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    Clinical Trial Results:
    A 12-month, open-label, multicenter, randomized, safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) study of two regimens of anti-CD40 monoclonal antibody, CFZ533 vs. standard of care control, in adult de novo liver transplant recipients with a 12-month additional follow-up and a long-term extension (CONTRAIL I)

    Summary
    EudraCT number
    		 2018-001836-24
    Trial protocol
    		 DE   BE   ES   GB   HU   FR   NL   IT  
    Global end of trial date
    20 Apr 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    20 Jul 2024
    First version publication date
    04 Apr 2024
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CCFZ533A2202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03781414
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    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 Apr 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Apr 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Apr 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the rate of composite efficacy failure (Biopsy Proven Acute Rejection (BPAR), graft loss or death) with CFZ533 600 mg and 300 mg regimens compared to TAC Control at Month 12 post-transplantation. The primary objective would be demonstrated, if the composite efficacy failure rate difference between any of the two CFZ533 arms and the TAC arm is below to the pre-defined non-inferiority margin (0.15) with probability >80%. Hence, the primary endpoint was met for CFZ533 300 mg and was not met for CFZ533 600 mg.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Oct 2019
    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
    Argentina: 6
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Czechia: 2
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    United States: 50
    Worldwide total number of subjects
    128
    EEA total number of subjects
    72
    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)
    101
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The patients were enrolled at 3 sites in Argentina, 1 in Belgium, 1 in Czech Republic, 4 in France, 4 in Germany, 1 in Hungary, 1 in Italy, 1 in The Netherlands, 4 in Spain and 9 in United States.

    Pre-assignment
    Screening details
    		 Patients were randomized at a ratio of 2:3:3 to TAC Control (Arm 1) or one of two maintenance regimens of CFZ533: 600 mg CFZ533 subcutaneous (SC) injections every 2 weeks (Arm 2) or 300 mg CFZ533 SC injections every 2 weeks (Arm 3) combined with MMF and CS.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CFZ533 300 mg regimen (CFZ533 300 mg + MMF)
    Arm description
    		 Single loading dose of 30 mg/kg IV on Day 8 (with +/- 2 days window). The SC administration of 300 mg (1 injection of 2 mL CFZ533 at 150 mg/mL) every 2 weeks started on Day 29, in combination with MMF and CS up to EOS.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CFZ533 300 mg
    Investigational medicinal product code
    Other name
    Iscalimab
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe, Solution for injection in pre-filled syringe, Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Single loading dose of 30 mg/kg IV on Day 8 (with +/- 2 days window). The SC administration of 300 mg (1 injection of 2 mL CFZ533 at 150 mg/mL) every 2 weeks started on Day 29, in combination with Mycophenolate mofetil (MMF) + Corticosteroids (CS) up to EOS.

    Arm title
    		 CFZ533 600 mg regimen (CFZ533 600 mg + MMF)
    Arm description
    		 Loading doses of 30 mg/kg IV on Day 8 (with +/- 2 days window), and 15 mg/kg IV on Day 15. The subcutaneous (SC) administration of 600 mg (2 injections of 2 mL CFZ533 at 150 mg/mL) every 2 weeks started on Day 29, in combination with MMF and CS up to EOS.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CFZ533 600 mg
    Investigational medicinal product code
    Other name
    Iscalimab
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe, Solution for injection in pre-filled syringe, Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Loading doses of 30 mg/kg IV on Day 8 (with +/- 2 days window), and 15 mg/kg IV on Day 15. The SC administration of 600 mg (2 injections of 2 mL CFZ533 at 150 mg/mL) every 2 weeks started on Day 29, in combination with Mycophenolate mofetil (MMF) + Corticosteroids (CS) up to EOS.

