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

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT01185821
Collaborator
(none)
185
Enrollment
46
Locations
5
Arms
73.4
Actual Duration (Months)
4
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

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

Condition or Disease Intervention/Treatment Phase
Phase 2

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 Design

Study Type:
Interventional
Actual Enrollment :
185 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention 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).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:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Masking continued during the double blind period of extension only.
Primary Purpose:
Treatment
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
Actual Study Start Date :
Aug 30, 2010
Actual Primary Completion Date :
Oct 10, 2016
Actual Study Completion Date :
Oct 10, 2016

Arms and Interventions

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

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Total Number of Adverse Events During Evaluation of Long Term Safety and Tolerability of BAF312A in Extension Study. [Baseline up to approximately 5 years]

      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.

    2. Number of Participants With Cardiac Conduction Abnormalities During the Titration Phase of the Study (Without Washout) [Baseline Extension up to day 10]

      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

    3. Number of Participants With Cardiac Conduction-IVCD Abnormality During the Titration Phase of the Study (With Washout) [Baseline Extension up to day 10]

      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

    4. Number of Participants With Changes in Blood Pressure for Overall Extension Study. (Extension Analysis Set) [Baseline Extension up to approximately 5 years]

      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.

    5. Number of Participants With Viral Infections of Interest Greater or Equal to 5% in Any Dose Group (Extension Set) [Baseline Extension up to approximately 5 years]

      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

    6. Number of Participants With Dermatologic Alterations - Basal Cell Carcinoma (Extension Set) [Baseline Extension up to approximately 5 years]

    Secondary Outcome Measures

    1. Number of Relapses in One Year - Annualized Relapse Rates for Overall Extension Study (ARR) (Extension Set) [Baseline extension up to approximately 5 years]

      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.

    2. Percentage of Participants Free of Magnetic Resonance Imaging (MRI) Identified Disease Activity at Any Scan During Extension Study (Extension Set) [Baseline Extension up to approximately 5 years]

      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.

    3. Percentage of Participants Free of Confirmed Disability Progression in Extension Study (Extension Set) [Baseline Extension up to approximately 5 years]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 56 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Novartis Investigative Site Miami Florida United States 33136
    2 Novartis Investigative Site Pompano Beach Florida United States 33060
    3 Novartis Investigative Site Tallahassee Florida United States 32308
    4 Novartis Investigative Site Chicago Illinois United States 60637
    5 Novartis Investigative Site Grand Rapids Michigan United States 49525
    6 Novartis Investigative Site Akron Ohio United States 44320
    7 Novartis Investigative Site Greenville South Carolina United States 29607
    8 Novartis Investigative Site Seattle Washington United States 98122
    9 Novartis Investigative Site Ottawa Ontario Canada K1H 8L6
    10 Novartis Investigative Site Gatineau Quebec Canada J9J 0A5
    11 Novartis Investigative Site Greenfield Park Quebec Canada J4V 2J2
    12 Novartis Investigative Site Helsinki Finland 00930
    13 Novartis Investigative Site Tampere Finland FIN-33520
    14 Novartis Investigative Site Dresden Germany 01307
    15 Novartis Investigative Site Ibbenbueren Germany 49477
    16 Novartis Investigative Site Muenchen Germany 81675
    17 Novartis Investigative Site Muenster Germany 48149
    18 Novartis Investigative Site Budapest Hungary 1076
    19 Novartis Investigative Site Budapest Hungary 1145
    20 Novartis Investigative Site Debrecen Hungary 4032
    21 Novartis Investigative Site Veszprem Hungary H-8200
    22 Novartis Investigative Site Montichiari BS Italy 25018
    23 Novartis Investigative Site Chieti CH Italy 66100
    24 Novartis Investigative Site Roma RM Italy 00133
    25 Novartis Investigative Site Roma RM Italy 00152
    26 Novartis Investigative Site Bergen Norway 5021
    27 Novartis Investigative Site Oslo Norway 0424
    28 Novartis Investigative Site Lodz Poland 90-324
    29 Novartis Investigative Site Lublin Poland 20-954
    30 Novartis Investigative Site Warszawa Poland 02-957
    31 Novartis Investigative Site Kazan Russian Federation 420103
    32 Novartis Investigative Site Moscow Russian Federation 125367
    33 Novartis Investigative Site Moscow Russian Federation 127018
    34 Novartis Investigative Site Saint Petersburg Russian Federation 197022
    35 Novartis Investigative Site Saint-Petersburg Russian Federation 194044
    36 Novartis Investigative Site Sevilla Andalucia Spain 41009
    37 Novartis Investigative Site Barcelona Catalunya Spain 08035
    38 Novartis Investigative Site Valencia Comunidad Valenciana Spain 46026
    39 Novartis Investigative Site Basel Switzerland 4031
    40 Novartis Investigative Site Lugano Switzerland 6900
    41 Novartis Investigative Site Zuerich Switzerland 8091
    42 Novartis Investigative Site Ankara Turkey 06100
    43 Novartis Investigative Site Haseki / Istanbul Turkey 34096
    44 Novartis Investigative Site Istanbul Turkey 34093
    45 Novartis Investigative Site Izmir Turkey 35340
    46 Novartis Investigative Site Kocaeli Turkey 41380

