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    Clinical Trial Results:
    A multicentre, randomised, open-label, controlled, 12-month follow-up study to assess impact on renal function of an immunosuppression regimen based on tacrolimus minimisation in association with everolimus in de novo liver transplant recipients. The REDUCE study.

    Summary
    EudraCT number
    		 2013-001191-38
    Trial protocol
    		 ES  
    Global end of trial date
    10 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Mar 2018
    First version publication date
    23 Mar 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001HES01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02040584
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111,
    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
    10 Feb 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the course of kidney function from randomisation (Week 4) until the end of the study (Week 52), through the percentage of patients who show clinical benefit, by comparing an immunosuppressive regimen based on minimisation of TAC plus EVR (rTAC+EVR: study group) vs. an immunosuppressive regimen based on the combination of TAC plus MMF (TAC+MMF: control group) in de novo liver-transplant recipients. Clinical benefit is defined as: - an improvement in 1 or 2 ranges of the eGFR, according to MDRD-4 at Week 52 post-transplant in patients with values of 30-<45 or 45-<60 mL/min/1.73 m2 at randomisation. or - stabilization of eGFR in patients with values ≥60 mL/min/1.73 m2 at randomisation and maintained at Week 52 post-transplant.
    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
    20 Dec 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 217
    Worldwide total number of subjects
    217
    EEA total number of subjects
    217
    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)
    173
    From 65 to 84 years
    44
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 291 recipients of a first liver transplant from a cadaver donor were screened, 217 patients were randomised to The safety population included all randomised patients who received at least one dose of the study medication. A total of 215 patients were included in safety population.

    Pre-assignment
    Screening details
    		 The ITT included 211 patients, 1 patient in the EVR group and 3 patients in the TAC group in the safety population were excluded due to missing MDRD-4 values after randomisation.

    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
    		 Experimental group
    Arm description
    		 Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids
    Arm type
    		 Experimental

    Investigational medicinal product name
    EVR
    Investigational medicinal product code
    Other name
    Certican
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1.0 mg tablets (also in 0.25 and 0.5 mg tablets). The EVR tablets should be taken whole, with a glass of water, and not broken before use. The study drug was administered in combination with corticosteroids. TAC minimisation was done, to reach trough levels (C-0h) ≤5 ng/mL no later than four weeks after randomisation and were maintained until Week 52 post-transplant.

    Arm title
    		 Control group
    Arm description
    		 Treatment with TAC + MMF + corticosteroids
    Arm type
    		 Active comparator

    Investigational medicinal product name
    TAC
    Investigational medicinal product code
    Other name
    Prograf, Advagraf
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    capsules of 0.5, 1.0 and 5.0 mg Between Weeks 2 and 3, all patients had to be in treatment with Advagraf in order to have stable levels of TAC prior to randomisation. Patients in treatment with twice-daily doses of Prograf® made the switch to Advagraf administered once daily at a 1:1 ratio (mg:mg), maintaining the total daily dose. Advagraf should be administered in the morning. During the course of the trial, the study medications were administered under a b.i.d. regimen, except for Advagraf, which was administered under a once daily regimen (s.i.d). MMF (CellCept) was provided in the form of capsules of 250-500 mg. The control arm was administered in combination with corticosteroids.

    Number of subjects in period 1 [1]
    		Experimental group Control group
    Started
    105
    106
    Completed
    70
    74
    Not completed
    35
    32
         Adverse event, serious fatal
    6
    3
         Transplant rejection/retransplant
    -
    1
         Adverse event, non-fatal
    13
    6
         Unsatisfactory therapeutic effect
    -
    1
         Immunosuppressant/prohibited med use
    7
    10
         Protocol deviation
    9
    11
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Different population was used for the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Experimental group
    Reporting group description
    		 Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids

    Reporting group title
    Control group
    Reporting group description
    		 Treatment with TAC + MMF + corticosteroids

