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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial to Evaluate the Efficacy and Safety of a Vaccine, ASP0113, in Cytomegalovirus (CMV)-Seronegative Kidney Transplant Recipients Receiving an Organ from a CMV-Seropositive Donor

    Summary
    EudraCT number
    		 2013-000464-29
    Trial protocol
    		 DE   ES  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    29 Apr 2017
    First version publication date
    29 Apr 2017
    Other versions
    		 v2 , v3

    Trial information

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    Trial identification
    Sponsor protocol code
    0113-CL-2001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01974206
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development, Inc.
    Sponsor organisation address
    1 Astellas Way, Northbrook, United States, 60062
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, 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?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    13 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 May 2016
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to evaluate efficacy and safety of ASP0113 compared to placebo in reducing the incidence of Cytomegalovirus (CMV) viremia through 1 year post first study drug injection in CMV-seronegative patients who received a kidney from a CMV-seropositive donor.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (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
    		 In the first 10 days after the transplant, patients received prophylactic valganciclovir or ganciclovir (dose per package insert) from the day of randomization to prevent Cytomegalovirus (CMV) disease. After randomization, patients continued to receive valganciclovir or ganciclovir until 100 days post-transplant. Valganciclovir or ganciclovir could be interrupted, dose adjusted or replaced by other CMV-specific antiviral prophylaxis (AVP) per standard of care after the day of randomization.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Nov 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 4 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 93
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Australia: 11
    Worldwide total number of subjects
    150
    EEA total number of subjects
    39
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    129
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 150 patients were enrolled across 6 countries over approximately 3.5 years. Eligible patients for the study were ≥18 years of age and CMV-seronegative at the time of the transplant. Furthermore they had a kidney allograft from a CMV-seropositive living or deceased donor.

    Pre-assignment
    Screening details
    		 Screening assessments were performed from 14-30 days after the transplant. Patients were randomized at day 30 ± 3, in relation to the day of the transplant, in a 1:1 ratio to ASP0113 or placebo. Patients were stratified by the use of antithymocyte globulin (ATG) prior to randomization and by the receipt of a kidney from a living or deceased donor.

    Period 1
    Period 1 title
    Primary Study Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor
    Blinding implementation details
    This was a double-blind study. Patients were randomized to receive ASP0113 or placebo in a double-blind fashion such that the investigator, sponsor’s study management team, clinical staff nor the patient knew which agent was being administered.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Patients received 1 mL of 5 mg/mL of placebo via injection in the deltoid muscle alternating sides with each dose on days 30, 60, 90, 120 and 180 in relation to the day of transplant (Day 0).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Patients received Placebo in 2-mL vials containing phosphate-buffered saline.

    Arm title
    		 ASP0113 5mg
    Arm description
    		 Patients received 1 mL of 5 mg/mL of ASP0113 via injection in the deltoid muscle alternating sides with each dose on days 30, 60, 90, 120 and 180 in relation to the day of transplant (Day 0).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ASP0113
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Patients received ASP0113 in single dose 2-ml vials containing 1.3 ml of 5 mg/mL of ASP0113.

    Number of subjects in period 1
    		Placebo ASP0113 5mg
    Started
    74
    76
    Completed
    68
    75
    Not completed
    6
    1
         Consent withdrawn by subject
    3
    -
         Physician decision
    1
    -
         Patient did not take study drug
    -
    1
         Death
    1
    -
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients received 1 mL of 5 mg/mL of placebo via injection in the deltoid muscle alternating sides with each dose on days 30, 60, 90, 120 and 180 in relation to the day of transplant (Day 0).

    Reporting group title
    ASP0113 5mg
    Reporting group description
    		 Patients received 1 mL of 5 mg/mL of ASP0113 via injection in the deltoid muscle alternating sides with each dose on days 30, 60, 90, 120 and 180 in relation to the day of transplant (Day 0).