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01185821
    Other Study ID Numbers:
    • CBAF312A2201E1
    • 2009-014392-51
    First Posted:
    Aug 20, 2010
    Last Update Posted:
    Mar 27, 2018
    Last Verified:
    Feb 1, 2018
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Novartis Pharmaceuticals
    BAF312
    siponimod
    Multiple Sclerosis
    Relapsing remitting Multiple Sclerosis
    Demyelinating Autoimmune Diseases
    MS
    RRMS
    inflammatory disease
    Additional relevant MeSH terms:
    Multiple Sclerosis
    Multiple Sclerosis, Relapsing-Remitting
    Sclerosis
    Siponimod

    Study Results

    Participant Flow

    Recruitment Details All patients enrolled in the Extension study had completed the Core study. All patients underwent a 10 day titration at the start of the dose blinded phase of the study
    Pre-assignment Detail During the double blind phase of the extension study patients received the same dose from the Core study. Placebo patients from Core Period 1 were randomized to 0.5, 2 or 10mg, those from Period 2 were randomized to 0.25 or 1.25 mg. All patients received 2mg in Open Label phase (.5 and .25mg were titrated up to 2mg)
    Arm/Group Title 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/Group 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
    Period Title: Overall Study
    STARTED 33 29 43 29 50
    Patients With Washout 33 29 39 29 33
    Patients Without Washout 0 0 4 0 17
    Patients on Placebo in Core 8 7 9 8 2
    COMPLETED 26 20 33 23 26
    NOT COMPLETED 7 9 10 6 24

    Baseline Characteristics

    Arm/Group Title 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 Total
    Arm/Group 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 Total of all reporting groups
    Overall Participants 33 29 43 29 50 184
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    36.8
    (9.09)
    35.1
    (9.16)
    34.0
    (7.57)
    35.2
    (9.10)
    37.2
    (8.42)
    35.7
    (8.59)
    Sex: Female, Male (Count of Participants)
    Female
    21
    63.6%
    18
    62.1%
    32
    74.4%
    18
    62.1%
    41
    82%
    130
    70.7%
    Male
    12
    36.4%
    11
    37.9%
    11
    25.6%
    11
    37.9%
    9
    18%
    54
    29.3%
    Expanded disability status scale (EDSS) (units on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [units on a scale]
    2.03
    (0.960)
    2.19
    (1.278)
    1.95
    (1.096)
    1.88
    (1.374)
    2.22
    (1.258)
    2.07
    (1.190)

    Outcome Measures

    1. Primary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 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/Group 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
    Measure Participants 33 29 43 29 50
    Serious adverse events
    4
    7
    6
    6
    8
    Other adverse events
    30
    26
    42
    29
    42
    2. Primary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 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/Group 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
    Measure Participants 33 29 39 29 33
    Conduction-Prolonged QTc
    5
    15.2%
    2
    6.9%
    5
    11.6%
    2
    6.9%
    4
    8%
    Conduction - IVCD
    3
    9.1%
    8
    27.6%
    1
    2.3%
    3
    10.3%
    0
    0%
    Conduction - AV Mobitz I
    1
    3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Con:1st degree AV block
    0
    0%
    1
    3.4%
    1
    2.3%
    1
    3.4%
    1
    2%
    Conduction - WPW
    0
    0%
    0
    0%
    0
    0%
    1
    3.4%
    0
    0%
    3. Primary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title BAF312 .25 mg/2 mg
    Arm/Group Description .25 mg dose in Double Blind Phase and 2 mg in Open Label Phase
    Measure Participants 4
    Number [participants]
    4
    12.1%
    4. Primary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 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/Group 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
    Measure Participants 33 29 43 29 50
    SBP Low: ≤ 90
    1
    3%
    3
    10.3%
    2
    4.7%
    1
    3.4%
    1
    2%
    SBP ≥ 20 decrease from baseline
    8
    24.2%
    10
    34.5%
    4
    9.3%
    6
    20.7%
    10
    20%
    SBP High: ≥ 160
    1
    3%
    1
    3.4%
    1
    2.3%
    3
    10.3%
    3
    6%
    SBP ≥ 20 increase from baseline
    9
    27.3%
    8
    27.6%
    12
    27.9%
    13
    44.8%
    18
    36%
    DBP Low: ≤ 50
    1
    3%
    0
    0%
    1
    2.3%
    0
    0%
    1
    2%
    DBP ≥ 15 decrease from baseline
    14
    42.4%
    8
    27.6%
    10
    23.3%
    10
    34.5%
    10
    20%
    DBP High: ≥ 100
    4
    12.1%
    7
    24.1%
    4
    9.3%
    4
    13.8%
    4
    8%
    DBP ≥ 15 increase from baseline
    9
    27.3%
    13
    44.8%
    13
    30.2%
    11
    37.9%
    17
    34%
    5. Primary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 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/Group 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
    Measure Participants 33 29 43 29 50
    Oral herpes
    5
    15.2%
    0
    0%
    4
    9.3%
    2
    6.9%
    4
    8%
    Herpes zoster
    5
    15.2%
    0
    0%
    3
    7%
    2
    6.9%
    0
    0%
    Influenza
    3
    9.1%
    4
    13.8%
    3
    7%
    6
    20.7%
    6
    12%
    6. Primary Outcome
    Title Number of Participants With Dermatologic Alterations - Basal Cell Carcinoma (Extension Set)
    Description
    Time Frame Baseline Extension up to approximately 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 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/Group 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
    Measure Participants 33 29 43 29 50
    Number [participants]
    1
    3%
    0
    0%
    1
    2.3%
    0
    0%
    1
    2%
    7. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 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/Group 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
    Measure Participants 33 29 43 29 50
    Mean (95% Confidence Interval) [Group level ARR]
    0.18
    0.15
    0.16
    0.19
    0.22
    8. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 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/Group 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
    Measure Participants 31 26 43 29 47
    Free of Gd-enhanced T1 lesions at any scan
    58.1
    176.1%
    57.7
    199%
    58.1
    135.1%
    44.8
    154.5%
    66.0
    132%
    Free of new/enlarging T2 lesions at any scan
    32.3
    97.9%
    42.3
    145.9%
    46.5
    108.1%
    20.7
    71.4%
    40.4
    80.8%
    Free of Gd-enhanced T1 and new enlarged T2 lesions
    32.3
    97.9%
    42.3
    145.9%
    44.2
    102.8%
    20.7
    71.4%
    40.4
    80.8%
    9. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 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/Group 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
    Measure Participants 33 29 43 29 50
    Number (95% Confidence Interval) [percentage of participants]
    72.3
    219.1%
    82.4
    284.1%
    84.8
    197.2%
    81.4
    280.7%
    78.6
    157.2%

