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    Clinical Trial Results:
    A multi-centre, double-blind, placebo controlled, proof of concept study to evaluate the efficacy and tolerability of BAF312 in patients with polymyositis

    Summary
    EudraCT number
    2012-002859-42
    Trial protocol
    HU   CZ   PL   BE  
    Global end of trial date
    04 Aug 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Aug 2017
    First version publication date
    06 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CBAF312X2205
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01801917
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Aug 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Aug 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Aug 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Main objective of the trial was to assess the clinical effect of 2 mg and 10 mg BAF312 once daily in patients with polymyositis (PM) over 12 weeks using both manual muscle testing (MMT)-24 and serum creatine kinase (CK) as a combined endpoint
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Apr 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    United States: 4
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Poland: 1
    Worldwide total number of subjects
    14
    EEA total number of subjects
    8
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    13
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The study initially had 2 treatment arms and 9 patients had been randomized to BAF312 2 mg and placebo in a 2:1 ratio until protocol amendment which added BAF312 10 mg treatment arm. The overall targeted randomization ratio after amendment was 1:1:1 among BAF312 10 mg: 2 mg: placebo but study was terminated after 14 patients were randomized

    Period 1
    Period 1 title
    Period 1 - Randomized
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BAF312 2mg/BAF312 2mg
    Arm description
    Patients in Period 1 continue on same 2 mg dose of BAF312 in Period 2
    Arm type
    Experimental

    Investigational medicinal product name
    BAF312 2 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg once daily + 4 placebo for BAF312 and 5 - 2 mg tablets for BAF312 for 10 mg arm

    Arm title
    BAF312 10 mg/BAF312 10 mg
    Arm description
    Patients in Period 1 continue on same 10 mg dose of BAF312 in Period 2
    Arm type
    Experimental

    Investigational medicinal product name
    BAF312 2 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg once daily + 4 placebo for BAF312 and 5 - 2 mg tablets for BAF312 for 10 mg arm

    Arm title
    Placebo/BAF312 2 mg
    Arm description
    Patients on placebo in Period 1 switch to active 2 mg BAF312 in Period 2
    Arm type
    Experimental

    Investigational medicinal product name
    BAF312 2 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg once daily + 4 placebo for BAF312 2 mg

    Arm title
    Placebo/BAF312 10 mg
    Arm description
    Patients on placebo in Period 1 switch to active 10 mg BAF312 in Period 2
    Arm type
    Experimental

    Investigational medicinal product name
    matching placebo for BAF312 2 mg arm
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg once daily

    Investigational medicinal product name
    BAF312 2 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg once daily + 4 placebo for BAF312 and 5 - 2 mg tablets for BAF312 for 10 mg arm

    Number of subjects in period 1
    BAF312 2mg/BAF312 2mg BAF312 10 mg/BAF312 10 mg Placebo/BAF312 2 mg Placebo/BAF312 10 mg
    Started
    7
    2
    4
    1
    Completed
    6
    2
    3
    1
    Not completed
    1
    0
    1
    0
         Adverse event, non-fatal
    1
    -
    1
    -
    Period 2
    Period 2 title
    Extension - All Active
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BAF312 2mg/BAF312 2mg
    Arm description
    Patients in Period 1 continue on same 2 mg dose of BAF312 in Period 2
    Arm type
    Experimental

    Investigational medicinal product name
    BAF312 2mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg tablet daily

    Arm title
    Placebo/BAF312 2 mg
    Arm description
    Patients on placebo in Period 1 switch to active 2 mg BAF312 in Period 2
    Arm type
    Experimental

    Investigational medicinal product name
    BAF312 2 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg once daily + 4 placebo for BAF312

    Number of subjects in period 2 [1]
    BAF312 2mg/BAF312 2mg Placebo/BAF312 2 mg
    Started
    6
    3
    Completed
    6
    3
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Patient and investigator determined if patient would enter extension period. Patients with disease worsening had to be approved by Central Unblinded Investigator.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BAF312 2mg/BAF312 2mg
    Reporting group description
    Patients in Period 1 continue on same 2 mg dose of BAF312 in Period 2

    Reporting group title
    BAF312 10 mg/BAF312 10 mg
    Reporting group description
    Patients in Period 1 continue on same 10 mg dose of BAF312 in Period 2

    Reporting group title
    Placebo/BAF312 2 mg
    Reporting group description
    Patients on placebo in Period 1 switch to active 2 mg BAF312 in Period 2

