.52 ]

0.01 0.1 1 10 100
Favours placebo Favours fingolimod

(1) The analysis involved 776 out of 1083 (72%) of partecipants.

(2) the analysis involved 1049 out of 1272 (82% of partecipants)

(3) The analysis involved 776 out of 1083 (72%) of partecipants.

Study or subgroup Fingolimod Control

Mean
Difference Weight

Mean Difference

N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

1 Fingolimod 0.5 mg versus placebo
Kappos 2010 (1) 372 3.4 (35.2) 361 18.7 (80.5)
Subtotal (95% CI) 372 361
Heterogeneity: not applicable
Test for overall effect: Z = 3.32 (P = 0.00091) 2 Fingolimod 1.25 mg versus placebo
Kappos 2010 (2) 345 2.7 (38.1) 361 18.7 (80.5)

Subtotal (95% CI) 345 361
Heterogeneity: not applicable
Test for overall effect: Z = 3.40 (P = 0.00068) 3 Fingolimod 0.5 mg versus interferon beta-1a
Cohen 2010 372 9.9 (37.3) 361 10.4 (42.8)

Subtotal (95% CI) 372 361
Heterogeneity: not applicable
Test for overall effect: Z = 0.17 (P = 0.87)
4 Fingolimod 1.25 mg versus interferon beta-1a
Cohen 2010 350 6.7 (31) 361 10.4 (42.8)

Subtotal (95% CI) 350 361
Heterogeneity: not applicable
Test for overall effect: Z = 1.32 (P = 0.19)
Test for subgroup differences: Chi2 = 12.68, df = 3 (P = 0.01), I2 =76%

100.0 % -15.30 [ -24.34, -6.26 ]

100.0 % -15.30 [ -24.34, -6.26 ]

100.0 % -16.00 [ -25.23, -6.77 ]

100.0 % -16.00 [ -25.23, -6.77 ]

100.0 % -0.50 [ -6.32, 5.32 ]

100.0 % -0.50 [ -6.32, 5.32 ]

100.0 % -3.70 [ -9.18, 1.78 ]

100.0 % -3.70 [ -9.18, 1.78 ]

-100 -50 0 50 100
Favours fingolimod Favours placebo

(1) data were reported in Radue Arch Neurol. 2012;69(10):1259-1269.

(2) Data reported in Radue 2012

Study or subgroup Fingolimod Control Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

1 Fingolimod 0.5 mg versus placebo
Calabresi 2014 (1) 262 13.74 (217.09) 247 25.06 (81.1)

23.3 % -11.32 [ -39.49, 16.85 ]

Kappos 2010 (2) 368 10.6 (103.5) 339 33.8 (106.9)
Subtotal (95% CI) 630 586
Heterogeneity: Tau2 = 0.0; Chi2 = 0.52, df = 1 (P = 0.47); I2 =0.0% Test for overall effect: Z = 2.94 (P = 0.0032)
2 Fingolimod 1.25 mg versus placebo
Calabresi 2014 242 -7.69 (24.77) 247 25.06 (81.1)

76.7 % -23.20 [ -38.73, -7.67 ]

100.0 % -20.43 [ -34.03, -6.83 ]

55.6 % -32.75 [ -43.33, -22.17 ]

Kappos 2010 343 1.6 (30.7) 339 33.8 (106.9)
Subtotal (95% CI) 585 586
Heterogeneity: Tau2 = 0.0; Chi2 = 0.00, df = 1 (P = 0.95); I2 =0.0% Test for overall effect: Z = 8.08 (P < 0.00001)
Test for subgroup differences: Chi2 = 2.27, df = 1 (P = 0.13), I2 =56%

44.4 % -32.20 [ -44.03, -20.37 ]
100.0 % -32.51 [ -40.39, -24.62 ]

-100 -50 0 50 100
Favours fingolimod Favours placebo

(1) Percentage change in T2 lesion volume (mm3) from baseline to month 24. The analysis involved 751 out of 1083 partecipants (69%)

(2) The value are expressed in percentage. The analsysis involved 1050 out of 1272 partecipants (82%)data are differente form those of RADUE chidere a Marco

Study or subgroup Mean Difference (SE)