    Arm title
    		 TAC Control (TAC + MMF)
    Arm description
    		 Tacrolimus (TAC) + Mycophenolate mofetil (MMF) + Corticosteroids (CS) up to End of Study (EOS). Initial TAC target trough were between 5-15 ng/mL during the run-in period. From randomization onwards, the TAC levels were adjusted as per local label.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tacrolimus (TAC) + Mycophenolate mofetil (MMF) + Corticosteroids (CS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe, Solution for injection in pre-filled syringe, Solution for injection/infusion in pre-filled syringe, Tablet
    Routes of administration
    Intravenous use, Subcutaneous use, Oral use
    Dosage and administration details
    Tacrolimus (TAC) + Mycophenolate mofetil (MMF) + Corticosteroids (CS) up to End of Study (EOS). Initial TAC target trough were between 5-15 ng/mL during the run-in period. From randomization onwards, the TAC levels were adjusted as per local label.

    Number of subjects in period 1
    		CFZ533 300 mg regimen (CFZ533 300 mg + MMF) CFZ533 600 mg regimen (CFZ533 600 mg + MMF) TAC Control (TAC + MMF)
    Started
    48
    48
    32
    Safety Set (SAF)
    48
    47
    32
    Completed
    0
    0
    0
    Not completed
    48
    48
    32
         Adverse event, serious fatal
    1
    4
    -
         Physician decision
    2
    -
    1
         Consent withdrawn by subject
    2
    3
    3
         Adverse event, non-fatal
    3
    6
    3
         Study terminated by sponsor
    39
    34
    25
         Lost to follow-up
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CFZ533 300 mg regimen (CFZ533 300 mg + MMF)
    Reporting group description
    		 Single loading dose of 30 mg/kg IV on Day 8 (with +/- 2 days window). The SC administration of 300 mg (1 injection of 2 mL CFZ533 at 150 mg/mL) every 2 weeks started on Day 29, in combination with MMF and CS up to EOS.

    Reporting group title
    CFZ533 600 mg regimen (CFZ533 600 mg + MMF)
    Reporting group description
    		 Loading doses of 30 mg/kg IV on Day 8 (with +/- 2 days window), and 15 mg/kg IV on Day 15. The subcutaneous (SC) administration of 600 mg (2 injections of 2 mL CFZ533 at 150 mg/mL) every 2 weeks started on Day 29, in combination with MMF and CS up to EOS.

    Reporting group title
    TAC Control (TAC + MMF)
    Reporting group description
    		 Tacrolimus (TAC) + Mycophenolate mofetil (MMF) + Corticosteroids (CS) up to End of Study (EOS). Initial TAC target trough were between 5-15 ng/mL during the run-in period. From randomization onwards, the TAC levels were adjusted as per local label.

    Reporting group values
    		 CFZ533 300 mg regimen (CFZ533 300 mg + MMF) CFZ533 600 mg regimen (CFZ533 600 mg + MMF) TAC Control (TAC + MMF) Total
    Number of subjects
    		 48 48 32 128
    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)
    		 36 39 26 101
        From 65-84 years
    		 12 9 6 27
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 56.7 ( 9.94 ) 56.2 ( 6.98 ) 54.0 ( 9.90 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 11 15 8 34
        Male
    		 37 33 24 94
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 45 46 29 120
        Black or African American
    		 3 2 2 7
        Unknown
    		 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    CFZ533 300 mg regimen (CFZ533 300 mg + MMF)
    Reporting group description
    		 Single loading dose of 30 mg/kg IV on Day 8 (with +/- 2 days window). The SC administration of 300 mg (1 injection of 2 mL CFZ533 at 150 mg/mL) every 2 weeks started on Day 29, in combination with MMF and CS up to EOS.

    Reporting group title
    CFZ533 600 mg regimen (CFZ533 600 mg + MMF)
    Reporting group description
    		 Loading doses of 30 mg/kg IV on Day 8 (with +/- 2 days window), and 15 mg/kg IV on Day 15. The subcutaneous (SC) administration of 600 mg (2 injections of 2 mL CFZ533 at 150 mg/mL) every 2 weeks started on Day 29, in combination with MMF and CS up to EOS.

