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    Clinical Trial Results:
    Clinical and laboratory evaluation of acute rejection, myocyte growth, repair and oxidative stress following de novo cardiac transplant: A comparison between Tacrolimus and Cyclosporine based immunoprophylactic regimens with mycophenolic acid therapeutic drug monitoring.

    Summary
    EudraCT number
    2015-001041-83
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    18 Jul 2008

    Results information
    Results version number
    v3(current)
    This version publication date
    20 May 2017
    First version publication date
    25 Jul 2015
    Other versions
    v1 , v2
    Version creation reason
    • Correction of full data set
    Results updated for consistency.

    Trial information

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    Trial identification
    Sponsor protocol code
    FKC-009
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00157014
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Inc
    Sponsor organisation address
    675 Cochrane Drive, Suite 500, Markham, Canada,
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Canada, Inc, Astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Canada, Inc, Astellas.resultsdisclosure@astellas.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?
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Jul 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jul 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jul 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to investigate changes in subcellular markers of growth, apoptosis, differentiation, survival, inflammation, and oxidative stress, in relationship with cellular acute rejection, in de novo cardiac transplant recipients receiving either tacrolimus or cyclosporine (CsA) as the primary immunosuppressant.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, ICH GCP Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    All patients received induction therapy per institutional protocol and adjunctive immunosuppression with mycophenolate mofetil (MMF). Study treatments (tacrolimus and CsA) were administered continuously beginning no earlier than pre-transplant and no later than 10 days post-transplant. Mycophenolate mofetil (MMF) was administered peri-operatively in a pre-operative dose of 1.0 g IV/PO. The post-operative dose of MMF was given within 6 hours of transplantation at 1.0g IV/P for one week post-transplant and then 1.0g PO BID throughout the study period. Methylprednisolone was administered pre-operatively for adult patients and intra-operatively for paediatric patients. Prednisone was administered daily and was tapered slowly throughout the study. It was administered orally daily in Weeks 1 to 4: 20 mg; Week 8: 10 mg ; Week 12: 7.5 mg ; Weeks 16 to 26: 5 mg ; Weeks 27 to 52; 0-5 mg. Prednisone was discontinued after Week 26 according to the investigator’s clinical judgment. During the study, all patients were treated with statins to control lipid profiles. The drug pravastatin and simvastatin were recommended as first-line statin therapy. Patients also received antihypertensive therapy with angiotensin-converting enzyme (ACE) inhibitors as standard per protocol medical management or prophylaxis of calcineurin inhibitor-induced hypertension. Patients also received ganciclovir either orally or IV for cytomegalovirus (CMV) prophylaxis at the discretion of the investigator.
    Evidence for comparator
    Tacrolimus (Tac, FK506) and cyclosporine (CsA) have played a major role in the control of acute rejection (AR) in all organ transplants. Tacrolimus-based immunoprophylaxis resulted in 50% less development of hypertension, lower cholesterol and low-density lipoprotein (LDL) - cholesterol, and better preservation of renal function in both cardiac and renal transplant recipients. The dosing of CsA, MMF, and corticosteroids was based on current standards of practice for the use of these products in immunoprophylaxis of cardiac transplant patients.
    Actual start date of recruitment
    10 May 2004
    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
    United States: 18
    Country: Number of subjects enrolled
    Canada: 93
    Worldwide total number of subjects
    111
    EEA total number of subjects
    0
    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)
    2
    Children (2-11 years)
    5
    Adolescents (12-17 years)
    4
    Adults (18-64 years)
    90
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Adult and pediatric (from birth) male and female de novo recipients of cadaveric heart transplants.

    Pre-assignment
    Screening details
    Screening (pre-transplant) period was Day -180 to -1;transplant was Day 0;Randomization conducted Days 0-10 post-transplant;133 adults were screened;100 were randomized and 17 pediatric participants were screened; 11 randomized.Patients were assigned treatment with either tacrolimus or cyclosporine in a 1:1 ratio within 10 days post-transplantatio

    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
    No

    Arm title
    Tacrolimus - Adult
    Arm description
    Adult primary cadaveric heart transplant recipients randomized to immunosuppression with Tacrolimus 0.05 – 0.10 mg/ kg/ day administered orally in 2 divided doses starting within 10 days of transplant.
    Arm type
    Experimental

    Investigational medicinal product name
    Tacrolimus-Adult Dose
    Investigational medicinal product code
    FK506
    Other name
    Prograf®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Adult Dose: Tacrolimus 0.05 to 0.10 mg/kg/day in 2 divided doses starting within 10 days of transplant supplied as 5-, 1-, or 0.5-mg capsules. Tacrolimus was administered on an empty stomach, 1 hour before or 2 hours after meals. Study treatments were administered continuously beginning no earlier than pre-transplant and no later than 10 days post-transplant.In the event that therapeutic levels could not be achieved with oral capsules in the immediate post-operative period, use of commercially–obtained tacrolimus intravenous (IV) solution (Prograf® IV 5mg/mL) was permitted.

    Arm title
    Cyclosporine – Adult
    Arm description
    Adult primary cadaveric heart transplant recipients randomized to immunosuppression with Cyclosporine 3-5 mg/kg/day administered orally in 2 divided doses starting within 10 days of transplant.
    Arm type
    Experimental

    Investigational medicinal product name
    Cyclosporine-Adult
    Investigational medicinal product code
    Other name
    Neoral
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Adult Dose: Starting within 10 days of transplant supplied as 10-, 25-, 50-, or 100-mg capsules. Study treatments were administered continuously beginning no earlier than pre-transplant and no later than 10 days post-transplant. In the event that therapeutic levels could not be achieved with oral capsules in the immediate post-operative period, use of commercially–obtained CsA IV solution (Sandimmune® IV 50 mg/mL) was permitted.

