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

• ClinicalTrials.gov Identifier: NCT01665144
• Recruitment Status: Active, not recruiting
• First Posted: August 15, 2012
• Results First Posted: October 31, 2018
• Last Update Posted: May 18, 2022
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: August 3, 2012
• First Posted Date: August 15, 2012
• Results First Submitted Date: August 6, 2018
• Results First Posted Date: October 31, 2018
• Last Update Posted Date: May 18, 2022
• Actual Study Start Date: December 20, 2012
• Actual Primary Completion Date: April 29, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 4, 2018)

Percentage of Participants With 3-month Confirmed Disibility 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). 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.

Original Primary Outcome Measures (submitted: August 14, 2012)

The delay in time to confirmed disability progression as measured by EDSS. [ Time Frame: up to the maximum of 60 months ]

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.

Current Secondary Outcome Measures (submitted: March 21, 2020)

• Efficacy of BAF312 Relative to Placebo in Confirmed Worsening of 25 Foot Walk Test [ Time Frame: Baseline , every 3 months up to the maximum of approximately 3 years ]
  Delay in time to 3 month confirmed worsening of at least 20% from baseline in the timed 25 foot walk test.
• Efficacy of BAF312 Relative to Placebo in Reducing the Increase in T2 Lesion Volume [ Time Frame: Baseline, every year up to the maximum of approximately 3 years ]
  The reduction of the increase in the T1 lesion volume.
• The Delay in Time to Confirmed Disability Progression as Measured by EDSS. [ Time Frame: Baseline, every 6 months up to the maximum of approximately 3 years ]
  Confirmed disability is defined as 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.
• Efficacy of BAF Relative to Placebo in Annualized Relapses Rate and Time to the First Relapse [ Time Frame: Baseline every 3 months up to the maximum of approximately 3 years ]
  BAF312 vs placebo measured by the effect on confirmed relapses rate, the time to the first relapse, and proportion of patient free from relapses.
• Overall Response Rate on the MSWS-12. [ Time Frame: Baseline, every 6 months up to the maximum of approximately 3 years ]
  The overall response of the effect of BAF312 compared to placebo patients on the patient reported outcome form MSWS-12.
• Effect on Inflammatory Disease Activity and Burden of Disease as Measured by MRI [ Time Frame: Baseline, every 12 month up to the maximum of approximately 3 years ]
  Effect of BAF312 relative to placebo on disease activity and burden of disease as measured by Gd-T1 lesion, new/enlarged T2 lesion, and brain atrophy on brain MRI scans.
• Effect on 3-month Confirmed Disability Progression as Defined by EDSS in Predefined Sub-groups [ Time Frame: Baseline, every 3 months up to the maximum of approximately 3 years ]
  effect on confirmed disability progression in pre-defined subgroups, including patients with or without superimposed relapses, rapidly evolving patients with 1.5 point or greater change in EDSS score in 2 years prior to enrollment into the study. Patients with score of 4 or more in MSSS and those who don't meet this criteria.

Original Secondary Outcome Measures (submitted: August 14, 2012)

• Efficacy of BAF312 relative to placebo in confirmed worsening of 25 foot walk test [ Time Frame: Baseline , every 3 months up to the maximum of 60 months ]
  Delay in time to 3 month confirmed worsening of at least 20% from baseline in the timed 25 foot walk test.
• Efficacy of BAF312 relative to placebo in reducing the increase in T2 lesion voluime [ Time Frame: Baseline, every year up to the maximum of 5 years ]
  The reduction of the increase in the T1 lesion volumne.
• The delay in time to confirmed disability progression as measured by EDSS. [ Time Frame: Baseline, every 6 months up to the maximum of 60 months ]
  Confirmed disabilty is defined as 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.
• Efficacy of BAF relative to placebo in annualized relapses rate and time to the first relapse [ Time Frame: Baseline every 3 months up to the maximum of 60 months ]
  BAF312 vs placebo measured by the effect on confirmed relapses rate, the time to the first relapse, and proportion of patient free from relapses.
• Ovearall response rate on the MSWS-12. [ Time Frame: Baseline, every 6 months up to the maximum of 60 months ]
  The overall reponse of the effect of BAF312 compared to placebo patients on the patient reported outcome form MSWS-12.
• Effect on inflammatory disease activity and burden of disease as measured by MRI [ Time Frame: Baseline, every 12 month up to the maximum of 60 months ]
  Effect of BAF312 relative to placebo on disease activtiy and burden of disease as measured by Gd-T1 lesion, new/enlarged T2 lesion, and brain atrophy on brain MRI scans.
• effect on 3-month confirmed disabilty progression as defined by EDSS in predefined sub-groups [ Time Frame: Baseline, every 3 months up to the maximum of 60 months ]
  effect on confirmed disabilty progression in pre-defined subgroups, including patients with or without superimposed relaspes, rapidly evolving patients with 1.5 point or greater change in EDSS score in 2 years prior to enrollment into the study. Patients with score of 4 or more in MSSS and those who don't meet this criteria.
• Number of patients with adverse event [ Time Frame: Baseline, every 3 months up to the maximum of 60 months ]
  Safety analysis will be performed on AE by CTCAE grade, serious AEs and Study drug related AEs and the AEs leading to discontinuation of study drug.
• Number of patients with abnormal lab tests [ Time Frame: Baseline, every 3 months up to the maximum of 60 months ]
  Safety analysis will be performed on lab abnormalities will be based on CTCAE grades