    Adverse Events

    Time Frame Adverse Events (AEs) are collected from First Patient First Visit (FPFV)until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    Adverse Event Reporting Description
    Arm/Group Title BAF312 10/2 mg BAF312 2/2 mg BAF312 1.25/2 mg BAF312 0.5/2 mg BAF312 0.25/2 mg All Patients
    Arm/Group Description BAF312 10/2 mg BAF312 2/2 mg BAF312 1.25/2 mg BAF312 0.5/2 mg BAF312 0.25/2 mg All patients
    All Cause Mortality
    BAF312 10/2 mg BAF312 2/2 mg BAF312 1.25/2 mg BAF312 0.5/2 mg BAF312 0.25/2 mg All Patients
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    BAF312 10/2 mg BAF312 2/2 mg BAF312 1.25/2 mg BAF312 0.5/2 mg BAF312 0.25/2 mg All Patients
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/33 (12.1%) 7/29 (24.1%) 6/43 (14%) 6/29 (20.7%) 8/50 (16%) 31/184 (16.8%)
    Blood and lymphatic system disorders
    Splenic cyst 0/33 (0%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 1/50 (2%) 1/184 (0.5%)
    Ear and labyrinth disorders
    Otosclerosis 0/33 (0%) 0/29 (0%) 0/43 (0%) 1/29 (3.4%) 0/50 (0%) 1/184 (0.5%)
    Eye disorders
    Glaucoma 0/33 (0%) 0/29 (0%) 1/43 (2.3%) 0/29 (0%) 0/50 (0%) 1/184 (0.5%)
    Gastrointestinal disorders
    Abdominal discomfort 0/33 (0%) 1/29 (3.4%) 0/43 (0%) 0/29 (0%) 0/50 (0%) 1/184 (0.5%)
    Gastritis 0/33 (0%) 1/29 (3.4%) 0/43 (0%) 0/29 (0%) 0/50 (0%) 1/184 (0.5%)
    Nausea 0/33 (0%) 0/29 (0%) 0/43 (0%) 1/29 (3.4%) 0/50 (0%) 1/184 (0.5%)
    Pancreatitis acute 0/33 (0%) 0/29 (0%) 0/43 (0%) 1/29 (3.4%) 0/50 (0%) 1/184 (0.5%)
    Vomiting 0/33 (0%) 0/29 (0%) 0/43 (0%) 1/29 (3.4%) 0/50 (0%) 1/184 (0.5%)
    General disorders
    Submandibular mass 1/33 (3%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 0/50 (0%) 1/184 (0.5%)
    Hepatobiliary disorders
    Biliary dyskinesia 0/33 (0%) 1/29 (3.4%) 0/43 (0%) 0/29 (0%) 0/50 (0%) 1/184 (0.5%)
    Immune system disorders
    Anaphylactic reaction 0/33 (0%) 0/29 (0%) 0/43 (0%) 1/29 (3.4%) 0/50 (0%) 1/184 (0.5%)
    Infections and infestations
    Oral herpes 0/33 (0%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 1/50 (2%) 1/184 (0.5%)
    Pyelonephritis 0/33 (0%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 1/50 (2%) 1/184 (0.5%)
    Pyelonephritis acute 0/33 (0%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 1/50 (2%) 1/184 (0.5%)
    Respiratory tract infection 0/33 (0%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 1/50 (2%) 1/184 (0.5%)
    Upper respiratory tract infection 0/33 (0%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 1/50 (2%) 1/184 (0.5%)
    Urinary tract infection 0/33 (0%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 1/50 (2%) 1/184 (0.5%)
    Injury, poisoning and procedural complications
    Ankle fracture 0/33 (0%) 0/29 (0%) 0/43 (0%) 1/29 (3.4%) 0/50 (0%) 1/184 (0.5%)
    Craniocerebral injury 0/33 (0%) 1/29 (3.4%) 0/43 (0%) 0/29 (0%) 0/50 (0%) 1/184 (0.5%)