    Reporting group values
    		 Placebo ASP0113 5mg Total
    Number of subjects
    		 74 76
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.9 ( 13.3 ) 50.8 ( 13.6 ) -
    Gender categorical
    Units:
        Male
    		 55 55 110
        Female
    		 19 21 40

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients received 1 mL of 5 mg/mL of placebo via injection in the deltoid muscle alternating sides with each dose on days 30, 60, 90, 120 and 180 in relation to the day of transplant (Day 0).

    Reporting group title
    ASP0113 5mg
    Reporting group description
    		 Patients received 1 mL of 5 mg/mL of ASP0113 via injection in the deltoid muscle alternating sides with each dose on days 30, 60, 90, 120 and 180 in relation to the day of transplant (Day 0).

    Primary: Incidence of Cytomegalovirus (CMV) Viremia Through One Year Post First Study Drug Injection

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    End point title
    		 Incidence of Cytomegalovirus (CMV) Viremia Through One Year Post First Study Drug Injection
    End point description
    CMV viremia was defined as presence of cytomegalovirus as measured in plasma viral load of ≥ 1000 IU/mL by central laboratory assay. A patient who discontinued the study without a positive CMV viral load was imputed as having a CMV viremia. A patient who had more than one viral load ≥ 1000 IU/mL by central assay was counted once in this summary. CMV viral loads after first injection (Day 1) through Day 380 (scheduled or unscheduled) were included in the analysis. The analysis population was the Full Analysis Set (FAS) which consisted of all randomized patients who received at least 1 dose of randomized study drug and who had at least 1 post dose viral load assessment within 1 year post first injection by central laboratory.
    End point type
    Primary
    End point timeframe
    From first study dose injection (Day 1) up to one year post study drug injection (up to Day 380)
    End point values
    		 Placebo ASP0113 5mg
    Number of subjects analysed
    73
    73
    Units: Percentage of Patients
    number (not applicable)
        Known CMV Viremia
    35.6
    35.6
        Imputed CMV Viremia Due to Discontinuation
    5.5
    0
    Statistical analysis title
    		 Common Odds Ratio for Patients With CMV
    Statistical analysis description
    The Cochran-Mantel-Haenszel (CMH) estimate of the common odds ratio (ASP0113 vs placebo) stratified by randomization strata, and the 90% CIs of the CMH odds ratio stratified by randomization group.
    Comparison groups
    Placebo v ASP0113 5mg
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.307 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Common Odds Ratio
    Point estimate
    0.79
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 1.47
    Notes
    [1] - P-value (1-sided) of the CMH adjusted odds ratio stratified by randomization group.

    Secondary: Proportion of Patients with Adjudicated CMV-Associated Disease, Including CMV Syndrome and CMV Tissue-Invasive Disease

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    End point title
    		 Proportion of Patients with Adjudicated CMV-Associated Disease, Including CMV Syndrome and CMV Tissue-Invasive Disease
    End point description
    An independent panel of medical experts reviewed/adjudicated events of CMV-associated disease including CMV syndrome and tissue invasive disease, which were defined according to the American Society of Transplantation Recommendations for Screening, Monitoring and Reporting of Infectious Complications in Immunosuppression Trials in Recipients of Organ Transplantation 2006. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    From first study dose injection (Day 1) up to one year post study drug injection (up to Day 380)
    End point values
    		 Placebo ASP0113 5mg
    Number of subjects analysed
    73
    73
    Units: Percentage of Patients
        number (not applicable)
    19.18
    19.18
    Statistical analysis title
    		 Common Odds Ratio for CMV-Associated Disease
    Statistical analysis description
    The exact Cochran-Mantel-Haenszel (CMH) estimate of the common odds ratio (ASP0113 vs placebo) stratified by randomization group, and the 90% CI of the exact CMH odds ratio stratified by randomization group.
    Comparison groups
    Placebo v ASP0113 5mg
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.576 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Common Odds Ratio
    Point estimate
    0.99
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 2.15
    Notes
    [2] - P-value (1-sided) of the exact CMH method adjusted odds ratio stratified by randomization group.