    Reporting group title
    Placebo/BAF312 10 mg
    Reporting group description
    Patients on placebo in Period 1 switch to active 10 mg BAF312 in Period 2

    Reporting group values
    BAF312 2mg/BAF312 2mg BAF312 10 mg/BAF312 10 mg Placebo/BAF312 2 mg Placebo/BAF312 10 mg Total
    Number of subjects
    7 2 4 1 14
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0
        Adults (18-64 years)
    6 2 4 1 13
        From 65-84 years
    1 0 0 0 1
        85 years and over
    0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    50.3 ± 14.78 47 ± 21.21 48 ± 8.83 53 ± 0 -
    Gender, Male/Female
    Units: Subjects
        Female
    5 2 2 1 10
        Male
    2 0 2 0 4
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    7 1 3 0 11
        Black
    0 0 0 1 1
        Asian
    0 1 1 0 2
    Taking DMARD at baseline
    Taking a disease-modifying antirheumatic drugs
    Units: Subjects
        DMRD at baseline
    7 2 4 1 14
    Study Specific Characteristic | Disease duration
    Units: years
        arithmetic mean (standard deviation)
    5.6 ± 4.46 5.4 ± 2.74 2.7 ± 1.67 16.9 ± 0 -
    Study Specific Characteristic | Baseline MMT24 Score
    Manual muscle testing in 26 muscle groups (MMT24, max value 260
    Units: score
        arithmetic mean (standard deviation)
    202.6 ± 41.74 184 ± 19.8 189.5 ± 45.65 166 ± 0 -

    End points

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    End points reporting groups
    Reporting group title
    BAF312 2mg/BAF312 2mg
    Reporting group description
    Patients in Period 1 continue on same 2 mg dose of BAF312 in Period 2

    Reporting group title
    BAF312 10 mg/BAF312 10 mg
    Reporting group description
    Patients in Period 1 continue on same 10 mg dose of BAF312 in Period 2

    Reporting group title
    Placebo/BAF312 2 mg
    Reporting group description
    Patients on placebo in Period 1 switch to active 2 mg BAF312 in Period 2

    Reporting group title
    Placebo/BAF312 10 mg
    Reporting group description
    Patients on placebo in Period 1 switch to active 10 mg BAF312 in Period 2
    Reporting group title
    BAF312 2mg/BAF312 2mg
    Reporting group description
    Patients in Period 1 continue on same 2 mg dose of BAF312 in Period 2

    Reporting group title
    Placebo/BAF312 2 mg
    Reporting group description
    Patients on placebo in Period 1 switch to active 2 mg BAF312 in Period 2

    Subject analysis set title
    BAF312 2mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    1 tablet of BAF312 2 mg + 4 tablets of Placebo daily during Period 1

    Subject analysis set title
    BAF312 10 mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    5 tablets of BAF312 2 mg daily during Period 1

    Subject analysis set title
    Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    matching placebo

    Subject analysis set title
    Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    matching placebo

    Subject analysis set title
    BAF312 2mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    1 tablet of BAF312 2 mg + 4 tablets of Placebo daily during Period 1

    Primary: Change from baseline at week 12 for BAF312 2 mg, 10 mg or placebo (once daily) for combined efficacy endpoint: Manual Muscle Testing (MMT24)