    Reporting group title
    TAC Control (TAC + MMF)
    Reporting group description
    		 Tacrolimus (TAC) + Mycophenolate mofetil (MMF) + Corticosteroids (CS) up to End of Study (EOS). Initial TAC target trough were between 5-15 ng/mL during the run-in period. From randomization onwards, the TAC levels were adjusted as per local label.

    Primary: Percentage of patients with composite event (Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death) over 12 months

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    End point title
    		 Percentage of patients with composite event (Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death) over 12 months
    End point description
    The occurrence of biopsy proven acute rejection (BPAR) was evaluated based on central pathologist evaluation. Graft loss and death was evaluated as per local evaluation.
    End point type
    Primary
    End point timeframe
    Baseline to Month 12
    End point values
    		 CFZ533 300 mg regimen (CFZ533 300 mg + MMF) CFZ533 600 mg regimen (CFZ533 600 mg + MMF) TAC Control (TAC + MMF)
    Number of subjects analysed
    48
    48
    32
    Units: Participants
    8
    12
    3
    Statistical analysis title
    		 Composite event (BPAR, Graft Loss or Death)
    Comparison groups
    CFZ533 600 mg regimen (CFZ533 600 mg + MMF) v TAC Control (TAC + MMF)
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    Method
    Parameter type
    		 Rate difference
    Point estimate
    0.1696
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.0072
         upper limit
    		 0.3276
    Notes
    [1] - The primary objective would be demonstrated, if the composite efficacy failure rate difference between any of the two CFZ533 arms and the TAC arm is less than the pre-defined non-inferiority margin (0.15) with probability >80%.
    Statistical analysis title
    		 Composite event (BPAR, Graft Loss or Death)
    Comparison groups
    CFZ533 300 mg regimen (CFZ533 300 mg + MMF) v TAC Control (TAC + MMF)
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    Method
    Parameter type
    		 Rate difference
    Point estimate
    0.0759
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0729
         upper limit
    		 0.2165
    Notes
    [2] - The primary objective would be demonstrated, if the composite efficacy failure rate difference between any of the two CFZ533 arms and the TAC arm is less than the pre-defined non-inferiority margin (0.15) with probability >80%.

    Secondary: Mean change in estimated Glomerular Filtration Rate (eGFR) from randomization to Month 12

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    End point title
    		 Mean change in estimated Glomerular Filtration Rate (eGFR) from randomization to Month 12
    End point description
    Renal function as measured by estimated Glomerular Filtration Rate (eGFR) was evaluated using the MDRD formula: eGFR = 175 x (serum concentration of creatinine (SCr))-1.154 x (age)-0.203 x 0.742 [if female] x 1.212 [if Black].
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12
    End point values
    		 CFZ533 300 mg regimen (CFZ533 300 mg + MMF) CFZ533 600 mg regimen (CFZ533 600 mg + MMF) TAC Control (TAC + MMF)
    Number of subjects analysed
    48
    48
    32
    Units: mL/min/1.73 m^2
        arithmetic mean (full range (min-max))
    2.05 (-60.4 to 71.5)
    -9.31 (-55.8 to 28.7)
    -14.74 (-104.0 to 20.6)
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment Emergent Adverse Events

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    End point title
    		 Number of Participants with Treatment Emergent Adverse Events
    End point description
    The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs), Deaths due to AEs and TEAEs leading to discontinuation, through the monitoring of relevant clinical and laboratory safety parameters.
    End point type
    Secondary
    End point timeframe
    Baseline up to 14 weeks after last dose of study medication (CFZ533 participants) and until 12 weeks for TAC participants, up to approx. 184 weeks.
    End point values
    		 CFZ533 300 mg regimen (CFZ533 300 mg + MMF) CFZ533 600 mg regimen (CFZ533 600 mg + MMF) TAC Control (TAC + MMF)
    Number of subjects analysed
    48
    47
    32
    Units: Participants
        TEAEs
    48
    44
    32
        TESAEs
    30
    29
    20
        Fatal TESAEs
    1
    4
    0
        TEAEs leading to discontinuation
    14
    17
    8
    No statistical analyses for this end point