Mean
Difference Weight

Mean Difference

IV,Random,95% CI IV,Random,95% CI

1 Fingolimod 1.25 mg versus placebo (Hamburg Quality of Life Questionnaire) Kappos 2006 (1) -0.14 (4.58673469)
Subtotal (95% CI)
Heterogeneity: not applicable
Test for overall effect: Z = 0.03 (P = 0.98)
2 Fingolimod 0.5 mg versus DMDs (Change in FS36 Mental component summary) Fox 2014 (2) 1.8 (0.70650984)
Subtotal (95% CI)
Heterogeneity: not applicable
Test for overall effect: Z = 2.55 (P = 0.011)
3 Fingolimod 0.5 mg versus DMDs (Change in FS36 Physical component summary) Fox 2014 (3) 1.3 (0.5102571)
Subtotal (95% CI)
Heterogeneity: not applicable
Test for overall effect: Z = 2.55 (P = 0.011)
Test for subgroup differences: Chi2 = 0.45, df = 2 (P = 0.80), I2 =0.0%

100.0 % -0.14 [ -9.13, 8.85 ]

100.0 % -0.14 [ -9.13, 8.85 ]

100.0 % 1.80 [ 0.42, 3.18 ]

100.0 % 1.80 [ 0.42, 3.18 ]

100.0 % 1.30 [ 0.30, 2.30 ]

100.0 % 1.30 [ 0.30, 2.30 ]

-10 -5 0 5 10
Favours control Favours fingolimod

(1) data were reported in Montalban, 2011 a

(2) Control group was treated with DMD. Data retrieved in Gudesblatt M, 2014

(3) Control group was treated with DMD. Data retrieved in Gudesblatt M, 2014

Study or subgroup Experimental Control Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

1 Fingolimod 0.5 mg versus placebo (Euro quality of life scale)
Calabresi 2014 (1) 358 -0.016 (0.199) 355 0 (0.23)

100.0 %

-0.01 [ -0.04, 0.02 ]

Subtotal (95% CI) 358 355
Heterogeneity: not applicable
Test for overall effect: Z = 0.74 (P = 0.46) Test for subgroup differences: Not applicable

100.0 % -0.01 [ -0.04, 0.02 ]

-50 -25 0 25 50
Favours fingolimod Favours placebo

(1) Only data for fingolimod 0.5 mg are reported

A D D I T I O N A L T A B L E S
Table 1. Outcome measures and time points

Study name
Clinical outcomes
Time point assessment
MRI outcomes
Time point assessment

Calabresi 2014
1. Annualised relapse rate
2. Time to disability pro- gression confirmed at 3 months
3. Time to disability pro- gression confirmed at 6 months
4. Safety
5. Time to first relapse
6. Proportion of relapse- free participants
7. Change from baseline to the end of study on the MSFC score
8. Quality of life using the Euro quality of life scale (EQ-5D)
9. Patient Reported Indices in Multiple Sclerosis
24 months
1. Percent brain-volume change from baseline at 24 months
2. Number and volume of gadolinium-enhancing T1 lesions
3. Number of new or newly enlarged T2 lesions
4. Proportion of partici- pants free of gadolinium- enhancing T1 lesions
5. Proportion of partici- pants free of new or newly enlarged T2 lesions
6. Proportion of partici- pants free of new inflam- matory activity (no gadolin- ium-enhancing T1 lesions
24 months

10. Fatigue using the Mod- ified Fatigue Impact Scale and no new or newly en- larged T2 lesions)
7. Percentage change from baseline in volume of gadolinium-enhanced T1 lesions
8. Percentage change from baseline in volume of new or newly enlarged T2 lesions
9. Brain volume

Cohen 2010
1. Annualised relapse rate
2. Progression of disability (confirmed at 3 months)
12 months
Number of new or enlarged lesions on T2-weighted scans
12 months

Fox 2014
1. Treatment satisfaction
2. Fatigue
3. Depression
4. Activities of daily living
5. Health-related Quality Of Life
6, Side effects
6 months
Not included

Kappos 2006
1. Number of participants remaining free of relapse
2. Annualised relapse rate 3, Time to the first relapse
6 months
1.Number of gadolinium- enhanced lesions per par- ticipant recorded on T1- weighted MRI at monthly intervals for 6 months 2.Total volume of gadolin- ium-enhanced lesions per participants
3. Proportion of partici- pants with gadolinium-en- hanced lesions
4. Total number of new le- sion per participant on T- weighted images
5. Changes in lesion volume on T2-weighted images
6. Brain volume from base- line to month 6
6 months

