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Completed

NCT Number: NCT01665144

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

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).

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Key information

Conditions

Secondary Progressive Multiple Sclerosis Autoimmune Diseases Autoimmune Diseases of the Nervous System Chronic Disease Demyelinating Autoimmune Diseases, CNS Demyelinating Diseases Disease Attributes Immune System Diseases Multiple Sclerosis Multiple Sclerosis, Chronic Progressive Nervous System Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms

Age range

18 year–60 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Novartis Investigative Site, CABA, Buenos Aires, Argentina

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

BAF312

Drug

0.25, 0.5, 1, and 2 mg film-coated tablets

Placebo

Drug

Film-coated tablets

Primary outcomes

  1. Percentage of Participants With 3-month Confirmed Disability Progression (CDP) Events as Measured by the Expanded Disability Status Scale (EDSS)

    Time frame: 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 outcomes

  1. Percentage of Participants With 3-month Confirmed Worsening in T25W of at Least 20% From Baseline

    Time frame: 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.

  2. Change From Baseline in T2 Lesion Volume

    Time frame: 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.

  3. Percentage of Participants With 6-month Confirmed Disability Progression (CDP) Events as Measured by the Expanded Disability Status Scale (EDSS)

    Time frame: 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.

  4. Annualized Relapse Rate (ARR) for Confirmed Relapses

    Time frame: 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.

  5. Percentage of Participants With First Relapse Events as Measured by Time to First Confirmed Relapse

    Time frame: 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.

  6. Percentage of Patients With Relapse (Confirmed Relapse and Any Relapse)

    Time frame: 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.

  7. Change From Baseline in MSWS-12 Converted Score

    Time frame: 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.

  8. Number of T1 Gd-enhancing Lesions Per Patient Per Scan

    Time frame: 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.

  9. Number of New or Enlarging T2 Lesions Per Patient Per Year

    Time frame: 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.

  10. Percent Brain Volume Change (PBVC) Relative to Baseline

    Time frame: 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.

  11. Number of Participants With 3-month CDP Events as Measured by EDSS in the Subgroup of SPMS Patients With/Without Superimposed Relapses

    Time frame: 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

  12. Number of Participants With 3-month CDP Events as Measured by EDSS in the Subgroup of Rapidly and Not Rapidly Evolving Patients

    Time frame: 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.

  13. Number of Participants With 3-month CDP Events as Measured by EDSS in the Subgroup of Patients With and Without Moderate/Severe Disease Course

    Time frame: 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.

Sponsors and collaborators

Lead sponsor

Novartis Pharmaceuticals

Industry

Registry information

Official study title

A Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled Variable Treatment Duration Study Evaluating the Efficacy and Safety of Siponimod (BAF312) in Patients With Secondary Progressive Multiple Sclerosis Followed by Extended Treatment With Open-label BAF312.

Important dates

Study start
2012
Primary completion
2016
Study completion
2023
First posted
Aug 15, 2012
Registry last updated
Jun 5, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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