    Secondary: Percentage of patients with dose interruptions and permanent discontinuation of study treatment

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    End point title
    		 Percentage of patients with dose interruptions and permanent discontinuation of study treatment
    End point description
    The number and percentage of participants with dose changes (MMF and TAC), dose interruptions (only in cases of ascites drainage), and permanent discontinuation was summarized. In the CFZ533 arms, during the immediate peri and post-transplant period, TAC was given to provide immunological coverage but TAC needed to be completely weaned off by Day 22.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    End point values
    		 CFZ533 300 mg regimen (CFZ533 300 mg + MMF) CFZ533 600 mg regimen (CFZ533 600 mg + MMF) TAC Control (TAC + MMF)
    Number of subjects analysed
    48
    47
    32
    Units: Participants
        CFZ533: Subjects with dose interrupted
    8
    5
    999
        CFZ533: Subjects with permanent d/c of study tx
    2
    3
    999
        TAC: Subjects with dose interrupted
    3
    3
    6
        TAC: Subjects with permanent d/c of study tx
    4
    8
    4
        MMF: Subjects with dose interrupted
    18
    23
    15
        MMF: Subjects with permanent d/c of study tx
    9
    5
    1
    No statistical analyses for this end point

    Post-hoc: All collected deaths

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    End point title
    		 All collected deaths
    End point description
    On-treatment deaths were reported from first dose of study treatment to 14 weeks after last dose of study medication (CFZ533 participants) and until 12 weeks for TAC participants, up to approx. 184 weeks. Post-treatment deaths were collected in the post treatment period from 15 weeks after last dose of study medication (CFZ533 participants, Arms 2 & 3) and from 13 weeks for TAC participants (Arm 1), up to approx. 184 weeks. These are not considered Adverse Events.
    End point type
    Post-hoc
    End point timeframe
    On-treatment deaths: Up to approximately 184 weeks. Post-treatment deaths: Up to approximately 184 weeks.
    End point values
    		 CFZ533 300 mg regimen (CFZ533 300 mg + MMF) CFZ533 600 mg regimen (CFZ533 600 mg + MMF) TAC Control (TAC + MMF)
    Number of subjects analysed
    48
    47
    32
    Units: Participants
        On-treatment deaths
    1
    3
    0
        Post-treatment deaths
    0
    1
    0
        All deaths
    1
    4
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment adverse events and deaths were reported from first dose of study treatment to 14 weeks after last dose of study medication (CFZ533 participants) and until 12 weeks for TAC participants, up to approx. 184 weeks.
    Adverse event reporting additional description
    Any sign or symptom that occurred during the conduct of the trial and safety follow-up. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    CFZ533 300 mg + MMF
    Reporting group description
    		 CFZ533 300 mg + MMF

    Reporting group title
    TAC + MMF
    Reporting group description
    		 TAC + MMF

    Reporting group title
    CFZ533 600 mg + MMF
    Reporting group description
    		 CFZ533 600 mg + MMF

