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    Clinical Trial Results:
    Dose-response relationship study of S42909 on leg ulcer healing after oral repeated administration in patients with active venous leg ulcer. A 10-week randomized, double-blind, placebo-controlled, prospective, international, multicentre, phase IIa study.

    Summary
    EudraCT number
    		 2016-004143-36
    Trial protocol
    		 AT   DK   CZ   SK   ES   PL   IT  
    Global end of trial date
    20 Jan 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Sep 2020
    First version publication date
    10 Sep 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CL2-42909-016
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03077165
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ilkos Therapeutic Inc.
    Sponsor organisation address
    500 boulevard Cartier Ouest Bureau 131, Laval, Québec, Canada, H7V 5B7
    Public contact
    M. DROUIN, Ilkos Therapeutic Inc., +1 450-680-3381 X2913,
    Scientific contact
    M. DROUIN, Ilkos Therapeutic Inc., +1 450-680-3381 X2913,
    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
    20 Jan 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Jan 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To detect the existence of an overall dose-response relationship with S42909 on improving healing of venous leg ulcers on top of standard of care (compression and local wound care) after 4 weeks of treatment.
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practice standards, ethical principles stated in the Declaration of Helsinki and applicable regulatory requirements. After the subject has ended his/her participation in the trial, the investigator provided appropriate medication and/or arranged access to appropriate care for the patient.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Sep 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 26
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United States: 8
    Country: Number of subjects enrolled
    Argentina: 11
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Brazil: 13
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Czech Republic: 26
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Poland: 2
    Worldwide total number of subjects
    121
    EEA total number of subjects
    87
    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)
    57
    From 65 to 84 years
    61
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Caucasian men or women, age ≥18 years old, 18.5 kg/m2 ≤ BMI≤ 45.0 kg/m2, with CVD documented by imaging to explore a venous disorder in both sub- and extra-fascial venous systems. At least one active venous leg ulcer localised in the gaiter area (CEAP C6) for more than 6 weeks and less than 2 years. Size of the reference ulcer ≥ 5 cm2 and ≤ 100 cm2

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 S42909 50 mg b.i.d
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    S42909
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During W000-W006 period, the participants were to take orally 3 tablets twice a day at the end of the meals: 3 tablets in the morning at the end of breakfast and 3 tablets in the evening at the end of dinner. Tablets of 0 and 50 mg of strength of S42909 were used to reach the daily dose of S42909 100 mg.

    Arm title
    		 S42909 100 mg b.i.d
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    S42909
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During W000-W006 period, the participants were to take orally 3 tablets twice a day at the end of the meals: 3 tablets in the morning at the end of breakfast and 3 tablets in the evening at the end of dinner. Tablets of 0 and 50 mg of strength of S42909 were used to reach the daily dose of S42909 200 mg.

    Arm title
    		 S42909 200 mg b.i.d
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    S42909
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During W000-W006 period, the participants were to take orally 3 tablets twice a day at the end of the meals: 3 tablets in the morning at the end of breakfast and 3 tablets in the evening at the end of dinner. Tablets of 0 and 200 mg of strength of S42909 were used to reach the daily dose of S42909 400 mg.

    Arm title
    		 S42909 400 mg b.i.d
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    S42909
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During W000-W006 period, the participants were to take orally 3 tablets twice a day at the end of the meals: 3 tablets in the morning at the end of breakfast and 3 tablets in the evening at the end of dinner. Tablets of 0 and 200 mg of strength of S42909 were used to reach the daily dose of S42909 800 mg.

    Arm title
    		 S42909 600 mg b.i.d
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    S42909
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During W000-W006 period, the participants were to take orally 3 tablets twice a day at the end of the meals: 3 tablets in the morning at the end of breakfast and 3 tablets in the evening at the end of dinner. Tablets of 200 mg of strength of S42909 were used to reach the daily dose of S42909 1200 mg.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During W000-W006 period, the participants were to take orally 3 tablets of placebo twice a day at the end of the meals: 3 tablets in the morning at the end of breakfast and 3 tablets in the evening at the end of the dinner.

    Number of subjects in period 1
    		S42909 50 mg b.i.d S42909 100 mg b.i.d S42909 200 mg b.i.d S42909 400 mg b.i.d S42909 600 mg b.i.d Placebo
    Started
    21
    22
    20
    19
    19
    20
    Completed
    20
    22
    20
    19
    16
    20
    Not completed
    1
    0
    0
    0
    3
    0
         Adverse event, non-fatal
    1
    -
    -
    -
    1
    -
         Non-medical reason
    -
    -
    -
    -
    1
    -
         Protocol deviation
    -
    -
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    S42909 50 mg b.i.d
    Reporting group description
    		 -

    Reporting group title
    S42909 100 mg b.i.d
    Reporting group description
    		 -

    Reporting group title
    S42909 200 mg b.i.d
    Reporting group description
    		 -

    Reporting group title
    S42909 400 mg b.i.d
    Reporting group description
    		 -

    Reporting group title
    S42909 600 mg b.i.d
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 S42909 50 mg b.i.d S42909 100 mg b.i.d S42909 200 mg b.i.d S42909 400 mg b.i.d S42909 600 mg b.i.d Placebo Total
    Number of subjects
    		 21 22 20 19 19 20 121
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 9 12 12 4 9 11 57
        From 65-84 years
    		 12 9 7 15 9 9 61
        85 years and over
    		 0 1 1 0 1 0 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.6 ( 11.8 ) 60.8 ( 13.1 ) 64.0 ( 11.2 ) 71.5 ( 11.4 ) 62.1 ( 14.5 ) 62.1 ( 14.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 9 10 13 14 10 66
        Male
    		 11 13 10 6 5 10 55

