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

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.

Time frame: Baseline, every 3 month up to the maximum of approximately 3 years

Population: The Full analysis set (FAS), which comprised all randomized patients with assigned treatments who took at least one dose of study medication, was considered for the analysis. Only participants from the FAS with non-missing covariates were analyzed for this outcome.

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.

Time frame: Up to maximum approximately 3 years

Population: All participants in the FAS

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.

Time frame: Baseline, Month 12 and Month 24

Population: Participants from the FAS with an available value for the MSWS-12 converted score at baseline and at least one post-baseline.

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.

Time frame: Baseline, Month 12 and Month 24

Population: Participants from the FAS with at least one post-baseline MRI scan and non-missing covariates for the model.

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.

Time frame: Baseline, Month 12 and Month 24

Population: Participants from the FAS with at least one post-baseline MRI scan and non-missing values for the covariates included in the model.

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.

Time frame: Baseline, every 3 months up to the maximum of approximately 3 years

Population: Participants from the FAS in each subgroup with an available value for the outcome measure.

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.

Time frame: Baseline, every 3 months up to the maximum of approximately 3 years

Population: Participants from the FAS in each subgroup with an available value for the outcome measure.

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

Time frame: Baseline, every 3 months up to the maximum of approximately 3 years

Population: Participants from the FAS in each subgroup with an available value for the outcome measure.

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.

Time frame: Baseline, Month 12 and Month 24

Population: Participants from the FAS with at least one post-baseline MRI scan and non-missing values for the covariates included in the model.

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.

Time frame: Baseline, every 3 months up to the maximum of approximately 3 years

Population: Participants from the FAS with non-missing covariates for the model.

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.

Time frame: Baseline, every 3 months up to the maximum of approximately 3 years

Population: Participants from the FAS with non-missing covariates for the model.

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.

Time frame: Up to maximum approximately 3 years

Population: Participants from the FAS with non-missing covariates for the model.

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 frame: Up to maximum approximately 3 years

Population: All participants in the FAS

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.

Time frame: Baseline, Month 12 and Month 24

Population: Participants from the FAS with at least one post-baseline MRI scan and non-missing values for the covariates included in the model.