Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND)

Phase 3

Completed

• Conditions: Secondary Progressive Multiple Sclerosis
• Interventions: Drug: BAF312; Drug: Placebo

• Registration Number: NCT01665144
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

Evaluate the safety and efficacy of Siponimod (BAF312) versus placebo in a variable treatment duration in patients with secondary progressive multiple sclerosis (Core Part) followed by extended treatment with open-label BAF312 to obtain data on long-term safety, tolerability and efficacy (Extension Part).

Detailed Description

This study had two parts, a Core Part and an Extension Part. The Core Part of the study was a randomized, multicenter, double-blind, placebo-controlled parallel-group study in patients with secondary progressive multiple sclerosis (SPMS). Eligible patients were randomized (2:1) to receive either siponimod or placebo. The duration of the Core Part of the study was variable for each patient, given that this was an event-driven study and terminated when a pre-defined number of confirmed disability progression (CDP) events had occurred irrespective of duration of individual patient participation. Patients who had 6-month CDP during the Treatment Epoch of the Core Part were provided with options that included starting treatment with open label siponimod as rescue medication.

Patients who were eligible to enter the Extension Part received open label siponimod.

Study Timeline

• Study First Submitted: 2012-08-03
• Study First Submitted QC: 2012-08-14
• Study First Posted: 2012-08-15
• Study Start: 2012-12-20
• Primary Completion: 2016-04-29
• Results First Submitted: 2018-08-06
• Results First Submitted QC: 2018-10-04
• Results First Posted: 2018-10-31
• Study Completion: 2023-03-31
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-07
• Last Update Posted: 2024-06-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 1651

Inclusion Criteria

• Prior history of relapsing remitting MS
• SPMS defined as progressive increase of disability over at least 6 months
• EDSS score of 3.0 to 6.5
• No relapse of corticosteroid treatment within 3 months

Exclusion Criteria

• Women of child bearing potential must use reliable forms of contraception.
• Diagnosis of Macular edema during screening period
• Any medically unstable condition determined by investigator.
• Unable to undergo MRI scans
• Hypersensitivity to any study drugs or drugs of similar class

