Long-term Safety, Tolerability and Efficacy of BAF312 Given Orally in Patients With Relapsing-remitting Multiple Sclerosis

A Dose Blinded Extension Study to the CBAF312A2201 Study to Evaluate Long-term Safety, Tolerability and Efficacy of BAF312 Given Orally Once Daily in Patients With Relapsing-remitting Multiple Sclerosis

This study consisted of a two year dose blinded phase during which patients received one of five doses of siponimod (10, 2, 1.25, 0.5 or 0.25mg) following which patients were switched to open label treatment with siponimod 2mg for approximately a further 3 years. It will provide data on long term safety, tolerability and efficacy of siponimod in the RRMS patient population

Study Overview

• Status: Completed
• Conditions: Relapsing Remitting Multiple Sclerosis
• Intervention / Treatment: Drug: BAF312

Detailed Description

This study was prematurely discontinued after approximately 5 years. The decision to prematurely discontinue the study was not taken due to safety-related concerns, rather due to a decision to focus the development of siponimod in MS on a different population.

• Study Type: Interventional
• Enrollment (Actual): 185
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Novartis Investigative Site
  • Quebec
    • Gatineau, Quebec, Canada, J9J 0A5
      • Novartis Investigative Site
    • Greenfield Park, Quebec, Canada, J4V 2J2
      • Novartis Investigative Site
• Finland
  • Helsinki, Finland, 00930
    • Novartis Investigative Site
  • Tampere, Finland, FIN-33520
    • Novartis Investigative Site
• Germany
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Ibbenbueren, Germany, 49477
    • Novartis Investigative Site
  • Muenchen, Germany, 81675
    • Novartis Investigative Site
  • Muenster, Germany, 48149
    • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, 1145
    • Novartis Investigative Site
  • Budapest, Hungary, 1076
    • Novartis Investigative Site
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
  • Veszprem, Hungary, H-8200
    • Novartis Investigative Site
• Italy
  • BS
    • Montichiari, BS, Italy, 25018
      • Novartis Investigative Site
  • CH
    • Chieti, CH, Italy, 66100
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00152
      • Novartis Investigative Site
    • Roma, RM, Italy, 00133
      • Novartis Investigative Site
• Norway
  • Bergen, Norway, 5021
    • Novartis Investigative Site
  • Oslo, Norway, 0424
    • Novartis Investigative Site
• Poland
  • Lodz, Poland, 90-324
    • Novartis Investigative Site
  • Lublin, Poland, 20-954
    • Novartis Investigative Site
  • Warszawa, Poland, 02-957
    • Novartis Investigative Site
• Russian Federation
  • Kazan, Russian Federation, 420103
    • Novartis Investigative Site
  • Moscow, Russian Federation, 127018
    • Novartis Investigative Site
  • Moscow, Russian Federation, 125367
    • Novartis Investigative Site
  • Saint Petersburg, Russian Federation, 197022
    • Novartis Investigative Site
  • Saint-Petersburg, Russian Federation, 194044
    • Novartis Investigative Site
• Spain
  • Andalucia
    • Sevilla, Andalucia, Spain, 41009
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46026
      • Novartis Investigative Site
• Switzerland
  • Basel, Switzerland, 4031
    • Novartis Investigative Site
  • Lugano, Switzerland, 6900
    • Novartis Investigative Site
  • Zuerich, Switzerland, 8091
    • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06100
    • Novartis Investigative Site
  • Haseki / Istanbul, Turkey, 34096
    • Novartis Investigative Site
  • Istanbul, Turkey, 34093
    • Novartis Investigative Site
  • Izmir, Turkey, 35340
    • Novartis Investigative Site
  • Kocaeli, Turkey, 41380
    • Novartis Investigative Site
• United States
  • Florida
    • Miami, Florida, United States, 33136
      • Novartis Investigative Site
    • Pompano Beach, Florida, United States, 33060
      • Novartis Investigative Site
    • Tallahassee, Florida, United States, 32308
      • Novartis Investigative Site
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Novartis Investigative Site
  • Michigan
    • Grand Rapids, Michigan, United States, 49525
      • Novartis Investigative Site
  • Ohio
    • Akron, Ohio, United States, 44320
      • Novartis Investigative Site
  • South Carolina
    • Greenville, South Carolina, United States, 29607
      • Novartis Investigative Site
  • Washington
    • Seattle, Washington, United States, 98122
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 56 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients completed the core study BAF312A2201
• Written informed consent provided before any assessment of the extension study
• Female patients at risk of becoming pregnant must have a negative pregnancy test and use simultaneously two forms of effective contraception

