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    Clinical Trial Results:
    Triple arm, prospective-randomised multi centre study phase IV to evaluate calcineurin inhibitor reduced, steroid free immunosuppression after renal transplantation in low-risk patients (HARMONY-Study)

    Summary
    EudraCT number
    		 2007-006516-31
    Trial protocol
    		 DE  
    Global end of trial date
    31 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Aug 2020
    First version publication date
    01 Aug 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IT1850071
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00724022
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical Center – University of Freiburg
    Sponsor organisation address
    Breisacher Str. 153, Freiburg, Germany, 79110
    Public contact
    Prof. Dr. Oliver Thomusch, Medical Center – University of Freiburg, +49 76127028060, oliver.thomusch@uniklinik-freiburg.de
    Scientific contact
    Prof. Dr. Oliver Thomusch, Medical Center – University of Freiburg, +49 76127028060, oliver.thomusch@uniklinik-freiburg.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Jul 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jul 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Ratio and severe of acute bioptical confirmed rejection reactions (to BANFF) as well as time to first bioptical assured rejection
    Protection of trial subjects
    The trial was performed in accordance with the Declaration of Helsinki as well as with the German Drug law and guidelines for the clinical testing of drugs. This trial was designed and monitored in accordance with the principles which have their origin in the Declaration of Helsinki and in accordance with sponsor and CRO standard operating procedures (SOPs). These SOPs comply with the ethical principles of Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Aug 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 587
    Worldwide total number of subjects
    587
    EEA total number of subjects
    587
    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)
    452
    From 65 to 84 years
    135
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 21 German centers enrolled and randomized 615 patients between January 1, 2008, and November 30, 2013.

    Pre-assignment
    Screening details
    		 The patients had to meet all inclusion criteria; patients meeting any exclusion criterion had to be excluded from the study. The inclusion and exclusion criteria referred to drug safety aspects, guidelines by regulatory authorities and the International Conference on Harmonization (ICH) / Good Clinical Practice (GCP).

    Pre-assignment period milestones
    Number of subjects started
    		 615 [1]
    Number of subjects completed
    		 587

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 No med. treatment, no kidney transplant.: 28
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 21 German centers enrolled and randomised 615 patients between 1 January 2008 and 30 November 2013; 587 patients were included in the IIT analyses.
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    After signing informed consent and after screening assessments patients were randomized 1:1:1 into either treatment arm A, B or C (no blinding).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Basiliximab and steroids
    Arm description
    		 Basiliximab induction with low-dose tacrolimus, mycophenolate mofetil, and corticosteroid maintenance therapy
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Basiliximab
    Investigational medicinal product code
    Other name
    Simulect
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Strength: 10mg, 20mg 1st dose (during initiation of the kidney transplantation): 20mg 2nd dose (day 4 after renal transplantation): 20mg

    Investigational medicinal product name
    MMF
    Investigational medicinal product code
    Other name
    CellCept
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Ocular use
    Dosage and administration details
    Strength: 500mg Preoperative and postoperative: 2 x 1000mg Day 1 until end of month 12: 2 x 1000mg

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Advagraf
    Pharmaceutical forms
    Prolonged-release capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Strength: 0.5mg, 1mg, 3mg, 5mg Operation day: 1 x 0.2 mg/kg body weight/day (preoperative) Day 1: 1 x 0.2 mg/kg body weight/day Day 2: 1 x 0.2 mg/kg body weight/day Day 3: 1 x 0.2 mg/kg body weight/day The further dose depends on the plasma concentration of TAC as follows had to be reached: Until end of month 1: 7-12 ng/ml Month 2+3: 6-10 ng/ml Month 4-12: 3-8 ng/ml

    Investigational medicinal product name
    Decortin H
    Investigational medicinal product code
    Other name
    Solu-Decortin H
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Strength: Solu-Decortin®: 10mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg Decortin ® H: 1mg, 5mg, 20mg, 50mg Day 0: 250 mg i.v. pre- and 250mg i.v. intraoperative Day 1: 100 mg i.v. Day 2: 75 mg p.o. Day 3: 50 mg p.o. Day 4-7: 25 mg p.o. From day 8: no further treatment