    Serious adverse events
    		 CFZ533 300 mg + MMF TAC + MMF CFZ533 600 mg + MMF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    30 / 48 (62.50%)
    20 / 32 (62.50%)
    29 / 47 (61.70%)
         number of deaths (all causes)
    1
    0
    3
         number of deaths resulting from adverse events
    0
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant peritoneal neoplasm
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (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
    Basal cell carcinoma
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 32 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Haematoma
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 32 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 48 (10.42%)
    0 / 32 (0.00%)
    5 / 47 (10.64%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Chest pain
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (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
    Immune system disorders
    Transplant rejection
         subjects affected / exposed
    4 / 48 (8.33%)
    2 / 32 (6.25%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver transplant rejection
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Graft versus host disease
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Dyspnoea
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 32 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Pulmonary mass
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Respiratory failure
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (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
    Mental status changes
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Liver function test abnormal
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    3 / 47 (6.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carbohydrate antigen 19-9 increased
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 32 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (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
    Anastomotic stenosis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (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
    Biliary anastomosis complication
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 32 (3.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stress fracture
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Seroma
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural bile leak
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (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
    Ulna fracture
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver transplant failure
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 32 (6.25%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Graft loss
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 32 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (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
    Complications of transplanted liver
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Peripancreatic fluid collection
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 32 (3.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (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
    Sinus arrhythmia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (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
    Atrioventricular block
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Nervous system disorders
    Lethargy
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Ischaemic stroke
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 32 (3.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Leukopenia
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 32 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Ascites
         subjects affected / exposed
    2 / 48 (4.17%)
    2 / 32 (6.25%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis noninfective
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Abdominal pain upper
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Abdominal pain
         subjects affected / exposed
    2 / 48 (4.17%)
    1 / 32 (3.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diaphragmatic hernia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Salivary gland calculus
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Pancreatitis acute
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Large intestine perforation
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (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
    Inguinal hernia strangulated
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Incarcerated umbilical hernia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (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
    Salivary gland enlargement
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Haematochezia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         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 haemorrhage
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (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
    Diarrhoea
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Small intestinal obstruction
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (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
    Vomiting
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Varices oesophageal
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Hepatobiliary disorders
    Hepatic artery stenosis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biloma