    Arm title
    Tacrolimus – Pediatric
    Arm description
    Pediatric primary cadaveric heart transplant transplant recipients randomized to immunosuppression with Tacrolimus 0.05-0.30 mg/kg/day administered orally in 2 or 3 divided doses starting within 10 days of transplant.
    Arm type
    Experimental

    Investigational medicinal product name
    Tacrolimus-Pediatric Dose
    Investigational medicinal product code
    FK506
    Other name
    Prograf®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Pediatric Dose: Oral Prograf® 0.05-0.30 mg/kg/day was given in two divided doses, beginning no earlier than pre-transplant and no later than day 10 post-transplant. Tacrolimus was administered on an empty stomach, 1 hour before or 2 hours after meals. Tacrolimus may have been administered via nasogastric tube. Intravenous administration of tacrolimus should have been undertaken only when therapeutic levels could be achieved via oral and enteric routes. Intravenous dosing of tacrolimus, if required, is by administration as a continuous 24-hour infusion. Tacrolimus IV solution should be diluted in 0.9% sodium chloride or 5% dextrose for injection and stored in a glass bottle or non-polyvinyl chloride (PVC) bag for no longer than 24 hours prior to infusion. Dose decreases for mild intolerance should be based on balancing other clinical assessments, e.g., acute rejection.

    Arm title
    Cyclosporine – Pediatric
    Arm description
    Pediatric primary cadaveric heart transplant transplant recipients randomized to immunosuppression with Cyclosporine 6-10 mg/kg/day in 2 or 3 divided doses starting within 10 days of transplant.
    Arm type
    Active comparator

    Investigational medicinal product name
    Cyclosporine - Pediatric Dose
    Investigational medicinal product code
    Other name
    Neoral®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Pediatric Dose: Pediatric patients: Administration of the Neoral® form of cyclosporine must start within the first 10 days post transplant. It will be given at a starting dose of 6-10 mg/kg per day orally in 2 or 3 divided doses based on actual body weight unless the patient has significant renal dysfunction. The dose will subsequently be adjusted to achieve the targeted blood levels. Intravenous dosing of cyclosporine, if required, is to be initiated as a continuous 24-hour infusion of 1-2 mg/kg over 24 hours. For IV administration 1 mg/kg of IV cyclosporine should be diluted in 0.9% sodium chloride for injection or 5% dextrose for injection and stored in a glass bottle for no greater than 24 hours prior to infusion. The cyclosporine dose should be decreased in the presence of adverse events as clinically warranted. Dose decreases for mild intolerance should be based on balancing other clinical assessments, for example, acute rejection.

    Number of subjects in period 1
    Tacrolimus - Adult Cyclosporine – Adult Tacrolimus – Pediatric Cyclosporine – Pediatric
    Started
    52
    46
    5
    6
    Completed
    45
    41
    4
    5
    Not completed
    7
    5
    1
    1
         Death
    4
    2
    1
    1
         Physician Discretion
    -
    1
    -
    -
         Medications withdrawn on request of family
    -
    1
    -
    -
         Patient withdrawn at investigator's discretion
    1
    -
    -
    -
         Patient living in a nursing home unable to return
    1
    -
    -
    -
         Patient would not have received transplant
    -
    1
    -
    -
         Consent withdrawn by subject
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Overall Study
    Reporting group description
    -

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Two patients randomized to study treatment were excluded from the ITT (adult) population. One patient was randomized to Tacrolimus but received Cyclosporine by the internal cardiologist without a waiver and the other patient died follwing transplant due to multi-organ failure.
    Reporting group values
    Overall Study Total
    Number of subjects
    109 109
    Age, Customized
    Units: Participants
        0 - ˂ 2 Years
    2 2
        2 - 10 Years
    3 3
        10 - ˂ 18 Years
    6 6
        18 - 49 Years
    32 32
        50 - 59 Years
    33 33
        60 - 69 Years
    30 30
        70 Years and Older
    3 3
    Gender categorical
    Units: Subjects
        Female
    27 27
        Male
    82 82
    Race / Ethnicity
    Units: Subjects
        European descent/ White
    97 97
        Black
    7 7
        East Indian
    3 3
        Latin American
    1 1
        Aboriginal
    1 1

    End points

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    End points reporting groups
    Reporting group title
    Tacrolimus - Adult
    Reporting group description
    Adult primary cadaveric heart transplant recipients randomized to immunosuppression with Tacrolimus 0.05 – 0.10 mg/ kg/ day administered orally in 2 divided doses starting within 10 days of transplant.

    Reporting group title
    Cyclosporine – Adult
    Reporting group description
    Adult primary cadaveric heart transplant recipients randomized to immunosuppression with Cyclosporine 3-5 mg/kg/day administered orally in 2 divided doses starting within 10 days of transplant.

    Reporting group title
    Tacrolimus – Pediatric
    Reporting group description
    Pediatric primary cadaveric heart transplant transplant recipients randomized to immunosuppression with Tacrolimus 0.05-0.30 mg/kg/day administered orally in 2 or 3 divided doses starting within 10 days of transplant.

    Reporting group title
    Cyclosporine – Pediatric
    Reporting group description
    Pediatric primary cadaveric heart transplant transplant recipients randomized to immunosuppression with Cyclosporine 6-10 mg/kg/day in 2 or 3 divided doses starting within 10 days of transplant.

    Subject analysis set title
    Tacrolimus - Pediatric
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant

    Subject analysis set title
    Cyclosporine – Pediatric
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant

    Subject analysis set title
    Cyclosporine - Adult
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant

    Subject analysis set title
    Tacrolimus – Adult
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Adults: 0.05 – 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant

    Primary: The change in the markers of growth, apoptosis, inflammation and oxidation measured in endomyocardial biopsies (TE)

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    End point title
    The change in the markers of growth, apoptosis, inflammation and oxidation measured in endomyocardial biopsies (TE) [1] [2]
    End point description
    The markers assessed were p-ERK ½ (phosphorylated extracellular signal-regulated kinase), p-JNK (phosphorylated jun N-terminal kinase) and p-p38 MAPK (phosphorylated mitogen-activated protein kinase). The data for each biopsy marker were expressed as a ratio of its densitometry / densitometry of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Change is defined as Week 52 assessment- Week 2 assessment. The number of participants analyzed per arm represents Treatment Exposure (TE) Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each marker is noted in the category titles, as "N".
    End point type
    Primary
    End point timeframe
    2 Weeks and 52 Weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    [2] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: Densitometry / Densitometry of GAPDH
    arithmetic mean (standard deviation)
        p-ERK ½ - Week 2 (N=36; 37)
    0.7 ± 0.5
    0.9 ± 0.641
        p-ERK ½ - Week 52 (N=30; 27)
    0.87 ± 0.539
    0.79 ± 0.674
        p-ERK ½ - Change from Week 2 (N=26; 25)
    0.05 ± 0.834
    -0.05 ± 0.662
        p-JNK - Week 2 (N=36; 37)
    1.1 ± 0.813
    1.23 ± 0.722
        p-JNK - Week 52 (N=30; 27)
    1.33 ± 0.89
    1.46 ± 0.792
        p-JNK - Change from Week 2 (N=26; 25)
    0.03 ± 1.188
    0.22 ± 0.957
        p-p38 MAPK - Week 2 (N=35; 37)
    0.48 ± 0.45
    0.54 ± 0.556
        p-p38 MAPK - Week 52 (N=28; 27)
    0.63 ± 0.664
    0.77 ± 0.717
        p-p38 MAPK - Change from Week 2 (N=25; 25)
    0.14 ± 0.733
    0.23 ± 0.828
    No statistical analyses for this end point