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    End point title
    Change from baseline at week 12 for BAF312 2 mg, 10 mg or placebo (once daily) for combined efficacy endpoint: Manual Muscle Testing (MMT24)
    End point description
    Manual Muscle Testing Scoring Sheet: Neck flexors, neck extensors and other designated muscles bilaterally (Biceps brachii, Deltoid middle, Quadriceps, Gluteus maximus, Gluteus medius, Trapezius, Iliopsoas, Hamstrings, Wrist extensors, Wrist Flexors, Ankle plantar flexors and Ankle dorsiflexors) were tested on a 0-10 scale by the Investigator. Note that due to system limitations in choices for intervals, Posterior credibility interval from Bayesian analysis is displayed as confidence interval in table. Also,all 4 statistical analysis results for posterior probability are entered in the P value data field (could not be entered into Parameter estimate because Confidence Interval was required and is not calculated with posterior probability).
    End point type
    Primary
    End point timeframe
    Baseline, at 12 weeks
    End point values
    BAF312 2mg BAF312 10 mg Placebo
    Number of subjects analysed
    7
    2
    5
    Units: scores
        arithmetic mean (confidence interval 90%)
    11.2 (3.5 to 19.2)
    39 (10.7 to 67.2)
    9.1 (-1.6 to 20)
    Statistical analysis title
    Increase in MMT24 and decrease in CK - 2mg group
    Statistical analysis description
    It was a Bayesian analysis with non-informative prior for co-primary endpoints, MMT-24 and CK, with dual criteria for statistical significance: ≥ 90% posterior probability (PP) of achieving an increase from baseline in MMT24 and decrease in CK and clinical relevance: ≥ 50% PP achieving an increase of 15 points in MMT24 and a decrease of 30% in CK vs. placebo. For this table the value is the posterior probability of achieving an increase in MMT24 and a decrease in CK in 2mg group vs. placebo
    Comparison groups
    BAF312 2mg v Placebo
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.586 [1]
    Method
    Bayesian
    Confidence interval
    Notes
    [1] - Value displayed is posterior probability from Bayesian analysis, it is NOT a P value. Eudract system required a confidence interval (not calculated for posterior probability) for Parameter estimate module and error prevented upload to the system.
    Statistical analysis title
    INCR of 15 pts in MMT24 and DCR of 30% in CK-2mg
    Statistical analysis description
    It was a Bayesian analysis with non-informative prior for co-primary endpoints, MMT-24 and CK, with dual criteria for statistical significance: ≥ 90% posterior probability (PP) of achieving an increase from baseline in MMT24 and decrease in CK and clinical relevance: ≥ 50% PP achieving an increase of 15 points in MMT24 and a decrease of 30% in CK vs. placebo. . For this table the value is the PP of achieving an increase of 15 points in MMT24 and a decrease of 30% in CK in 2mg group vs. placebo
    Comparison groups
    BAF312 2mg v Placebo
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.022 [2]
    Method
    Bayesian
    Confidence interval
    Notes
    [2] - Value displayed is posterior probability from Bayesian analysis, it is NOT a P value. Eudract system required a confidence interval (not calculated for posterior probability) for Parameter estimate module and error prevented upload to the system.
    Statistical analysis title
    Increase in MMT24 and decrease in CK - 10mg group
    Statistical analysis description
    It was a Bayesian analysis with non-informative prior for co-primary endpoints, MMT-24 and CK, with dual criteria for statistical significance: ≥ 90% posterior probability (PP) of achieving an increase from baseline in MMT24 and decrease in CK and clinical relevance: ≥ 50% PP achieving an increase of 15 points in MMT24 and a decrease of 30% in CK vs. placebo. For this table the value is the posterior probability of achieving an increase in MMT24 and a decrease in CK in 10mg group vs. placebo
    Comparison groups
    BAF312 10 mg v Placebo
    Number of subjects included in analysis
    7
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.963 [3]
    Method
    Bayesian
    Confidence interval
    Notes
    [3] - Value displayed is posterior probability from Bayesian analysis, it is NOT a P value. Eudract system required a confidence interval (not calculated for posterior probability) for Parameter estimate module and error prevented upload to the system.
    Statistical analysis title
    INCR of 15 pts in MMT24 and DCR of 30% in CK-10mg
    Statistical analysis description
    It was a Bayesian analysis with non-informative prior for co-primary endpoints, MMT-24 and CK, with dual criteria for statistical significance: ≥ 90% posterior probability (PP) of achieving an increase from baseline in MMT24 and decrease in CK and clinical relevance: ≥ 50% PP achieving an increase of 15 points in MMT24 and a decrease of 30% in CK vs. placebo. . For this table the value is the PP of achieving an increase of 15 points in MMT24 and a decrease of 30% in CK in 10mg group vs. placebo
    Comparison groups
    BAF312 10 mg v Placebo
    Number of subjects included in analysis
    7
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.837 [4]
    Method
    Bayesian
    Confidence interval
    Notes
    [4] - Value displayed is posterior probability from Bayesian analysis, it is NOT a P value. Eudract system required a confidence interval (not calculated for posterior probability) for Parameter estimate module and error prevented upload to the system.

    Primary: Percent change from baseline at week 12 for BAF312 2 mg, 10 mg or placebo (once daily) serum creatine kinase (CK) levels.

