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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, multicentre proof-of-concept trial of IVA337 in the treatment of diffuse cutaneous systemic sclerosis.

    Summary
    EudraCT number
    		 2015-001617-27
    Trial protocol
    		 IT   ES   GB   DE   NL   SI   BG  
    Global end of trial date
    12 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Apr 2021
    First version publication date
    24 Apr 2021
    Other versions
    Summary report(s)
    		 FASST synopsis CSR

    Trial information

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    Trial identification
    Sponsor protocol code
    IVA_01_337_HSSC_15_001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02503644
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Inventiva S.A.
    Sponsor organisation address
    50 rue de Dijon, Daix, France, 21121
    Public contact
    Regulatory Affairs Manager, Inventiva, +33 380447500, fasst.public@inventivapharma.com
    Scientific contact
    Chief Medical Officer, Inventiva, +33 380447500, fasst.scientists@inventivapharma.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 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate in patients suffering from diffuse cutaneous SSc (DcSSc) the effect of 800mg and 1200mg IVA337 daily on the skin compared to placebo. The modified Rodnan Skin Score (MRSS) was used to determine the changes in skin.
    Protection of trial subjects
    The protocol, the patient information sheet, and the consent form were reviewed and approved by an appropriately constituted Ethics Committee (EC) at each study site and by the Competent Authorities (CA) before the start of the clinical study. All applicable European and local regulations were followed. All changes in the research activity and all unanticipated problems involving risks to humans were reported to the EC/CA as applicable. No substantial changes were made to the protocol without prior Sponsor and EC/CA approval, except where necessary to eliminate apparent immediate hazards to study patients.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Oct 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
    Poland: 57
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Slovenia: 4
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Bulgaria: 12
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Switzerland: 4
    Worldwide total number of subjects
    145
    EEA total number of subjects
    141
    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)
    136
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted from 29-Oct-2015, date of first patient first visit to 12-Oct-2018, and was conducted in 10 countries in Europe.

    Pre-assignment
    Screening details
    		 A total of 161 patients were screened, and 145 patients were randomized in the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LAN1200
    Arm description
    		 Patients who receive 1200mg of lanifibranor: 3 capsules of lanifibranor 200mg twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanifibranor
    Investigational medicinal product code
    IVA337
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Capsules of 200mg to be taken orally

    Arm title
    		 LAN800
    Arm description
    		 Patients who receive 800 mg of lanifibranor: 2 capsules of lanifibranor 200mg and one capsule of placebo, twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lanifibranor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Capsules of 200mg to be taken orally

    Arm title
    		 Placebo
    Arm description
    		 Patients who receive placebo: 3 capsules of placebo, twice daily
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to match lanifibranor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    3 capsules of placebo to be taken orally, twice a day

    Number of subjects in period 1
    		LAN1200 LAN800 Placebo
    Started
    48
    49
    48
    Completed
    32
    34
    40
    Not completed
    16
    15
    8
         Adverse event, serious fatal
    -
    1
    -
         Consent withdrawn by subject
    1
    2
    3
         Physician decision
    -
    -
    1
         Adverse event, non-fatal
    13
    11
    4
         other
    1
    1
    -
         Protocol deviation
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LAN1200
    Reporting group description
    		 Patients who receive 1200mg of lanifibranor: 3 capsules of lanifibranor 200mg twice daily

    Reporting group title
    LAN800
    Reporting group description
    		 Patients who receive 800 mg of lanifibranor: 2 capsules of lanifibranor 200mg and one capsule of placebo, twice daily

    Reporting group title
    Placebo
    Reporting group description
    		 Patients who receive placebo: 3 capsules of placebo, twice daily

    Reporting group values
    		 LAN1200 LAN800 Placebo Total
    Number of subjects
    		 48 49 48 145
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 45 46 45 136
        From 65-84 years
    		 3 3 3 9
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 40 45 35 120
        Male
    		 8 4 13 25