    Femur fracture 0/33 (0%) 1/29 (3.4%) 0/43 (0%) 0/29 (0%) 0/50 (0%) 1/184 (0.5%)
    Tendon rupture 0/33 (0%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 1/50 (2%) 1/184 (0.5%)
    Investigations
    Smear cervix abnormal 0/33 (0%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 1/50 (2%) 1/184 (0.5%)
    Metabolism and nutrition disorders
    Decreased appetite 0/33 (0%) 0/29 (0%) 0/43 (0%) 1/29 (3.4%) 0/50 (0%) 1/184 (0.5%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma 1/33 (3%) 0/29 (0%) 1/43 (2.3%) 0/29 (0%) 0/50 (0%) 2/184 (1.1%)
    Breast cancer 0/33 (0%) 0/29 (0%) 1/43 (2.3%) 0/29 (0%) 1/50 (2%) 2/184 (1.1%)
    Colon cancer metastatic 0/33 (0%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 1/50 (2%) 1/184 (0.5%)
    Nervous system disorders
    Dysaesthesia 0/33 (0%) 0/29 (0%) 1/43 (2.3%) 0/29 (0%) 0/50 (0%) 1/184 (0.5%)
    Generalised tonic-clonic seizure 0/33 (0%) 1/29 (3.4%) 0/43 (0%) 0/29 (0%) 0/50 (0%) 1/184 (0.5%)
    Headache 0/33 (0%) 0/29 (0%) 0/43 (0%) 1/29 (3.4%) 0/50 (0%) 1/184 (0.5%)
    Multiple sclerosis relapse 0/33 (0%) 0/29 (0%) 1/43 (2.3%) 0/29 (0%) 2/50 (4%) 3/184 (1.6%)
    Sciatica 1/33 (3%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 0/50 (0%) 1/184 (0.5%)
    Seizure 0/33 (0%) 1/29 (3.4%) 0/43 (0%) 0/29 (0%) 0/50 (0%) 1/184 (0.5%)
    Pregnancy, puerperium and perinatal conditions
    Abortion 0/33 (0%) 1/29 (3.4%) 0/43 (0%) 0/29 (0%) 0/50 (0%) 1/184 (0.5%)
    Psychiatric disorders
    Depression 1/33 (3%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 0/50 (0%) 1/184 (0.5%)
    Drug abuse 0/33 (0%) 0/29 (0%) 0/43 (0%) 1/29 (3.4%) 0/50 (0%) 1/184 (0.5%)
    Mental disorder 0/33 (0%) 0/29 (0%) 0/43 (0%) 1/29 (3.4%) 0/50 (0%) 1/184 (0.5%)
    Renal and urinary disorders
    Stress urinary incontinence 0/33 (0%) 0/29 (0%) 1/43 (2.3%) 0/29 (0%) 0/50 (0%) 1/184 (0.5%)
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 0/33 (0%) 0/29 (0%) 0/43 (0%) 1/29 (3.4%) 0/50 (0%) 1/184 (0.5%)
    Metrorrhagia 1/33 (3%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 0/50 (0%) 1/184 (0.5%)
    Uterine cervical metaplasia 0/33 (0%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 1/50 (2%) 1/184 (0.5%)
    Other (Not Including Serious) Adverse Events
    BAF312 10/2 mg BAF312 2/2 mg BAF312 1.25/2 mg BAF312 0.5/2 mg BAF312 0.25/2 mg All Patients
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 30/33 (90.9%) 26/29 (89.7%) 42/43 (97.7%) 29/29 (100%) 42/50 (84%) 169/184 (91.8%)
    Blood and lymphatic system disorders
    Leukopenia 0/33 (0%) 1/29 (3.4%) 0/43 (0%) 2/29 (6.9%) 0/50 (0%) 3/184 (1.6%)
    Lymphadenitis 0/33 (0%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 2/50 (4%) 2/184 (1.1%)
    Lymphopenia 6/33 (18.2%) 5/29 (17.2%) 4/43 (9.3%) 6/29 (20.7%) 3/50 (6%) 24/184 (13%)
    Cardiac disorders
    Palpitations 0/33 (0%) 2/29 (6.9%) 0/43 (0%) 0/29 (0%) 1/50 (2%) 3/184 (1.6%)
    Tachycardia 0/33 (0%) 0/29 (0%) 1/43 (2.3%) 0/29 (0%) 2/50 (4%) 3/184 (1.6%)