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    End point title
    Percent change from baseline at week 12 for BAF312 2 mg, 10 mg or placebo (once daily) serum creatine kinase (CK) levels. [5]
    End point description
    Serum creatine kinase (CK) were analyzed as part of the blood chemistry panel. The variable CK was log-transformed for statistical analysis and after estimation was converted to percent change from baseline divided by the mean baseline
    End point type
    Primary
    End point timeframe
    Baseline, at 12 weeks
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis presented in primary outcome measurement 1 analyzes the data from primary outcome measurement 1 and 2
    End point values
    BAF312 2mg BAF312 10 mg Placebo
    Number of subjects analysed
    7
    2
    5
    Units: U/L
        arithmetic mean (confidence interval 90%)
    -19.7 (-32.3 to -4.7)
    -55.6 (-77.1 to -13.5)
    -0.5 (-21.8 to 25.9)
    No statistical analyses for this end point

    Secondary: Six-minute walking distance (6MWD) at week 12

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    End point title
    Six-minute walking distance (6MWD) at week 12
    End point description
    This test assessed the distance a patient could walk in 6 minutes (Rutkove et al 2002). If the patient was not able to walk for 6 minutes then a 2 minute walking test was conducted
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    BAF312 2mg BAF312 10 mg Placebo
    Number of subjects analysed
    7
    2
    4
    Units: meters
    arithmetic mean (standard deviation)
        Period 1, Baseline
    341.99 ± 110.88
    280 ± 127.279
    319.6 ± 104.61
        Period 1, Week 12 (6,1,4)
    362.47 ± 52.02
    393 ± 0
    303.1 ± 112.48
        Distance walked,change from BL at Wk 12 (6,1,4)
    46.82 ± 65.64
    23 ± 0
    -6.4 ± 21.981
    No statistical analyses for this end point

    Secondary: Six-minute walking distance (6MWD) at week 24

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    End point title
    Six-minute walking distance (6MWD) at week 24
    End point description
    This test assessed the distance a patient could walk in 6 minutes (Rutkove et al 2002). If the patient was not able to walk for 6 minutes then a 2 minute walking test was conducted
    End point type
    Secondary
    End point timeframe
    Baseline, 24 weeks
    End point values
    BAF312 2mg/BAF312 2mg Placebo/BAF312 2 mg
    Number of subjects analysed
    6
    3
    Units: meters
    arithmetic mean (standard deviation)
        Period 2, Week 24
    364.6 ± 73.803
    329.33 ± 186.551
        Distance walked,change from baseline at Wk 24
    48.95 ± 91.922
    4.33 ± 51.637
    No statistical analyses for this end point

    Secondary: BAF312 trough plasma concentrations

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    End point title
    BAF312 trough plasma concentrations
    End point description
    All blood samples were taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein. For each sample, approximately 2 mL of blood was drawn. BAF312 was determined in ethylenediaminetetraacetic acid (EDTA) plasma using a validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) bioanalytical method for the quantification. The anticipated lower limit of quantification (LLOQ) was 0.02 ng/mL using 0.1 mL of plasma
    End point type
    Secondary
    End point timeframe
    -7 Baseline, day 28, 56, 84
    End point values
    BAF312 10 mg BAF312 2mg
    Number of subjects analysed
    2
    6
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day - 7 (6,2)
    0 ± 0
    0 ± 0
        Day 28 (6,1)
    182 ± 0
    25.3 ± 11.2
        Day 56 (5,1)
    270 ± 0
    25.1 ± 12.6
        Day 84 (6,1)
    240 ± 0
    21.4 ± 10.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).  All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Period 1 BAF312 2mg
    Reporting group description
    Period 1 BAF312 2mg

    Reporting group title
    Period 1 BAF312 10mg
    Reporting group description
    Period 1 BAF312 10mg

    Reporting group title
    Period 1 Placebo
    Reporting group description
    Period 1 Placebo

    Reporting group title
    Period 2 BAF312 2mg/ BAF312 2mg
    Reporting group description
    Period 2 BAF312 2mg/ BAF312 2mg

    Reporting group title
    Period 2 Placebo/ BAF312 2mg
    Reporting group description
    Period 2 Placebo/ BAF312 2mg