    Reporting group values
    		 Experimental group Control group Total
    Number of subjects
    		 105 106 211
    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)
    		 77 91 168
        From 65-84 years
    		 28 15 43
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.43 ( 6.37 ) 55.84 ( 7.45 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 14 16 30
        Male
    		 91 90 181

    End points

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    End points reporting groups
    Reporting group title
    Experimental group
    Reporting group description
    		 Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids

    Reporting group title
    Control group
    Reporting group description
    		 Treatment with TAC + MMF + corticosteroids

    Subject analysis set title
    <= 14
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Experimenatl group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score <= 14

    Subject analysis set title
    15 to 19
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Experimenatl group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 15-19

    Subject analysis set title
    20 to 24
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Experimenatl group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 20 to 24

    Subject analysis set title
    25 to 29
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Experimenatl group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 25 to 29

    Subject analysis set title
    > = 30
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Experimenatl group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score > = 30

    Subject analysis set title
    <= 14 Control group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Control group (Treatment with TAC + MMF + corticosteroids) with MELD score <= 14

    Subject analysis set title
    15 to 19 Control group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 15 to 19

    Subject analysis set title
    20 to 24 Control group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 20 to 24

    Subject analysis set title
    25 to 29 Control group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 25 to 29

    Subject analysis set title
    > = 30 Control group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Control group (Treatment with TAC + MMF + corticosteroids) with MELD score > = 30

    Primary: Percentages of participants showing clinical benefit by renal function startification

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    End point title
    		 Percentages of participants showing clinical benefit by renal function startification
    End point description
    Clinical benefit is defined as: • an improvement in 1 or 2 ranges of the eGFR, according to MDRD-4 at Week 52 post-transplant in patients with values of 30-<45 or 45-<60 mL/min/1.73 m2 in Week 4. or • stabilisation of eGFR in patients with values ≥60 mL/min/1.73 m2 at Week 4 and maintained at Week 52 post-transplant.
    End point type
    Primary
    End point timeframe
    week 4, week 52.
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    105
    106
    Units: Percentages of partcipants
    number (not applicable)
        > = 30 - 45 ml/min/1.73m2 at Week 52
    4.76
    3.77
        > = 45 - <60 ml/min/1.73m2 at Week 52
    14.29
    16.04
        > = 60 ml/min/1.73m2 at Week 52
    79.05
    79.25
    Statistical analysis title
    		 Clinical Benefit by Renal Function Startification
    Statistical analysis description
    Null hypothesis (H0): there were no differences in kidney function between the two groups, in contrast with the alternative hypothesis (H1), in which there were differences: HO: CBS = CBC versus H1: CBS ≠ CBC, where CBS and CBC were percentages of patients who showed clinical benefit at Week 52 for the study group and control group, respectively.
    Comparison groups
    Experimental group v Control group
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9423
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Changes in creatinine clearance - Cockcroft-Gault formula

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    End point title
    		 Changes in creatinine clearance - Cockcroft-Gault formula
    End point description
    Kidney function was assessed over time by creatine clearance based on the Cockcroft-Gault formula. Estimated creatinine clearance (mL/min) = [(140 – age) x (weight) x (0.85 if female)] / (72 x serum creatinine). Units: age (years); weight (kg); serum creatinine (mg/dL).
    End point type
    Secondary
    End point timeframe
    Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-trasplant
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    105
    106
    Units: ml/min/1.73m2
    arithmetic mean (standard deviation)
        Screening
    104.67 ( 36.40 )
    109.69 ( 48.47 )
        Week 1
    116.93 ( 44.82 )
    118.09 ( 44.82 )
        Week 4
    80.19 ( 28.00 )
    91.26 ( 37.60 )
        Week 12
    87.76 ( 26.51 )
    90.14 ( 35.82 )
        Week 24
    89.57 ( 32.89 )
    87.93 ( 35.92 )
        Week 36
    94.46 ( 30.26 )
    90.91 ( 35.96 )
        Week 52
    92.21 ( 29.96 )
    91.04 ( 37.26 )
    No statistical analyses for this end point

