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    Clinical Trial Results:
    A multicenter, randomized, double-blind, placebo-controlled, dose-response study to investigate the biological activity, safety, tolerability, and pharmacokinetics of ACT-334441 in subjects with systemic lupus erythematosus.

    Summary
    EudraCT number
    2014-002984-14
    Trial protocol
    BG  
    Global end of trial date
    28 Feb 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    07 Nov 2019
    First version publication date
    16 Mar 2018
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Change of Sponsor

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-064A201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02472795
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Idorsia Pharmaceuticals Ltd
    Sponsor organisation address
    Hegenheimermattweg 91, ​Allschwil , Switzerland,
    Public contact
    Global Clinical Study Disclosure, Idorsia Pharmaceuticals Ltd, clinical-trials-disclosure@idorsia.com
    Scientific contact
    Global Clinical Study Disclosure, Idorsia Pharmaceuticals Ltd, clinical-trials-disclosure@idorsia.com
    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
    12 Jan 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the pharmacodynamics of ACT-334441, its safety and tolerability profile in adult systemic lupus erythematosus (SLE) subjects.
    Protection of trial subjects
    Prior to the start of the study, each study site consulted an Independent Ethics Committee (IEC) or Institutional Review Board (IRB), i.e., a review panel that was responsible for ensuring the protection of the rights, safety, and well being of human subjects involved in a clinical investigation. The sponsor and the investigators ensured that the study was conducted in full compliance with International Council for Harmonisation (ICH)-Good Clinical Practice (GCP) Guidelines, the principles of the “Declaration of Helsinki” and with the laws and regulations of the countries in which the research was conducted.
    Background therapy
    Standard of care therapies for SLE were allowed
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Jun 2015
    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
    Bulgaria: 19
    Country: Number of subjects enrolled
    Belarus: 7
    Country: Number of subjects enrolled
    Georgia: 6
    Country: Number of subjects enrolled
    Russian Federation: 22
    Country: Number of subjects enrolled
    Ukraine: 9
    Country: Number of subjects enrolled
    United States: 4
    Worldwide total number of subjects
    67
    EEA total number of subjects
    19
    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)
    67
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study was conducted at 18 sites in 6 countries (BLR, BGR, GEO, RUS, UKR, and USA) from 1 Jun 2015 to 28 Feb 2017 (First subject, first visit to last subject, last visit)

    Pre-assignment
    Screening details
    The screening period started at the time the ICF was signed (up to 30 days before Randomization), and ended with subject randomization. The period included Visit 1 (Screening) and the pre-randomization (pre-dose) assessments at Visit 2 (Day 1).

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Monitor, Data analyst, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    ACT-334441 - 0.5 mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    ACT-334441
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One capsule of cenerimod was taken orally o.d. irrespective of food intake. The capsule was to be swallowed whole. It was preferable that the capsule was taken each day at approximately the same time (preferably each morning).

    Arm title
    ACT-334441 - 1.0 mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    ACT-334441
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One capsule of cenerimod was taken orally o.d. irrespective of food intake. The capsule was to be swallowed whole. It was preferable that the capsule was taken each day at approximately the same time (preferably each morning).

    Arm title
    ACT-334441 - 2.0 mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    ACT-334441
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One capsule of cenerimod was taken orally o.d. irrespective of food intake. The capsule was to be swallowed whole. It was preferable that the capsule was taken each day at approximately the same time (preferably each morning).

    Arm title
    ACT-334441 - 4.0 mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    ACT-334441
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One capsule of cenerimod was taken orally o.d. irrespective of food intake. The capsule was to be swallowed whole. It was preferable that the capsule was taken each day at approximately the same time (preferably each morning).

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One capsule of placebo was taken orally o.d. irrespective of food intake. The capsule was to be swallowed whole. It was preferable that the capsule was taken each day at approximately the same time (preferably each morning).