    Secondary: Proportion of Patients with CMV Viremia Defined as Plasma Viral Load ≥ the Lower Limit of Quantification (LLOQ) Assessed by Central Laboratory

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    End point title
    		 Proportion of Patients with CMV Viremia Defined as Plasma Viral Load ≥ the Lower Limit of Quantification (LLOQ) Assessed by Central Laboratory
    End point description
    The central laboratory had the LLOQ level for CMV viral load assessment. When the viral load was below the LLOQ the actual reading was not possible and was denoted as ≤LLOQ. If the patient had any CMV viral load assessments greater than the LLOQ,set up by the central laboratory, patient was classified as viremic and was included in the analysis. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    From first study dose injection (Day 1) up to one year post study drug injection (up to Day 380)
    End point values
    		 Placebo ASP0113 5mg
    Number of subjects analysed
    73
    73
    Units: Percentage of Patients
        number (not applicable)
    49.32
    46.58
    Statistical analysis title
    		 Common Odds Ratio for Patients with CMV Viremia
    Statistical analysis description
    The exact Cochran-Mantel-Haenszel (CMH) estimate of the common odds ratio (ASP0113 vs placebo) stratified by randomization group, and the 90% CI of the exact CMH odds ratio stratified by randomization group.
    Comparison groups
    Placebo v ASP0113 5mg
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.408 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Common Odds Ratio
    Point estimate
    0.88
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.59
    Notes
    [3] - P-value (1-sided) of the exact CMH method adjusted odds ratio stratified by randomization group.

    Secondary: Proportion of Patients Who Took Adjudicated CMV-specific antiviral therapy (AVT) for the Treatment of CMV Viremia or Disease

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    End point title
    		 Proportion of Patients Who Took Adjudicated CMV-specific antiviral therapy (AVT) for the Treatment of CMV Viremia or Disease
    End point description
    An independent panel of medical experts reviewed/adjudicated events of CMV-specific AVT for treatment of CMV viremia or disease. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    From first study dose injection (Day 1) up to one year post study drug injection (up to Day 380)
    End point values
    		 Placebo ASP0113 5mg
    Number of subjects analysed
    73
    73
    Units: Percentage of Patients
        number (not applicable)
    45.21
    42.47
    Statistical analysis title
    		 Common Odds Ratio for Patients With CMV-AVT
    Statistical analysis description
    The exact Cochran-Mantel-Haenszel (CMH) estimate of the common odds ratio (ASP0113 vs placebo) stratified by randomization group, and the 90% CI of the exact CMH odds ratio stratified by randomization group.
    Comparison groups
    Placebo v ASP0113 5mg
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.419 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Common Odds Ratio
    Point estimate
    0.88
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.61
    Notes
    [4] - P-value (1-sided) of the exact CMH method adjusted odds ratio stratified by randomization group.

    Secondary: Proportion of Patients with Graft Survival

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    End point title
    		 Proportion of Patients with Graft Survival
    End point description
    Graft survival was defined for any patient that did not fit the definition of graft loss. Graft loss was defined as patient death, re-transplant, nephrectomy, or return to permanent dialysis (i.e., for > 30 days). Missing values for graft survival were not included in the denominator when making the proportion. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    From first study dose injection (Day 1) up to one year post study drug injection (up to Day 380)
    End point values
    		 Placebo ASP0113 5mg
    Number of subjects analysed
    68
    71
    Units: Percentage of Patients
        number (not applicable)
    98.53
    100
    Statistical analysis title
    		 Common Odds Ratio of Patients with Graft Survival
    Statistical analysis description
    Exact Cochran-Mantel-Haenszel estimate of the common odds ratio (ASP0113 versus Placebo) could not be estimated and is denoted as "9999." Moreover, upper limit of 90% CI of oods ratio is an infinity value and is also denoted as "9999."
    Comparison groups
    Placebo v ASP0113 5mg
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Common Odds Ratio
    Point estimate
    9999
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.11
         upper limit
    		 9999
    Notes
    [5] - P-value (1-sided) of the Exact Cochran-Mantel-Haenszel method adjusted odds ratio stratified by randomization group.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1- Day 380
    Adverse event reporting additional description
    Treatment Emergent Adverse Event (TEAE) was defined as an adverse event observed after the first study drug injection Day 1 through Day 380. Drug-related Adverse Event (AE) was defined as any AE with at least possible relationship to study treatment as assessed by the investigator or with missing assessment of the causal relationship.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    ASP0113 5mg
    Reporting group description
    		 Patients received 1 mL of 5 mg/mL of ASP0113 via injection in the deltoid muscle alternating sides with each dose on days 30, 60, 90, 120 and 180 in relation to the day of transplant (Day 0).