    Secondary: Changes in eGFR based on the MDRD-4 formula

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    End point title
    		 Changes in eGFR based on the MDRD-4 formula
    End point description
    Kidney function was assessed over time by changes in eGFR according to the MDRD-4 formula. The MDRD-4 formula (Levey et al., 2000) was used based on serum concentration of creatinine (conventional units): eGFR (mL/min/1.73 m2) = 186 x (serum creatinine)-1.154 x (age)-0.203 x (0.742 if female) x (1.210 if of African descent). Units: serum creatinine (mg/dL); age (years).
    End point type
    Secondary
    End point timeframe
    Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-trasplant
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    105
    106
    Units: ml/min/1.73m2
    arithmetic mean (standard deviation)
        Screening
    100.20 ( 38.74 )
    99.42 ( 43.09 )
        Week 1
    112.86 ( 50.06 )
    112.15 ( 48.16 )
        Week 4
    82.18 ( 28.47 )
    88.39 ( 34.32 )
        Week 12
    85.99 ( 25.13 )
    83.57 ( 28.19 )
        Week 24
    86.02 ( 31.97 )
    82.00 ( 26.93 )
        Week 36
    87.68 ( 32.49 )
    83.04 ( 25.56 )
        Week 52
    86.09 ( 27.87 )
    83.23 ( 25.24 )
    No statistical analyses for this end point

    Secondary: eGFR values(MDRD-4 formula) according to the MELD score

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    End point title
    		 eGFR values(MDRD-4 formula) according to the MELD score
    End point description
    Model for End Stage Liver Disease (MELD) score: (≤14, 15-19, 20-24, 25-29, ≥30
    End point type
    Secondary
    End point timeframe
    Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-trasplant
    End point values
    		 <= 14 15 to 19 20 to 24 25 to 29 > = 30 <= 14 Control group 15 to 19 Control group 20 to 24 Control group 25 to 29 Control group > = 30 Control group
    Number of subjects analysed
    52
    25
    21
    5
    1
    56
    24
    18
    3
    4
    Units: ml/min/1.73m2
    median (inter-quartile range (Q1-Q3))
        Screening
    96.63 (76.31 to 119.50)
    90.29 (65.64 to 114.92)
    88.89 (70.03 to 114.67)
    104.45 (93.21 to 123.90)
    38.35 (38.35 to 38.35)
    102.27 (75.09 to 120.19)
    93.85 (73.93 to 123.19)
    91.45 (68.74 to 116.49)
    99.50 (19.76 to 137.89)
    53.73 (38.82 to 66.97)
        Week 1
    114.00 (94.24 to 142.51)
    93.31 (76.61 to 127.75)
    83.45 (66.76 to 114.06)
    137.61 (124.30 to 148.67)
    82.04 (82.04 to 82.04)
    108.64 (83.22 to 138.55)
    92.98 (55.41 to 129.49)
    119.19 (100.53 to 147.60)
    156.41 (29.81 to 184.87)
    86.45 (57.98 to 117.96)
        Week 4
    81.37 (63.46 to 92.20)
    85.19 (66.09 to 99.26)
    70.57 (51.90 to 99.02)
    75.94 (50.93 to 121.86)
    69.43 (69.43 to 69.43)
    89.44 (62.78 to 107.55)
    72.76 (51.64 to 113.93)
    89.67 (63.89 to 133.44)
    85.23 (42.83 to 109.13)
    78.57 (51.47 to 108.61)
        Week 12
    85.81 (64.65 to 98.87)
    88.76 (65.92 to 118.20)
    83.91 (68.46 to 94.96)
    94.82 (50.94 to 106.28)
    56.67 (56.67 to 56.67)
    83.63 (69.33 to 101.35)
    67.00 (48.31 to 99.84)
    87.22 (67.63 to 107.01)
    65.01 (43.15 to 96.53)
    81.92 (58.33 to 87.43)
        Week 24
    80.76 (64.37 to 107.89)
    81.41 (57.22 to 104.86)
    78.88 (62.22 to 94.68)
    84.86 (68.54 to 101.19)
    60.37 (60.37 to 60.37)
    80.01 (66.16 to 97.47)
    70.27 (55.26 to 93.99)
    82.64 (65.25 to 113.80)
    88.34 (30.17 to 104.72)
    62.74 (47.46 to 75.65)
        Week 36
    81.96 (64.82 to 111.44)
    92.44 (68.05 to 113.18)
    75.62 (61.64 to 100.46)
    83.09 (55.72 to 110.46)
    58.07 (58.07 to 58.07)
    86.72 (72.09 to 97.40)
    67.90 (54.34 to 90.95)
    86.17 (68.59 to 107.21)
    68.32 (57.01 to 79.63)
    65.58 (45.11 to 73.55)
        Week 52
    86.14 (66.70 to 101.59)
    88.94 (65.24 to 114.50)
    71.60 (62.48 to 89.66)
    83.94 (60.69 to 107.20)
    53.93 (53.93 to 53.93)
    80.92 (68.98 to 104.03)
    70.32 (54.12 to 82.38)
    90.66 (74.52 to 113.18)
    74.82 (69.00 to 80.63)
    63.26 (45.52 to 79.77)
    No statistical analyses for this end point