Kappos 2010
1. Annualised relapse rate
2. Time to confirmed dis- ability progression (con- firmed after 3 months )
3. Time to a first relapse
4. Time to disability pro- gression (confirmed after 6 months)
24 months
1. Number of gadolinium- enhancing lesions
2. Proportion of partici- pants free from gadolinium- enhancing lesions
3. Number of new or enlarged lesions on T2-
24 months

5. Changes in the EDSS weighted MRI scans
score 4. Proportion of partici-
6. Changes in the MSFC z pants free from new or
score between baseline and enlarged lesions on T2-
24 months weighted scan
5. Volumes of hyperintense
lesions on T2-weighted scan
6. Volumes of
hypointense lesions on T1-
weighted scans
7. Change in brain vol-
ume between baseline and
24 months
8. Safety and tolerability
measures

Saida 2012
Percentage of participants free from relapse
6 months
Partici-
pants free from gadolinium- enhancing lesions
6 months
EDSS: Expanded Disability Status Scale; MSFC: Multiple Sclerosis Functional Composite The primary outcome of each study is underlined

Table 2. Baseline characteristics of the population included in the RCTs

Study name
Drugs
No. par- tici- pants
Female (%)
Course of disease of RR- SP (%)
Age, years, mean (SD)
Mean EDSS
score (SD)
Dis- ease du- ration, mean (SD)
Pre-1 year number of re- lapses, mean (SD)
Percent- age
of pre- study treat- ment- naive partici- pants
Percent- age of partici- pants with MRI en- hancing lesions
Mean lesion volume on T2- weighted images (mm3 )
(SD)

Cal-
Placebo
355
81
100 - 0 40·1 2·2 (1·5) 10·6 1·5 (0·9)
27
36
5553
abresi (8·4) (7·9) (7841)
2014
Fin- 358 77 100 - 0 40·6 2·2 (1·4) 10·4 1·4 (0·9) 26 39 5484
golimod (8·4) (8·0) (8000)
0.5 mg

Fin-
370
76
100 - 0 40·9 2·3 (2·0) 10·8 1·5 (1·0)
22
31
4936
golimod (8·9) (8·2) (7286)
1.25 mg

Cohen
Inter-
435
67.8
100 - 0
36.0
(8.
2.19
(1.
7.4 (6.3)
1.5 (0.8)
43.7
36.9
4924
2010 feron 3) 26) (5711)
beta-1a
(Avonex)

Fin-
431
65.4
100 - 0
36.7
(8.
2.24
(1.
7.5 (6.2)
1.5 (1.2)
44.8
32.6
5170
golimod 8) 33) (6642)
0.5 mg

Fin-
426
68.8
100 - 0
35.8
(8.
2.21
(1.
7.3 (6.0)
1.5 (0.9)
41.5
34.5
5085
golimod 4) 31) (5962)
1.25 mg

Fox 2014 DMD§
263
79.1
100 - 0
45.1
82)
(9.
2.4
32)
(1.
11.7
44)
(8.
0.8
32)
(1.
0
NR
NR

Fin- golimod
0.5 mg
790
76.1
100 - 0
46.0
82)
(9.
2.4
32)
(1.
12.1
38)
(8.
0.8
20)
(1.
0
NR
NR

Kappos
Placebo
93
66
90 - 10
37.1
2.6 (0.0-
8.4 (0.2-
1.2 (0-5)
NR
51
8805
2006 (19-56)* 6.5)* 28.2)* * (123-62,
218)*

Fin-
94
75
89 - 11
38.0
2.7 (0.0-
8.6 (0.3-
1.3 (0-5)
NR
47
10,219
golimod (19-60)* 6.0)* 50.2)* * (293-
1.25 mg 104,
504)*

Fin-
94
71
87 - 13
38.3
2.5 (0.0-
9.5 (0.5-
1.3 (0-4)
NR
57
8722
golimod (18-59)* 6.0)* 42.2)* * (349-70,
5.0 mg 218)*

Kappos
Placebo
418
71.3
100 - 0
37.2
(8.
2.5 (1.3)
8.1 (6.4)
1.4 (0.7)
59.6
37
6162
2010 6) (7085)