    Primary: The change in the markers of growth, apoptosis, inflammation and oxidation measured in endomyocardial biopsies (Pediatric Population)

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    End point title
    The change in the markers of growth, apoptosis, inflammation and oxidation measured in endomyocardial biopsies (Pediatric Population) [3] [4]
    End point description
    The markers assessed were p-ERK ½, p-JNK and p-p38 MAPK.The data for each biopsy marker were expressed as a ratio of its densitometry / densitometry of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Change is defined as Week 52 assessment- Week 2 assessment. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each marker is noted in the category titles, as "N".
    End point type
    Primary
    End point timeframe
    2 Weeks and 52 Weeks
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.
    [4] - 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: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.
    End point values
    Tacrolimus – Pediatric Cyclosporine – Pediatric
    Number of subjects analysed
    5
    6
    Units: Densitometry / Densitometry of GAPDH
    arithmetic mean (standard deviation)
        p-ERK ½ - Week 2 (N=3; 5)
    1.74 ± 0.972
    1.67 ± 0.682
        p-ERK ½ - Week 52 (N= 2; 4)
    0.93 ± 0.184
    1.22 ± 0.633
        p-ERK ½ - Change from Week 2 (N= 1; 3)
    -0.09 ± 0
    -0.27 ± 0.309
        p-JNK - Week 2 (N=3; 5)
    1.17 ± 0.42
    0.91 ± 0.43
        p-JNK - Week 52 (N= 2; 4)
    0.57 ± 0.085
    0.82 ± 0.537
        p-JNK - Change from Week 2 (N=1; 3)
    -0.21 ± 0
    0.04 ± 0.189
        p-p38 MAPK - Week 2 (N=3; 5)
    0.83 ± 0.467
    0.43 ± 0.364
        p-p38 MAPK - Week 52 (N=2; 4)
    0.24 ± 0.014
    0.58 ± 0.432
        p-p38 MAPK - Change from Week 2 (N=1; 3)
    -0.04 ± 0
    0.34 ± 0.63
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: MCP-1 (TE)

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    End point title
    Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: MCP-1 (TE) [5]
    End point description
    Change is defined as Week 52 assessment – Pre-Transplant assessment. MCP-1= monocyte chemoattractant protein-1. The number of participants analyzed per arm represents Treatment Exposure (TE) Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [5] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: pg/mL
    arithmetic mean (standard deviation)
        Pre-Transplant (N=48; 44)
    233.05 ± 292.832
    193.63 ± 144.696
        Week 52 (N=42; 40)
    229.96 ± 263.084
    180.9 ± 145.067
        Change from Pre-Transplant at Week 52 (N=42; 40)
    42.92 ± 165.517
    -16.49 ± 126.586
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: s-ICAM (TE)

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    End point title
    Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: s-ICAM (TE) [6]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment. s-ICAM= soluble-intracellular adhesion molecule. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [6] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: ng/mL
    arithmetic mean (standard deviation)
        Pre-Transplant (N= 50; 45)
    766.58 ± 449.572
    674.46 ± 429.036
        Week 52 (N= 41; 40)
    590.3 ± 369.942
    503.71 ± 305.531
        Change from Pre-Transplant at Week 52 (N= 41; 40)
    -227.58 ± 366.136
    -183.96 ± 250.382
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: E-selectin (TE)

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    End point title
    Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: E-selectin (TE) [7]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [7] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: ng/mL
    arithmetic mean (standard deviation)
        Pre-Transplant (N= 50; 43)
    90.4 ± 72.801
    98.96 ± 89.153
        Week 52 (N= 41; 40)
    68.6 ± 51.911
    80.93 ± 70.383
        Change from Pre-Transplant at Week 52 (N= 41; 40)
    -18.58 ± 48.247
    -19.16 ± 52.08
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Homocysteine (TE)

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    End point title
    Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Homocysteine (TE) [8]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [8] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: μmol/L
    arithmetic mean (standard deviation)
        Pre-Transplant (N= 50; 44)
    14.2 ± 6.94
    15.9 ± 6.97
        Week 52 (N= 40; 40)
    13.5 ± 4.19
    15.8 ± 5.33
        Change from Pre-Transplant at Week 52 (N= 40; 40)
    0.3 ± 5.02
    0.7 ± 7.61
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: hsCRP (TE)

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    End point title
    Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: hsCRP (TE) [9]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment. hsCRP= high-sensitivity C Reactive Protein. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [9] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: mg/L
    arithmetic mean (standard deviation)
        Pre-Transplant (N= 49; 45)
    32.85 ± 50.859
    21.83 ± 33.547
        Week 52 (N= 42; 40)
    3.01 ± 3.313
    3.95 ± 5.273
        Change from Pre-Transplant at Week 52 (N= 42; 40)
    -34.32 ± 54.257
    -18.69 ± 35.354
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: F2 isoprostanes (TE)

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    End point title
    Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: F2 isoprostanes (TE) [10]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [10] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: pg/mL
    arithmetic mean (standard deviation)
        Pre-Transplant (N= 48; 45)
    52.03 ± 76.09
    53.94 ± 78.476
        Week 52 (N= 42; 40)
    30.08 ± 25.905
    50.44 ± 68.416
        Change from Pre-Transplant at Week 52 (N= 42; 40)
    -13.29 ± 40.543
    -3.43 ± 103.457
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: T-bars (TE)

