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EXPAND

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

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Year of Publication: 2018

Authors: Ludwig Kappos, Amit Bar-Or, Bruce A C Cree, ..., for the EXPAND Clinical Investigators

Journal: The Lancet

Citation: Lancet 2018; 391: 1263–73

Link: https://clinicaltrials.gov/ct2/show/NCT01665144

Clinical Question

Does siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, reduce disability progression compared to placebo in patients with secondary progressive multiple sclerosis?

Bottom Line

Siponimod significantly reduced the risk of 3-month confirmed disability progression by 21% (and 6-month CDP by 26%) compared to placebo in a representative SPMS population, including 64% who had not relapsed in 2 years and 56% requiring walking assistance. This is the first large trial to show superiority over placebo for disability progression in SPMS. The effect was consistent across subgroups but appeared more pronounced in patients with signs of inflammatory activity.

        Major Points
        First large trial to demonstrate efficacy in slowing disability progression in a representative SPMS population
21% relative risk reduction in 3-month CDP (HR 0.79, p=0.013) - primary endpoint met
26% relative risk reduction in 6-month CDP (HR 0.74, p=0.0058)
55% reduction in annualized relapse rate (0.07 vs 0.16, p<0.0001)
46% reduction in time to first confirmed relapse (HR 0.54, p<0.0001)
T2 lesion volume increase reduced by 79% (183.9 vs 879.2 mm³, p<0.0001)
Brain volume loss reduced by 23% (−0.50% vs −0.65%, p=0.0002)
No significant effect on T25FW (HR 0.94, p=0.44) - likely due to high variability in this disabled population
64% of patients had not relapsed in 2 years before enrollment; only 21% had Gd+ lesions at baseline
56% of patients required walking assistance (EDSS ≥6.0) at baseline
Subgroup analyses favored siponimod across all predefined subgroups, though effect appeared attenuated with increasing age, disability, and diminishing inflammatory activity
Dose titration mitigated first-dose cardiac effects

      

Design

Study Type: Randomized, double-blind, double-dummy, placebo-controlled, event-driven and exposure-driven, phase 3 trial

Randomization: 1

Blinding: Double-blind; patients, study staff, EDSS assessors (trained and certified, not involved in patient management) all masked; independent physician monitored patients during dose titration; lymphocyte counts withheld unless notable abnormalities

Enrollment Period: February 5, 2013 to June 2, 2015

Follow-up Duration: Up to 3 years or until 374 CDP events; median time on study 21 months (range 0.2-37); median drug exposure 18 months

Centers: 292

Countries: 31 countries (not individually specified)

Sample Size: 1651

Analysis: Intention-to-treat; Cox proportional hazards model for time-to-event endpoints; negative binomial regression for lesion counts and ARR; mixed model for repeated measures for T2 lesion volume and brain volume; O'Brien-Fleming correction for primary endpoint (α=0.0434); hierarchical testing for key secondary endpoints

Inclusion Criteria

Age 18-60 years
Diagnosis of SPMS
EDSS score 3.0-6.5 at screening
History of relapsing-remitting MS (2010 McDonald criteria)
Documented EDSS progression in the 2 years before the study
No evidence of relapse in the 3 months before randomization

Exclusion Criteria

Substantial immunological, cardiac, or pulmonary conditions
Ongoing macular oedema
Uncontrolled diabetes
CYP2C9*3/*3 genotype
Varicella zoster virus antibody negative status

Arms

Field	Siponimod	Control
Intervention	Siponimod 2 mg oral once daily after 6-day dose titration (starting at 0.25 mg on day 1, titrated up to 2 mg maintenance dose); re-titration required if treatment interrupted ≥4 consecutive days	Matching oral placebo once daily
Duration	Up to 3 years	Up to 3 years