Exclusion Criteria:

• Newly diagnosed systemic disease other than MS (which may require immunosuppressive treatment)
• Malignancies, diabetes, significant cardiovascular and pulmonary diseases and conditions
• Active infections

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: BAF312 10 mg/2 mg; 10 mg dose in Double Blind Phase and 2 mg in Open Label Phase	Drug: BAF312; BAF312 was supplied in film-coated tablets in strengths of 5, 4 ,2, 1, .5 and .25 mg. The actual doses taken were 10, 2, 1.25, .5 and .25 mg taken orally once a day.; Other Names: siponimod
EXPERIMENTAL: BAF312 2 mg/2 mg; 2 mg dose in Double Blind Phase and 2 mg in Open Label Phase	Drug: BAF312; BAF312 was supplied in film-coated tablets in strengths of 5, 4 ,2, 1, .5 and .25 mg. The actual doses taken were 10, 2, 1.25, .5 and .25 mg taken orally once a day.; Other Names: siponimod
EXPERIMENTAL: BAF312 1.25 mg/2 mg; 1.25 mg dose in Double Blind Phase and 2 mg in Open Label Phase	Drug: BAF312; BAF312 was supplied in film-coated tablets in strengths of 5, 4 ,2, 1, .5 and .25 mg. The actual doses taken were 10, 2, 1.25, .5 and .25 mg taken orally once a day.; Other Names: siponimod
EXPERIMENTAL: BAF312 .5 mg/2 mg; .5 mg dose in Double Blind Phase and 2 mg in Open Label Phase	Drug: BAF312; BAF312 was supplied in film-coated tablets in strengths of 5, 4 ,2, 1, .5 and .25 mg. The actual doses taken were 10, 2, 1.25, .5 and .25 mg taken orally once a day.; Other Names: siponimod
EXPERIMENTAL: BAF312 .25 mg/2 mg; .25 mg dose in Double Blind Phase and 2 mg in Open Label Phase	Drug: BAF312; BAF312 was supplied in film-coated tablets in strengths of 5, 4 ,2, 1, .5 and .25 mg. The actual doses taken were 10, 2, 1.25, .5 and .25 mg taken orally once a day.; Other Names: siponimod