    Ear and labyrinth disorders
    Ear pain 0/33 (0%) 1/29 (3.4%) 2/43 (4.7%) 0/29 (0%) 1/50 (2%) 4/184 (2.2%)
    Tinnitus 1/33 (3%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 2/50 (4%) 3/184 (1.6%)
    Vertigo 4/33 (12.1%) 1/29 (3.4%) 3/43 (7%) 2/29 (6.9%) 6/50 (12%) 16/184 (8.7%)
    Vertigo positional 0/33 (0%) 0/29 (0%) 0/43 (0%) 2/29 (6.9%) 1/50 (2%) 3/184 (1.6%)
    Eye disorders
    Conjunctivitis 1/33 (3%) 0/29 (0%) 2/43 (4.7%) 1/29 (3.4%) 1/50 (2%) 5/184 (2.7%)
    Eye pain 2/33 (6.1%) 0/29 (0%) 0/43 (0%) 1/29 (3.4%) 0/50 (0%) 3/184 (1.6%)
    Iridocyclitis 0/33 (0%) 0/29 (0%) 2/43 (4.7%) 0/29 (0%) 0/50 (0%) 2/184 (1.1%)
    Vision blurred 2/33 (6.1%) 0/29 (0%) 3/43 (7%) 0/29 (0%) 0/50 (0%) 5/184 (2.7%)
    Gastrointestinal disorders
    Abdominal pain 0/33 (0%) 1/29 (3.4%) 2/43 (4.7%) 1/29 (3.4%) 3/50 (6%) 7/184 (3.8%)
    Abdominal pain upper 0/33 (0%) 1/29 (3.4%) 3/43 (7%) 5/29 (17.2%) 3/50 (6%) 12/184 (6.5%)
    Aphthous ulcer 0/33 (0%) 0/29 (0%) 1/43 (2.3%) 2/29 (6.9%) 0/50 (0%) 3/184 (1.6%)
    Constipation 1/33 (3%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 3/50 (6%) 4/184 (2.2%)
    Diarrhoea 1/33 (3%) 2/29 (6.9%) 7/43 (16.3%) 3/29 (10.3%) 6/50 (12%) 19/184 (10.3%)
    Dyspepsia 1/33 (3%) 1/29 (3.4%) 1/43 (2.3%) 0/29 (0%) 2/50 (4%) 5/184 (2.7%)
    Enteritis 0/33 (0%) 2/29 (6.9%) 0/43 (0%) 0/29 (0%) 0/50 (0%) 2/184 (1.1%)
    Gastritis 0/33 (0%) 2/29 (6.9%) 0/43 (0%) 1/29 (3.4%) 0/50 (0%) 3/184 (1.6%)
    Gastrooesophageal reflux disease 1/33 (3%) 0/29 (0%) 1/43 (2.3%) 3/29 (10.3%) 1/50 (2%) 6/184 (3.3%)
    Irritable bowel syndrome 0/33 (0%) 0/29 (0%) 0/43 (0%) 2/29 (6.9%) 0/50 (0%) 2/184 (1.1%)
    Nausea 1/33 (3%) 0/29 (0%) 0/43 (0%) 3/29 (10.3%) 4/50 (8%) 8/184 (4.3%)
    Toothache 0/33 (0%) 2/29 (6.9%) 4/43 (9.3%) 1/29 (3.4%) 4/50 (8%) 11/184 (6%)
    Vomiting 1/33 (3%) 3/29 (10.3%) 0/43 (0%) 0/29 (0%) 3/50 (6%) 7/184 (3.8%)
    General disorders
    Asthenia 0/33 (0%) 1/29 (3.4%) 2/43 (4.7%) 0/29 (0%) 1/50 (2%) 4/184 (2.2%)
    Fatigue 1/33 (3%) 4/29 (13.8%) 5/43 (11.6%) 2/29 (6.9%) 6/50 (12%) 18/184 (9.8%)
    Gait disturbance 3/33 (9.1%) 0/29 (0%) 0/43 (0%) 1/29 (3.4%) 0/50 (0%) 4/184 (2.2%)
    Influenza like illness 1/33 (3%) 0/29 (0%) 2/43 (4.7%) 1/29 (3.4%) 1/50 (2%) 5/184 (2.7%)
    Non-cardiac chest pain 3/33 (9.1%) 0/29 (0%) 1/43 (2.3%) 0/29 (0%) 2/50 (4%) 6/184 (3.3%)
    Oedema peripheral 0/33 (0%) 2/29 (6.9%) 0/43 (0%) 1/29 (3.4%) 0/50 (0%) 3/184 (1.6%)
    Pyrexia 2/33 (6.1%) 1/29 (3.4%) 4/43 (9.3%) 3/29 (10.3%) 5/50 (10%) 15/184 (8.2%)
    Infections and infestations
    Acute sinusitis 0/33 (0%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 3/50 (6%) 3/184 (1.6%)
    Bronchitis 0/33 (0%) 2/29 (6.9%) 5/43 (11.6%) 3/29 (10.3%) 6/50 (12%) 16/184 (8.7%)
    Conjunctivitis 2/33 (6.1%) 0/29 (0%) 1/43 (2.3%) 0/29 (0%) 0/50 (0%) 3/184 (1.6%)
    Cystitis 3/33 (9.1%) 1/29 (3.4%) 2/43 (4.7%) 1/29 (3.4%) 1/50 (2%) 8/184 (4.3%)