    Arm title
    		 Arm B: Basiliximab and rapid steroid withdrawal
    Arm description
    		 Basiliximab induction with low-dose tacrolimus, mycophenolate mofetil, and rapid corticosteroid withdrawal on day 8
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Basiliximab
    Investigational medicinal product code
    Other name
    Simulect
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Strength: 10mg, 20mg 1st dose (during initiation of the kidney transplantation): 20mg 2nd dose (day 4 after renal transplantation): 20mg

    Investigational medicinal product name
    MMF
    Investigational medicinal product code
    Other name
    CellCept
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Ocular use
    Dosage and administration details
    Strength: 500mg Preoperative and postoperative: 2 x 1000mg Day 1 until end of month 12: 2 x 1000mg

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Advagraf
    Pharmaceutical forms
    Prolonged-release capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Strength: 0.5mg, 1mg, 3mg, 5mg Operation day: 1 x 0.2 mg/kg body weight/day (preoperative) Day 1: 1 x 0.2 mg/kg body weight/day Day 2: 1 x 0.2 mg/kg body weight/day Day 3: 1 x 0.2 mg/kg body weight/day The further dose depends on the plasma concentration of TAC as follows had to be reached: Until end of month 1: 7-12 ng/ml Month 2+3: 6-10 ng/ml Month 4-12: 3-8 ng/ml

    Investigational medicinal product name
    Decortin H
    Investigational medicinal product code
    Other name
    Solu-Decortin H
    Pharmaceutical forms
    Tablet, Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Strength: Solu-Decortin®: 10mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg Decortin ® H: 1mg, 5mg, 20mg, 50mg Day 0: 250 mg i.v. pre- and 250mg i.v. intraoperative Day 1: 100 mg i.v. Day 2: 75 mg p.o. Day 3: 50 mg p.o. Day 4-7: 25 mg p.o. From day 8: no further treatment

    Arm title
    		 Arm C: Rabbit ATG induction therapy + rapid steroid withdrawal
    Arm description
    		 Rabbit antithymocyte globulin (rabbit ATG) induction therapy, and rapid corticosteroid withdrawal on day 8
    Arm type
    		 Experimental

    Investigational medicinal product name
    rATG
    Investigational medicinal product code
    Other name
    Thymoglobulin
    Pharmaceutical forms
    Powder for solution for infusion, Solvent for solution for infusion
    Routes of administration
    Intracavernous use
    Dosage and administration details
    Strength: 5 mg/ml Day 0 intraoperative: 1.5 mg/kg body weight Day 1: 1.5 mg/kg body weight Day 2: 1.5 mg/kg body weight Day 3: 1.5 mg/kg body weight (provided lymphocytes > 200/µl)

    Investigational medicinal product name
    MMF
    Investigational medicinal product code
    Other name
    CellCept
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Ocular use
    Dosage and administration details
    Strength: 500mg Preoperative and postoperative: 2 x 1000mg Day 1 until end of month 12: 2 x 1000mg

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Advagraf
    Pharmaceutical forms
    Prolonged-release capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Strength: 0.5mg, 1mg, 3mg, 5mg Operation day: 1 x 0.2 mg/kg body weight/day (preoperative) Day 1: 1 x 0.2 mg/kg body weight/day Day 2: 1 x 0.2 mg/kg body weight/day Day 3: 1 x 0.2 mg/kg body weight/day

    Investigational medicinal product name
    Decortin H
    Investigational medicinal product code
    Other name
    Solu-Decortin H
    Pharmaceutical forms
    Powder for suspension for injection, Solvent for solution for infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Strength: Solu-Decortin®: 10mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg Decortin ® H: 1mg, 5mg, 20mg, 50mg Day 0: 250 mg i.v. pre- and 250mg i.v. intraoperative Day 1: 100 mg i.v. Day 2: 75 mg p.o. Day 3: 50 mg p.o. Day 4-7: 25 mg p.o. From day 8: no further treatment