    End points

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    End points reporting groups
    Reporting group title
    LAN1200
    Reporting group description
    		 Patients who receive 1200mg of lanifibranor: 3 capsules of lanifibranor 200mg twice daily

    Reporting group title
    LAN800
    Reporting group description
    		 Patients who receive 800 mg of lanifibranor: 2 capsules of lanifibranor 200mg and one capsule of placebo, twice daily

    Reporting group title
    Placebo
    Reporting group description
    		 Patients who receive placebo: 3 capsules of placebo, twice daily

    Primary: Absolute change of the MRSS from baseline to 48 weeks

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    End point title
    		 Absolute change of the MRSS from baseline to 48 weeks
    End point description
    MRSS is a validated measure of the skin thickness, which is a commonly used outcome measure of dcSSc. Measurement of skin thickness is a surrogate measure of disease severity and mortality in patients with dcSSc; increase in skin thickness is associated with involvment of internal organs and increased mortality. MRSS is calculated by adding skin thickness scores rated by clinical physician using a 0-3 scale (from 0 = severe thickness with inability to pinch the skin into a fold) for the following 17 anatomic surface areas of the body: face, anterior chest, abdomen, and right and left separately: fingers, forearms, upper arms, tights, lower legs, dorsum of hands and feet.
    End point type
    Primary
    End point timeframe
    From baseline to Week 48.
    End point values
    		 LAN1200 LAN800 Placebo
    Number of subjects analysed
    48
    49
    48
    Units: number
        arithmetic mean (standard error)
    -4.39 ( 0.65 )
    -3.75 ( 0.64 )
    -5.03 ( 0.65 )
    Statistical analysis title
    		 Treatment effect : dose response relationship
    Comparison groups
    LAN1200 v LAN800 v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.3614
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [1] - For the primary analysis, the dose-response relationship at Week 48 was assessed in the mITT population using the MMRM (mixed model for repeated measures) and the primary missing data imputation method (‘linear interpretation+placebo slope’).

    Secondary: Overall progression of the disease

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    End point title
    		 Overall progression of the disease
    End point description
    Overall progression of the disease is defined as presence of escape therapy and/or presence of severe organ involvment (SOI) or presence of an "unable to adjucate" SOI.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 48
    End point values
    		 LAN1200 LAN800 Placebo
    Number of subjects analysed
    48
    49
    48
    Units: Percentage
    number (confidence interval 95%)
        Yes
    10.4 (3.5 to 22.7)
    6.1 (1.3 to 16.9)
    8.3 (2.3 to 20)
    No statistical analyses for this end point

    Secondary: Absolute change from baseline in pulmonary function test: %FVC

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    End point title
    		 Absolute change from baseline in pulmonary function test: %FVC
    End point description
    % predictive Forced Vital Capacity
    End point type
    Secondary
    End point timeframe
    From baseline to Week 48. Missing data at Week 48 were imputed by taking the primary missing date imputation method (1 linear interpretation + placebo slope).
    End point values
    		 LAN1200 LAN800 Placebo
    Number of subjects analysed
    48
    49
    48
    Units: number
        arithmetic mean (standard error)
    -0.68 ( 1.07 )
    -0.34 ( 1.06 )
    0.58 ( 1.07 )
    No statistical analyses for this end point

    Secondary: Digital Ulcer Count

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    End point title
    		 Digital Ulcer Count
    End point description
    Evolution of digital ulcer over the study period for the mITT population.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 48
    End point values
    		 LAN1200 LAN800 Placebo
    Number of subjects analysed
    31
    34
    39
    Units: Decimal number
        Missing
    1
    0
    1
        Patients with at least one DU
    2
    1
    2
        Decrease or no change from basseline
    29
    33
    38
        Increase
    2
    1
    1
    No statistical analyses for this end point