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Siponimod (BAF312)	BAF312	Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on the treatment epoch for 3 months. During the Core Part of the study, participants participated in a maximum of 3 epochs. Following the Core Part, eligible patients enter the Extension Part during which all receive open-label BAF312.
Placebo	Placebo	Matching placebo to BAF312 was administered orally during the Core Part of the trial. Following the Core Part, eligible participants enter the Extension Part during which all receive open-label BAF312.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With 3-month Confirmed Disability Progression (CDP) Events as Measured by the Expanded Disability Status Scale (EDSS)	Baseline, every 3 month up to the maximum of approximately 3 years	The EDSS uses an ordinal scale to assess neurologic impairment in MS based on a neurological examination. Scores in each of 7 functional systems (Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel \& Bladder, and Cerebral) and an ambulation score were combined to determine the EDSS steps, ranging from 0 (normal) to 10 (death due to MS). 3-month confirmed disability progression is defined as an increase of score of 1 point in patients with baseline score of 3.0 to 5.0 and 0.5 point increase with baseline score of 5.5 to 6.5 sustained for at least 3 months.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With 3-month Confirmed Worsening in T25W of at Least 20% From Baseline	Baseline, every 3 months up to the maximum of approximately 3 years	The Timed 25-Foot Walk Test (T25W) measured the time, in seconds, to walk 25 feet (7.62 meters).; A 3-month confirmed worsening of at least 20% from baseline in the T25W was defined as an increase from baseline sustained for at least 3 months.; This outcome measure was analyzed using a Cox proportional hazards model.
Percentage of Patients With Relapse (Confirmed Relapse and Any Relapse)	Up to maximum approximately 3 years	Multiple sclerosis (MS) relapse was defined as appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. Additionally, the abnormality had to be present for at least 24 hours and occur in the absence of fever (\<37.5°C) or known infection.; A confirmed MS relapse was defined as accompanied by a clinically-relevant change in the EDSS, as defined in the study protocol, performed by the Independent EDSS Rater.
Change From Baseline in T2 Lesion Volume	Baseline, Month 12 and Month 24	Magnetic resonance imaging (MRI) scans of the brain were performed every 12 months. MRI evaluation during the Core Part included the total volume of T2 lesions. Each MRI scan was reviewed by a local neurologist and by a central blinded MRI reading center.; The change from baseline in T2 lesion volume was analyzed using a mixed model for repeated measures (MMRM) with visit as a categorical factor and an unstructured covariance matrix and with adjustment for baseline covariates.
Number of T1 Gd-enhancing Lesions Per Patient Per Scan	Baseline, Month 12 and Month 24	Magnetic resonance imaging (MRI) scans of the brain were performed every 12 months. MRI evaluation during the Core Part included the number of T1 gadolinium (Gd)-enhancing lesions. Each MRI scan was reviewed by a local neurologist and by a central blinded MRI reading center.; The number of T1 Gd-enhancing lesions per patient per scan was analyzed using a negative binomial regression model.
Percentage of Participants With 6-month Confirmed Disability Progression (CDP) Events as Measured by the Expanded Disability Status Scale (EDSS)	Baseline, every 3 months up to the maximum of approximately 3 years	The EDSS uses an ordinal scale to assess neurologic impairment in multiple sclerosis (MS) based on a neurological examination. Scores in each of 7 functional systems (Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel \& Bladder, and Cerebral) and an ambulation score were combined to determine the EDSS steps, ranging from 0 (normal) to 10 (death due to MS).; 6-month confirmed disability progression is defined as an increase of score of 1 point in patients with baseline score of 3.0 to 5.0 and 0.5 point increase with baseline score of 5.5 to 6.5 sustained for at least 6 months.; This outcome measure was analyzed using a Cox proportional hazards model.
Annualized Relapse Rate (ARR) for Confirmed Relapses	Up to maximum approximately 3 years	Multiple sclerosis (MS) relapse was defined as appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. Additionally, the abnormality had to be present for at least 24 hours and occur in the absence of fever (\<37.5°C) or known infection.; A confirmed MS relapse was defined as accompanied by a clinically-relevant change in the EDSS, as defined in the study protocol, performed by the Independent EDSS Rater.; ARR was defined as the average number of confirmed relapses per year. ARR was analyzed using a negative binomial regression model.
Number of New or Enlarging T2 Lesions Per Patient Per Year	Baseline, Month 12 and Month 24	Magnetic resonance imaging (MRI) scans of the brain were performed every 12 months. MRI evaluation during the Core Part included the number of new or enlarging T2 lesions. Each MRI scan was reviewed by a local neurologist and by a central blinded MRI reading center.; The number of new or enlarging T2 lesions compared to previous scan was analyzed using a repeated measures negative binomial regression model.
Percentage of Participants With First Relapse Events as Measured by Time to First Confirmed Relapse	Up to maximum approximately 3 years	Multiple sclerosis (MS) relapse was defined as appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. Additionally, the abnormality had to be present for at least 24 hours and occur in the absence of fever (\<37.5°C) or known infection.; A confirmed MS relapse was defined as accompanied by a clinically-relevant change in the EDSS, as defined in the study protocol, performed by the Independent EDSS Rater.; Time to first relapse was defined as the time from Day 1 until the start of relapse symptoms. Patients without relapse were censored at the latest known date to be at risk.; This outcome measure was analyzed using a Cox proportional hazards model.
Change From Baseline in MSWS-12 Converted Score	Baseline, Month 12 and Month 24	The Multiple Sclerosis Walking Scale (MSWS-12) version 2 is a patient-rated measure of walking consisting of 12 items. Walking limitations were reported by the patients using categories, generating a total transformed score ranging from 0-100. Higher scores reflected greater impairment.; The change from baseline in MSWS-12 converted score was analyzed using a repeated measures model.
Percent Brain Volume Change (PBVC) Relative to Baseline	Baseline, Month 12 and Month 24	Magnetic resonance imaging (MRI) scans of the brain were performed every 12 months. MRI evaluation during the Core Part included the percentage change in brain volume. Each MRI scan was reviewed by a local neurologist and by a central blinded MRI reading center.; PBVC relative to baseline was analyzed using a repeated measures model (for normally distributed data) with visit as a categorical factor.
Number of Participants With 3-month CDP Events as Measured by EDSS in the Subgroup of SPMS Patients With/Without Superimposed Relapses	Baseline, every 3 months up to the maximum of approximately 3 years	The Expanded Disability Status Scale (EDSS) assesses neurologic impairment in multiple sclerosis (MS). EDSS scale ranges from 0 (normal) to 10 (death due to MS). Confirmed disability is defined as an increase of score of 1 point in patients with baseline score of 3.0 to 5.0 and 0.5 point increase with baseline score of 5.5 to 6.5.; The definition of 3-month confirmed disability progression (CDP) was an increase from baseline in EDSS as defined before sustained for at least 3 months.; The following secondary progressive multiple sclerosis (SPMS) groups were defined for the analysis of this endpoint: * Without superimposed relapses in the 2 years prior to study start (baseline definition); * With superimposed relapses in the 2 years prior to study start (baseline definition); * Without superimposed relapses during the Core Part of study (post-treatment); * With superimposed relapses during the Core Part of study (post-treatment) Data was analyzed using a Cox proportional hazard model
Number of Participants With 3-month CDP Events as Measured by EDSS in the Subgroup of Rapidly and Not Rapidly Evolving Patients	Baseline, every 3 months up to the maximum of approximately 3 years	The Expanded Disability Status Scale (EDSS) assesses neurologic impairment in multiple sclerosis (MS). EDSS scale ranges from 0 (normal) to 10 (death due to MS). Confirmed disability is defined as an increase of score of 1 point in patients with baseline score of 3.0 to 5.0 and 0.5 point increase with baseline score of 5.5 to 6.5.; The definition of 3-month confirmed disability progression (CDP) was an increase from baseline in EDSS as defined before sustained for at least 3 months.; Rapidly evolving patients are defined as subjects with 1.5 or greater EDSS change in the 2 years prior to or at study start and disability progression in the 2 years prior to study start was not adjudicated.; Data was analyzed using a Cox proportional hazard model.
Number of Participants With 3-month CDP Events as Measured by EDSS in the Subgroup of Patients With and Without Moderate/Severe Disease Course	Baseline, every 3 months up to the maximum of approximately 3 years	The Expanded Disability Status Scale (EDSS) assesses neurologic impairment in multiple sclerosis (MS). EDSS scale ranges from 0 (normal) to 10 (death due to MS). Confirmed disability is defined as an increase of score of 1 point in patients with baseline score of 3.0 to 5.0 and 0.5 point increase with baseline score of 5.5 to 6.5.; The definition of 3-month confirmed disability progression (CDP) was an increase from baseline in EDSS as defined before sustained for at least 3 months.; Moderate or severe course of disease is defined as global Multiple Sclerosis Severity Score (MSSS) of 4 or more at baseline.; Data was analyzed using a Cox proportional hazard model.

Trial Locations

Locations (1)

Novartis Investigative Site; 🇬🇧 Newcastle Upon Tyne, United Kingdom