    End points

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    End points reporting groups
    Reporting group title
    S42909 50 mg b.i.d
    Reporting group description
    		 -

    Reporting group title
    S42909 100 mg b.i.d
    Reporting group description
    		 -

    Reporting group title
    S42909 200 mg b.i.d
    Reporting group description
    		 -

    Reporting group title
    S42909 400 mg b.i.d
    Reporting group description
    		 -

    Reporting group title
    S42909 600 mg b.i.d
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    In accordance with the intention-to-treat principle and Section 5.2.1 of the ICH E9 guideline, all randomised patients who received at least one dose of IMP and who had at least one baseline value and one value of Reference ulcer (RU) area (primary efficacy criterion) at W004

    Primary: Relative reduction of RU area after 4 weeks

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    End point title
    		 Relative reduction of RU area after 4 weeks
    End point description
    The primary efficacy endpoint was defined as the relative reduction of reference ulcer (RU) area after 4 weeks of treatment on top of standard of care compared with the baseline RU area assessed during study visits using a digital 3D imaging device.
    End point type
    Primary
    End point timeframe
    RU area was assessed at ASSE, W000, W001, W002, W003, W004, W006 and W008 visits (The primary efficacy endpoint was the relative reduction of RU area after 4 weeks of treatment).
    End point values
    		 S42909 50 mg b.i.d S42909 100 mg b.i.d S42909 200 mg b.i.d S42909 400 mg b.i.d S42909 600 mg b.i.d Placebo
    Number of subjects analysed
    20
    22
    20
    19
    17
    20
    Units: cm2
        arithmetic mean (standard deviation)
    -52.85 ( 37.79 )
    -46.42 ( 33.30 )
    -31.07 ( 38.73 )
    -43.33 ( 28.37 )
    -41.10 ( 33.99 )
    -41.23 ( 43.71 )
    Statistical analysis title
    		 MCP-Mod - Test statistics
    Statistical analysis description
    The MCP-Mod method was applied to the primary efficacy endpoint in the FAS. The MCP-Mod method includes the MCP-step, which corresponds to the establishment of a dose-response signal, and the Mod-step that estimates the dose-response curve. Of note, the MCP-step procedure was based on a multi-contrast test. The best dose-response was to be identified as the contrast test with the maximum test statistics among the set of relevant dose-response models (i.e. models with adjusted p-value < 0.025).
    Comparison groups
    Placebo v S42909 600 mg b.i.d v S42909 400 mg b.i.d v S42909 200 mg b.i.d v S42909 100 mg b.i.d v S42909 50 mg b.i.d
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.025
    Method
    		 MCP-Mod approach
    Parameter type
    		 dose response model
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events which occurred or worsened or became serious according to the investigator, or upgraded by the Sponsor, from the date the participant signed the information and consent form, irrespective of the period of the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    S42909 50 mg b.i.d
    Reporting group description
    		 -

    Reporting group title
    S42909 100 mg b.i.d
    Reporting group description
    		 -

    Reporting group title
    S42909 200 mg b.i.d
    Reporting group description
    		 -

    Reporting group title
    S42909 400 mg b.i.d
    Reporting group description
    		 -

    Reporting group title
    S42909 600 mg b.i.d
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 S42909 50 mg b.i.d S42909 100 mg b.i.d S42909 200 mg b.i.d S42909 400 mg b.i.d S42909 600 mg b.i.d Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4.5%
    Non-serious adverse events
    		 S42909 50 mg b.i.d S42909 100 mg b.i.d S42909 200 mg b.i.d S42909 400 mg b.i.d S42909 600 mg b.i.d Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 21 (19.05%)
    6 / 22 (27.27%)
    8 / 20 (40.00%)
    6 / 19 (31.58%)
    8 / 19 (42.11%)
    6 / 20 (30.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon adenoma
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Pallor
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Increased bronchial secretion
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Productive cough
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    International normalised ratio decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Incorrect product administration duration
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Overdose
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Skin laceration
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Headache
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    0
    1
    0
    0
    4
    Somnolence
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Leukopenia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    2 / 19 (10.53%)
    3 / 19 (15.79%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    3
    4
    0
    Food poisoning
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Pseudopolyposis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Toothache
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dermatitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Drug eruption
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Eczema
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pruritus generalised
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Psoriasis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Skin ulcer
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    1 / 19 (5.26%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    4
    2
    1
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Ureterolithiasis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Conjunctivitis bacterial
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Infected skin ulcer
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 22 (9.09%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    1
    0
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Tonsillitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Urinary tract infection staphylococcal
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 May 2017
    Amendment 1: It was set up, mainly in order to adapt selection/inclusion criteria to new medical data, to clarify wording relative to selection/inclusion criteria, to add withdrawal criteria, to specify items regarding standard of care, and to adjust the investigation schedule during the selection period.
    29 Jun 2017
    Amendement 2: was implemented to tighten up the eligibility criteria by removing the investigator’s judgement on the arterial duplex scan from the non-selection criterion N°26. Protocol Appendix 2 was modified accordingly in order to capture the data from the arterial duplex scan based on the different methods used in the participating sites and countries.
    29 Jun 2017
    Amendment 3: was implemented to integrate prior amendments Nos.°1 and 2 (for European countries where amendment No. 1 had not yet been submitted for regulatory and ethic review at the time of issuance of amendment No. 2).
    05 Mar 2018
    Amendment 4: was implemented in order to adapt selection/inclusion criteria to new considerations and new medical data, to clarify new timelines of the study, to add a 3D picture of the RU on the day of the inclusion visit after randomisation, and to broaden the study population notably to diabetic patients.

    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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