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    Clinical Trial Results:
    Safety, Tolerability and Efficacy of anti-IL-6 Antibody Clazakizumab in Late Antibody-Mediated Rejection after Kidney Transplantation - A Pilot Trial

    Summary
    EudraCT number
    		 2017-001604-30
    Trial protocol
    		 AT   DE  
    Global end of trial date
    09 Apr 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 May 2022
    First version publication date
    07 May 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03444103
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Charité Berlin
    Sponsor organisation address
    Charitépl. 1, Berlin, Germany, 10117
    Public contact
    Office-Dept. Clinical Pharmacology, Medical University of Vienna, +43 1 404002981, klin-pharmakologie@meduniwien.ac.at
    Scientific contact
    Office-Dept. Clinical Pharmacology, Medical University of Vienna, +43 1 404002981, klin-pharmakologie@meduniwien.ac.at
    Sponsor organisation name
    Medizinische Universität Wien
    Sponsor organisation address
    Spitalgasse 23, Vienna, Austria, 1090
    Public contact
    Prof. Dr. Georg Böhmig, Medical University of Vienna, georg.boehmig@meduniwien.ac.at
    Scientific contact
    Prof. Dr. Georg Böhmig, Medical University of Vienna, georg.boehmig@meduniwien.ac.at
    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
    09 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate safety and tolerability of Interleukin-6 blockade by clazakizumab in kidney transplant recipients on baseline immunosuppresion.
    Protection of trial subjects
    The study was approved by the institutional review board of the Medical University of Vienna (EK1428/2017), the Berlin State Ethics Committee (17/0485– EK 15), and the regulatory authorities in Austria (Federal Office for Safety in Health Care, Austrian Agency for Health and Food Safety) and Germany (Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich Institute). All patients provided written informed consent before study inclusion, and the study was conducted in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice requirements, Good Laboratory Practice, the principles of the Declaration of Helsinki 2008, and the Declaration of Istanbul. Adverse events were closely monitored throughout the study and classified using the Medical Dictionary for Regulatory Activities Version 23.0. The study was monitored by an independent data and safety monitoring board (DSMB), and included two interim analyses, the first after 10 and the second after 20 subjects had completed part Aof the study. The DSMB was instructed to consider stopping the trial if the pattern of related serious adverse events or safety laboratory results strongly supported a major safety signal.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Nov 2017
    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
    Austria: 16
    Country: Number of subjects enrolled
    Germany: 4
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    20
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The recruitment period was January 2018 to April 2019.

    Pre-assignment
    Screening details
    		 22 Donor-specific antibody-positive kidney transplant recipients were assessed for eligibility. 2 Were not eligible.

    Period 1
    Period 1 title
    Part A of the trial
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer
    Blinding implementation details
    Study participants, care providers, and those assessing outcomes were unaware of the randomization sequence. The allocation sequencewas generated, and medication or placebowas prepared by independent nonblinded study pharmacists. Study physicians and nurses were provided with blinded subcutaneous medication. The participating investigators, staff with medical interaction, and the study participants were blinded to group allocation until the last patient had completed part A.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Clazakizumab Group
    Arm description
    		 Clazakizumab is a humanized monoclonal IgG1 antibody with high affinity for IL-6 and a long t1/2 of approximately 30 days. This antibody has been systematically evaluated in rheumatoid and psoriatic arthritis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clazakizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Clazakizumab (25 mg in 1 ml single-dose vials) were administered via subcutaneous injection in 4-weekly intervals. After amendment dosage reduced to 12.6mg per injection.

    Arm title
    		 Placebo
    Arm description
    		 placebo (0.9% saline)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Isotonische Kochsalzlösung Fresenius Infusionslösung
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    placebo (0.9% saline) were administered via subcutaneous injection in 4-weekly intervals

    Number of subjects in period 1
    		Clazakizumab Group Placebo
    Started
    10
    10
    Completed
    9
    10
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -
    Period 2
    Period 2 title
    Part B of the trail
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 clazakizumab (all) Group
    Arm description
    		 a 40-week open-label extension where all participants received clazakizumab (part B). The rationale behind this design was to offer all participants the option of a potentially effective treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clazakizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Clazakizumab (12.6 mg in 1 ml single-dose vials) were administered via subcutaneous injection in 4-weekly intervals.