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    End point title
    Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: T-bars (TE) [11]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment. T-bars = thiobarbituric acid reactive substances. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [11] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: nmol/mL
    arithmetic mean (standard deviation)
        Pre-Transplant (N= 50; 45)
    3.78 ± 1.586
    3.91 ± 2.059
        Week 52 (N= 40; 39)
    3.25 ± 1.365
    3.14 ± 1.198
        Change from Pre-Transplant at Week 52 (N= 40; 39)
    -0.64 ± 1.724
    -0.77 ± 2.182
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Nitrotyrosine (TE)

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    End point title
    Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Nitrotyrosine (TE) [12]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received (TE) regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [12] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: nM
    arithmetic mean (standard deviation)
        Pre-Transplant (N= 50; 45)
    422.63 ± 393.554
    482.43 ± 390.702
        Week 52 (N= 41; 39)
    451.88 ± 443.372
    368.95 ± 262.693
        Change from Pre-Transplant at Week 52 (N= 41; 39)
    71.44 ± 332.351
    -99.79 ± 228.268
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: GSH/GSSG (TE)

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    End point title
    Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: GSH/GSSG (TE) [13]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment. GSH/GSSG= ratio of reduced to oxidised glutathione.The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [13] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: Ratio
    arithmetic mean (standard deviation)
        Pre-Transplant (N= 49; 45)
    55.07 ± 62.78
    58.83 ± 71.289
        Week 52 (N= 39; 38)
    51.69 ± 55.721
    53.72 ± 55.264
        Change from Pre-Transplant at Week 52 (N= 39; 38)
    -2.07 ± 70.036
    -5.55 ± 80.49
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: BNP (TE)

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    End point title
    Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: BNP (TE) [14]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment. BNP= Brain Natriuretic Peptide. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [14] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: ng/L
    arithmetic mean (standard deviation)
        Pre-Transplant (N= 49; 44)
    4314.8 ± 4861.78
    4240.8 ± 4673.72
        Week 52 (N= 42; 40)
    670.1 ± 1053.21
    1856.8 ± 5077.26
        Change from Pre-Transplant at Week 52 (N= 42; 40)
    -4018.4 ± 5043.28
    -1446.7 ± 6460.33
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Troponin T (TE)

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    End point title
    Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Troponin T (TE) [15]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment. The number of participants analyzed per arm represents Treatment Exposure (TE) Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [15] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: ug/L
    arithmetic mean (standard deviation)
        Pre-Transplant (N= 49; 44)
    0.3 ± 0.686
    0.28 ± 0.878
        Week 52 (N= 42; 40)
    0.03 ± 0.116
    0.04 ± 0.12
        Change from Pre-Transplant at Week 52 (N= 42; 40)
    -0.32 ± 0.768
    -0.27 ± 0.958
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Osteopontin (TE)

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    End point title
    Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Osteopontin (TE) [16]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [16] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: ng/mL
    arithmetic mean (standard deviation)
        Pre-Transplant (N= 50; 44)
    11.88 ± 9.528
    11.14 ± 12.278
        Week 52 (N= 41; 38)
    8.77 ± 10.462
    10.49 ± 8.987
        Change from Pre-Transplant at Week 52 (N= 41; 38)
    -2.22 ± 10.615
    0.2 ± 11.158
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Fibrinogen (TE)

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    End point title
    Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Fibrinogen (TE) [17]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment.
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [17] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: g/L
    arithmetic mean (standard deviation)
        Pre-Transplant (N= 48; 44)
    4.4 ± 1.27
    4.4 ± 1.23
        Week 52 (N= 40; 40)
    3.4 ± 0.87
    3.8 ± 0.77
        Change from Pre-Transplant at Week 52 (N= 40; 40)
    -1.1 ± 1.48
    -0.5 ± 1.23
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: IL-6 (TE)

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    End point title
    Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: IL-6 (TE) [18]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment. IL= Interleukin The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [18] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: pg/mL
    arithmetic mean (standard deviation)
        Pre-Transplant (N= 48; 45)
    3.36 ± 4.221
    2.54 ± 3.159
        Week 52 (N= 42; 40)
    0.98 ± 0.743
    0.9 ± 0.651
        Change from Pre-Transplant at Week 52 (N= 42; 40)
    -2.84 ± 4.635
    -1.56 ± 3.146
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: IL-18 (TE)

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    End point title
    Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: IL-18 (TE) [19]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [19] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: pg/mL
    arithmetic mean (standard deviation)
        Pre-Transplant (N= 48; 45)
    574 ± 291.89
    496.2 ± 246.9
        Week 52 (N= 40; 40)
    534.6 ± 290.38
    427.2 ± 217.07
        Change from Pre-Transplant at Week 52 (N=40; 40)
    5.2 ± 289.66
    -71 ± 243.81
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Cystatin-C (TE)

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    End point title
    Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Cystatin-C (TE) [20]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [20] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: mg/L
    arithmetic mean (standard deviation)
        Pre-Transplant (N= 49; 45)
    1.21 ± 0.414
    1.29 ± 0.49
        Week 52 (N= 42; 40)
    1.29 ± 0.533
    1.48 ± 0.714
        Change from Pre-Transplant at Week 52 (N= 42; 40)
    0.06 ± 0.464
    0.27 ± 0.744
    No statistical analyses for this end point

    Secondary: Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria (TE)

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    End point title
    Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria (TE) [21]
    End point description
    Acute rejection was defined as a rejection with ISHLT Grade ≥3A or by the presence of hemodynamic compromise. ISHLT Grades ≥3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. Patients may report more than one acute rejection.
    End point type
    Secondary
    End point timeframe
    52 Weeks
    Notes
    [21] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: Rejection Episodes
    number (not applicable)
        Total Acute Rejection Episodes
    8
    8
        Acute Rejection Episodes with ISHLT Grade ≥3A
    3
    7
        Acute Rejection Episodes w/ Hemodynamic Compromise
    6
    2
    No statistical analyses for this end point

    Secondary: Time to first acute rejection episode following de novo cardiac transplant (TE)

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    End point title
    Time to first acute rejection episode following de novo cardiac transplant (TE) [22]
    End point description
    Acute Rejection was defined as a rejection with ISHLT Grade ≥3A or by the presence of hemodynamic compromise. ISHLT Grades ≥3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection. Time to first acute rejection is defined as: date of onset - date of transplant.The population analyzed represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. Only participants who experienced acute rejection were included in the analysis.
    End point type
    Secondary
    End point timeframe
    52 Weeks
    Notes
    [22] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Cyclosporine – Adult Cyclosporine – Pediatric
    Number of subjects analysed
    8
    6
    Units: Days
        arithmetic mean (standard deviation)
    166.6 ± 132.86
    55 ± 35.6
    No statistical analyses for this end point