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Biliary tract disorder
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary ischaemia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (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
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hepatitis cholestatic
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Hepatic haemorrhage
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic haematoma
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Hepatic artery thrombosis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic mass
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Rash
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Petechiae
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal cyst ruptured
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Acute kidney injury
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis bacterial
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Abscess
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    4 / 48 (8.33%)
    2 / 32 (6.25%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus hepatitis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Cytomegalovirus infection
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 32 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterococcal infection
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Escherichia sepsis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Herpes zoster disseminated
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    2 / 48 (4.17%)
    1 / 32 (3.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (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
    Wound infection
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxoplasmosis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Subcutaneous abscess
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (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
    Sepsis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Pyelonephritis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Pneumonia cytomegaloviral
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Pneumonia
         subjects affected / exposed
    2 / 48 (4.17%)
    1 / 32 (3.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (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
    Hypokalaemia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    0 / 47 (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
    Hyponatraemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (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
    Hyperglycaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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
    		 CFZ533 300 mg + MMF TAC + MMF CFZ533 600 mg + MMF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 48 (93.75%)
    30 / 32 (93.75%)
    42 / 47 (89.36%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 48 (6.25%)
    6 / 32 (18.75%)
    3 / 47 (6.38%)
         occurrences all number
    3
    6
    3
    Hypotension
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 32 (3.13%)
    2 / 47 (4.26%)
         occurrences all number
    3
    1
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 48 (10.42%)
    5 / 32 (15.63%)
    5 / 47 (10.64%)
         occurrences all number
    7
    6
    5
    Oedema peripheral
         subjects affected / exposed
    12 / 48 (25.00%)
    4 / 32 (12.50%)
    6 / 47 (12.77%)
         occurrences all number
    12
    4
    6
    Peripheral swelling
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 32 (6.25%)
    1 / 47 (2.13%)
         occurrences all number
    1
    2
    1
    Pyrexia
         subjects affected / exposed
    7 / 48 (14.58%)
    5 / 32 (15.63%)
    8 / 47 (17.02%)
         occurrences all number
    22
    5
    24
    Asthenia
         subjects affected / exposed
    2 / 48 (4.17%)
    3 / 32 (9.38%)
    2 / 47 (4.26%)
         occurrences all number
    2
    3
    2
    Immune system disorders
    Liver transplant rejection
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 32 (6.25%)
    1 / 47 (2.13%)
         occurrences all number
    1
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    5 / 48 (10.42%)
    3 / 32 (9.38%)
    2 / 47 (4.26%)
         occurrences all number
    5
    5
    2
    Dyspnoea
         subjects affected / exposed
    4 / 48 (8.33%)
    3 / 32 (9.38%)
    5 / 47 (10.64%)
         occurrences all number
    5
    3
    6
    Cough
         subjects affected / exposed
    7 / 48 (14.58%)
    0 / 32 (0.00%)
    5 / 47 (10.64%)
         occurrences all number
    9
    0
    7
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 48 (12.50%)
    3 / 32 (9.38%)
    3 / 47 (6.38%)
         occurrences all number
    6
    3
    3
    Anxiety
         subjects affected / exposed
    5 / 48 (10.42%)
    2 / 32 (6.25%)
    3 / 47 (6.38%)
         occurrences all number
    5
    2
    3
    Alcoholism
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    1
    0
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 32 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    2
    0
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    6 / 48 (12.50%)
    1 / 32 (3.13%)
    6 / 47 (12.77%)
         occurrences all number
    6
    1
    6
    Blood creatinine increased
         subjects affected / exposed
    1 / 48 (2.08%)
    4 / 32 (12.50%)
    0 / 47 (0.00%)
         occurrences all number
    1
    4
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 32 (3.13%)
    2 / 47 (4.26%)
         occurrences all number
    4
    1