    Fungal infection 3/33 (9.1%) 1/29 (3.4%) 0/43 (0%) 1/29 (3.4%) 1/50 (2%) 6/184 (3.3%)
    Fungal skin infection 2/33 (6.1%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 0/50 (0%) 2/184 (1.1%)
    Gastroenteritis 0/33 (0%) 2/29 (6.9%) 1/43 (2.3%) 3/29 (10.3%) 4/50 (8%) 10/184 (5.4%)
    Gastroenteritis viral 0/33 (0%) 0/29 (0%) 3/43 (7%) 0/29 (0%) 2/50 (4%) 5/184 (2.7%)
    Herpes zoster 5/33 (15.2%) 0/29 (0%) 3/43 (7%) 2/29 (6.9%) 0/50 (0%) 10/184 (5.4%)
    Influenza 4/33 (12.1%) 4/29 (13.8%) 5/43 (11.6%) 7/29 (24.1%) 7/50 (14%) 27/184 (14.7%)
    Nasopharyngitis 10/33 (30.3%) 8/29 (27.6%) 17/43 (39.5%) 11/29 (37.9%) 18/50 (36%) 64/184 (34.8%)
    Onychomycosis 1/33 (3%) 1/29 (3.4%) 0/43 (0%) 0/29 (0%) 3/50 (6%) 5/184 (2.7%)
    Oral herpes 5/33 (15.2%) 0/29 (0%) 4/43 (9.3%) 2/29 (6.9%) 4/50 (8%) 15/184 (8.2%)
    Otitis media 1/33 (3%) 1/29 (3.4%) 0/43 (0%) 0/29 (0%) 3/50 (6%) 5/184 (2.7%)
    Pharyngitis 1/33 (3%) 4/29 (13.8%) 3/43 (7%) 6/29 (20.7%) 3/50 (6%) 17/184 (9.2%)
    Pneumonia 1/33 (3%) 1/29 (3.4%) 0/43 (0%) 0/29 (0%) 2/50 (4%) 4/184 (2.2%)
    Respiratory tract infection 0/33 (0%) 1/29 (3.4%) 1/43 (2.3%) 1/29 (3.4%) 2/50 (4%) 5/184 (2.7%)
    Rhinitis 3/33 (9.1%) 2/29 (6.9%) 1/43 (2.3%) 0/29 (0%) 1/50 (2%) 7/184 (3.8%)
    Sinusitis 3/33 (9.1%) 2/29 (6.9%) 3/43 (7%) 5/29 (17.2%) 5/50 (10%) 18/184 (9.8%)
    Subcutaneous abscess 0/33 (0%) 2/29 (6.9%) 0/43 (0%) 0/29 (0%) 0/50 (0%) 2/184 (1.1%)
    Tinea versicolour 0/33 (0%) 2/29 (6.9%) 2/43 (4.7%) 0/29 (0%) 1/50 (2%) 5/184 (2.7%)
    Tonsillitis 1/33 (3%) 1/29 (3.4%) 5/43 (11.6%) 2/29 (6.9%) 1/50 (2%) 10/184 (5.4%)
    Tooth infection 1/33 (3%) 2/29 (6.9%) 1/43 (2.3%) 1/29 (3.4%) 0/50 (0%) 5/184 (2.7%)
    Upper respiratory tract infection 4/33 (12.1%) 6/29 (20.7%) 4/43 (9.3%) 7/29 (24.1%) 9/50 (18%) 30/184 (16.3%)
    Urinary tract infection 6/33 (18.2%) 4/29 (13.8%) 2/43 (4.7%) 4/29 (13.8%) 4/50 (8%) 20/184 (10.9%)
    Vaginal infection 0/33 (0%) 0/29 (0%) 1/43 (2.3%) 2/29 (6.9%) 2/50 (4%) 5/184 (2.7%)
    Vulvovaginal candidiasis 0/33 (0%) 0/29 (0%) 1/43 (2.3%) 1/29 (3.4%) 2/50 (4%) 4/184 (2.2%)
    Injury, poisoning and procedural complications
    Contusion 2/33 (6.1%) 2/29 (6.9%) 0/43 (0%) 3/29 (10.3%) 1/50 (2%) 8/184 (4.3%)
    Fall 3/33 (9.1%) 3/29 (10.3%) 0/43 (0%) 2/29 (6.9%) 1/50 (2%) 9/184 (4.9%)
    Joint injury 1/33 (3%) 0/29 (0%) 2/43 (4.7%) 0/29 (0%) 0/50 (0%) 3/184 (1.6%)
    Ligament sprain 2/33 (6.1%) 0/29 (0%) 2/43 (4.7%) 2/29 (6.9%) 1/50 (2%) 7/184 (3.8%)
    Limb injury 0/33 (0%) 0/29 (0%) 0/43 (0%) 1/29 (3.4%) 2/50 (4%) 3/184 (1.6%)
    Investigations
    Alanine aminotransferase increased 3/33 (9.1%) 5/29 (17.2%) 3/43 (7%) 2/29 (6.9%) 2/50 (4%) 15/184 (8.2%)
    Blood bilirubin increased 0/33 (0%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 2/50 (4%) 2/184 (1.1%)
    Blood cholesterol increased 0/33 (0%) 0/29 (0%) 1/43 (2.3%) 2/29 (6.9%) 1/50 (2%) 4/184 (2.2%)
