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 approximately 3 years ] [ 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 approximately 3 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 approximately 3 years ] [ 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 approximately 3 years ] [ 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 approximately 3 years ] [ 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 approximately 3 years ] [ 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 approximately 3 years ] [ 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 events during the Core Part [ Time Frame: Baseline, every 3 months up to the maximum of approximately 3 years ] [ 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 during the Core Part [ Time Frame: Baseline, every 3 months up to the maximum of approximately 3 years ] [ Designated as safety issue: Yes ]
  Safety analysis will be performed on lab abnormalities will be based on CTCAE grades
• Number of patients with adverse events during the Extension Part [ Time Frame: Following the Core Part of the study, every 3 months for one year and then every 6 months up to the maximum of 84 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 during the Extension Part [ Time Frame: Following the Core Part of the study, every 3 months for the first year and then every 6 months up to the maximum of 84 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

• 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
  1090 patients will be randomized to receive BAF312 during the trial for a maximum of approximately 3 years (Core Part). Patients who meet all inclusion and none of the exclusion criteria will be treated with BAF312 daily. Following the Core Part, eligible patients enter the Extension Part during which all receive open-label BAF312 for a maximum of 84 additional months.
  Intervention: Drug: BAF312
• Placebo Comparator: Placebo
  Matching Placebo administered orally during the Core Part of the trial. Following the Core Part, eligible patients enter the Extension Part during which all receive open-label BAF312 for a maximum of 84 additional months.
  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.