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received 1 mL of 5 mg/mL of placebo via injection in the deltoid muscle alternating sides with each dose on days 30, 60, 90, 120 and 180 in relation to the day of transplant (Day 0).

    Serious adverse events
    		 ASP0113 5mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    44 / 75 (58.67%)
    36 / 74 (48.65%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Invasive lobular breast carcinoma
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Prostate cancer
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 75 (0.00%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 75 (0.00%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 75 (0.00%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocele
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Nephrectomy
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transurethral prostatectomy
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteral stent removal
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urostomy
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 75 (4.00%)
    3 / 74 (4.05%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney transplant rejection
         subjects affected / exposed
    3 / 75 (4.00%)
    4 / 74 (5.41%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    5 / 75 (6.67%)
    4 / 74 (5.41%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HLA marker study positive
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immunosuppressant drug level increased
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Bone fissure
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft haemorrhage
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft thrombosis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perinephric collection
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematuria
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 75 (2.67%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Angle closure glaucoma
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphthous stomatitis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 75 (2.67%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal artery stenosis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    10 / 75 (13.33%)
    6 / 74 (8.11%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal tubular necrosis
         subjects affected / exposed
    0 / 75 (0.00%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric stenosis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder atrophy
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract disorder
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinoma
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperparathyroidism tertiary
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess soft tissue
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BK virus infection
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    7 / 75 (9.33%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus mucocutaneous ulcer
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus oesophagitis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus syndrome
         subjects affected / exposed
    2 / 75 (2.67%)
    5 / 74 (6.76%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    5 / 75 (6.67%)
    3 / 74 (4.05%)
         occurrences causally related to treatment / all
    3 / 7
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis bacterial
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epstein-Barr viraemia
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    5 / 75 (6.67%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected lymphocele
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumocystis jiroveci pneumonia
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia cytomegaloviral
         subjects affected / exposed
    3 / 75 (4.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia necrotising
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyomavirus-associated nephropathy
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 75 (0.00%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 75 (4.00%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    3 / 75 (4.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection enterococcal