    C-reactive protein increased 1/33 (3%) 1/29 (3.4%) 0/43 (0%) 0/29 (0%) 3/50 (6%) 5/184 (2.7%)
    Gamma-glutamyltransferase increased 3/33 (9.1%) 3/29 (10.3%) 2/43 (4.7%) 3/29 (10.3%) 2/50 (4%) 13/184 (7.1%)
    Hepatic enzyme increased 2/33 (6.1%) 1/29 (3.4%) 1/43 (2.3%) 0/29 (0%) 1/50 (2%) 5/184 (2.7%)
    Lymphocyte count decreased 4/33 (12.1%) 2/29 (6.9%) 4/43 (9.3%) 2/29 (6.9%) 3/50 (6%) 15/184 (8.2%)
    Metabolism and nutrition disorders
    Hypercholesterolaemia 2/33 (6.1%) 4/29 (13.8%) 2/43 (4.7%) 1/29 (3.4%) 3/50 (6%) 12/184 (6.5%)
    Hypoglycaemia 0/33 (0%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 2/50 (4%) 2/184 (1.1%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 4/33 (12.1%) 3/29 (10.3%) 2/43 (4.7%) 2/29 (6.9%) 3/50 (6%) 14/184 (7.6%)
    Back pain 6/33 (18.2%) 2/29 (6.9%) 5/43 (11.6%) 3/29 (10.3%) 3/50 (6%) 19/184 (10.3%)
    Intervertebral disc degeneration 0/33 (0%) 0/29 (0%) 2/43 (4.7%) 0/29 (0%) 0/50 (0%) 2/184 (1.1%)
    Joint swelling 2/33 (6.1%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 1/50 (2%) 3/184 (1.6%)
    Muscle spasms 1/33 (3%) 0/29 (0%) 2/43 (4.7%) 1/29 (3.4%) 1/50 (2%) 5/184 (2.7%)
    Muscular weakness 2/33 (6.1%) 0/29 (0%) 2/43 (4.7%) 0/29 (0%) 0/50 (0%) 4/184 (2.2%)
    Musculoskeletal pain 1/33 (3%) 2/29 (6.9%) 4/43 (9.3%) 0/29 (0%) 2/50 (4%) 9/184 (4.9%)
    Myalgia 0/33 (0%) 0/29 (0%) 1/43 (2.3%) 0/29 (0%) 3/50 (6%) 4/184 (2.2%)
    Neck pain 1/33 (3%) 2/29 (6.9%) 1/43 (2.3%) 0/29 (0%) 2/50 (4%) 6/184 (3.3%)
    Pain in extremity 2/33 (6.1%) 1/29 (3.4%) 0/43 (0%) 4/29 (13.8%) 5/50 (10%) 12/184 (6.5%)
    Tendonitis 0/33 (0%) 2/29 (6.9%) 0/43 (0%) 2/29 (6.9%) 2/50 (4%) 6/184 (3.3%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Fibrous histiocytoma 0/33 (0%) 1/29 (3.4%) 3/43 (7%) 1/29 (3.4%) 0/50 (0%) 5/184 (2.7%)
    Melanocytic naevus 2/33 (6.1%) 1/29 (3.4%) 6/43 (14%) 2/29 (6.9%) 7/50 (14%) 18/184 (9.8%)
    Seborrhoeic keratosis 2/33 (6.1%) 1/29 (3.4%) 0/43 (0%) 0/29 (0%) 4/50 (8%) 7/184 (3.8%)
    Skin papilloma 2/33 (6.1%) 3/29 (10.3%) 1/43 (2.3%) 2/29 (6.9%) 2/50 (4%) 10/184 (5.4%)
    Uterine leiomyoma 2/33 (6.1%) 0/29 (0%) 0/43 (0%) 1/29 (3.4%) 0/50 (0%) 3/184 (1.6%)
    Nervous system disorders
    Burning sensation 0/33 (0%) 0/29 (0%) 1/43 (2.3%) 0/29 (0%) 2/50 (4%) 3/184 (1.6%)
    Dizziness 1/33 (3%) 1/29 (3.4%) 1/43 (2.3%) 1/29 (3.4%) 4/50 (8%) 8/184 (4.3%)
    Headache 9/33 (27.3%) 4/29 (13.8%) 9/43 (20.9%) 4/29 (13.8%) 10/50 (20%) 36/184 (19.6%)
    Hypoaesthesia 1/33 (3%) 0/29 (0%) 0/43 (0%) 1/29 (3.4%) 2/50 (4%) 4/184 (2.2%)
    Migraine 2/33 (6.1%) 0/29 (0%) 3/43 (7%) 1/29 (3.4%) 0/50 (0%) 6/184 (3.3%)
    Muscle spasticity 0/33 (0%) 2/29 (6.9%) 0/43 (0%) 3/29 (10.3%) 0/50 (0%) 5/184 (2.7%)
    Neuralgia 1/33 (3%) 0/29 (0%) 4/43 (9.3%) 0/29 (0%) 0/50 (0%) 5/184 (2.7%)
    Paraesthesia 4/33 (12.1%) 0/29 (0%) 0/43 (0%) 2/29 (6.9%) 3/50 (6%) 9/184 (4.9%)
    Psychiatric disorders