    Secondary: Urine protein/creatinine ratio

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    End point title
    		 Urine protein/creatinine ratio
    End point description
    The urine protein/creatinine ratio was assessed throughout follow-up in both treatment groups.
    End point type
    Secondary
    End point timeframe
    Screening visit, week 1,4,18,24, and 52
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    105
    106
    Units: mg/g
    arithmetic mean (standard deviation)
        Screening
    199.89 ( 582.03 )
    131.56 ( 178.95 )
        Week 1
    252.48 ( 308.22 )
    349.46 ( 396.44 )
        Week 4
    134.77 ( 175.05 )
    141.71 ( 187.11 )
        Week 18
    204.26 ( 688.05 )
    105.02 ( 79.61 )
        Week 24
    200.17 ( 466.55 )
    120.52 ( 108.04 )
        Week 52
    219.41 ( 406.52 )
    143.05 ( 220.72 )
    No statistical analyses for this end point

    Secondary: Incidence of proteinuria

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    End point title
    		 Incidence of proteinuria
    End point description
    The incidence of proteinuria (≥0.5-0.9 g/day, ≥1.0-2.9 g/day and ≥3.0 g/day) was assessed throughout follow-up in both treatment groups. Proteinuria was defined as protein/creatinine ration ≥ 0.5.
    End point type
    Secondary
    End point timeframe
    Screening visit, week 1,4,18,24, and 52
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    105
    106
    Units: Percentages of participants
    number (not applicable)
        ≥ 0.5-1.0 g/day at screening
    0.00
    3.77
        ≥ 1.0-3.0 g/day at screening
    2.00
    1.89
        ≥ 3.0 g/day at screening
    2.00
    0.00
        ≥ 0.5-1.0 g/day at Week 1
    3.23
    18.31
        ≥ 1.0-3.0 g/day at Week 1
    6.45
    5.63
        ≥ 3.0 g/day at Week 1
    0.00
    0.00
        ≥ 0.5-1.0 g/day at Week 4
    5.21
    1.05
        ≥ 1.0-3.0 g/day at Week 4
    0.00
    1.05
        ≥ 3.0 g/day at Week 4
    0.00
    0.00
        ≥ 0.5-1.0 g/day at Week 18
    0.00
    0.00
        ≥ 1.0-3.0 g/day at Week 18
    1.39
    0.00
        ≥ 3.0 g/day at Week 18
    1.39
    0.00
        ≥ 0.5-1.0 g/day at Week 24
    7.58
    1.52
        ≥ 1.0-3.0 g/day at Week 24
    0.00
    0.00
        ≥ 3.0 g/day at Week 24
    1.52
    0.00
        ≥ 0.5-1.0 g/day at Week 52
    6.67
    1.89
        ≥ 1.0-3.0 g/day at Week 52
    3.33
    1.89
        ≥ 3.0 g/day at Week 52
    0.00
    0.00
    No statistical analyses for this end point