    Number of subjects in period 2
    		clazakizumab (all) Group
    Started
    19
    Completed
    18
    Not completed
    1
         Adverse event, non-fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Clazakizumab Group
    Reporting group description
    		 Clazakizumab is a humanized monoclonal IgG1 antibody with high affinity for IL-6 and a long t1/2 of approximately 30 days. This antibody has been systematically evaluated in rheumatoid and psoriatic arthritis.

    Reporting group title
    Placebo
    Reporting group description
    		 placebo (0.9% saline)

    Reporting group values
    		 Clazakizumab Group Placebo Total
    Number of subjects
    		 10 10 20
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 9 10 19
        From 65-84 years
    		 1 0 1
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 47.2 (38.7 to 62.1) 39.6 (30.2 to 59.6) -
    Gender categorical
    Units: Subjects
        Female
    		 3 7 10
        Male
    		 7 3 10
    DSA characterisstics
    Units: Subjects
        HLA class I DSA only,
    		 1 1 2
        HLA class II DSA only
    		 7 7 14
        HLA class I and II DSA
    		 2 2 4
    DSA characteristics
    Units: Subjects
        Anti-DQ DSA
    		 7 8 15
        no anti-DQ DSA
    		 3 2 5
    Variables recorded at trial inclusion: duration until inlcusion
    Years to inclusion in the trial
    Units: Years
        median (inter-quartile range (Q1-Q3))
    		 9.7 (4.1 to 16.7) 11.4 (5.9 to 16.1) -
    Variables recorded at trial inclusion eGFR
    Units: ml/min
        median (inter-quartile range (Q1-Q3))
    		 40.5 (33.3 to 49.8) 39.2 (32.9 to 51.7) -
    Variables recorded at trial inclusion: Protein/creatinine ratio
    Units: mg/g
        median (inter-quartile range (Q1-Q3))
    		 727 (197 to 1311) 1387 (532 to 3575) -
    DSA characteristics: MFI of the peak DSA
    Units: Intensity
        median (inter-quartile range (Q1-Q3))
    		 10789 (3092 to 15437) 14207 (1252 to 19144) -
    DSA characteristics: MFI sum of detected
    Units: Intensity
        median (inter-quartile range (Q1-Q3))
    		 10789 (4244 to 18102) 16126 (1252 to 19302) -

    End points

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    End points reporting groups
    Reporting group title
    Clazakizumab Group
    Reporting group description
    		 Clazakizumab is a humanized monoclonal IgG1 antibody with high affinity for IL-6 and a long t1/2 of approximately 30 days. This antibody has been systematically evaluated in rheumatoid and psoriatic arthritis.

    Reporting group title
    Placebo
    Reporting group description
    		 placebo (0.9% saline)
    Reporting group title
    clazakizumab (all) Group
    Reporting group description
    		 a 40-week open-label extension where all participants received clazakizumab (part B). The rationale behind this design was to offer all participants the option of a potentially effective treatment.

    Primary: Safty: overall AEs during Part A and B

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    End point title
    		 Safty: overall AEs during Part A and B
    End point description
    This phase 2 pilot trial, the first randomized controlled trial evaluating IL-6 signaling blockade in transplantation, assessing the safety and tolerability. For more details see category Adverse Events
    End point type
    Primary
    End point timeframe
    51 Weeks
    End point values
    		 Clazakizumab Group Placebo clazakizumab (all) Group
    Number of subjects analysed
    10
    10
    19
    Units: Events
        Adverse Event
    50
    44
    129
        serious AE
    3
    1
    9
        non-serious AEs
    47
    43
    120
    Statistical analysis title
    		 group comparisons
    Comparison groups
    Clazakizumab Group v Placebo v clazakizumab (all) Group
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [1]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [1] - Intergroup differences were tested at a two-sided significance level of 5%. For statistical analysis, IBM SPSS Statistics version 24.

    Secondary: Efficacy: HLA Antibody and Ig Levels

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    End point title
    		 Efficacy: HLA Antibody and Ig Levels
    End point description
    Comparison to baseline. Extension of treatment in part B led to a further decrease of DSA levels (P,0.001) see attchment: DSAlvls
    End point type
    Secondary
    End point timeframe
    51 weeks
    End point values
    		 Clazakizumab Group Placebo
    Number of subjects analysed
    10
    10
    Units: Percentage
    median (inter-quartile range (Q1-Q3))
        DSA MFI
    77 (63 to 101)
    103 (94 to 104)
    Attachments
    		 DSA lvls
    No statistical analyses for this end point