    Secondary: Number of patients requiring antilymphocyte antibodies or steroids for treatment of severe acute rejection

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    End point title
    Number of patients requiring antilymphocyte antibodies or steroids for treatment of severe acute rejection [23]
    End point description
    Severe Acute Rejection is defined as rejection with ISHLT Grade 4.
    End point type
    Secondary
    End point timeframe
    52 Weeks
    Notes
    [23] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: Patients
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of cardiac rejection episodes requiring treatment (TE)

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    End point title
    Number of cardiac rejection episodes requiring treatment (TE) [24]
    End point description
    The number of rejection episodes requiring treatment (medications started/ stopped, non-medication treatment, or both) regardless of biopsy grade or presence of hemodynamic compromise. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation.
    End point type
    Secondary
    End point timeframe
    52 Weeks
    Notes
    [24] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: Rejection Episodes
        number (not applicable)
    12
    11
    No statistical analyses for this end point

    Secondary: Mean cases of acute rejection (MCAR) per patient

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    End point title
    Mean cases of acute rejection (MCAR) per patient [25]
    End point description
    MCAR represents the average number of acute rejections among all patients in each treatment group. Results were based on rejection episodes with endomyocardial biopsies. Acute rejection was defined as a rejection with ISHLT Grade ≥3A or by the presence of hemodynamic compromise. ISHLT Grades ≥3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation.
    End point type
    Secondary
    End point timeframe
    52 Weeks
    Notes
    [25] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: MCAR per patient
        arithmetic mean (standard deviation)
    0.15 ± 0.46
    0.17 ± 0.38
    Statistical analysis title
    Mean Cases of Acute Rejection (MCAR)
    Comparison groups
    Tacrolimus - Adult v Cyclosporine – Adult
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.4725 [26]
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
         level
    95%
    Notes
    [26] - No adjustments for multiple comparisons were performed.

    Secondary: Number of patients with successful steroid taper or withdrawal at weeks 26 and 52 (TE)

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    End point title
    Number of patients with successful steroid taper or withdrawal at weeks 26 and 52 (TE)
    End point description
    A successful steroid taper or withdrawal was defined as steroids (prednisone) being discontinued or tapered to the suggested dose level after week 26. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation.
    End point type
    Secondary
    End point timeframe
    26 Weeks and 52 Weeks
    End point values
    Cyclosporine - Adult Tacrolimus – Adult
    Number of subjects analysed
    46
    52
    Units: Patients
    number (not applicable)
        Week 26
    16
    22
        Week 52
    29
    33
    No statistical analyses for this end point

    Secondary: Number of patients with treatment failure and crossover for treatment failure

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    End point title
    Number of patients with treatment failure and crossover for treatment failure [27]
    End point description
    Treatment failure was defined as death, re-transplantation, withdrawal due to an Adverse Event, or a switch of main immunosuppressant medication, whichever came first. Crossover was defined as a switch from originally administered primary immunosuppressant (tacrolimus or cyclosporine) to the alternate primary immunosuppressant.
    End point type
    Secondary
    End point timeframe
    52 Weeks
    Notes
    [27] - 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: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.
    End point values
    Tacrolimus - Adult Cyclosporine – Adult
    Number of subjects analysed
    52
    46
    Units: Patients
    number (not applicable)
        Treatment Failures
    6
    11
        Crossover for Treatment Failures
    2
    8
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation and oxidation: F2 isoprostanes (Pediatric Population)

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    End point title
    Changes in circulating markers of inflammation and oxidation: F2 isoprostanes (Pediatric Population) [28]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [28] - 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: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.
    End point values
    Tacrolimus – Pediatric Cyclosporine – Pediatric
    Number of subjects analysed
    5
    6
    Units: pg/mL
    arithmetic mean (standard deviation)
        Pre-Transplant (N= 5; 5)
    106.06 ± 37.974
    104.68 ± 53.812
        Week 52 (N= 3; 4)
    69.71 ± 38.62
    66.48 ± 33.298
        Change from Pre-Transplant at Week 52 (N= 3; 4)
    -38.31 ± 47.563
    -30.07 ± 80.246
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation and oxidation: nitrotyrosine (Pediatric Population)

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    End point title
    Changes in circulating markers of inflammation and oxidation: nitrotyrosine (Pediatric Population) [29]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [29] - 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: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.
    End point values
    Tacrolimus – Pediatric Cyclosporine – Pediatric
    Number of subjects analysed
    5
    6
    Units: nM
    arithmetic mean (standard deviation)
        Pre-Transplant (N= 5; 5)
    233.08 ± 211.491
    12701.21 ± 21666.231
        Week 52 (N= 3; 4)
    5462.99 ± 7988.134
    41147.62 ± 37565.74
        Change from Pre-Transplant at Week 52 (N= 3; 4)
    5148.42 ± 7849.554
    21514.62 ± 49626.968
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation and oxidation: hsCRP (Pediatric Population)

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    End point title
    Changes in circulating markers of inflammation and oxidation: hsCRP (Pediatric Population) [30]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [30] - 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: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.
    End point values
    Tacrolimus – Pediatric Cyclosporine – Pediatric
    Number of subjects analysed
    5
    6
    Units: mg/L
    arithmetic mean (standard deviation)
        Pre-Transplant (N= 5; 4)
    30.46 ± 32.274
    12.08 ± 14.771
        Week 52 (N= 3; 4)
    26.31 ± 45.109
    2.43 ± 1.348
        Change from Pre-Transplant at Week 52 (N= 3; 4)
    -7.85 ± 78.126
    -13.94 ± 16.461
    No statistical analyses for this end point

    Secondary: Changes in circulating markers of inflammation and oxidation: Cystatin-C (Pediatric Population)