    Secondary: Absolute change from baseline in pulmonary function test: %pcDLCO

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    End point title
    		 Absolute change from baseline in pulmonary function test: %pcDLCO
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to Week 48. Missing data at Week 48 were imputed by taking the primary missing data imputation method (1 linear interpretation + placebo slope).
    End point values
    		 LAN1200 LAN800 Placebo
    Number of subjects analysed
    48
    49
    48
    Units: unit
        arithmetic mean (standard error)
    -3.6 ( 1.06 )
    0.2 ( 1.06 )
    -0.47 ( 1.06 )
    No statistical analyses for this end point

    Secondary: Change in the Digital Ulcer burden over time

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    End point title
    		 Change in the Digital Ulcer burden over time
    End point description
    Total number of ulcers at a certain time point minus number of ulcers at baseline and proportion of patients with: - decrease or no change OR - increase
    End point type
    Secondary
    End point timeframe
    Between baseline and Week 48.
    End point values
    		 LAN1200 LAN800 Placebo
    Number of subjects analysed
    31
    34
    39
    Units: Decimal number
        Decrease or no change from baseline
    29
    33
    38
        Increase
    2
    1
    1
    No statistical analyses for this end point

    Secondary: Absolute change from baseline in the HAQ-DI from SHAQ questionnaire

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    End point title
    		 Absolute change from baseline in the HAQ-DI from SHAQ questionnaire
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to Week 48 (observed cases under treatment).
    End point values
    		 LAN1200 LAN800 Placebo
    Number of subjects analysed
    30
    34
    40
    Units: Score
        arithmetic mean (standard deviation)
    -0.08 ( 0.37 )
    -0.10 ( 0.34 )
    -0.05 ( 0.34 )
    No statistical analyses for this end point

    Secondary: Absolute change from baseline in VAS physician Global Assessment of Disease Activity

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    End point title
    		 Absolute change from baseline in VAS physician Global Assessment of Disease Activity
    End point description
    End point type
    Secondary
    End point timeframe
    From basline to Week 48.
    End point values
    		 LAN1200 LAN800 Placebo
    Number of subjects analysed
    46
    48
    47
    Units: Score
        arithmetic mean (standard deviation)
    -12.9 ( 16.8 )
    -15.4 ( 16.6 )
    -7.1 ( 20.4 )
    No statistical analyses for this end point

    Secondary: Absolute change from baseline in VAS patient Global Assessment of Disease activity

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    End point title
    		 Absolute change from baseline in VAS patient Global Assessment of Disease activity
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to Week 48.
    End point values
    		 LAN1200 LAN800 Placebo
    Number of subjects analysed
    44
    47
    47
    Units: Score
        arithmetic mean (standard deviation)
    -11.8 ( 16.9 )
    -10.2 ( 21.1 )
    -2.7 ( 19.3 )
    No statistical analyses for this end point

    Secondary: MRSS responder rate at 48 weeks - initial definition

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    End point title
    		 MRSS responder rate at 48 weeks - initial definition
    End point description
    Initial definition of responder is a reduction ≥5 points and ≥25% of MRSS compared to baseline.
    End point type
    Secondary
    End point timeframe
    baseline to w48
    End point values
    		 LAN1200 LAN800 Placebo
    Number of subjects analysed
    48
    49
    48
    Units: Percentage
    number (confidence interval 95%)
        Percentage of responders (initial definition)
    35.4 (22.2 to 50.5)
    28.6 (16.6 to 43.3)
    54.2 (39.2 to 68.6)
    No statistical analyses for this end point

    Secondary: MRSS responder at Week 48- additional definition

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    End point title
    		 MRSS responder at Week 48- additional definition
    End point description
    Additional definition of responder is a reduction ≥4 points and ≥20% MRSS compared to baseline. .
    End point type
    Secondary
    End point timeframe
    From baseline to Week 48.
    End point values
    		 LAN1200 LAN800 Placebo
    Number of subjects analysed
    48
    49
    48
    Units: Percentage
    number (confidence interval 95%)
        Percentage of responder (additional definition)
    45.8 (31.4 to 60.8)
    42.9 (28.8 to 57.8)
    60.4 (45.3 to 74.2)
    No statistical analyses for this end point

