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

• 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 ] [ Designated as safety issue: No ]
  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 5 years ] [ Designated as safety issue: No ]
  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 60 months ] [ Designated as safety issue: No ]
  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 60 months ] [ Designated as safety issue: No ]
  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 60 months ] [ Designated as safety issue: No ]
  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 60 months ] [ Designated as safety issue: No ]
  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 60 months ] [ Designated as safety issue: No ]
  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.
• Number of patients with adverse event [ Time Frame: Baseline, every 3 months up to the maximum of 60 months ] [ Designated as safety issue: Yes ]
  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 ] [ Designated as safety issue: Yes ]
  Safety analysis will be performed on lab abnormalities will be based on CTCAE grades

• 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 ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: Yes ]
  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 ] [ Designated as safety issue: Yes ]
  Safety analysis will be performed on lab abnormalities will be based on CTCAE grades

Evaluate the safety and efficacy of Siponimod (BAF312) versus placebo in a variable treatment duration in patients with secondary progressive multiple sclerosis.

• Drug: BAF312
  Patients will be randomized to receive BAF312. BAF312 will be provided in a dose titration from 0.25 mg to a 2 mg dose.
• Drug: Placebo
  Placebo

• Experimental: BAF312
  1020 patients will be randomized to receive BAF312 during the trial for a duration of 23 to 42 months with a maximum of 60 months. Patients who meet all inclusion and none of the exclusion criteria will be treated with BAF312 daily.
  Intervention: Drug: BAF312
• Placebo Comparator: Placebo
  Matching Placebo administered orally.
  Intervention: Drug: Placebo

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.