    Investigational medicinal product name
    Basiliximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1st dose (during initiation of the kidney transplantation): 20mg 2nd dose (day 4 after renal transplantation): 20mg

    Number of subjects in period 1
    		Arm A: Basiliximab and steroids Arm B: Basiliximab and rapid steroid withdrawal Arm C: Rabbit ATG induction therapy + rapid steroid withdrawal
    Started
    206
    189
    192
    Completed
    135
    123
    115
    Not completed
    71
    66
    77
         Graft losses
    6
    5
    9
         Withdrawal by participants
    18
    15
    15
         Adverse events
    11
    5
    11
         Screening failures
    3
    1
    3
         Other
    6
    19
    13
         Deaths
    11
    4
    5
         Lost to follow-up
    5
    3
    7
         Lack of efficacy
    2
    4
    3
         Protocol deviation
    9
    10
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Basiliximab and steroids
    Reporting group description
    		 Basiliximab induction with low-dose tacrolimus, mycophenolate mofetil, and corticosteroid maintenance therapy

    Reporting group title
    Arm B: Basiliximab and rapid steroid withdrawal
    Reporting group description
    		 Basiliximab induction with low-dose tacrolimus, mycophenolate mofetil, and rapid corticosteroid withdrawal on day 8

    Reporting group title
    Arm C: Rabbit ATG induction therapy + rapid steroid withdrawal
    Reporting group description
    		 Rabbit antithymocyte globulin (rabbit ATG) induction therapy, and rapid corticosteroid withdrawal on day 8

    Reporting group values
    		 Arm A: Basiliximab and steroids Arm B: Basiliximab and rapid steroid withdrawal Arm C: Rabbit ATG induction therapy + rapid steroid withdrawal Total
    Number of subjects
    		 206 189 192 587
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 159 139 154 452
        From 65-84 years
    		 47 50 38 135
        85 years and over
    		 0 0 0 0
    Age continuous
    Demographic and other Baseline Characteristics of the intention to treat / safety population (N=587)
    Units: years
        arithmetic mean (standard deviation)
    		 54.5 ( 11.9 ) 54.0 ( 12.8 ) 53.6 ( 11.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 65 67 68 200
        Male
    		 141 122 124 387
    Subject analysis sets

    Subject analysis set title
    Intention-to-treat / Safety
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    intention to treat / safety population: N=587

    Subject analysis sets values
    		 Intention-to-treat / Safety
    Number of subjects
    587
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    452
        From 65-84 years
    135
        85 years and over
    0
    Age continuous
    Demographic and other Baseline Characteristics of the intention to treat / safety population (N=587)
    Units: years
        arithmetic mean (standard deviation)
    54.1 ( 12.2 )
    Gender categorical
    Units: Subjects
        Female
    200
        Male
    387

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Basiliximab and steroids
    Reporting group description
    		 Basiliximab induction with low-dose tacrolimus, mycophenolate mofetil, and corticosteroid maintenance therapy

    Reporting group title
    Arm B: Basiliximab and rapid steroid withdrawal
    Reporting group description
    		 Basiliximab induction with low-dose tacrolimus, mycophenolate mofetil, and rapid corticosteroid withdrawal on day 8

    Reporting group title
    Arm C: Rabbit ATG induction therapy + rapid steroid withdrawal
    Reporting group description
    		 Rabbit antithymocyte globulin (rabbit ATG) induction therapy, and rapid corticosteroid withdrawal on day 8

    Subject analysis set title
    Intention-to-treat / Safety
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    intention to treat / safety population: N=587

    Primary: Biopsy proven rejection rate (excluding borderline)