    Secondary: MRSS progressor rate at Week 48: initial definition

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    End point title
    		 MRSS progressor rate at Week 48: initial definition
    End point description
    Initial definition of pregressor rate is a reduction ≥5 points and ≥25% of MRSS compared to baseline.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 48.
    End point values
    		 LAN1200 LAN800 Placebo
    Number of subjects analysed
    48
    49
    48
    Units: Percentage
    number (confidence interval 95%)
        Progressors (initial definition)
    4.2 (0.5 to 14.3)
    0 (0.0 to 7.3)
    0 (0.0 to 7.4)
    No statistical analyses for this end point

    Secondary: MRSS progressor rate at Week 48: additional definition

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    End point title
    		 MRSS progressor rate at Week 48: additional definition
    End point description
    Additional definition of progessor rate is a reduction ≥4 points and ≥20% MRSS compared to baseline.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 48.
    End point values
    		 LAN1200 LAN800 Placebo
    Number of subjects analysed
    48
    49
    48
    Units: number
    number (confidence interval 95%)
        Progressor (additional definition)
    4.2 (0.5 to 14.3)
    2.0 (0.1 to 10.9)
    2.1 (0.1 to 11.1)
    No statistical analyses for this end point

    Secondary: Absolute change from baseline in Cochin Hand Function Scale

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    End point title
    		 Absolute change from baseline in Cochin Hand Function Scale
    End point description
    To evaluate the changes in regard to hand function.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 48 (observed cases under treatment).
    End point values
    		 LAN1200 LAN800 Placebo
    Number of subjects analysed
    31
    33
    40
    Units: score
        arithmetic mean (standard deviation)
    -3.97 ( 5.31 )
    -3.27 ( 9.47 )
    -2.18 ( 10.48 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On or after the first dose of treatment up to 30 days post-last dose.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    LAN1200
    Reporting group description
    		 Patients who receive 1200mg of lanifibranor: 3 capsules of lanifibranor twice daily

    Reporting group title
    LAN800
    Reporting group description
    		 Patients who receive lanifibranor: 2 capsules of lanifibranor 200mg and one capsule of placebo, twice daily

    Reporting group title
    Placebo
    Reporting group description
    		 Patients who receive placebo: 3 capsules of placebo, twice daily.