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    End point title
    Changes in circulating markers of inflammation and oxidation: Cystatin-C (Pediatric Population) [31]
    End point description
    Change is defined as Week 52 assessment - Pre-Transplant assessment
    End point type
    Secondary
    End point timeframe
    Pre-Transplant and 52 Weeks
    Notes
    [31] - 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: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.
    End point values
    Tacrolimus – Pediatric Cyclosporine – Pediatric
    Number of subjects analysed
    5
    6
    Units: mg/L
    arithmetic mean (standard deviation)
        Pre-Transplant ( N= 5; 4)
    0.86 ± 0.248
    0.77 ± 0.194
        Week 52 (N= 3; 4)
    0.87 ± 0.133
    0.84 ± 0.111
        Change from Pre-Transplant at Week 52 (N= 3; 4)
    -0.11 ± 0.197
    -0.01 ± 0.108
    No statistical analyses for this end point

    Secondary: Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria (Pediatric Population)

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    End point title
    Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria (Pediatric Population) [32]
    End point description
    Acute rejection was defined as a rejection with ISHLT Grade ≥3A or by the presence of hemodynamic compromise. ISHLT Grades ≥3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection. Patients may report more than one rejection episode.
    End point type
    Secondary
    End point timeframe
    52 Weeks
    Notes
    [32] - 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: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.
    End point values
    Cyclosporine – Pediatric Tacrolimus - Pediatric
    Number of subjects analysed
    6
    5
    Units: Rejection Episodes
    number (not applicable)
        Total Acute Rejection Episodes
    3
    3
        Acute Rejection Episodes with ISHLT Grade ≥3A
    3
    3
        Acute Rejection Episodes w/ Hemodynamic Compromise
    0
    0
    No statistical analyses for this end point

    Secondary: Time to first acute rejection episode following de novo cardiac transplant (Pediatric Population)

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    End point title
    Time to first acute rejection episode following de novo cardiac transplant (Pediatric Population) [33]
    End point description
    Acute Rejection was defined as a rejection with ISHLT Grade ≥3A or by the presence of hemodynamic compromise. ISHLT Grades ≥3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection. Time to first acute rejection is defined as: date of onset - date of transplant.
    End point type
    Secondary
    End point timeframe
    52 Weeks
    Notes
    [33] - 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: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.
    End point values
    Cyclosporine – Pediatric
    Number of subjects analysed
    3
    Units: Days
        arithmetic mean (standard deviation)
    49 ± 15.62
    No statistical analyses for this end point

    Secondary: Number of patients requiring antilymphocyte antibodies or steroids for treatment of severe acute rejection (Pediatric Population)

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    End point title
    Number of patients requiring antilymphocyte antibodies or steroids for treatment of severe acute rejection (Pediatric Population) [34]
    End point description
    Severe Acute Rejection was defined as rejection with ISHLT Grade 4.
    End point type
    Secondary
    End point timeframe
    52 Weeks
    Notes
    [34] - 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: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.
    End point values
    Tacrolimus – Pediatric Cyclosporine – Pediatric
    Number of subjects analysed
    5
    6
    Units: Patients
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of cardiac rejection episodes requiring treatment (Pediatric Population)

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    End point title
    Number of cardiac rejection episodes requiring treatment (Pediatric Population) [35]
    End point description
    A summary of rejection episodes requiring treatment regardless of biopsy grade or presence of hemodynamic compromise.
    End point type
    Secondary
    End point timeframe
    52 Weeks
    Notes
    [35] - 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: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.
    End point values
    Tacrolimus – Pediatric Cyclosporine – Pediatric
    Number of subjects analysed
    5
    6
    Units: Rejection Episodes
        number (not applicable)
    3
    3
    No statistical analyses for this end point

    Secondary: Mean cases of acute rejection (MCAR) per patient (Pediatric Population)

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    End point title
    Mean cases of acute rejection (MCAR) per patient (Pediatric Population) [36]
    End point description
    MCAR represents the average number of acute rejections among all patients in each treatment group. Results were based on rejection episodes with endomyocardial biopsies. Acute rejection was defined as a rejection with ISHLT Grade ≥3A or by the presence of hemodynamic compromise. ISHLT Grades ≥3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection.
    End point type
    Secondary
    End point timeframe
    52 Weeks
    Notes
    [36] - 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: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.
    End point values
    Tacrolimus – Pediatric Cyclosporine – Pediatric
    Number of subjects analysed
    5
    6
    Units: MCAR per patient
        arithmetic mean (standard deviation)
    0.6 ± 0.55
    0.5 ± 0.55
    Statistical analysis title
    STATISTICAL_ANALYSIS_TITLE
    Comparison groups
    Tacrolimus – Pediatric v Cyclosporine – Pediatric
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.8373 [37]
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
         level
    95%
    Notes
    [37] - No adjustments for multiple comparisons were performed.

    Secondary: Number of patients with successful steroid taper or withdrawal at weeks 26 and 52 (Pediatric Population)

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    End point title
    Number of patients with successful steroid taper or withdrawal at weeks 26 and 52 (Pediatric Population) [38]
    End point description
    A successful steroid taper or withdrawal was defined as steroids (prednisone) being discontinued or tapered to the suggested dose level after week 26.
    End point type
    Secondary
    End point timeframe
    26 Weeks and 52 Weeks
    Notes
    [38] - 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: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.
    End point values
    Tacrolimus – Pediatric Cyclosporine – Pediatric
    Number of subjects analysed
    5
    6
    Units: Patients
    number (not applicable)
        Week 26
    2
    3
        Week 52
    1
    1
    No statistical analyses for this end point

    Secondary: Number of patients with treatment failure and crossover for treatment failure (Pediatric Population)

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    End point title
    Number of patients with treatment failure and crossover for treatment failure (Pediatric Population) [39]
    End point description
    Treatment failure was defined as death, re-transplantation, withdrawal due to an Adverse Event, or a switch of main immunosuppressant medication, whichever came first. Crossover was defined as a switch from originally administered primary immunosuppressant (tacrolimus or cyclosporine) to the alternate primary immunosuppressant.
    End point type
    Secondary
    End point timeframe
    52 Weeks
    Notes
    [39] - 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: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.
    End point values
    Cyclosporine – Pediatric Tacrolimus - Pediatric
    Number of subjects analysed
    6
    5
    Units: Patients
    number (not applicable)
        Treatment Failures
    3
    1
        Crossover for Treatment Failures
    3
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After the initiation of study drug up to 30 days after the last dose of study drug.
    Adverse event reporting additional description
    Treatment Emergent Adverse Events were reported. Within a preferred term, participants were counted once.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    8.0
    Reporting groups
    Reporting group title
    Tacrolimus - Adult
    Reporting group description
    Adults: 0.05 – 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant

    Reporting group title
    Cyclosporine – Adult
    Reporting group description
    Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant

    Reporting group title
    Tacrolimus – Pediatric
    Reporting group description
    Pediatrics: 0.05 – 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant

    Reporting group title
    Cyclosporine – Pediatric
    Reporting group description
    Pediatrics: 6 – 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant

    Serious adverse events
    Tacrolimus - Adult Cyclosporine – Adult Tacrolimus – Pediatric Cyclosporine – Pediatric
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 52 (40.38%)
    24 / 46 (52.17%)
    3 / 5 (60.00%)
    5 / 6 (83.33%)
         number of deaths (all causes)
    4
    3
    1
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inferior vena caval occlusion
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Temporal arteritis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer stage III
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal carcinoma
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphoproliferative disorder
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Heart transplant rejection
         subjects affected / exposed
    2 / 52 (3.85%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Transplant rejection
         subjects affected / exposed
    2 / 52 (3.85%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter related complication
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Haemothorax
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 52 (1.92%)
    2 / 46 (4.35%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis constrictive
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiogenic pulmonary oedema
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 52 (1.92%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory alkalosis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope vasovagal
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tension headache
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Blindness cortical
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic disorder
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephropathy toxic
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 52 (0.00%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal mass
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    American trypanosomiasis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus gastritis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mediastinitis
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 52 (0.00%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Tacrolimus - Adult Cyclosporine – Adult Tacrolimus – Pediatric Cyclosporine – Pediatric
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 52 (100.00%)
    46 / 46 (100.00%)
    5 / 5 (100.00%)
    6 / 6 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    21 / 52 (40.38%)
    26 / 46 (56.52%)
    3 / 5 (60.00%)
    4 / 6 (66.67%)
         occurrences all number
    25
    29
    3
    4
    Hypotension
         subjects affected / exposed
    13 / 52 (25.00%)
    7 / 46 (15.22%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    15
    10
    0
    0
    Surgical and medical procedures
    Removal of foreign body
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    1
    Immune system disorders
    Transplant rejection
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 52 (9.62%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    2
    0
    0
    Chest pain
         subjects affected / exposed
    4 / 52 (7.69%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    2
    0
    0
    Chills
         subjects affected / exposed
    1 / 52 (1.92%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Hyperthermia
         subjects affected / exposed
    2 / 52 (3.85%)
    4 / 46 (8.70%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    4
    0
    0
    Fatigue
         subjects affected / exposed
    2 / 52 (3.85%)
    7 / 46 (15.22%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    10
    0
    0
    Influenza like illness
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Oedema Peripheral
         subjects affected / exposed
    21 / 52 (40.38%)
    21 / 46 (45.65%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    32
    24
    0
    2
    Oedema
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Pyrexia
         subjects affected / exposed
    4 / 52 (7.69%)
    4 / 46 (8.70%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    5
    5
    0
    3
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    3 / 52 (5.77%)
    4 / 46 (8.70%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    4
    0
    0
    Anxiety
         subjects affected / exposed
    5 / 52 (9.62%)
    5 / 46 (10.87%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    6
    0
    0
    Confusional state
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Insomnia
         subjects affected / exposed
    8 / 52 (15.38%)
    12 / 46 (26.09%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    9
    12
    0
    1
    Depression
         subjects affected / exposed
    6 / 52 (11.54%)
    5 / 46 (10.87%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    6
    5
    0
    1
    Injury, poisoning and procedural complications
    Incision site pain
         subjects affected / exposed
    5 / 52 (9.62%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    4
    0
    0
    Wound
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    0
    1
    Joint sprain
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    2 / 52 (3.85%)
    5 / 46 (10.87%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    9
    0
    0
    Cardiac murmur
         subjects affected / exposed
    3 / 52 (5.77%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    5
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 52 (0.00%)
    3 / 46 (6.52%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    1
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 52 (0.00%)
    4 / 46 (8.70%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Weight increased
         subjects affected / exposed
    10 / 52 (19.23%)
    9 / 46 (19.57%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    10
    9
    1
    0
    Epstein-Barr virus antibody positive
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Cytomegalovirus antigen positive
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    White blood cell count increased
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    6 / 52 (11.54%)
    4 / 46 (8.70%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    8
    5
    0
    0
    Atrial flutter
         subjects affected / exposed
    3 / 52 (5.77%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    3
    0
    0
    Bradycardia
         subjects affected / exposed
    6 / 52 (11.54%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    3
    0
    0
    Oedema due to cardiac disease
         subjects affected / exposed
    3 / 52 (5.77%)
    4 / 46 (8.70%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    4
    0
    0
    Mitral valve incompetence
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    0
    Palpitations
         subjects affected / exposed
    3 / 52 (5.77%)
    6 / 46 (13.04%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    7
    0
    0
    Pulmonary oedema
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Pericardial effusion
         subjects affected / exposed
    5 / 52 (9.62%)
    6 / 46 (13.04%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    7
    1
    0
    Right ventricular dysfunction
         subjects affected / exposed
    4 / 52 (7.69%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    3
    0
    0
    Tricuspid valve incompetence
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    0
    Arrhythmia
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Congenital, familial and genetic disorders
    Becker's muscular dystrophy
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 52 (17.31%)
    6 / 46 (13.04%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    12
    8
    0
    0
    Atelectasis
         subjects affected / exposed
    2 / 52 (3.85%)
    4 / 46 (8.70%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    5
    0
    0
    Dyspnoea
         subjects affected / exposed
    8 / 52 (15.38%)
    5 / 46 (10.87%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    11
    7
    0
    0
    Pleural effusion
         subjects affected / exposed
    10 / 52 (19.23%)
    18 / 46 (39.13%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    11
    21
    0
    0
    Pneumothorax
         subjects affected / exposed
    5 / 52 (9.62%)
    4 / 46 (8.70%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    4
    0
    0
    Aspiration
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory distress
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Aneamia
         subjects affected / exposed
    18 / 52 (34.62%)
    15 / 46 (32.61%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