    Secondary: Incidence of patients with acute rejection, BPAR, and treated BPAR

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    End point title
    		 Incidence of patients with acute rejection, BPAR, and treated BPAR
    End point description
    Liver biopsy had to be performed in all cases where acute rejection was suspected. Results of the biopsy were interpreted by the local pathologist (who did not known the treatment given to the patient) according to the Banff classification (1997). Biopsy-proven acute rejection (BPAR) defined as clinical suspicion of acute rejection confirmed in biopsy. Treated BPAR was deemed to be an episode of acute rejection in which the interpretation of the local pathologist showed that it reached any grade of acute rejection under the Banff classification, and for which anti-rejection therapy was administered. Loss of the liver allograft was deemed to have occurred the day that the patient was again included on the waiting list for liver transplant, the day he or she received another allograft or upon the death of the patient. All suspected hepatic allograft rejections were considered acute rejection
    End point type
    Secondary
    End point timeframe
    Throughout the study period, approximately 3 years
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    105
    106
    Units: Percentages of participants
    number (not applicable)
        Patients with suspected acute rejection
    17.14
    15.09
        Patients with BPAR
    5.71
    3.77
        Patients with treated BPAR
    4.76
    1.89
    No statistical analyses for this end point

    Secondary: Time to rejection

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    End point title
    		 Time to rejection
    End point description
    Time to acute rejection was calculated from the date of transplantation. Acute rejection date was taken from biopsy date, as the date of rejection was not collected. Time to treated BPAR was calculated from the date of transplantation.
    End point type
    Secondary
    End point timeframe
    Throughout study period, approximately 3 years
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    105
    106
    Units: months
    arithmetic mean (standard deviation)
        Time to acute rejection
    3.74 ( 3.15 )
    2.91 ( 2.89 )
        Time to treated BPAR
    2.65 ( 1.50 )
    3.85 ( 5.25 )
    No statistical analyses for this end point

    Secondary: Severity of rejection

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    End point title
    		 Severity of rejection
    End point description
    Severity of acute rejection and treated BPAR was graded according to Banff criteria. Severity grade: mild, moderate, severe.
    End point type
    Secondary
    End point timeframe
    Throughout study period, approximately 3 years
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    105
    106
    Units: Percentages of participants
    number (not applicable)
        Severity of acute rejection: Mild (Grade I)
    13.64
    11.11
        Severity of acute rejection: Moderate(Grade II)
    13.64
    5.56
        Severity of acute rejection: Severe(Grade III)
    0.00
    5.56
        Severity of treated BPAR: Mild (Grade I)
    33.33
    0.00
        Severity of treated BPAR: Moderate(Grade II)
    50.00
    50.00
        Severity of treated BPAR: Severe(Grade III)
    0.00
    50.00
    No statistical analyses for this end point

    Secondary: Percentages of participants with HCV-positive and HCV genotype

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    End point title
    		 Percentages of participants with HCV-positive and HCV genotype
    End point description
    The viral load of HCV-RNA and HCV genotype (describing the genotypes present) was assessed in HCV-positive patients.
    End point type
    Secondary
    End point timeframe
    approxiately 3 years
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    105
    106
    Units: Percentages of participants
    number (not applicable)
        Hepatitis C virus (HVC) positive
    33.33
    36.79
        HCV genotypic 01
    80.00
    76.92
        HCV genotype 02
    0.00
    0.00
        HCV genotype 03
    17.14
    10.26
        HCV genotype 04
    2.86
    2.56
        HCV genotype 05
    0.00
    0.00
        HCV genotype 06
    0.00
    0.00
        HCV genotype 07
    0.00
    0.00
        non-responders
    0.00
    10.26
    No statistical analyses for this end point

