Elsevier

The Lancet

Volume 391, Issue 10127, 31 March–6 April 2018, Pages 1263-1273
The Lancet

Articles
Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study

https://doi.org/10.1016/S0140-6736(18)30475-6Get rights and content

Summary

Background

No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor1,5 modulator, on disability progression in patients with SPMS.

Methods

This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144.

Findings

1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups.

Interpretation

Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS.

Funding

Novartis Pharma AG.

Introduction

More than 50% of patients with relapsing-remitting multiple sclerosis (RRMS) transition to secondary progressive multiple sclerosis (SPMS) within 15–20 years.1, 2 Relapses are absent or infrequent in SPMS, yet disability continues to worsen gradually.3, 4 Most disease-modifying treatments for multiple sclerosis are indicated for relapsing forms of the disease, which include RRMS and SPMS with relapses. However, none of these therapies consistently showed efficacy in slowing disability progression in the subgroup of patients with SPMS.5, 6, 7, 8, 9

Siponimod selectively modulates sphingosine-1-phosphate (S1P) receptors S1P1 and S1P5.10 Functional antagonism of S1P1 reduces egress of lymphocytes from lymphoid tissues and prevents recirculation of peripheral lymphocytes to the CNS.11 Siponimod readily crosses the blood–brain barrier,12 and findings from preclinical studies suggest that it might prevent synaptic neurodegeneration13 and promote remyelination in the CNS.14 In a phase 2 dose-finding study in patients with RRMS, siponimod 2 mg/day reduced active brain lesion counts and annualised relapse rate (ARR) by approximately two-thirds.15 Here, we report results from a phase 3, randomised, parallel-group, double-blind, placebo-controlled, event-driven, and exposure-driven trial (EXploring the efficacy and safety of siponimod in PAtients with secoNDary progressive multiple sclerosis [EXPAND]) that investigated the efficacy and safety of siponimod in patients with SPMS.

Research in context

Evidence before this study

A MEDLINE search from inception to Nov 9, 2017, with language restrictions, with the search terms (“secondary progressive multiple sclerosis”[Title] OR “secondary progressive MS”[Title] OR “SPMS”[Title]), identified 320 articles; search results were supplemented by a review of abstracts from recent major neurology conferences. Ten primary reports of randomised, masked, placebo-controlled clinical trials were identified as relevant. Five studies assessed interferon beta, whereas one each investigated the myelin-basic protein-derived synthetic peptide MBP8298, the antineoplastic agent mitoxantrone, the anti-α4-integrin monoclonal antibody natalizumab, intravenous immunoglobulins, and the immunomodulator linomide; this latter study was terminated prematurely. No active comparator studies were identified. The primary endpoint in six of the nine completed studies was disability progression confirmed by changes in Expanded Disability Status Scale (EDSS) score; this was a secondary endpoint in one study of interferon beta-1a, the primary endpoint of which was disability progression assessed using the Multiple Sclerosis Functional Composite scale. Two studies had composite primary endpoints: one study combined results of the EDSS, the timed 25-foot walk test, and the 9-hole peg test; the other study combined five clinical measures (change in EDSS, change in ambulation index, number of relapses requiring corticosteroids, time to first untreated relapse, and change in standardised neurological status). In the European interferon beta-1b study, patients receiving interferon beta-1b benefited from a significant reduction in time to confirmed disability progression (assessed by EDSS) compared with placebo, whereas patients in the subsequent US and Canadian interferon beta-1b study did not. Post-hoc analyses of the combined populations from these two trials showed that patients with active relapsing disease and above-average progressive disease before enrolment were most likely to benefit from treatment. In the study of intramuscular interferon beta-1a, patients receiving active treatment benefited from a reduction in disability worsening on the Multiple Sclerosis Functional Composite scale, but not on the EDSS relative to placebo. Mitoxantrone reduced disability progression and clinical exacerbations (as a composite endpoint) in a small study of fewer than 200 patients with worsening relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis (SPMS). Data supporting an effect on disability progression in the SPMS subgroup were not provided. None of the other trials showed a delay in disability progression.

Added value of this study

So far, no drug has consistently been shown to reduce disability progression in a representative SPMS population. EXPAND recruited a large population of patients with fewer signs of inflammatory disease activity and higher levels of disability at baseline than was the case in the European interferon beta-1b study, ensuring that outcomes were relevant to a representative SPMS population. For patients with SPMS, even numerically small changes in EDSS score can correspond to substantial changes in neurological function and daily activities. Accordingly, the delay in disability on EDSS (primary endpoint) and the benefits observed for several other clinical and MRI-related secondary outcomes are clinically relevant.

Implications of all available evidence

The siponimod EXPAND study is, to our knowledge, the first large trial of any disease-modifying therapy to show superiority over placebo in terms of disability progression in a representative population of patients with SPMS, including a large proportion of patients who had reached the non-relapsing stage of SPMS and had a high level of established disability.

Section snippets

Study design and patients

This multicentre study was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries (appendix p 7). The core part of the study was randomised, double blind, and placebo controlled. The core part was followed by an ongoing open-label extension part (appendix p 9), in which information is collected on long-term efficacy and safety for up to 10 years. Results reported here are from the core part of the study only.

We planned to do the primary analysis when a minimum

Results

From Feb 5, 2013, to June 2, 2015, 1651 patients were randomly assigned: 1105 to siponimod, and 546 to placebo (figure 1). In the siponimod group, five patients never received study drug, and one patient did not provide signed informed consent before starting study procedures; these patients were excluded from safety and efficacy analyses (figure 1). Baseline characteristics were similar between groups (table 1). Median time on study was 21 months (range 0·2–37·0). Median exposure to study drug

Discussion

In this large randomised controlled trial, siponimod significantly reduced 3-month CDP compared with placebo, with a safety profile similar to other drugs in the class. Overall, the results of EXPAND suggest that siponimod might be a useful treatment for patients with SPMS.

Our trial included a typical SPMS population, with characteristics compatible with natural history data and with other studies in SPMS.1, 6, 7, 8 By definition, SPMS includes patients, who after a relapsing-remitting phase,

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