    3
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 32 (6.25%)
    4 / 47 (8.51%)
         occurrences all number
    1
    3
    4
    Liver function test increased
         subjects affected / exposed
    8 / 48 (16.67%)
    2 / 32 (6.25%)
    4 / 47 (8.51%)
         occurrences all number
    11
    2
    6
    Weight increased
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    1
    0
    3
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 32 (6.25%)
    1 / 47 (2.13%)
         occurrences all number
    0
    2
    1
    Overdose
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 32 (6.25%)
    0 / 47 (0.00%)
         occurrences all number
    0
    2
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 32 (0.00%)
    4 / 47 (8.51%)
         occurrences all number
    2
    0
    4
    Palpitations
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 32 (6.25%)
    1 / 47 (2.13%)
         occurrences all number
    0
    2
    1
    Nervous system disorders
    Syncope
         subjects affected / exposed
    4 / 48 (8.33%)
    0 / 32 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    4
    0
    1
    Headache
         subjects affected / exposed
    5 / 48 (10.42%)
    7 / 32 (21.88%)
    10 / 47 (21.28%)
         occurrences all number
    6
    8
    11
    Tremor
         subjects affected / exposed
    5 / 48 (10.42%)
    7 / 32 (21.88%)
    6 / 47 (12.77%)
         occurrences all number
    6
    9
    6
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    14 / 48 (29.17%)
    4 / 32 (12.50%)
    10 / 47 (21.28%)
         occurrences all number
    18
    4
    12
    Lymphopenia
         subjects affected / exposed
    2 / 48 (4.17%)
    1 / 32 (3.13%)
    5 / 47 (10.64%)
         occurrences all number
    2
    1
    5
    Leukopenia
         subjects affected / exposed
    17 / 48 (35.42%)
    9 / 32 (28.13%)
    16 / 47 (34.04%)
         occurrences all number
    20
    11
    20
    Anaemia
         subjects affected / exposed
    4 / 48 (8.33%)
    4 / 32 (12.50%)
    5 / 47 (10.64%)
         occurrences all number
    4
    4
    5
    Thrombocytopenia
         subjects affected / exposed
    0 / 48 (0.00%)
    3 / 32 (9.38%)
    3 / 47 (6.38%)
         occurrences all number
    0
    3
    3
    Eye disorders
    Vision blurred
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 32 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    3
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    6 / 48 (12.50%)
    3 / 32 (9.38%)
    1 / 47 (2.13%)
         occurrences all number
    7
    3
    2
    Vomiting
         subjects affected / exposed
    7 / 48 (14.58%)
    4 / 32 (12.50%)
    3 / 47 (6.38%)
         occurrences all number
    11
    5
    3
    Nausea
         subjects affected / exposed
    8 / 48 (16.67%)
    5 / 32 (15.63%)
    4 / 47 (8.51%)
         occurrences all number
    10
    7
    8
    Intra-abdominal fluid collection
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 32 (6.25%)
    1 / 47 (2.13%)
         occurrences all number
    1
    3
    1
    Diarrhoea
         subjects affected / exposed
    12 / 48 (25.00%)
    9 / 32 (28.13%)
    8 / 47 (17.02%)
         occurrences all number
    15
    9
    12
    Constipation
         subjects affected / exposed
    6 / 48 (12.50%)
    4 / 32 (12.50%)
    4 / 47 (8.51%)
         occurrences all number
    7
    4
    4
    Abdominal pain upper
         subjects affected / exposed
    5 / 48 (10.42%)
    1 / 32 (3.13%)
    5 / 47 (10.64%)
         occurrences all number
    5
    2
    5
    Abdominal pain
         subjects affected / exposed
    5 / 48 (10.42%)
    8 / 32 (25.00%)
    7 / 47 (14.89%)
         occurrences all number
    6
    10
    7
    Ascites
         subjects affected / exposed
    8 / 48 (16.67%)
    3 / 32 (9.38%)
    2 / 47 (4.26%)
         occurrences all number
    11
    4
    2
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 32 (0.00%)
    4 / 47 (8.51%)
         occurrences all number
    3
    0
    4
    Cholangitis
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 32 (6.25%)
    1 / 47 (2.13%)
         occurrences all number
    1
    2
    1
    Portal vein stenosis
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 32 (6.25%)
    0 / 47 (0.00%)
         occurrences all number
    1
    2
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 48 (4.17%)
    4 / 32 (12.50%)
    2 / 47 (4.26%)
         occurrences all number
    3
    6
    3
    Night sweats
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    1
    0
    3
    Actinic keratosis
         subjects affected / exposed
    0 / 48 (0.00%)
    3 / 32 (9.38%)
    0 / 47 (0.00%)
         occurrences all number
    0
    3
    0
    Rash
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 32 (3.13%)
    5 / 47 (10.64%)
         occurrences all number
    3
    1
    5
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 32 (6.25%)
    0 / 47 (0.00%)
         occurrences all number
    0
    2
    0
    Proteinuria
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 32 (6.25%)
    1 / 47 (2.13%)
         occurrences all number
    0
    2
    1
    Haematuria
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 32 (6.25%)
    1 / 47 (2.13%)
         occurrences all number
    0
    2
    1
    Dysuria
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 32 (3.13%)
    1 / 47 (2.13%)
         occurrences all number
    4
    1
    1
    Acute kidney injury
         subjects affected / exposed
    2 / 48 (4.17%)
    3 / 32 (9.38%)
    0 / 47 (0.00%)
         occurrences all number