    Secondary: Concentration of p-P70S6K

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    End point title
    		 Concentration of p-P70S6K [1]
    End point description
    the biomarker of personal response to everolimus, monitoring of the activity of the target, kinase P70 S6, in its total and phosphorylated form at Thr389
    End point type
    Secondary
    End point timeframe
    week 6,8,12,18,24,36,52
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: no statistical analyses done for this endpoint.
    End point values
    		 Experimental group
    Number of subjects analysed
    74
    Units: ng/ml
    arithmetic mean (standard deviation)
        Cmin EVR week 6
    3.8 ( 1.7 )
        C1h EVR week 6
    6.8 ( 6.3 )
        Cmin EVR week 8
    4.7 ( 1.6 )
        C1h EVR week 8
    9.5 ( 4.9 )
        Cmin EVR week 12
    4.4 ( 1.8 )
        C1h EVR week 12
    16 ( 9.5 )
        Cmin EVR week 18
    6.8 ( 2.7 )
        C1h EVR week 18
    14.6 ( 6.7 )
        Cmin EVR week 24
    5.3 ( 2.13 )
        C1h EVR week 24
    18 ( 7.2 )
        Cmin EVR week 36
    5.1 ( 1.35 )
        C1h EVR week 36
    12.7 ( 4.2 )
        Cmin EVR week 52
    5.35 ( 0.97 )
        C1h EVR week 52
    16.1 ( 7.6 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).  All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Experimental group
    Reporting group description
    		 Experimental group

    Reporting group title
    Control group
    Reporting group description
    		 Control group