    Serious adverse events
    Period 1 BAF312 2mg Period 1 BAF312 10mg Period 1 Placebo Period 2 BAF312 2mg/ BAF312 2mg Period 2 Placebo/ BAF312 2mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Haemolytic anaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemolytic uraemic syndrome
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Period 1 BAF312 2mg Period 1 BAF312 10mg Period 1 Placebo Period 2 BAF312 2mg/ BAF312 2mg Period 2 Placebo/ BAF312 2mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 7 (85.71%)
    2 / 2 (100.00%)
    4 / 5 (80.00%)
    4 / 6 (66.67%)
    2 / 3 (66.67%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Chest discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 2 (50.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Feeling cold
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Epicondylitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Investigations
    Carbon monoxide diffusing capacity decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Cardiac murmur
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Nervous system disorders
    Cerebral artery stenosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 2 (50.00%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Headache
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 2 (0.00%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Eye pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 2 (50.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Vitreous detachment
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 2 (50.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Papule
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Polymyositis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Spinal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 2 (50.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Aug 2012
    Added safety measures imposed by health authorities in the Phase III program studying BAF312 in secondary progressive multiple sclerosis. The safety measures also included new exclusion criteria that reflected updates to the label for Gilenya®, which belongs to the same pharmacological class
    01 Jan 2014
    The planned expansion of the study to more countries, in some of which the MCT system was not available. The cardiac monitoring was performed with a Holter ECG instead of the MCT used in the other participating countries. New clinical information had become available (study CBAF312A2116) that justified the concomitant use of beta blockers with study drug; corresponding changes were made to the eligibility criteria to allow the use of beta blockers. Azathioprine was added as permitted background medication (methotrexate or azathioprine) since it was a frequently used steroid-sparing agent in this patient population. The ivIg therapy washout window was decreased to 3 months to allow more patients in to the study. Changes were made to update safety and tolerability information on BAF312, and to align and make consistent eligibility criteria with another similar study of BAF312 in dermatomyositis patients.
    01 Apr 2014
    The addition of recent findings in a mouse carcinogenicity study. A section of efficacy data in PM/DM was updated with final data of a completed proof-of-concept that had become available. The study stopping rules were modified to allow for a full safety review prior to discontinuation of all subjects in case of 2 patients experiencing a study drug related AE, as specified in the stopping rules
    01 Jun 2015
    The requirement for vital signs to be within defined ranges at screening and baseline was deleted (systolic blood pressure 90 - 140 mm Hg; diastolic blood pressure 50 -90 mm Hg; pulse rate, 50- 90 bpm). The requirement for elevated levels of blood creatine kinase at baseline (≥1.3 × ULN) was changed to allow for alternative indicators of active muscle inflammation, i.e. other muscle enzymes, MRI imaging, or recent biopsy. The inclusion requirement for muscle weakness based on an MMT8 score of no more than 135/150 was changed to be based on the MMT24 scoring system, i.e. patients had an MMT24 score of no more than 245/260. The assessment of 6-minutes-walking distance (6MWD) was moved from exploratory to secondary objective. The requirement for previous treatment failure or toxicities to previous treatment was removed. The washout times for immunosuppressive regimens were adapted based on current knowledge about the duration of physiological effects of individual drugs and clinical practice for switching therapeutic regimens. If a patient had interrupted the intake of study drug, the permitted duration of treatment pause was changed from “48 hours” to less than four missed doses. In patients with specific genetic variants of CYP2C9 (CYP2C9*1*3 and *2*3), new restrictions applied for the use of CYP3A4 inhibitors. Potent CYP2C9 inhibitors as well as potent CYP2C9 and/or CYP3A4 inducers were not permitted during the study. The screening and baseline windows were expanded for logistical reasons. An additional dose arm of 10 mg BAF312 was added. The titration period was increased for all dosing arms. A new set of randomization numbers were generated to modify the ratio of subjects assigned to the placebo, 2 mg and 10 mg. The total number of subjects to be enrolled was increased from 30 to up to 45.
    01 Apr 2016
    To ensure that the maximum exposure reported at maximum tolerated dose (MTD) (20 mg q.d.) in the multiple ascending dose (MAD) study 2105 won’t be exceeded, especially in the 10 mg dose group, specific exclusions criteria in terms of 2C9/3A4 inhibitors were defined for CYP2C9 *1/*3, *2/*2 and *2/*3 carriers. Further to the CYP2C9*3 genotyping at screening, this amendment additionally described the need for CYP2C9*2 genotyping

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Study terminated due to slow recruitment and lack of efficacy in parallel study in dermatomyositis (similar pathophysiology). The overall results for this study for all outcome measurements are inconclusive due to small sample size
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