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    3 / 75 (4.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 75 (1.33%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ASP0113 5mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    75 / 75 (100.00%)
    72 / 74 (97.30%)
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    4 / 75 (5.33%)
    1 / 74 (1.35%)
         occurrences all number
    4
    1
    Hypertension
         subjects affected / exposed
    12 / 75 (16.00%)
    9 / 74 (12.16%)
         occurrences all number
    12
    14
    Hypotension
         subjects affected / exposed
    11 / 75 (14.67%)
    8 / 74 (10.81%)
         occurrences all number
    16
    10
    Orthostatic hypotension
         subjects affected / exposed
    0 / 75 (0.00%)
    4 / 74 (5.41%)
         occurrences all number
    0
    5
    Surgical and medical procedures
    Ureteral stent removal
         subjects affected / exposed
    1 / 75 (1.33%)
    6 / 74 (8.11%)
         occurrences all number
    1
    6
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 75 (6.67%)
    8 / 74 (10.81%)
         occurrences all number
    5
    8
    Chills
         subjects affected / exposed
    2 / 75 (2.67%)
    4 / 74 (5.41%)
         occurrences all number
    2
    4
    Fatigue
         subjects affected / exposed
    27 / 75 (36.00%)
    24 / 74 (32.43%)
         occurrences all number
    59
    38
    Injection site erythema
         subjects affected / exposed
    8 / 75 (10.67%)
    2 / 74 (2.70%)
         occurrences all number
    14
    2
    Injection site pain
         subjects affected / exposed
    47 / 75 (62.67%)
    18 / 74 (24.32%)
         occurrences all number
    277
    46
    Oedema
         subjects affected / exposed
    5 / 75 (6.67%)
    3 / 74 (4.05%)
         occurrences all number
    5
    3
    Oedema peripheral
         subjects affected / exposed
    9 / 75 (12.00%)
    5 / 74 (6.76%)
         occurrences all number
    13
    8
    Pyrexia
         subjects affected / exposed
    9 / 75 (12.00%)
    13 / 74 (17.57%)
         occurrences all number
    11
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 75 (9.33%)
    4 / 74 (5.41%)
         occurrences all number
    8
    4
    Dyspnoea
         subjects affected / exposed
    5 / 75 (6.67%)
    8 / 74 (10.81%)
         occurrences all number
    9
    10
    Oropharyngeal pain
         subjects affected / exposed
    4 / 75 (5.33%)
    5 / 74 (6.76%)
         occurrences all number
    4
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    8 / 75 (10.67%)
    6 / 74 (8.11%)
         occurrences all number
    11
    8
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    11 / 75 (14.67%)
    16 / 74 (21.62%)
         occurrences all number
    17
    19
    Weight increased
         subjects affected / exposed
    4 / 75 (5.33%)
    3 / 74 (4.05%)
         occurrences all number
    4
    3
    White blood cell count decreased
         subjects affected / exposed
    1 / 75 (1.33%)
    4 / 74 (5.41%)
         occurrences all number
    1
    12
    Injury, poisoning and procedural complications
    Complications of transplant surgery
         subjects affected / exposed
    2 / 75 (2.67%)
    4 / 74 (5.41%)
         occurrences all number
    2
    4
    Complications of transplanted kidney
         subjects affected / exposed
    4 / 75 (5.33%)
    4 / 74 (5.41%)
         occurrences all number
    4
    4
    Procedural pain
         subjects affected / exposed
    6 / 75 (8.00%)
    2 / 74 (2.70%)
         occurrences all number
    10
    2
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    5 / 75 (6.67%)
    3 / 74 (4.05%)
         occurrences all number
    5
    3
    Tachycardia
         subjects affected / exposed
    5 / 75 (6.67%)
    3 / 74 (4.05%)
         occurrences all number
    5
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 75 (4.00%)
    9 / 74 (12.16%)
         occurrences all number
    3
    12
    Headache
         subjects affected / exposed
    13 / 75 (17.33%)
    12 / 74 (16.22%)
         occurrences all number
    13
    14
    Tremor
         subjects affected / exposed
    10 / 75 (13.33%)
    7 / 74 (9.46%)
         occurrences all number
    11
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 75 (9.33%)
    4 / 74 (5.41%)
         occurrences all number
    7
    4
    Leukopenia
         subjects affected / exposed
    29 / 75 (38.67%)