    Number of subjects in period 1
    ACT-334441 - 0.5 mg ACT-334441 - 1.0 mg ACT-334441 - 2.0 mg ACT-334441 - 4.0 mg Placebo
    Started
    12
    12
    13
    13
    17
    Completed
    12
    11
    13
    13
    14
    Not completed
    0
    1
    0
    0
    3
         Adverse event, non-fatal
    -
    1
    -
    -
    2
         Consent withdrawn by subject
    -
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ACT-334441 - 0.5 mg
    Reporting group description
    -

    Reporting group title
    ACT-334441 - 1.0 mg
    Reporting group description
    -

    Reporting group title
    ACT-334441 - 2.0 mg
    Reporting group description
    -

    Reporting group title
    ACT-334441 - 4.0 mg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    ACT-334441 - 0.5 mg ACT-334441 - 1.0 mg ACT-334441 - 2.0 mg ACT-334441 - 4.0 mg Placebo Total
    Number of subjects
    12 12 13 13 17 67
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    12 12 13 13 17 67
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    41.4 ± 13.2 37.0 ± 6.4 39.2 ± 11.8 41.7 ± 8.1 41.0 ± 9.5 -
    Gender categorical
    Units: Subjects
        Female
    11 12 12 10 16 61
        Male
    1 0 1 3 1 6
    Race
    Units: Subjects
        Black or African American
    0 0 0 0 2 2
        White
    12 12 13 13 15 65
    Body mass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    25.2 ± 5.1 27.4 ± 8.0 26.0 ± 5.1 27.5 ± 4.7 25.4 ± 6.8 -
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full analysis set included all subjects randomized to a study treatment.

    Subject analysis set title
    Pharmacodynamics set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PD set included all subjects who received at least 21 days of study treatment, with lymphocyte count measurements at baseline and post-baseline

    Subject analysis set title
    Safety set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety set included all subjects who received at least one dose of study treatment. Unless otherwise stated, any analysis using the Safety set used all available safety data up to EOS

    Subject analysis sets values
    Full analysis set Pharmacodynamics set Safety set
    Number of subjects
    67
    64
    67
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    67
    64
    67
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    40.1 ± 9.9
    40.6 ± 9.8
    40.1 ± 9.9
    Gender categorical
    Units: Subjects
        Female
    61
    59
    61
        Male
    6
    5
    6
    Race
    Units: Subjects
        Black or African American
    2
    2
    2
        White
    65
    62
    65
    Body mass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    26.2 ± 6.0
    26.5 ± 6.0
    26.2 ± 6.0

    End points

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    End points reporting groups
    Reporting group title
    ACT-334441 - 0.5 mg
    Reporting group description
    -

    Reporting group title
    ACT-334441 - 1.0 mg
    Reporting group description
    -

    Reporting group title
    ACT-334441 - 2.0 mg
    Reporting group description
    -

    Reporting group title
    ACT-334441 - 4.0 mg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full analysis set included all subjects randomized to a study treatment.

    Subject analysis set title
    Pharmacodynamics set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PD set included all subjects who received at least 21 days of study treatment, with lymphocyte count measurements at baseline and post-baseline

    Subject analysis set title
    Safety set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety set included all subjects who received at least one dose of study treatment. Unless otherwise stated, any analysis using the Safety set used all available safety data up to EOS

    Primary: Total lymphocyte count, absolute change from baseline to EOT 

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    End point title
    Total lymphocyte count, absolute change from baseline to EOT 
    End point description
    End point type
    Primary
    End point timeframe
     From baseline to End of Treatment
    End point values
    ACT-334441 - 0.5 mg ACT-334441 - 1.0 mg ACT-334441 - 2.0 mg ACT-334441 - 4.0 mg Placebo
    Number of subjects analysed
    12
    10
    13
    13
    16
    Units: 10^9/L
        arithmetic mean (standard deviation)
    -0.26 ± 0.48
    -0.96 ± 0.68
    -0.86 ± 0.61
    -0.87 ± 1.24
    -0.33 ± 0.72
    Statistical analysis title
    Lymphocyte count analysis 0.5 mg vs placebo
    Comparison groups
    ACT-334441 - 0.5 mg v Placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.39
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.56
         upper limit
    0.22
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Statistical analysis title
    Lymphocyte count analysis 1 mg vs placebo
    Comparison groups
    ACT-334441 - 1.0 mg v Placebo
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.02
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.91
         upper limit
    -0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Statistical analysis title
    Lymphocyte count analysis 2 mg vs placebo
    Comparison groups
    ACT-334441 - 2.0 mg v Placebo
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.95
         upper limit
    -0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.19
    Statistical analysis title
    Lymphocyte count analysis 4 mg vs placebo
    Comparison groups
    ACT-334441 - 4.0 mg v Placebo
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.06
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.75
         upper limit
    0.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.19

    Primary: Total lymphocyte count, absolute change from baseline to each post-baseline analysis visit