    Anxiety 3/33 (9.1%) 1/29 (3.4%) 1/43 (2.3%) 0/29 (0%) 4/50 (8%) 9/184 (4.9%)
    Depression 1/33 (3%) 1/29 (3.4%) 6/43 (14%) 3/29 (10.3%) 7/50 (14%) 18/184 (9.8%)
    Insomnia 1/33 (3%) 2/29 (6.9%) 8/43 (18.6%) 3/29 (10.3%) 6/50 (12%) 20/184 (10.9%)
    Sleep disorder 0/33 (0%) 1/29 (3.4%) 0/43 (0%) 2/29 (6.9%) 0/50 (0%) 3/184 (1.6%)
    Renal and urinary disorders
    Bladder dysfunction 0/33 (0%) 0/29 (0%) 2/43 (4.7%) 0/29 (0%) 0/50 (0%) 2/184 (1.1%)
    Micturition urgency 2/33 (6.1%) 1/29 (3.4%) 1/43 (2.3%) 0/29 (0%) 1/50 (2%) 5/184 (2.7%)
    Nephrolithiasis 2/33 (6.1%) 2/29 (6.9%) 0/43 (0%) 1/29 (3.4%) 0/50 (0%) 5/184 (2.7%)
    Urinary retention 1/33 (3%) 0/29 (0%) 0/43 (0%) 2/29 (6.9%) 0/50 (0%) 3/184 (1.6%)
    Respiratory, thoracic and mediastinal disorders
    Catarrh 1/33 (3%) 0/29 (0%) 1/43 (2.3%) 2/29 (6.9%) 0/50 (0%) 4/184 (2.2%)
    Cough 3/33 (9.1%) 3/29 (10.3%) 3/43 (7%) 4/29 (13.8%) 2/50 (4%) 15/184 (8.2%)
    Dyspnoea 0/33 (0%) 0/29 (0%) 2/43 (4.7%) 0/29 (0%) 1/50 (2%) 3/184 (1.6%)
    Epistaxis 0/33 (0%) 0/29 (0%) 0/43 (0%) 2/29 (6.9%) 0/50 (0%) 2/184 (1.1%)
    Oropharyngeal pain 3/33 (9.1%) 1/29 (3.4%) 3/43 (7%) 0/29 (0%) 3/50 (6%) 10/184 (5.4%)
    Rhinitis allergic 0/33 (0%) 0/29 (0%) 2/43 (4.7%) 0/29 (0%) 2/50 (4%) 4/184 (2.2%)
    Wheezing 0/33 (0%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 2/50 (4%) 2/184 (1.1%)
    Skin and subcutaneous tissue disorders
    Actinic keratosis 0/33 (0%) 0/29 (0%) 2/43 (4.7%) 0/29 (0%) 0/50 (0%) 2/184 (1.1%)
    Alopecia 2/33 (6.1%) 0/29 (0%) 2/43 (4.7%) 0/29 (0%) 1/50 (2%) 5/184 (2.7%)
    Dermal cyst 1/33 (3%) 0/29 (0%) 0/43 (0%) 2/29 (6.9%) 0/50 (0%) 3/184 (1.6%)
    Dermatitis 0/33 (0%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 2/50 (4%) 2/184 (1.1%)
    Dermatitis allergic 0/33 (0%) 0/29 (0%) 0/43 (0%) 2/29 (6.9%) 2/50 (4%) 4/184 (2.2%)
    Dermatitis contact 1/33 (3%) 0/29 (0%) 0/43 (0%) 2/29 (6.9%) 0/50 (0%) 3/184 (1.6%)
    Eczema 3/33 (9.1%) 2/29 (6.9%) 2/43 (4.7%) 0/29 (0%) 1/50 (2%) 8/184 (4.3%)
    Hyperkeratosis 2/33 (6.1%) 0/29 (0%) 0/43 (0%) 0/29 (0%) 0/50 (0%) 2/184 (1.1%)
    Pigmentation disorder 2/33 (6.1%) 2/29 (6.9%) 1/43 (2.3%) 0/29 (0%) 0/50 (0%) 5/184 (2.7%)
    Pruritus 1/33 (3%) 0/29 (0%) 2/43 (4.7%) 1/29 (3.4%) 3/50 (6%) 7/184 (3.8%)
    Urticaria 0/33 (0%) 0/29 (0%) 3/43 (7%) 1/29 (3.4%) 1/50 (2%) 5/184 (2.7%)
    Vascular disorders
    Hypertension 1/33 (3%) 1/29 (3.4%) 3/43 (7%) 3/29 (10.3%) 8/50 (16%) 16/184 (8.7%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.

    Results Point of Contact

    Name/Title Study Director
    Organization Novartis Pharmaceuticals
    Phone 862-778-8300
    Email Novartis.email@novartis.com
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01185821
    Other Study ID Numbers:
    • CBAF312A2201E1
    • 2009-014392-51
    First Posted:
    Aug 20, 2010
    Last Update Posted:
    Mar 27, 2018
    Last Verified:
    Feb 1, 2018