    19 / 74 (25.68%)
         occurrences all number
    32
    23
    Neutropenia
         subjects affected / exposed
    10 / 75 (13.33%)
    6 / 74 (8.11%)
         occurrences all number
    11
    6
    Thrombocytopenia
         subjects affected / exposed
    1 / 75 (1.33%)
    5 / 74 (6.76%)
         occurrences all number
    1
    6
    Eye disorders
    Vision blurred
         subjects affected / exposed
    5 / 75 (6.67%)
    1 / 74 (1.35%)
         occurrences all number
    5
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    8 / 75 (10.67%)
    6 / 74 (8.11%)
         occurrences all number
    9
    7
    Abdominal pain upper
         subjects affected / exposed
    5 / 75 (6.67%)
    3 / 74 (4.05%)
         occurrences all number
    5
    3
    Constipation
         subjects affected / exposed
    4 / 75 (5.33%)
    6 / 74 (8.11%)
         occurrences all number
    4
    7
    Diarrhoea
         subjects affected / exposed
    23 / 75 (30.67%)
    24 / 74 (32.43%)
         occurrences all number
    33
    38
    Dyspepsia
         subjects affected / exposed
    5 / 75 (6.67%)
    3 / 74 (4.05%)
         occurrences all number
    6
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 75 (1.33%)
    6 / 74 (8.11%)
         occurrences all number
    1
    7
    Nausea
         subjects affected / exposed
    13 / 75 (17.33%)
    14 / 74 (18.92%)
         occurrences all number
    22
    19
    Vomiting
         subjects affected / exposed
    9 / 75 (12.00%)
    9 / 74 (12.16%)
         occurrences all number
    12
    13
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 75 (5.33%)
    2 / 74 (2.70%)
         occurrences all number
    4
    2
    Alopecia
         subjects affected / exposed
    3 / 75 (4.00%)
    8 / 74 (10.81%)
         occurrences all number
    3
    9
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    5 / 75 (6.67%)
    6 / 74 (8.11%)
         occurrences all number
    5
    6
    Haematuria
         subjects affected / exposed
    6 / 75 (8.00%)
    7 / 74 (9.46%)
         occurrences all number
    8
    7
    Kidney fibrosis
         subjects affected / exposed
    7 / 75 (9.33%)
    4 / 74 (5.41%)
         occurrences all number
    7
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 75 (6.67%)
    8 / 74 (10.81%)
         occurrences all number
    7
    10
    Back pain
         subjects affected / exposed
    5 / 75 (6.67%)
    8 / 74 (10.81%)
         occurrences all number
    6
    9
    Muscle spasms
         subjects affected / exposed
    3 / 75 (4.00%)
    5 / 74 (6.76%)
         occurrences all number
    3
    6
    Muscular weakness
         subjects affected / exposed
    0 / 75 (0.00%)
    4 / 74 (5.41%)
         occurrences all number
    0
    4
    Musculoskeletal discomfort
         subjects affected / exposed
    4 / 75 (5.33%)
    6 / 74 (8.11%)
         occurrences all number
    11
    7
    Musculoskeletal pain
         subjects affected / exposed
    4 / 75 (5.33%)
    2 / 74 (2.70%)
         occurrences all number
    4
    2
    Myalgia
         subjects affected / exposed
    21 / 75 (28.00%)
    15 / 74 (20.27%)
         occurrences all number
    38
    22
    Pain in extremity
         subjects affected / exposed
    4 / 75 (5.33%)
    8 / 74 (10.81%)
         occurrences all number
    5
    9
    Infections and infestations
    BK virus infection
         subjects affected / exposed
    16 / 75 (21.33%)
    16 / 74 (21.62%)
         occurrences all number
    17
    18
    Cytomegalovirus infection
         subjects affected / exposed
    3 / 75 (4.00%)
    5 / 74 (6.76%)
         occurrences all number
    4
    7
    Cytomegalovirus syndrome
         subjects affected / exposed
    7 / 75 (9.33%)
    6 / 74 (8.11%)
         occurrences all number
    7
    6
    Cytomegalovirus viraemia
         subjects affected / exposed
    22 / 75 (29.33%)
    19 / 74 (25.68%)
         occurrences all number
    30
    22
    Escherichia urinary tract infection
         subjects affected / exposed
    6 / 75 (8.00%)
    5 / 74 (6.76%)
         occurrences all number
    9
    5
    Nasopharyngitis
         subjects affected / exposed
    8 / 75 (10.67%)
    8 / 74 (10.81%)
         occurrences all number
    10
    10
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 75 (10.67%)
    7 / 74 (9.46%)
         occurrences all number
    9
    7