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    End point title
    Total lymphocyte count, absolute change from baseline to each post-baseline analysis visit [1]
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to End of Treatment
    Notes
    [1] - 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: Not applicable.
    End point values
    ACT-334441 - 0.5 mg ACT-334441 - 1.0 mg ACT-334441 - 2.0 mg ACT-334441 - 4.0 mg Placebo
    Number of subjects analysed
    12
    12
    13
    13
    17
    Units: 10^9/L
    arithmetic mean (standard deviation)
        Baseline
    1.37 ± 0.52
    1.71 ± 0.82
    1.62 ± 0.75
    1.88 ± 0.77
    1.65 ± 0.88
        Week 2
    -0.13 ± 0.56
    -0.48 ± 0.56
    -0.52 ± 1.03
    -1.09 ± 0.65
    -0.16 ± 0.75
        Week 4
    -0.28 ± 0.42
    -0.69 ± 0.76
    -0.86 ± 0.63
    -0.68 ± 1.32
    -0.33 ± 0.69
        Week 8
    -0.28 ± 0.60
    -0.92 ± 0.60
    -0.89 ± 0.68
    -1.03 ± 1.12
    -0.09 ± 0.82
        Week 12
    -0.26 ± 0.48
    -0.72 ± 1.03
    -0.86 ± 0.61
    -0.87 ± 1.24
    -0.29 ± 0.73
        End of Treatment
    -0.26 ± 0.48
    -0.72 ± 1.03
    -0.86 ± 0.61
    -0.87 ± 1.24
    -0.30 ± 0.71
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Enter description here
    Adverse event reporting additional description
    Enter description here
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo

    Reporting group title
    ACT-334441 0.5 mg
    Reporting group description
    ACT-334441 0.5 mg

    Reporting group title
    ACT-334441 1.0 mg
    Reporting group description
    ACT-334441 1.0 mg

    Reporting group title
    ACT-334441 2.0 mg
    Reporting group description
    ACT-334441 2.0 mg

    Reporting group title
    ACT-334441 4.0 mg
    Reporting group description
    ACT-334441 4.0 mg

    Serious adverse events
    Placebo ACT-334441 0.5 mg ACT-334441 1.0 mg ACT-334441 2.0 mg ACT-334441 4.0 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Pancreatitis chronic
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis chronic
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 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
    Post cholecystectomy syndrome
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 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: 1%
    Non-serious adverse events
    Placebo ACT-334441 0.5 mg ACT-334441 1.0 mg ACT-334441 2.0 mg ACT-334441 4.0 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 17 (52.94%)
    5 / 12 (41.67%)
    5 / 12 (41.67%)
    6 / 13 (46.15%)
    5 / 13 (38.46%)
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Blood fibrinogen decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Electrocardiogram T wave amplitude decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Intraocular pressure increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Laboratory test abnormal
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Lymphopenia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Neutropenia
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Pneumonitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    Eye disorders
    Age-related macular degeneration
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Cataract
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Dry age-related macular degeneration
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Visual acuity reduced
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Abdominal pain lower
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Gastroduodenitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Hepatobiliary disorders
    Chronic hepatitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Nitrituria
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Proteinuria
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Nail dystrophy
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Joint swelling
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Infections and infestations
    Asymptomatic bacteriuria
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Erysipelas
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    2
    0
    0
    0
    1
    Periodontitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Tracheobronchitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Mar 2015
    Summary of most relevant changes: • Study-specific stopping rules per FDA recommendations were introduced, • ECG discharge criteria from hospital on Day 1 and on the first day of re-initiation following treatment interruption were clarified, • Respiratory system criteria for interruption / premature discontinuation of study treatment per FDA recommendations were revised, • The safety endpoint/variable Occurrence of treatment-emergent decrease of FEV1 or FVC was modified, • Analysis of pulmonary safety events was to include treatment-emergent decrease of FEV1 or FVC to < 85% of baseline values instead of < 80% of baseline values, • Since at Visit 3 and re-initiation visits, study drug was not to be allocated by the IRT system, the compliance could not be calculated automatically in the eCRF. During these visits, a compliance review based on study drug accountability was to be performed by the investigator (or delegate) and recorded in the eCRF, • In case of no medical justification available for study treatment interruption, compliance < 80% was to be reported as a protocol deviation, • Clarifications were added in the laboratory sections, • In order to shorten the time window between assessments during the follow-up period (at 6 and 16 weeks after last dose of study treatment intake), a follow-up assessment via telephone was added at 11 weeks after last dose of study treatment intake to collect SAEs and pregnancy test results, • Informed Consent Form was amended to reflect the changes introduced by the amendment.

    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.
    None reported
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