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

Primary Purpose

Relapsing Remitting Multiple Sclerosis

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
BAF312
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Relapsing Remitting Multiple Sclerosis focused on measuring BAF312, siponimod, Multiple Sclerosis, Relapsing remitting Multiple Sclerosis, Demyelinating Autoimmune Diseases, MS, RRMS, inflammatory disease

Eligibility Criteria

18 Years - 56 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

BAF312 10 mg/2 mg

BAF312 2 mg/2 mg

BAF312 1.25 mg/2 mg

BAF312 .5 mg/2 mg

BAF312 .25 mg/2 mg

Arm Description

10 mg dose in Double Blind Phase and 2 mg in Open Label Phase

2 mg dose in Double Blind Phase and 2 mg in Open Label Phase

1.25 mg dose in Double Blind Phase and 2 mg in Open Label Phase

.5 mg dose in Double Blind Phase and 2 mg in Open Label Phase

.25 mg dose in Double Blind Phase and 2 mg in Open Label Phase

Outcomes

Primary Outcome Measures

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.
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
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
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.
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
Number of Participants With Dermatologic Alterations - Basal Cell Carcinoma (Extension Set)

Secondary Outcome Measures

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.
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.
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.

Full Information

First Posted
August 19, 2010
Last Updated
February 27, 2018
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01185821
Brief Title
Long-term Safety, Tolerability and Efficacy of BAF312 Given Orally in Patients With Relapsing-remitting Multiple Sclerosis
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
February 2018
Overall Recruitment Status
Completed
Study Start Date
August 30, 2010 (Actual)
Primary Completion Date
October 10, 2016 (Actual)
Study Completion Date
October 10, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Relapsing Remitting Multiple Sclerosis
Keywords
BAF312, siponimod, Multiple Sclerosis, Relapsing remitting Multiple Sclerosis, Demyelinating Autoimmune Diseases, MS, RRMS, inflammatory disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
This extension study was originally set up as a 2 year dose-blinded extension study to maintain blinding of ongoing Core study. Study was later amended to include a subsequent Open-Label treatment phase after Core study was unblinded. During the Dose-Blinded phase of the extension study patients received the same dose from the Core study. Patients who received placebo in Period 1 during the Core Study were equally randomized to 1 of the 3 active doses of siponimod used during Period 1 (0.5, 2.0, or 10 mg) and patients who received placebo in Period 2 were equally randomized to 1 of the 2 active doses of siponimod used during Period 2 (0.25 mg or 1.25 mg).
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Masking continued during the double blind period of extension only.
Allocation
Randomized
Enrollment
185 (Actual)