    Serious adverse events
    		 Experimental group Control group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    55 / 106 (51.89%)
    48 / 109 (44.04%)
         number of deaths (all causes)
    6
    5
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cholangiocarcinoma
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal cancer
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm of thorax
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary gland neoplasm
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Arterial stenosis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial thrombosis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Steal syndrome
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Bile duct stent removal
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hospitalisation
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 106 (5.66%)
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Strangulated hernia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Liver transplant rejection
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular cyst
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Testicular disorder
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchiectasis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragmatic paralysis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device ineffective
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Biopsy liver
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure increased
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endoscopic retrograde cholangiopancreatography
         subjects affected / exposed
    4 / 106 (3.77%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laboratory test
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic stenosis
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary anastomosis complication
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complications of transplanted liver
         subjects affected / exposed
    3 / 106 (2.83%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver graft loss
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural bile leak
         subjects affected / exposed
    4 / 106 (3.77%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant dysfunction
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ventricular fibrillation
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyskinesia
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 106 (1.89%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukoencephalopathy
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurotoxicity
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 106 (1.89%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Leukopenia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 106 (2.83%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal strangulated hernia
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute abdomen
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    3 / 106 (2.83%)
    4 / 109 (3.67%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 106 (0.94%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dieulafoy's vascular malformation
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Duodenal ulcer
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated umbilical hernia
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    3 / 106 (2.83%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia strangulated
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised intraabdominal fluid collection
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    4 / 106 (3.77%)
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract disorder
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Budd-Chiari syndrome
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    2 / 106 (1.89%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    2 / 106 (1.89%)
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dilatation intrahepatic duct acquired
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic artery stenosis
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic artery thrombosis
         subjects affected / exposed
    2 / 106 (1.89%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic ischaemia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis cholestatic
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Jaundice cholestatic
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal hypertension
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pruritus generalised
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 106 (1.89%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 106 (1.89%)
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal tubular disorder
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder polyp
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus hepatitis
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus oesophagitis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungaemia
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    6 / 106 (5.66%)
    4 / 109 (3.67%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster disseminated
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangitis
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas bronchitis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    5 / 106 (4.72%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 106 (1.89%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 106 (1.89%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Experimental group Control group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    97 / 106 (91.51%)
    105 / 109 (96.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    24 / 106 (22.64%)
    26 / 109 (23.85%)
         occurrences all number
    27
    28
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    11 / 106 (10.38%)
    16 / 109 (14.68%)
         occurrences all number
    11
    19
    Oedema
         subjects affected / exposed
    8 / 106 (7.55%)
    5 / 109 (4.59%)
         occurrences all number
    8
    6
    Oedema peripheral
         subjects affected / exposed
    39 / 106 (36.79%)
    27 / 109 (24.77%)
         occurrences all number
    52
    32
    Pyrexia
         subjects affected / exposed
    15 / 106 (14.15%)
    17 / 109 (15.60%)
         occurrences all number
    19
    22
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    15 / 106 (14.15%)
    17 / 109 (15.60%)
         occurrences all number
    16
    17
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    7 / 106 (6.60%)
    3 / 109 (2.75%)
         occurrences all number
    8
    3
    Insomnia
         subjects affected / exposed
    17 / 106 (16.04%)
    10 / 109 (9.17%)
         occurrences all number
    17
    10
    Investigations
    Transaminases increased
         subjects affected / exposed
    9 / 106 (8.49%)
    6 / 109 (5.50%)
         occurrences all number
    9
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 106 (10.38%)
    12 / 109 (11.01%)
         occurrences all number
    13
    19
    Tremor
         subjects affected / exposed
    13 / 106 (12.26%)
    19 / 109 (17.43%)
         occurrences all number
    14
    23
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    30 / 106 (28.30%)
    36 / 109 (33.03%)
         occurrences all number
    32
    39
    Leukocytosis
         subjects affected / exposed
    6 / 106 (5.66%)
    7 / 109 (6.42%)
         occurrences all number
    8
    7
    Leukopenia
         subjects affected / exposed
    14 / 106 (13.21%)
    10 / 109 (9.17%)
         occurrences all number
    16
    10
    Neutropenia
         subjects affected / exposed
    4 / 106 (3.77%)
    12 / 109 (11.01%)
         occurrences all number
    4
    14
    Thrombocytopenia
         subjects affected / exposed
    24 / 106 (22.64%)
    22 / 109 (20.18%)
         occurrences all number
    27
    23
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    8 / 106 (7.55%)
    11 / 109 (10.09%)
         occurrences all number
    11
    12
    Abdominal pain upper
         subjects affected / exposed
    6 / 106 (5.66%)
    3 / 109 (2.75%)
         occurrences all number
    6
    3
    Ascites
         subjects affected / exposed
    24 / 106 (22.64%)
    17 / 109 (15.60%)
         occurrences all number
    28
    18
    Constipation
         subjects affected / exposed
    13 / 106 (12.26%)
    7 / 109 (6.42%)
         occurrences all number
    14
    10
    Diarrhoea
         subjects affected / exposed
    20 / 106 (18.87%)
    29 / 109 (26.61%)
         occurrences all number
    28
    36
    Ileus paralytic
         subjects affected / exposed
    2 / 106 (1.89%)
    8 / 109 (7.34%)
         occurrences all number
    2
    8
    Vomiting
         subjects affected / exposed
    7 / 106 (6.60%)
    14 / 109 (12.84%)
         occurrences all number
    9
    15
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    22 / 106 (20.75%)
    19 / 109 (17.43%)
         occurrences all number
    23
    20
    Jaundice
         subjects affected / exposed
    2 / 106 (1.89%)
    6 / 109 (5.50%)
         occurrences all number
    2
    6
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    9 / 106 (8.49%)
    8 / 109 (7.34%)
         occurrences all number
    9
    10
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 106 (4.72%)
    6 / 109 (5.50%)
         occurrences all number
    5
    6
    Proteinuria
         subjects affected / exposed
    11 / 106 (10.38%)
    2 / 109 (1.83%)
         occurrences all number
    12
    2
    Renal failure
         subjects affected / exposed
    12 / 106 (11.32%)
    16 / 109 (14.68%)
         occurrences all number
    12
    17
    Renal impairment
         subjects affected / exposed
    9 / 106 (8.49%)
    16 / 109 (14.68%)
         occurrences all number
    11
    19
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    17 / 106 (16.04%)
    13 / 109 (11.93%)
         occurrences all number
    19
    15
    Infections and infestations
    Hepatitis C
         subjects affected / exposed
    6 / 106 (5.66%)
    4 / 109 (3.67%)
         occurrences all number
    6
    4
    Urinary tract infection
         subjects affected / exposed
    6 / 106 (5.66%)
    8 / 109 (7.34%)
         occurrences all number
    6
    10
    Metabolism and nutrition disorders
    Cell death
         subjects affected / exposed
    4 / 106 (3.77%)
    6 / 109 (5.50%)
         occurrences all number
    4
    6
    Decreased appetite
         subjects affected / exposed
    4 / 106 (3.77%)
    6 / 109 (5.50%)
         occurrences all number
    4
    7
    Diabetes mellitus
         subjects affected / exposed
    6 / 106 (5.66%)
    13 / 109 (11.93%)
         occurrences all number
    6
    15
    Dyslipidaemia
         subjects affected / exposed
    11 / 106 (10.38%)
    2 / 109 (1.83%)
         occurrences all number
    11
    2
    Hypercholesterolaemia
         subjects affected / exposed
    13 / 106 (12.26%)
    8 / 109 (7.34%)
         occurrences all number
    13
    8
    Hyperglycaemia
         subjects affected / exposed
    16 / 106 (15.09%)
    17 / 109 (15.60%)
         occurrences all number
    18
    18
    Hyperkalaemia
         subjects affected / exposed
    2 / 106 (1.89%)
    6 / 109 (5.50%)
         occurrences all number
    2
    7
    Hypertriglyceridaemia
         subjects affected / exposed
    6 / 106 (5.66%)
    7 / 109 (6.42%)
         occurrences all number
    6
    7
    Hypomagnesaemia
         subjects affected / exposed
    5 / 106 (4.72%)
    9 / 109 (8.26%)
         occurrences all number
    6
    9