    Secondary: Evolution of Rejection: the changes in ABMR

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    End point title
    		 Evolution of Rejection: the changes in ABMR
    End point description
    ABMR,antibody-mediated rejection; significant intergroup differences in rejection-relatedmolecular and morphologic scores see attachment: Evolution of Rejection
    End point type
    Secondary
    End point timeframe
    51 weeks
    End point values
    		 clazakizumab (all) Group
    Number of subjects analysed
    19
    Units: Subjects
        negative ABMR score
    7
        resolution of ABMR activity
    4
        disappearance of capillary C4d deposits
    5
    Attachments
    		 Evolution of Rejection
    No statistical analyses for this end point

    Secondary: slowed eGFR decline

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    End point title
    		 slowed eGFR decline
    End point description
    Kidney allograft function: The individual course of eGFR shown in attachment
    End point type
    Secondary
    End point timeframe
    51 weeks
    End point values
    		 Clazakizumab Group Placebo
    Number of subjects analysed
    10
    10
    Units: ml/min/mm²
    arithmetic mean (confidence interval 95%)
        Part A eGFR
    -0.96 (-1.96 to 0.03)
    -2.43 (-3.40 to -1.46)
        Part B eGFR
    -0.29 (-0.85 to 0.26)
    -0.64 (-1.13 to -0.14)
    Attachments
    		 Kidney allograft function
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    51 Weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Part A clazakizumab
    Reporting group description
    		 -

    Reporting group title
    Part A Placebo
    Reporting group description
    		 -

    Reporting group title
    Part B clazakizumab
    Reporting group description
    		 -

    Serious adverse events
    		 Part A clazakizumab Part A Placebo Part B clazakizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 10 (10.00%)
    7 / 19 (36.84%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Surgical and medical procedures
    Pleurodesis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Permanent thorax cavity drainage
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticulitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute renal injury
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 19 (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
    		 Part A clazakizumab Part A Placebo Part B clazakizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    10 / 10 (100.00%)
    18 / 19 (94.74%)
    Vascular disorders
    Accelerated hypertension
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 10 (30.00%)
    3 / 19 (15.79%)
         occurrences all number
    2
    3
    3
    Hypotension
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Deep vein thrombosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Thrombophlebitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Surgical and medical procedures
    Mole excision
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    Nasal septum operation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Permanent thorax cavity drainage
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Pleurodesis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Oedema
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 10 (30.00%)
    6 / 19 (31.58%)
         occurrences all number
    2
    3
    6
    Injection site reactions
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    1
    0
    3
    Fatigue
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    1
    2
    Malaise
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Rash
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Dyspnea
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    1
    2
    Cough
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    0
    3
    Chest pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Nasal dryness
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Pleural effusion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Small airway disease
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Sleep disturbance
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    0
    3
    Injury, poisoning and procedural complications
    Transplant biopsy complication
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 10 (20.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    2
    0
    Traumatic bone or joint injury
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Bradycardia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Palpitations
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 10 (30.00%)
    4 / 19 (21.05%)
         occurrences all number
    0
    3
    4
    Numbness
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    2
    1
    Leukopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Otitis media
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Ocular infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 10 (40.00%)
    3 / 10 (30.00%)
    6 / 19 (31.58%)
         occurrences all number
    4
    3
    6
    Abdominal pain
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 10 (30.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    3
    0
    Gastroenenteritis
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 10 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    2
    2
    2
    Nausea and/or vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    2
    Diverticulitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Aphtous ulcer
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    1
    Dry mouth
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Noninfective gingivitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Pancreatic enzyme abnormality
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Erysipela
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Alopecia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Eczema
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Pruritus
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    1
    0
    Blister
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Hirsutism
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Impetigo
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Intertrigo
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Acute renal injury
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Aggravated proteinuria
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Dysuria
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 10 (10.00%)
    3 / 19 (15.79%)
         occurrences all number
    2
    1
    3
    Muscle cramps
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 10 (10.00%)
    1 / 19 (5.26%)
         occurrences all number
    3
    1
    1
    Tenosynovitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 10 (50.00%)
    6 / 10 (60.00%)
    8 / 19 (42.11%)
         occurrences all number
    5
    6
    8
    Urethritis and/or cystitis
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 10 (20.00%)
    3 / 19 (15.79%)
         occurrences all number
    1
    2
    3
    Bronchitis fungal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    0
    0
    4
    Herpes simplex
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    0
    3
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Aseptic meningitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Coxsackie viral infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Ovarian abscess
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Pyelonephritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Skin papilloma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Folate deficiency
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Hyperkalemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    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
    06 Jun 2019
    changes in the protocol

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33443079
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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