Outcomes

Outcome	Type	HR / OR / RR	P-value
Time to 3-month confirmed disability progression (CDP). CDP defined as 1-point EDSS increase if baseline 3.0-5.0, or 0.5-point increase if baseline 5.5-6.5, confirmed at scheduled visit ≥3 months later	Primary	0.79	0.013
Time to 3-month confirmed ≥20% worsening in T25FW (key secondary)	Secondary	0.94	0.44 (not significant)
Change in T2 lesion volume - mean over months 12 and 24 (key secondary)	Secondary		<0.0001
Time to 6-month CDP	Secondary	0.74	0.0058
Annualized relapse rate	Secondary		<0.0001
Time to first confirmed relapse	Secondary	0.54	<0.0001
MSWS-12 score change - mean over all visits	Secondary		0.057 (not significant)
Brain volume change - mean over months 12 and 24	Secondary		0.0002
Brain volume change at month 12	Secondary		<0.0001
Gd+ lesions per T1 MRI scan (cumulative to month 24)	Secondary		<0.0001
Patients free of Gd+ lesions on all post-baseline scans	Secondary
New or enlarging T2 lesions (mean over all visits)	Secondary		<0.0001
Patients free of new/enlarging T2 lesions on all post-baseline scans	Secondary
Any adverse event	Adverse
Any serious adverse event	Adverse
Non-serious AE leading to discontinuation	Adverse
Serious AE leading to discontinuation	Adverse
Death	Adverse
Liver-related investigations/signs/symptoms	Adverse
Hypertension	Adverse
Infections and infestations	Adverse
Herpes viral infections	Adverse
Herpes zoster	Adverse
Skin neoplasms, malignant/unspecified	Adverse
Lymphopenia	Adverse
Macular oedema	Adverse
Convulsions (all seizure types)	Adverse
Bradycardia during treatment initiation	Adverse
Bradyarrhythmia during treatment initiation	Adverse
Peripheral oedema	Adverse
ALT increased (serious)	Adverse
Basal cell carcinoma (serious)	Adverse
UTI (serious)	Adverse

Subgroup Analysis

Predefined subgroups for 3-month CDP: All favored siponimod. With superimposed relapses in prior 2 years: HR 0.67 (0.49-0.91); Without: HR 0.87 (0.68-1.11). Rapid progression (≥1.5 EDSS increase in 2 years): HR 0.65 (0.46-0.91); No rapid progression: HR 0.86 (0.69-1.09). Baseline MSSS ≥4: HR 0.80 (0.65-0.99); MSSS <4: HR 0.73 (0.47-1.13). Treatment effect appeared to attenuate with increasing age, disability, disease duration, and diminishing inflammatory activity.

Criticisms

T25FW key secondary endpoint not significant - high variability in this disabled population reduces sensitivity
Median placebo-controlled treatment duration of 18 months is shorter than most SPMS trials
17% of placebo patients switched to open-label siponimod as rescue medication vs 11% of siponimod patients - may have reduced power for secondary endpoints
Effect appears attenuated in patients without inflammatory activity - may not benefit all SPMS patients equally
Event-driven design led to protocol amendment and potentially shorter follow-up than initially planned
Cannot definitively distinguish anti-inflammatory effects from direct neuroprotective effects
Convulsions occurred more frequently with siponimod (2% vs <1%) - mechanism unclear
Long-term persistence of benefit not established during placebo-controlled phase

Funding

Novartis Pharma AG

Based on: EXPAND (The Lancet, 2018)

Authors: Ludwig Kappos, Amit Bar-Or, Bruce A C Cree, ..., for the EXPAND Clinical Investigators

Citation: Lancet 2018; 391: 1263–73

Content summarized and formatted by NeuroTrials.ai.