    Serious adverse events
    		 LAN1200 LAN800 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 48 (14.58%)
    10 / 49 (20.41%)
    1 / 48 (2.08%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 49 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial ischaemia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 49 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 49 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Oroantral fistula
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Scleroderma associated digital ulcer
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Systemic scleroderma
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 49 (4.08%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibromyalgia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 49 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 49 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 49 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LAN1200 LAN800 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 48 (85.42%)
    44 / 49 (89.80%)
    43 / 48 (89.58%)
    Investigations
    Weight increased
         subjects affected / exposed
    19 / 48 (39.58%)
    10 / 49 (20.41%)
    1 / 48 (2.08%)
         occurrences all number
    21
    10
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 49 (2.04%)
    1 / 48 (2.08%)
         occurrences all number
    3
    1
    1
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    3 / 48 (6.25%)
    2 / 49 (4.08%)
    0 / 48 (0.00%)
         occurrences all number
    3
    2
    0
    Weight decreased
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
    3 / 48 (6.25%)
         occurrences all number
    0
    1
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 48 (12.50%)
    2 / 49 (4.08%)
    6 / 48 (12.50%)
         occurrences all number
    6
    3
    6
    Headache
         subjects affected / exposed
    4 / 48 (8.33%)
    7 / 49 (14.29%)
    2 / 48 (4.17%)
         occurrences all number
    7
    9
    3
    Sciatica
         subjects affected / exposed
    0 / 48 (0.00%)
    4 / 49 (8.16%)
    2 / 48 (4.17%)
         occurrences all number
    0
    6
    2
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    13 / 48 (27.08%)
    16 / 49 (32.65%)
    0 / 48 (0.00%)
         occurrences all number
    18
    23
    0
    Peripheral swelling
         subjects affected / exposed
    3 / 48 (6.25%)
    6 / 49 (12.24%)
    1 / 48 (2.08%)
         occurrences all number
    6
    10
    1
    Fatigue
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 49 (2.04%)
    0 / 48 (0.00%)
         occurrences all number
    4
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 48 (12.50%)
    2 / 49 (4.08%)
    3 / 48 (6.25%)
         occurrences all number
    6
    2
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 48 (16.67%)
    3 / 49 (6.12%)
    5 / 48 (10.42%)
         occurrences all number
    12
    3
    8
    Nausea
         subjects affected / exposed
    7 / 48 (14.58%)
    4 / 49 (8.16%)
    4 / 48 (8.33%)
         occurrences all number
    8
    4
    4
    Flatulence
         subjects affected / exposed
    1 / 48 (2.08%)
    5 / 49 (10.20%)
    1 / 48 (2.08%)
         occurrences all number
    1
    6
    1
    Vomiting
         subjects affected / exposed
    4 / 48 (8.33%)
    2 / 49 (4.08%)
    2 / 48 (4.17%)
         occurrences all number
    4
    2
    2
    Dyspepsia
         subjects affected / exposed
    3 / 48 (6.25%)
    3 / 49 (6.12%)
    1 / 48 (2.08%)
         occurrences all number
    3
    4
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 49 (6.12%)
    3 / 48 (6.25%)
         occurrences all number
    1
    3
    4
    Abdominal pain upper
         subjects affected / exposed
    1 / 48 (2.08%)
    4 / 49 (8.16%)
    1 / 48 (2.08%)
         occurrences all number
    1
    4
    1
    Abdominal distension
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 49 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    3
    0
    3
    Toothache
         subjects affected / exposed
    0 / 48 (0.00%)
    3 / 49 (6.12%)
    1 / 48 (2.08%)
         occurrences all number
    0
    4
    1
    Abdominal pain
         subjects affected / exposed
    5 / 48 (10.42%)
    4 / 49 (8.16%)
    1 / 48 (2.08%)
         occurrences all number
    6
    5
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 48 (10.42%)
    1 / 49 (2.04%)
    2 / 48 (4.17%)
         occurrences all number
    6
    1
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 48 (0.00%)
    5 / 49 (10.20%)
    1 / 48 (2.08%)
         occurrences all number
    0
    6
    1
    Rales
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
    3 / 48 (6.25%)
         occurrences all number
    0
    1
    3
    Skin and subcutaneous tissue disorders
    Scleroderma associated digital ulcer
         subjects affected / exposed
    3 / 48 (6.25%)
    5 / 49 (10.20%)
    3 / 48 (6.25%)
         occurrences all number
    3
    6
    6
    Swelling face
         subjects affected / exposed
    3 / 48 (6.25%)
    3 / 49 (6.12%)
    0 / 48 (0.00%)
         occurrences all number
    3
    4
    0
    Pruritus
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 49 (2.04%)
    1 / 48 (2.08%)
         occurrences all number
    3
    1
    1
    Dry skin
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 49 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    3
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 49 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    0
    3
    Musculoskeletal and connective tissue disorders
    Systemic scleroderma
    Additional description: All NSAEs coded as systemic scleroderma were associated with an exacerbation/worsening of SSc condition or increase in MRSS.
         subjects affected / exposed
    3 / 48 (6.25%)
    7 / 49 (14.29%)
    3 / 48 (6.25%)
         occurrences all number
    3
    9
    3
    Arthralgia
         subjects affected / exposed
    6 / 48 (12.50%)
    4 / 49 (8.16%)
    4 / 48 (8.33%)
         occurrences all number
    7
    5
    6
    Joint swelling
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 49 (4.08%)
    3 / 48 (6.25%)
         occurrences all number
    2
    3
    3
    Myalgia
         subjects affected / exposed
    3 / 48 (6.25%)
    3 / 49 (6.12%)
    1 / 48 (2.08%)
         occurrences all number
    4
    3
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 48 (16.67%)
    13 / 49 (26.53%)
    4 / 48 (8.33%)
         occurrences all number
    9
    18
    5
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 48 (6.25%)
    5 / 49 (10.20%)
    8 / 48 (16.67%)
         occurrences all number
    6
    8
    12
    Influenza
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 49 (4.08%)
    3 / 48 (6.25%)
         occurrences all number
    0
    2
    3
    Urinary tract infection
         subjects affected / exposed
    3 / 48 (6.25%)
    3 / 49 (6.12%)
    3 / 48 (6.25%)
         occurrences all number
    3
    3
    4
    Rhinitis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
    3 / 48 (6.25%)
         occurrences all number
    0
    1
    3
    Metabolism and nutrition disorders
    Hyperhomocysteinaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
    5 / 48 (10.42%)
         occurrences all number
    0
    1
    6