    3
    6
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    2 / 48 (4.17%)
    2 / 32 (6.25%)
    2 / 47 (4.26%)
         occurrences all number
    2
    2
    2
    Muscle spasms
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 32 (6.25%)
    1 / 47 (2.13%)
         occurrences all number
    0
    2
    1
    Flank pain
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 32 (3.13%)
    3 / 47 (6.38%)
         occurrences all number
    0
    1
    3
    Back pain
         subjects affected / exposed
    8 / 48 (16.67%)
    4 / 32 (12.50%)
    5 / 47 (10.64%)
         occurrences all number
    8
    4
    5
    Arthralgia
         subjects affected / exposed
    9 / 48 (18.75%)
    2 / 32 (6.25%)
    6 / 47 (12.77%)
         occurrences all number
    11
    2
    6
    Infections and infestations
    COVID-19
         subjects affected / exposed
    15 / 48 (31.25%)
    8 / 32 (25.00%)
    15 / 47 (31.91%)
         occurrences all number
    15
    10
    16
    Cellulitis
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 32 (6.25%)
    0 / 47 (0.00%)
         occurrences all number
    0
    2
    0
    Cystitis
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 32 (9.38%)
    2 / 47 (4.26%)
         occurrences all number
    2
    3
    2
    Cytomegalovirus infection
         subjects affected / exposed
    8 / 48 (16.67%)
    4 / 32 (12.50%)
    5 / 47 (10.64%)
         occurrences all number
    8
    4
    8
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    2 / 48 (4.17%)
    2 / 32 (6.25%)
    5 / 47 (10.64%)
         occurrences all number
    7
    5
    8
    Cytomegalovirus viraemia
         subjects affected / exposed
    5 / 48 (10.42%)
    2 / 32 (6.25%)
    6 / 47 (12.77%)
         occurrences all number
    10
    2
    7
    Nasopharyngitis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 32 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    1
    0
    3
    Oral herpes
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 32 (6.25%)
    1 / 47 (2.13%)
         occurrences all number
    0
    2
    1
    Sinusitis
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 32 (6.25%)
    0 / 47 (0.00%)
         occurrences all number
    0
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 32 (6.25%)
    1 / 47 (2.13%)
         occurrences all number
    1
    2
    1
    Urinary tract infection
         subjects affected / exposed
    4 / 48 (8.33%)
    7 / 32 (21.88%)
    4 / 47 (8.51%)
         occurrences all number
    9
    8
    6
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 32 (6.25%)
    1 / 47 (2.13%)
         occurrences all number
    0
    2
    1
    Iron deficiency
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 32 (3.13%)
    0 / 47 (0.00%)
         occurrences all number
    3
    1
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 32 (3.13%)
    3 / 47 (6.38%)
         occurrences all number
    1
    1
    4
    Hypokalaemia
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 32 (3.13%)
    3 / 47 (6.38%)
         occurrences all number
    4
    1
    3
    Hypoglycaemia
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 32 (9.38%)
    1 / 47 (2.13%)
         occurrences all number
    1
    5
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 32 (0.00%)
    6 / 47 (12.77%)
         occurrences all number
    0
    0
    8
    Hyperkalaemia
         subjects affected / exposed
    2 / 48 (4.17%)
    4 / 32 (12.50%)
    2 / 47 (4.26%)
         occurrences all number
    2
    5
    2
    Hyperglycaemia
         subjects affected / exposed
    2 / 48 (4.17%)
    2 / 32 (6.25%)
    2 / 47 (4.26%)
         occurrences all number
    2
    2
    2
    Decreased appetite
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 32 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    2
    0
    3
    Cell death
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 32 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    3
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jul 2019
    Amendment 1 introduced optional liver biopsies to explore the effect of the study drugs on histology of the liver over time up to 12 months after transplant.
    05 Mar 2020
    Amendment 2 clarified that the stopping rule for biopsy proven acute rejection is based on moderate and severe events (Rejection Activity Index (RAI) >= 6) evaluated by a blinded central pathologist; introduced the change of the screening period from 6 months to 2 months; increased the visit window for the randomization visit at Day 8 from +/- 1 to +/- 2 days; and clarified inclusion/exclusion criteria.
    20 Aug 2020
    Amendment 3 introduced pre-filled syringes (PFS) to allow for self-administration after Month 12 visit, to offer more flexibility and improve adherence; and added three inclusion/exclusion criteria. The protocol amendment 3 also changed the LPLV date as at time of last EOS visit. However, per GCP the LPLV has to be at the end of the safety-FU period. For this reason, the LPLV date was changed to the end of safety-FU period.
    05 Mar 2021
    Amendment 4 allowed to increase the study duration by adding an extension period to collect long-term data in a controlled, clinical trial setting; clarified one exclusion criterion (history of coagulopathy); and added a new exclusion criterion (exclude donors with confirmed history of SARS-CoV-2 infection).

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete trial results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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