    Urinary tract infection
         subjects affected / exposed
    10 / 75 (13.33%)
    4 / 74 (5.41%)
         occurrences all number
    17
    5
    Urinary tract infection bacterial
         subjects affected / exposed
    8 / 75 (10.67%)
    3 / 74 (4.05%)
         occurrences all number
    11
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 75 (4.00%)
    5 / 74 (6.76%)
         occurrences all number
    3
    5
    Diabetes mellitus
         subjects affected / exposed
    4 / 75 (5.33%)
    1 / 74 (1.35%)
         occurrences all number
    4
    1
    Hypercalcaemia
         subjects affected / exposed
    4 / 75 (5.33%)
    5 / 74 (6.76%)
         occurrences all number
    4
    5
    Hyperglycaemia
         subjects affected / exposed
    2 / 75 (2.67%)
    5 / 74 (6.76%)
         occurrences all number
    2
    6
    Hyperkalaemia
         subjects affected / exposed
    12 / 75 (16.00%)
    8 / 74 (10.81%)
         occurrences all number
    16
    8
    Hyperlipidaemia
         subjects affected / exposed
    4 / 75 (5.33%)
    3 / 74 (4.05%)
         occurrences all number
    4
    3
    Hypoglycaemia
         subjects affected / exposed
    1 / 75 (1.33%)
    6 / 74 (8.11%)
         occurrences all number
    1
    7
    Hypomagnesaemia
         subjects affected / exposed
    7 / 75 (9.33%)
    6 / 74 (8.11%)
         occurrences all number
    13
    6
    Hyponatraemia
         subjects affected / exposed
    5 / 75 (6.67%)
    1 / 74 (1.35%)
         occurrences all number
    7
    1
    Hypophosphataemia
         subjects affected / exposed
    7 / 75 (9.33%)
    7 / 74 (9.46%)
         occurrences all number
    8
    8
    Metabolic acidosis
         subjects affected / exposed
    11 / 75 (14.67%)
    4 / 74 (5.41%)
         occurrences all number
    12
    4
    Vitamin D deficiency
         subjects affected / exposed
    7 / 75 (9.33%)
    4 / 74 (5.41%)
         occurrences all number
    7
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Aug 2013
    Key changes in Substantial Amendment 1, dated 13 Aug 2013, are summarized below. • Patients with graft failure would be discontinued from treatment • 1-sided P value (not 2-sided) would be used for testing the hypothesis • Urinalysis with microscopic evaluation was added to the safety labs • Vital signs for reactogenicity assessments were added • Screening laboratory tests could be repeated once • Collect creatinine values during the long-term follow-up period, if available
    06 Jan 2014
    Key changes in Substantial Amendment 2, dated 06 Jan 2014, are summarized below. ● Screening period could begin -14 days from transplant to day of randomization ● Redefined CMV viremia as plasma viral load ≥ 1000 IU/mL ● Expanded stratification criteria for ATG to day of randomization ● Revised CMV AVP period of adjustment to after the day of randomization ● Added vital signs and evaluation of patients 15 minutes after study drug injection ● Inclusion Criterion 5 - clarified patients received valganciclovir or ganciclovir per regulatory label (package insert) ● Exclusion Criteria: Excluded patients who required dialysis on day of randomization, Deleted criterion that excluded patients who had an episode of hyperacute or acuterejection prior to Randomization, Excluded patients who received eculizumab, bortezomib, and intravenous immunoglobulin (IVIG) and/or plasmapheresis from day of transplantation through day of randomization, Clarified contraindications to prophylaxis of CMV viremia/disease with valganciclovir and ganciclovir, Clarified a contraindication to an intramuscular injection also included those who were expected to have a contraindication to the injection, Clarified aspartate aminotransferase (AST) or alanine aminotransferase (ALT) criteria was within 3 days prior to randomization, Concomitant medications – included several clarifications (dose adjustments, interruptions to therapy, time periods for prohibited medications, recording) and additional prohibited medications, Spontaneously reported SAEs during long-term follow-up that were possibly or probably related to study drug should be reported. ● Patients with a temperature ≥ 100.4°F should not receive study drug ● Transplant surgery on day 0 would not be considered an AE or SAE

    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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