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    End point title
    		 Biopsy proven rejection rate (excluding borderline)
    End point description
    Biopsy proven rejection rates (excluding borderline) (additional analysis)
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Arm A: Basiliximab and steroids Arm B: Basiliximab and rapid steroid withdrawal Arm C: Rabbit ATG induction therapy + rapid steroid withdrawal Intention-to-treat / Safety
    Number of subjects analysed
    206 [1]
    189 [2]
    192 [3]
    587 [4]
    Units: Rejections
        Yes
    23
    20
    19
    62
        No
    183
    169
    173
    525
    Notes
    [1] - IIT / Safety population
    [2] - IIT / Safety population
    [3] - IIT / Safety population
    [4] - ITT / Safety population
    Statistical analysis title
    		 Primary efficacy analysis BPAR rate: group A vs C
    Statistical analysis description
    The primary efficacy analysis was performed according to the intention-to-treat principle.
    Comparison groups
    Arm A: Basiliximab and steroids v Arm C: Rabbit ATG induction therapy + rapid steroid withdrawal v Intention-to-treat / Safety
    Number of subjects included in analysis
    985
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7452
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Primary efficacy analysis BPAR rate: group B vs C
    Statistical analysis description
    The primary efficacy analysis was performed according to the intention-to-treat principle.
    Comparison groups
    Arm B: Basiliximab and rapid steroid withdrawal v Arm C: Rabbit ATG induction therapy + rapid steroid withdrawal v Intention-to-treat / Safety
    Number of subjects included in analysis
    968
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8669
    Method
    		 Fisher exact
    Confidence interval

    Primary: Severity of biopsy proven rejections (BANFF)

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    End point title
    		 Severity of biopsy proven rejections (BANFF)
    End point description
    End point type
    Primary
    End point timeframe
    Within the first year after renal transplantation
    End point values
    		 Arm A: Basiliximab and steroids Arm B: Basiliximab and rapid steroid withdrawal Arm C: Rabbit ATG induction therapy + rapid steroid withdrawal Intention-to-treat / Safety
    Number of subjects analysed
    206
    189
    192
    587
    Units: Number of patients
        Acute T-cell mediated rejection (Banff 1A)
    8
    9
    5
    22
        Acute T-cell mediated rejection (Banff 1b)
    1
    1
    1
    3
        Acute T-cell mediated rejection (Banff 2a)
    7
    7
    2
    16
        Acute T-cell mediated rejection (Banff 2B)
    0
    1
    0
    1
        Acute antibody-mediated rejection (BANFF 1)
    2
    1
    1
    4
        Acute antibody-mediated rejection (BANFF 2)
    1
    1
    2
    4
        Acute antibody-mediated rejection (BANFF 3)
    0
    0
    1
    1
    Statistical analysis title
    		 Severity of biopsy proven rejections
    Comparison groups
    Arm B: Basiliximab and rapid steroid withdrawal v Arm C: Rabbit ATG induction therapy + rapid steroid withdrawal v Arm A: Basiliximab and steroids v Intention-to-treat / Safety
    Number of subjects included in analysis
    1174
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.88
    Method
    		 Fisher exact
    Confidence interval

    Post-hoc: Biopsy proven rejection rate (including borderline)

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    End point title
    		 Biopsy proven rejection rate (including borderline)
    End point description
    The primary objective was the rate and degree of severity of acute rejections confirmed by biopsy and also assessment of the time to first rejection confirmed by biopsy.
    End point type
    Post-hoc
    End point timeframe
    12 months
    End point values
    		 Arm A: Basiliximab and steroids Arm B: Basiliximab and rapid steroid withdrawal Arm C: Rabbit ATG induction therapy + rapid steroid withdrawal Intention-to-treat / Safety
    Number of subjects analysed
    206 [5]
    189 [6]
    192 [7]
    587 [8]
    Units: Rejections
        Yes
    34
    28
    27
    89
        No
    172
    161
    165
    498
    Notes
    [5] - IIT / Safety population
    [6] - IIT / Safety population
    [7] - IIT / Safety population
    [8] - IIT / Safety population
    Statistical analysis title
    		 Biopsy proven rejection rates (incl. borderline)
    Statistical analysis description
    Analysis of Efficacy: Biopsy proven rejection rates (including borderline) (additional analysis)
    Comparison groups
    Arm A: Basiliximab and steroids v Arm C: Rabbit ATG induction therapy + rapid steroid withdrawal v Intention-to-treat / Safety
    Number of subjects included in analysis
    985
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.578
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Biopsy proven rejection rates (incl. borderline)
    Statistical analysis description
    Analysis of Efficacy: Biopsy proven rejection rates (including borderline) (additional analysis)
    Comparison groups
    Arm A: Basiliximab and steroids v Arm B: Basiliximab and rapid steroid withdrawal v Intention-to-treat / Safety
    Number of subjects included in analysis
    982
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.12