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND)
• Official 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.
• 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: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Secondary Progressive Multiple Sclerosis

Intervention

• Drug: BAF312
  0.25, 0.5, 1, and 2 mg film-coated tablets
• Drug: Placebo
  Film-coated tablets

Study Arms

• Experimental: Siponimod (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.
  Intervention: Drug: BAF312
• Placebo Comparator: 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.
  Intervention: Drug: Placebo

Publications *

• Cree BA, Arnold DL, Fox RJ, Gold R, Vermersch P, Benedict RH, Bar-Or A, Piani-Meier D, Rouyrre N, Ritter S, Kilaru A, Karlsson G, Giovannoni G, Kappos L. Long-term efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis: Analysis of EXPAND core and extension data up to >5 years. Mult Scler. 2022 Apr 5:13524585221083194. doi: 10.1177/13524585221083194. [Epub ahead of print]
• Leppert D, Kropshofer H, Häring DA, Dahlke F, Patil A, Meinert R, Tomic D, Kappos L, Kuhle J. Blood Neurofilament Light in Progressive Multiple Sclerosis: Post Hoc Analysis of 2 Randomized Controlled Trials. Neurology. 2022 May 24;98(21):e2120-e2131. doi: 10.1212/WNL.0000000000200258. Epub 2022 Apr 4.
• Arnold DL, Piani-Meier D, Bar-Or A, Benedict RH, Cree BA, Giovannoni G, Gold R, Vermersch P, Arnould S, Dahlke F, Hach T, Ritter S, Karlsson G, Kappos L, Fox RJ; EXPAND Clinical Investigators. Effect of siponimod on magnetic resonance imaging measures of neurodegeneration and myelination in secondary progressive multiple sclerosis: Gray matter atrophy and magnetization transfer ratio analyses from the EXPAND phase 3 trial. Mult Scler. 2022 Mar 9:13524585221076717. doi: 10.1177/13524585221076717. [Epub ahead of print]
• Schur N, Gudala K, Vudumula U, Vadapalle S, Bhadhuri A, Casanova A, Adlard N, Schwenkglenks M. Cost Effectiveness and Budget Impact of Siponimod Compared to Interferon Beta-1a in the Treatment of Adult Patients with Secondary Progressive Multiple Sclerosis with Active Disease in Switzerland. Pharmacoeconomics. 2021 May;39(5):563-577. doi: 10.1007/s40273-021-01023-8. Epub 2021 Apr 1.
• Benedict RHB, Tomic D, Cree BA, Fox R, Giovannoni G, Bar-Or A, Gold R, Vermersch P, Pohlmann H, Wright I, Karlsson G, Dahlke F, Wolf C, Kappos L. Siponimod and Cognition in Secondary Progressive Multiple Sclerosis: EXPAND Secondary Analyses. Neurology. 2021 Jan 19;96(3):e376-e386. doi: 10.1212/WNL.0000000000011275. Epub 2020 Dec 16.
• Kappos L, Bar-Or A, Cree BAC, Fox RJ, Giovannoni G, Gold R, Vermersch P, Arnold DL, Arnould S, Scherz T, Wolf C, Wallström E, Dahlke F; EXPAND Clinical Investigators. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018 Mar 31;391(10127):1263-1273. doi: 10.1016/S0140-6736(18)30475-6. Epub 2018 Mar 23. Erratum in: Lancet. 2018 Nov 17;392(10160):2170.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: August 10, 2021): 1653
• Original Estimated Enrollment (submitted: August 14, 2012): 1530
• Estimated Study Completion Date: March 1, 2024
• Actual Primary Completion Date: April 29, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 Other protocol defined inclusion/exclusion may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Bulgaria, Canada, China, Czechia, Estonia, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Japan, Latvia, Lithuania, Netherlands, Poland, Portugal, Romania, Russian Federation, Slovakia, Spain, Sweden, Switzerland, Turkey, United Kingdom, United States
• Removed Location Countries: Czech Republic, Egypt

Administrative Information

• NCT Number: NCT01665144
• Other Study ID Numbers: CBAF312A2304
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Locations: central Contact Info Novartis.email@novartis.com

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: May 2022