Fin-
425
69.6
100 - 0
36.6
(8.
2.3 (1.3)
8.0 (6.6)
1.5 (0.8)
57.4
38
6128
golimod 8) (7623)
0.5 mg

Fin-
429
68.8
100 - 0
37.4
(8.
2.4 (1.4)
8.4 (6.9)
1.5 (0.8)
60.4
39.4
6829
golimod 9) (8491)
1.25 mg

Saida 2012
Placebo
57
68.4
100 - 0
35.0
9)
(8.
2.1 (1.7)
8.2 (7.3)
1.7 (1.6)
NR
42.1
31.6 (22.6)**

Fin-
57
70.2
94.7
- 5.
35.0
(9.
2.3 (1.9)
8.2 (6.8)
1.4 (1.0)
NR
42.1
30.4
golimod 3 0) (22.7)**
0.5 mg
Fin- 57 68.4 98.2 - 1. 36.0 (9. 1.8 (1.7) 7.1 (5.3) 1.5 (0.9) NR 49.1 31.7
golimod 8 3) (23.3)**
1.25 mg
DMD: disease-modifying drug;EDSS: Expanded Disability Status Scale; MRI: magnetic resonance imaging; NR: not reported; RR:
relapsing-remitting; SD: standard deviation; SP: secondary progressive
* Range (SD was not provided)
** Number of T2 lesions (volume was not provided)
§ interferon beta-1b (Extavia® or Betaseron®) 0.25 mg injected subcutaneously every other day (46 participants); interferon beta- 1a (Avonex®) 30 µg intramuscular injected once a week (60 participants); interferon beta-1a (Rebif®) 22 µg or 44 µg injected subcutaneously three times a week (65 participants); or glatiramer acetate (Copaxone®) 20 mg injected subcutaneously once-daily (92 participants)

Table 3. Methods of adverse events monitoring

Study name
Risk of bias
Did the researchers actively monitor for adverse events (AEs) (low risk of bias) or did they simply provide sponta- neous reporting of AEs that arose (high risk of bias)?
Risk of bias
Did the authors define serious AEs (SAEs) ac- cording to an accepted international classifica- tion and report the number of SAEs?

Calabresi 2014
Low
”We did extensive safety and tol- erability assessments, in part as a response to preclinical safety concerns raised by the FDA and additional safety areas of inter- est identified in previous phase 2 and earlier clinical studies. We also recorded adverse events, se- rious adverse events, serious ad- verse events of special interest, 24 h Holter electrocardiography (ECG) post first-dose and at 3 months, first-dose bradycardia events, infections, laboratory tests, vital signs, ECG, echocardiogra- phy, pulmonary function. tests, chest high-resolution CT,chest radiographs, ophthalmic exami- nations, including serial optical coherence tomography, and der-
Unclear
“We also recorded adverse events, serious adverse events, serious adverse events of special interest, 24 h Holter electrocardiography (ECG) post fist-dose and at 3 months, first-dose bradycardia events, infec- tions, laboratory tests, vital signs, ECG, echocardio- graphy, pulmonary function tests, chest high-reso- lution CT,chest radiographs, ophthalmic examina- tions, including serial optical coherence tomography, and dermatological assessments”

matological assessments.“ Clini- cal assessments were performed at screening and at randomisation (baseline), and study visits, in- cluding safety assessments, were scheduled at 2 weeks and 1, 2,
3, 6, 9, 12, 15, 18, 21, and 24
months after randomisation”

Cohen 2010
Low
“An independent data and sa- fety monitoring board evaluated overall safety in the fingolimod phase 3 program” and “Safety assessments were conducted dur- ing screening, at baseline, and at months 1, 2, 3, 6, 9, and 12” (pg
404)
Low
SAEs were predefined per standard criteria (death, life-threatening event, persistent disability, con- genital defect, unplanned hospitalisation, or oth- erwise medically significant) (FDA 2010 Clinical review of safety pg 151)

Fox 2014
Low
“Safety and tolerability (sec- ondary study objectives) were as- sessed via reporting of
adverse events (AEs) and through physical examinations (ophthal- mologist
examinations, and evaluations of vital signs, chest x-rays, and elec- trocardiograms
[ECGs]), laboratory evaluations (measurement of hematology pa- rameters, chemistry, urinalysis, serology, and lymphocyte counts)”
Unclear
Not specified