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Date of Randomization to End of Treatment
    Adverse event reporting additional description
    Safety was evaluated by clinical assessment including vital signs and laboratory analyses designed to determine the incidence of all adverse and serious adverse events, infections, malignancies, and death throughout the study. Documentation of clinical signs and laboratory data were obtained at baseline, day 7, day 14, months 1, 3, 6, 9, and 12.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    TRT Group A
    Reporting group description
    		 -

    Reporting group title
    TRT Group B
    Reporting group description
    		 -

    Reporting group title
    TRT Group C
    Reporting group description
    		 -

    Serious adverse events
    		 TRT Group A TRT Group B TRT Group C
    Total subjects affected by serious adverse events
         subjects affected / exposed
    118 / 206 (57.28%)
    129 / 189 (68.25%)
    111 / 192 (57.81%)
         number of deaths (all causes)
    8
    3
    6
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm malignant
         subjects affected / exposed
    5 / 206 (2.43%)
    0 / 189 (0.00%)
    4 / 192 (2.08%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    17 / 206 (8.25%)
    7 / 189 (3.70%)
    8 / 192 (4.17%)
         occurrences causally related to treatment / all
    2 / 19
    0 / 8
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Surgical and medical procedures
    Surgical procedures
         subjects affected / exposed
    3 / 206 (1.46%)
    6 / 189 (3.17%)
    3 / 192 (1.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    General disorders and administration site conditions
    General disorders
         subjects affected / exposed
    15 / 206 (7.28%)
    8 / 189 (4.23%)
    8 / 192 (4.17%)
         occurrences causally related to treatment / all
    3 / 15
    1 / 8
    1 / 9
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    1 / 3
    Immune system disorders
    Immune system disorder
         subjects affected / exposed
    13 / 206 (6.31%)
    18 / 189 (9.52%)
    9 / 192 (4.69%)
         occurrences causally related to treatment / all
    6 / 13
    8 / 18
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Social problem
         subjects affected / exposed
    0 / 206 (0.00%)
    1 / 189 (0.53%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Reproductive tract disorder
         subjects affected / exposed
    4 / 206 (1.94%)
    4 / 189 (2.12%)
    2 / 192 (1.04%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorder
         subjects affected / exposed
    7 / 206 (3.40%)
    5 / 189 (2.65%)
    4 / 192 (2.08%)
         occurrences causally related to treatment / all
    0 / 7
    2 / 5
    2 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Psychiatric disorders
    Psychiatric symptom
         subjects affected / exposed
    1 / 206 (0.49%)
    7 / 189 (3.70%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Investigation
         subjects affected / exposed
    29 / 206 (14.08%)
    37 / 189 (19.58%)
    30 / 192 (15.63%)
         occurrences causally related to treatment / all
    4 / 39
    17 / 25
    9 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Poisoning
         subjects affected / exposed
    17 / 206 (8.25%)
    21 / 189 (11.11%)
    24 / 192 (12.50%)
         occurrences causally related to treatment / all
    3 / 19
    5 / 24
    5 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac disorder
         subjects affected / exposed
    15 / 206 (7.28%)
    9 / 189 (4.76%)
    11 / 192 (5.73%)
         occurrences causally related to treatment / all
    2 / 16
    0 / 9
    1 / 12
         deaths causally related to treatment / all
    1 / 2
    0 / 2
    0 / 2
    Nervous system disorders
    Nervous system disorder
         subjects affected / exposed
    4 / 206 (1.94%)
    3 / 189 (1.59%)
    3 / 192 (1.56%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    Blood and lymphatic system disorders
    Blood disorder
         subjects affected / exposed
    4 / 206 (1.94%)
    8 / 189 (4.23%)
    7 / 192 (3.65%)
         occurrences causally related to treatment / all