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Number of Adverse Events During Evaluation of Long Term Safety and Tolerability of BAF312A in Extension Study.	Refer to adverse events for complete listing of serious adverse events and other adverse events. Adverse events of interest were presented in separate tables. There were no reports of macular edema.	Baseline up to approximately 5 years
Number of Participants With Cardiac Conduction Abnormalities During the Titration Phase of the Study (Without Washout)	Number of patients with abnormal ECG conduction findings during dose-blinded titration at any visit post-dose, by type of abnormality and treatment (Extension Set). Number analyzed represent participants who had ECG results. Washout was defined as not being on treatment drug between Core and Extension for >7 days. Abbreviation: Con=conduction, IVCD=intraventricular conduction defect , WPW=Wolff-Parkinson-White syndrome	Baseline Extension up to day 10
Number of Participants With Cardiac Conduction-IVCD Abnormality During the Titration Phase of the Study (With Washout)	Number of patients with abnormal ECG conduction findings during dose-blinded titration at any visit post-dose, by type of abnormality and treatment (Extension Set). Number analyzed represent participants who had ECG results. Washout was defined as not being on treatment drug between Core and Extension for >7 days. Abbreviations: washout = WO, Con=conduction	Baseline Extension up to day 10
Number of Participants With Changes in Blood Pressure for Overall Extension Study. (Extension Analysis Set)	Sitting blood pressure was measured in triplicate. The categories of notably low and high values and changes are presented for systolic (SBP) and diastolic (DBP). Multiple occurrences for a patient are counted as one occurrence in this table.	Baseline Extension up to approximately 5 years
Number of Participants With Viral Infections of Interest Greater or Equal to 5% in Any Dose Group (Extension Set)	Most infections were clinical diagnoses and were not confirmed by microbiology / virologic investigations. A patient with multiple occurrences of an infection for a preferred term is counted only once in each specific category. Events identified as infections by the Investigator and defined as an AE with onset on or after the first dose of Extension Study drug up to and including 30 days after the date of the last dose	Baseline Extension up to approximately 5 years
Number of Participants With Dermatologic Alterations - Basal Cell Carcinoma (Extension Set)		Baseline Extension up to approximately 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Relapses in One Year - Annualized Relapse Rates for Overall Extension Study (ARR) (Extension Set)	Group level ARR (raw) is calculated as the total number of relapses for all the patients in the treatment group divided by the total number of days on study for all patients in the group and multiplied by 365.25 to obtain the annual rate. Model estimates are based on a negative binomial regression model, adjusted for treatment group, age, baseline EDSS, baseline number of Gd-enhanced T1 lesions and number of relapses in previous 2 years as covariates, with log(time on study in years) as the offset variable, using the log link.	Baseline extension up to approximately 5 years
Percentage of Participants Free of Magnetic Resonance Imaging (MRI) Identified Disease Activity at Any Scan During Extension Study (Extension Set)	Free of MRI disease activity is defined as free of Gadolinium enhanced T1 lesions at any scan; free of new or enlarging T2 lesions at any scan: free of both gadolinium enhanced T1 lesions and new or enlarging T2 lesions at any scan. Number of patients analyzed = patients with at least one MRI scan during the specified time period. New lesions at a specific visit are assessed relative to the previous scheduled visit scan. No imputation of missing scans is performed. As a result missing scans can lead to an overestimation of the proportion of patients free of a specific MRI activity.	Baseline Extension up to approximately 5 years
Percentage of Participants Free of Confirmed Disability Progression in Extension Study (Extension Set)	Six-month disability progression was defined relative to extension baseline EDSS score: 1.5 point increase in patients with baseline EDSS score of 0, 1.0 increase in patients with baseline EDSS score of between 0.5 to 5.0, inclusive and 0.5 increase in patients with baseline EDSS score of ≥ 5.5. The criteria for 6-month disability progression included detection of onset of progression and confirmation of progression for a period of at least 6 months.	Baseline Extension up to approximately 5 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Kappos L, Li DK, Stuve O, Hartung HP, Freedman MS, Hemmer B, Rieckmann P, Montalban X, Ziemssen T, Hunter B, Arnould S, Wallstrom E, Selmaj K. Safety and Efficacy of Siponimod (BAF312) in Patients With Relapsing-Remitting Multiple Sclerosis: Dose-Blinded, Randomized Extension of the Phase 2 BOLD Study. JAMA Neurol. 2016 Sep 1;73(9):1089-98. doi: 10.1001/jamaneurol.2016.1451.

Helpful Links

• Publication from the Journal of the American Medical Association (JAMA) - Neurology

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 30, 2010
• Primary Completion (ACTUAL): October 10, 2016
• Study Completion (ACTUAL): October 10, 2016

Study Registration Dates

• First Submitted: August 19, 2010
• First Submitted That Met QC Criteria: August 19, 2010
• First Posted (ESTIMATE): August 20, 2010

Study Record Updates

• Last Update Posted (ACTUAL): March 27, 2018
• Last Update Submitted That Met QC Criteria: February 27, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; RRMS; MS; siponimod; Demyelinating Autoimmune Diseases; inflammatory disease; BAF312; Relapsing remitting Multiple Sclerosis
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Sphingosine 1 Phosphate Receptor Modulators; Siponimod
• Other Study ID Numbers: CBAF312A2201E1; 2009-014392-51 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No