         occurrences all number
    18
    16
    2
    3
    Leukocytosis
         subjects affected / exposed
    9 / 52 (17.31%)
    9 / 46 (19.57%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    10
    9
    0
    0
    Leukopenia
         subjects affected / exposed
    12 / 52 (23.08%)
    9 / 46 (19.57%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    15
    9
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    5 / 52 (9.62%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    7
    1
    0
    0
    Neutropenia
         subjects affected / exposed
    2 / 52 (3.85%)
    2 / 46 (4.35%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    4
    1
    1
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    0
    3
    Dizziness
         subjects affected / exposed
    6 / 52 (11.54%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    3
    0
    0
    Paraesthesia
         subjects affected / exposed
    3 / 52 (5.77%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    3
    0
    0
    Headache
         subjects affected / exposed
    11 / 52 (21.15%)
    13 / 46 (28.26%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    16
    15
    1
    1
    Hypoaesthesia
         subjects affected / exposed
    1 / 52 (1.92%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Tremor
         subjects affected / exposed
    23 / 52 (44.23%)
    13 / 46 (28.26%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    28
    14
    0
    1
    Syncope
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    0
    1
    Eye disorders
    Amblyopia
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    4 / 52 (7.69%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    3
    0
    0
    Abdominal pain
         subjects affected / exposed
    6 / 52 (11.54%)
    5 / 46 (10.87%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    5
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    0
    Diarrhoea
         subjects affected / exposed
    26 / 52 (50.00%)
    8 / 46 (17.39%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    36
    10
    0
    1
    Constipation
         subjects affected / exposed
    6 / 52 (11.54%)
    13 / 46 (28.26%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    7
    13
    0
    0
    Dysphagia
         subjects affected / exposed
    4 / 52 (7.69%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    0
    0
    Gingival hyperplasia
         subjects affected / exposed
    0 / 52 (0.00%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 52 (0.00%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Nausea
         subjects affected / exposed
    8 / 52 (15.38%)
    15 / 46 (32.61%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    9
    24
    1
    0
    Gastritis
         subjects affected / exposed
    2 / 52 (3.85%)
    1 / 46 (2.17%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Vomiting
         subjects affected / exposed
    3 / 52 (5.77%)
    9 / 46 (19.57%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
         occurrences all number
    4
    9
    2
    2
    Gingival hypertrophy
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    1
    1
    0
    3
    Tooth discolouration
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    11 / 52 (21.15%)
    12 / 46 (26.09%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    14
    13
    0
    0
    Renal failure acute
         subjects affected / exposed
    4 / 52 (7.69%)
    4 / 46 (8.70%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    4
    0
    0
    Renal failure chronic
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Renal impairment
         subjects affected / exposed
    0 / 52 (0.00%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    4 / 52 (7.69%)
    6 / 46 (13.04%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    7
    0
    0
    Hypertrichosis
         subjects affected / exposed
    1 / 52 (1.92%)
    4 / 46 (8.70%)
    0 / 5 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    1
    4
    0
    3
    Rash
         subjects affected / exposed
    3 / 52 (5.77%)
    4 / 46 (8.70%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    4
    0
    0
    Skin lesion
         subjects affected / exposed
    7 / 52 (13.46%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    7
    2
    0
    0
    Skin ulcer
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 52 (5.77%)
    5 / 46 (10.87%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    5
    0
    0
    Back pain
         subjects affected / exposed
    4 / 52 (7.69%)
    5 / 46 (10.87%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    5
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 52 (3.85%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    0
    0
    Muscle spasms
         subjects affected / exposed
    8 / 52 (15.38%)
    8 / 46 (17.39%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    8
    8
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    7 / 52 (13.46%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    7
    2
    0
    0
    Myalgia
         subjects affected / exposed
    4 / 52 (7.69%)
    6 / 46 (13.04%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    7
    0
    0
    Pain in extremity
         subjects affected / exposed
    4 / 52 (7.69%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    3
    0
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    6 / 52 (11.54%)
    11 / 46 (23.91%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    6
    12
    0
    1
    Dyslipidaemia
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    0
    Fluid overload
         subjects affected / exposed
    7 / 52 (13.46%)
    10 / 46 (21.74%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
         occurrences all number
    8
    17
    2
    0
    Hyperglycaemia
         subjects affected / exposed
    6 / 52 (11.54%)
    3 / 46 (6.52%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    3
    1
    0
    Gout
         subjects affected / exposed
    2 / 52 (3.85%)
    5 / 46 (10.87%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    5
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    5 / 52 (9.62%)
    7 / 46 (15.22%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    6
    7
    0
    2
    Hyperlipidaemia
         subjects affected / exposed
    5 / 52 (9.62%)
    8 / 46 (17.39%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    6
    10
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    6 / 52 (11.54%)
    4 / 46 (8.70%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    8
    4
    0
    0
    Hypokalaemia
         subjects affected / exposed
    8 / 52 (15.38%)
    6 / 46 (13.04%)
    2 / 5 (40.00%)
    2 / 6 (33.33%)
         occurrences all number
    8
    7
    2
    2
    Hypomagnesaemia
         subjects affected / exposed
    13 / 52 (25.00%)
    4 / 46 (8.70%)
    2 / 5 (40.00%)
    2 / 6 (33.33%)
         occurrences all number
    14
    4
    2
    2
    Hypovolaemia
         subjects affected / exposed
    6 / 52 (11.54%)
    4 / 46 (8.70%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    7
    4
    0
    0
    Fluid retention
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 46 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 52 (7.69%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    2
    0
    0
    Diverticulitis
         subjects affected / exposed
    0 / 52 (0.00%)
    3 / 46 (6.52%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Influenza
         subjects affected / exposed
    1 / 52 (1.92%)
    4 / 46 (8.70%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    4
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 52 (3.85%)
    6 / 46 (13.04%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    7
    0
    0
    Pneumonia
         subjects affected / exposed
    6 / 52 (11.54%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    7
    2
    0
    1
    Sinusitis
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    0
    Staphylococcal infection
         subjects affected / exposed
    4 / 52 (7.69%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 52 (7.69%)
    6 / 46 (13.04%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
         occurrences all number
    4
    6
    1
    2
    Urinary tract infection
         subjects affected / exposed
    6 / 52 (11.54%)
    2 / 46 (4.35%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    7
    2
    0
    0
    Adenovirus infection
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Clostridial infection
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 46 (4.35%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Oral herpes
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 46 (2.17%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tooth abscess
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    1
    Wound infection pseudomonas
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Viral upper repiratory tract infection
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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