EXPAND

(2018)

Objective

To assess the effect of siponimod, a selective S1P receptor 1,5 modulator, on disability progression in patients with secondary progressive multiple sclerosis (SPMS)

Study Summary

• Siponimod reduced 3-month CDP risk by 21% vs placebo (HR 0.79, p=0.013)
• 6-month CDP reduced by 26% (HR 0.74, p=0.0058)
• ARR reduced by 55% (RR 0.45, p<0.0001); T25FW not significant

Intervention

Siponimod 2 mg oral once daily (after 6-day titration from 0.25 mg) vs placebo for up to 3 years

Inclusion Criteria

Age 18-60 years, SPMS diagnosis, EDSS 3.0-6.5, history of RRMS (McDonald 2010), documented EDSS progression in prior 2 years, no relapse in 3 months before randomization

Study Design

Arms: Siponimod 2 mg oral daily, Placebo

Patients per Arm: 1099 siponimod, 546 placebo

Outcome

• Primary: 3-month CDP 26% vs 32% (HR 0.79, 95% CI 0.65-0.95, p=0.013)
• 6-month CDP: 20% vs 26% (HR 0.74, p=0.0058)
• ARR: 0.07 vs 0.16 (55% reduction, p<0.0001)
• Brain volume loss reduced (−0.50% vs −0.65%, p=0.0002)

Bottom Line

Major Points

First large trial to demonstrate efficacy in slowing disability progression in a representative SPMS population
21% relative risk reduction in 3-month CDP (HR 0.79, p=0.013) - primary endpoint met
26% relative risk reduction in 6-month CDP (HR 0.74, p=0.0058)
55% reduction in annualized relapse rate (0.07 vs 0.16, p<0.0001)
46% reduction in time to first confirmed relapse (HR 0.54, p<0.0001)
T2 lesion volume increase reduced by 79% (183.9 vs 879.2 mm³, p<0.0001)
Brain volume loss reduced by 23% (−0.50% vs −0.65%, p=0.0002)
No significant effect on T25FW (HR 0.94, p=0.44) - likely due to high variability in this disabled population
64% of patients had not relapsed in 2 years before enrollment; only 21% had Gd+ lesions at baseline
56% of patients required walking assistance (EDSS ≥6.0) at baseline
Subgroup analyses favored siponimod across all predefined subgroups, though effect appeared attenuated with increasing age, disability, and diminishing inflammatory activity
Dose titration mitigated first-dose cardiac effects

Study Design

Study Type: Randomized, double-blind, double-dummy, placebo-controlled, event-driven and exposure-driven, phase 3 trial
Randomization: Yes
Blinding: Double-blind; patients, study staff, EDSS assessors (trained and certified, not involved in patient management) all masked; independent physician monitored patients during dose titration; lymphocyte counts withheld unless notable abnormalities
Sample Size: 1651
Follow-up: Up to 3 years or until 374 CDP events; median time on study 21 months (range 0.2-37); median drug exposure 18 months
Centers: 292
Countries: 31 countries (not individually specified)

Primary Outcome

Definition: Time to 3-month confirmed disability progression (CDP). CDP defined as 1-point EDSS increase if baseline 3.0-5.0, or 0.5-point increase if baseline 5.5-6.5, confirmed at scheduled visit ≥3 months later

Control	Intervention	HR/OR	P-value
-	-	0.79 (0.65-0.95)	0.013

Limitations & Criticisms

T25FW key secondary endpoint not significant - high variability in this disabled population reduces sensitivity
Median placebo-controlled treatment duration of 18 months is shorter than most SPMS trials
17% of placebo patients switched to open-label siponimod as rescue medication vs 11% of siponimod patients - may have reduced power for secondary endpoints
Effect appears attenuated in patients without inflammatory activity - may not benefit all SPMS patients equally
Event-driven design led to protocol amendment and potentially shorter follow-up than initially planned
Cannot definitively distinguish anti-inflammatory effects from direct neuroprotective effects
Convulsions occurred more frequently with siponimod (2% vs <1%) - mechanism unclear
Long-term persistence of benefit not established during placebo-controlled phase

Citation

Lancet 2018; 391: 1263–73

View Original Publication →

EXPAND

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

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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