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jul 2013
    The Ethics Reference Committee requested clarifications and changes regarding General-ICF and Biomarkers Substudy-ICF. These changes were included in the Protocol version submitted to Heath Authorities.
    03 Sep 2013
    Calculation of eGFR formula (CKD-EPI) was added Information about the pathology at transplant was grouped according to patients with hepatocellular carcinoma (HCC) or without HCC Some changes in biochemistry parameters and urine analysis were added.
    31 Mar 2014
    HCC diagnosis will be obtained at the inclusion of patient on the waiting list. Some changes in the treatment of patients with hepatitis C were added. Some changes in prohibited medication were implemented. Determination of P70-S6 and cytokines will be done after administration of (15 ml) and 1h after de administration of 15 ml, whenever possible. Infections will be registered in the CRF Infections registry (not in the AEs registry). Weight will not only be determined at screening, also at baseline if conditions permit. Some changes in hematology and biochemistry parameters were added.
    30 May 2014
    Randomisation visit (change in the window period). Change in inclusion criteria for randomisation.
    19 Nov 2014
    Some clarifications were done related to: -The randomisation window period -The recommendation that blood trough levels should be obtained at 5 ± 2 days after a dose change, both for TAC and EVR. -The dose reduction of TAC (experimental group) will be maintained to be performed within 4 weeks post-randomisation.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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