8. Arms, Groups, and Interventions

Arm Title
BAF312 10 mg/2 mg
Arm Type
Experimental
Arm Description
10 mg dose in Double Blind Phase and 2 mg in Open Label Phase
Arm Title
BAF312 2 mg/2 mg
Arm Type
Experimental
Arm Description
2 mg dose in Double Blind Phase and 2 mg in Open Label Phase
Arm Title
BAF312 1.25 mg/2 mg
Arm Type
Experimental
Arm Description
1.25 mg dose in Double Blind Phase and 2 mg in Open Label Phase
Arm Title
BAF312 .5 mg/2 mg
Arm Type
Experimental
Arm Description
.5 mg dose in Double Blind Phase and 2 mg in Open Label Phase
Arm Title
BAF312 .25 mg/2 mg
Arm Type
Experimental
Arm Description
.25 mg dose in Double Blind Phase and 2 mg in Open Label Phase
Intervention Type
Drug
Intervention Name(s)
BAF312
Other Intervention Name(s)
siponimod
Intervention Description
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.
Primary Outcome Measure Information:
Title
Total Number of Adverse Events During Evaluation of Long Term Safety and Tolerability of BAF312A in Extension Study.
Description
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.
Time Frame
Baseline up to approximately 5 years
Title
Number of Participants With Cardiac Conduction Abnormalities During the Titration Phase of the Study (Without Washout)
Description
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
Time Frame
Baseline Extension up to day 10
Title
Number of Participants With Cardiac Conduction-IVCD Abnormality During the Titration Phase of the Study (With Washout)
Description
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
Time Frame
Baseline Extension up to day 10
Title
Number of Participants With Changes in Blood Pressure for Overall Extension Study. (Extension Analysis Set)
Description
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.
Time Frame
Baseline Extension up to approximately 5 years
Title
Number of Participants With Viral Infections of Interest Greater or Equal to 5% in Any Dose Group (Extension Set)
Description
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
Time Frame
Baseline Extension up to approximately 5 years
Title
Number of Participants With Dermatologic Alterations - Basal Cell Carcinoma (Extension Set)
Time Frame
Baseline Extension up to approximately 5 years
Secondary Outcome Measure Information:
Title
Number of Relapses in One Year - Annualized Relapse Rates for Overall Extension Study (ARR) (Extension Set)
Description
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.
Time Frame
Baseline extension up to approximately 5 years
Title
Percentage of Participants Free of Magnetic Resonance Imaging (MRI) Identified Disease Activity at Any Scan During Extension Study (Extension Set)
Description
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.
Time Frame
Baseline Extension up to approximately 5 years
Title
Percentage of Participants Free of Confirmed Disability Progression in Extension Study (Extension Set)
Description
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.
Time Frame
Baseline Extension up to approximately 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
56 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Novartis Investigative Site
City
Pompano Beach
State/Province
Florida
ZIP/Postal Code
33060
Country
United States
Facility Name
Novartis Investigative Site
City
Tallahassee
State/Province
Florida
ZIP/Postal Code
32308
Country
United States
Facility Name
Novartis Investigative Site
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Novartis Investigative Site
City
Grand Rapids
State/Province
Michigan
ZIP/Postal Code
49525
Country
United States
Facility Name
Novartis Investigative Site
City
Akron
State/Province
Ohio
ZIP/Postal Code
44320
Country
United States
Facility Name
Novartis Investigative Site
City
Greenville
State/Province
South Carolina
ZIP/Postal Code
29607
Country
United States
Facility Name
Novartis Investigative Site
City
Seattle
State/Province
Washington
ZIP/Postal Code
98122
Country
United States
Facility Name
Novartis Investigative Site
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
K1H 8L6
Country
Canada
Facility Name
Novartis Investigative Site
City
Gatineau
State/Province
Quebec
ZIP/Postal Code
J9J 0A5
Country
Canada
Facility Name
Novartis Investigative Site
City
Greenfield Park
State/Province
Quebec
ZIP/Postal Code
J4V 2J2
Country
Canada
Facility Name
Novartis Investigative Site
City
Helsinki
ZIP/Postal Code
00930
Country
Finland
Facility Name
Novartis Investigative Site
City
Tampere
ZIP/Postal Code
FIN-33520
Country
Finland
Facility Name
Novartis Investigative Site
City
Dresden
ZIP/Postal Code
01307
Country
Germany
Facility Name
Novartis Investigative Site
City
Ibbenbueren
ZIP/Postal Code
49477
Country
Germany
Facility Name
Novartis Investigative Site
City
Muenchen
ZIP/Postal Code
81675
Country
Germany
Facility Name
Novartis Investigative Site
City
Muenster
ZIP/Postal Code
48149
Country
Germany
Facility Name
Novartis Investigative Site
City
Budapest
ZIP/Postal Code
1076
Country
Hungary
Facility Name
Novartis Investigative Site
City
Budapest
ZIP/Postal Code
1145
Country
Hungary
Facility Name
Novartis Investigative Site
City
Debrecen
ZIP/Postal Code
4032
Country
Hungary
Facility Name
Novartis Investigative Site
City
Veszprem
ZIP/Postal Code
H-8200
Country
Hungary
Facility Name
Novartis Investigative Site
City
Montichiari
State/Province
BS
ZIP/Postal Code
25018
Country
Italy
Facility Name
Novartis Investigative Site
City
Chieti
State/Province
CH
ZIP/Postal Code
66100
Country
Italy
Facility Name
Novartis Investigative Site
City
Roma
State/Province
RM
ZIP/Postal Code
00133
Country
Italy
Facility Name
Novartis Investigative Site
City
Roma
State/Province
RM
ZIP/Postal Code
00152
Country
Italy
Facility Name
Novartis Investigative Site
City
Bergen
ZIP/Postal Code
5021
Country
Norway
Facility Name
Novartis Investigative Site
City
Oslo
ZIP/Postal Code
0424
Country
Norway
Facility Name
Novartis Investigative Site
City
Lodz
ZIP/Postal Code
90-324
Country
Poland
Facility Name
Novartis Investigative Site
City
Lublin
ZIP/Postal Code
20-954
Country
Poland
Facility Name
Novartis Investigative Site
City
Warszawa
ZIP/Postal Code
02-957
Country
Poland
Facility Name
Novartis Investigative Site
City
Kazan
ZIP/Postal Code
420103
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Moscow
ZIP/Postal Code
125367
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Moscow
ZIP/Postal Code
127018
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Saint Petersburg
ZIP/Postal Code
197022
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Saint-Petersburg
ZIP/Postal Code
194044
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Sevilla
State/Province
Andalucia
ZIP/Postal Code
41009
Country
Spain
Facility Name
Novartis Investigative Site
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08035
Country
Spain
Facility Name
Novartis Investigative Site
City
Valencia
State/Province
Comunidad Valenciana
ZIP/Postal Code
46026
Country
Spain
Facility Name
Novartis Investigative Site
City
Basel
ZIP/Postal Code
4031
Country
Switzerland
Facility Name
Novartis Investigative Site
City
Lugano
ZIP/Postal Code
6900
Country
Switzerland
Facility Name
Novartis Investigative Site
City
Zuerich
ZIP/Postal Code
8091
Country
Switzerland
Facility Name
Novartis Investigative Site
City
Ankara
ZIP/Postal Code
06100
Country
Turkey
Facility Name
Novartis Investigative Site
City
Haseki / Istanbul
ZIP/Postal Code
34096
Country
Turkey
Facility Name
Novartis Investigative Site
City
Istanbul
ZIP/Postal Code
34093
Country
Turkey
Facility Name
Novartis Investigative Site
City
Izmir
ZIP/Postal Code
35340
Country
Turkey
Facility Name
Novartis Investigative Site
City
Kocaeli
ZIP/Postal Code
41380
Country
Turkey

12. IPD Sharing Statement

Citations:
PubMed Identifier
27380540
Citation
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.
Results Reference
derived
Links:
URL
https://jamanetwork.com/journals/jamaneurology/fullarticle/2532101
Description
Publication from the Journal of the American Medical Association (JAMA) - Neurology

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

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