Kappos 2006
Low
“An independent external data and safety monitoring board eval- uated adverse events and other safety data” and “Adverse events were assessed and reported at each visit (scheduled andunscheduled) by the treating physicians. Lab- oratory evaluations were under- taken at a central laboratory”. “Vital signs were obtained at each visit, and laboratory and hema- tologic measures were obtained at baseline, day 1, and months 1,3,
6,9, and 12. Electrocardiograms were obtained at baseline, ondays 1 and 7, andat months 1,3,6,12,
and 24 hour Holter electrocar-
Low
Categorisation of SAEs conformed to ICH guide- lines (International Conference on Harmonisa- tion of Technical Requirements for Registration of Pharmaceuticals for Human Use)

diographic monitoring was per- formed at selected sites at baseline, day 1, and month 3. Pulmonary function tests... were performed at screening and months 6 and 12”
(pg 1126)

Kappos 2010
Low
“An independent data and safety monitoring board evaluated the safety” and “Study visits, includ- ing safety assessments, were sched- uled at 2 weeks and 1, 2, 3, 6, 9,
12, 15, 18, 21, and 24 months after randomization” (pg 389)
Low
SAEs were predefined per standard criteria (death, life-threatening event, persistent disability, con- genital defect, unplanned hospitalisation, or oth- erwise medically significant) (FDA 2010 Clinical review of safety pg 151)

Saida 2012
Low
“Adverse events, serious adverse events assessments were conducted at screening, baseline, days 1 and 15, and months 1,2,3,4,5 and
6” (pg 2) and “Safety assessment included recording of AEs, SAEs, hematology values, vital signs, re- sults of dermatological and oph- thalmological examinations and results of pulmonary and liver function tests” (Supplementary data online appendix)
Low
Categorisation of SAEs conformed to ICH guide- lines (International Conference on Harmonisa- tion of Technical Requirements for Registration of Pharmaceuticals for Human Use)
AE: adverse event; CT: chest tomography; ECG: electrocardiography; FDA: Food and Drug Administration; SAE: serious adverse event

A P P E N D I C E S

Appendix 1. Keywords
{fingolimod} OR {FTY720} OR {FTY 720} OR {fingolimod hydrochloride} OR {FTY-720} OR {2-amino-2-(2-(4-octylphenyl)ethyl)- 1,3-propanediol hydrochloride} OR {Gilenya} OR {sphingosine-fosphate-receptor antagonist} AND {relapsing remitting} OR {relaps- ing-remitting }OR {remitting-relapsing}OR {remitting relapsing}

Last assessed as up-to-date: 15 February 2016.

Date
Event
Description

9 June 2015
Amended
The author team has been amended

C O N T R I B U T I O N S O F A U T H O R S

Roles and responsibilities

Drafting the protocol
All review authors

Selecting which studies to include
LLM, RP, IP

Planning data sheet for study data extraction
LLM,IP

Extracting data from studies
LLM, IT, IP

Assessing risk of bias of studies
LLM, IP, IT

Entering data into RevMan
LLM, IP, IT

Carrying out data analysis and interpreting results
LLM, IT, GF

Drafting the manuscript and final review
LLM, GF

Editing
LLM

Approving the final version
All review authors

D E C L A R A T I O N S O F I N T E R E S T
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).

• Background was amended.
• Types of studies: cohort studies, case-control studies, case reports or case-series were not included in this review because an ad hoc review has been planned.
• Participants: MS diagnostic criteria, which we accepted for inclusion of participants, have been added.
• Primary outcome measures: 1) number of participants relapse-free at six, 12 and 24 months, and number of participants free
from disability progression at 12, 24 and 36 months were included as primary outcome measures more relevant to participants; 2) annualised relapse rate was moved to secondary outcomes; 3) number of participants who withdrew from the study because of serious adverse events was added as a primary outcome, and the rate of serious adverse events was excluded.
• Secondary outcomes were amended.
• Electronic searches were amended.
• Dealing with missing data: a likely scenario was used as a sensitivity analysis to deal with missing data. An intention-to-treat
analysis, using the last reported observed response (’carry forward’), previously reported in the review protocol, was not performed according to the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 8.13.2.3) (Higgins 2011b).
• ’Summary of findings’ tables were added.