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jul 2015
    - addition of visits V7 at Week 20, V11 at Week 36 and V13 at Week 44 - modification of authorisation of emergency unblinding - addition of detailed description of birth control methods pertaining to exclusion criterion "pregnancy" - addition of development of SOI, deterioration in cardiac status, ALT levels >3xULN, jaundice, marked elevated CK levels (to be confirmed by a second test), myopathy, photo or hypersensitivity, to reasons for withdrawal from the study - addition of information on mycophenolic acid properties in the permitted concomitant treatments (low therapeutic index, large inter-individual pharmakokinetic variability and uncertain dose-concentration relationship) - patients who develop SOI were to be withdrawn from the study, to be treated adequately, and considered as non-responders in the subsequent analysis - changes in Raynaud's condition score assessment - detailed instructions for handling and preparing the blood samples provided with the kit supplied by the Sponsor - PK time points detailed and details on bioanalytical study removed - addition of hypoglycemia and additional urinary test for pregnancy at V0
    10 Dec 2015
    - addition of Dr Denton in the list of principal investigators - modification of patients to be included from 105 to 132 - update of unblinding procedures - addition of 2 exclusion criteria: diabetic ketoacidosis and co-therapy with biologics - modification of adequate contraceptive measures: sexual abstinence was deleted and a warning regarding resumption of ovulation was added - update of the text on assignment to study groups - addition of iloprost for stable patients with mild vascular manifestations to the list of permitted concomitant treatments - addition of biologics and PPAR agonists to the list of prohibited concomitant treatments - modification of definition of SOI - update of assessment of other outcomes of interest - modification of the list of lab tests to be performed - rewritening of statistical part of the protocol
    27 Feb 2017
    • A short name to the study was added: For A Systemic Sclerosis Treatment (FASST). • The follow-up after the completion of the study was changed from 12 weeks to 4 weeks and total protocol completion per patient and V15 modified from 60 to 52 weeks. • The planned inclusion period was increased from 12 to 24 months and the end of study was modified to December 2018. Additional countries and centres were added. • The following examinations scheduled for V15 were removed: MRSS, digital ulcer count, joint/tendon assessment, Cochin hand function test, patient reported outcomes (SHAQ, PROMIS-29, GIT, SF36) and patient/physician overall visual analogue scale test. Study drug accountability was added in the flowchart as procedure to perform. • Clinmark was added among the CRO monitoring. • A DSMB was set up and details of procedures were described. • Tocilizumab was added to the list of co-therapy with biologics exclusion criteria. Any other significant heart disease or any clinically significant ECG abnormality reported by central ECG reading was also added to the exclusion criteria. • Pregnancy was added to reasons for withdrawal from the study. • A general clarification was added regarding withdrawal management: patient withdrawn need to come for a follow-up study 4 weeks after the premature discontinuation.

    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.
    Not applicable.
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