    4 / 4
    6 / 8
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorder
    Additional description: From Date of Randomization to End of Treatment
         subjects affected / exposed
    13 / 206 (6.31%)
    20 / 189 (10.58%)
    10 / 192 (5.21%)
         occurrences causally related to treatment / all
    5 / 15
    8 / 21
    3 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatobiliary disease
         subjects affected / exposed
    3 / 206 (1.46%)
    3 / 189 (1.59%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin disorder
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 189 (0.00%)
    0 / 192 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal disorder
         subjects affected / exposed
    29 / 206 (14.08%)
    24 / 189 (12.70%)
    20 / 192 (10.42%)
         occurrences causally related to treatment / all
    8 / 39
    5 / 25
    6 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal disorder
         subjects affected / exposed
    1 / 206 (0.49%)
    0 / 189 (0.00%)
    1 / 192 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infection
    Additional description: From Date of Randomization to End of Treatment
         subjects affected / exposed
    36 / 206 (17.48%)
    35 / 189 (18.52%)
    31 / 192 (16.15%)
         occurrences causally related to treatment / all
    17 / 48
    22 / 47
    28 / 38
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Metabolic disorder
    Additional description: From Date of Randomization to End of Treatment
         subjects affected / exposed
    5 / 206 (2.43%)
    5 / 189 (2.65%)
    5 / 192 (2.60%)
         occurrences causally related to treatment / all
    5 / 5
    2 / 6
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TRT Group A TRT Group B TRT Group C
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    196 / 206 (95.15%)
    185 / 189 (97.88%)
    183 / 192 (95.31%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm malignant
         subjects affected / exposed
    14 / 206 (6.80%)
    8 / 189 (4.23%)
    12 / 192 (6.25%)
         occurrences all number
    15
    14
    14
    Vascular disorders
    Vascular
         subjects affected / exposed
    65 / 206 (31.55%)
    58 / 189 (30.69%)
    48 / 192 (25.00%)
         occurrences all number
    93
    82
    68
    Surgical and medical procedures
    Surgical and medical procedures
         subjects affected / exposed
    12 / 206 (5.83%)
    11 / 189 (5.82%)
    10 / 192 (5.21%)
         occurrences all number
    13
    12
    11
    General disorders and administration site conditions
    General symptom
         subjects affected / exposed
    81 / 206 (39.32%)
    66 / 189 (34.92%)
    55 / 192 (28.65%)
         occurrences all number
    120
    106
    88
    Immune system disorders
    Immune system disorder
         subjects affected / exposed
    18 / 206 (8.74%)
    23 / 189 (12.17%)
    15 / 192 (7.81%)
         occurrences all number
    18
    23
    15
    Reproductive system and breast disorders
    Reproductive tract disorder
         subjects affected / exposed
    22 / 206 (10.68%)
    15 / 189 (7.94%)
    14 / 192 (7.29%)
         occurrences all number
    23
    16
    17
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorder
         subjects affected / exposed
    32 / 206 (15.53%)
    39 / 189 (20.63%)
    38 / 192 (19.79%)
         occurrences all number
    54
    56
    56
    Psychiatric disorders
    Psychiatric symptom
         subjects affected / exposed
    54 / 206 (26.21%)
    67 / 189 (35.45%)
    51 / 192 (26.56%)
         occurrences all number
    65
    82
    72
    Investigations
    Investigation
         subjects affected / exposed
    84 / 206 (40.78%)
    97 / 189 (51.32%)
    90 / 192 (46.88%)
         occurrences all number
    110
    134
    132
    Injury, poisoning and procedural complications
    Poisoning
         subjects affected / exposed
    91 / 206 (44.17%)
    91 / 189 (48.15%)
    90 / 192 (46.88%)
         occurrences all number
    142
    145
    139
    Cardiac disorders
    Cardiac disorder
         subjects affected / exposed
    38 / 206 (18.45%)
    26 / 189 (13.76%)
    33 / 192 (17.19%)
         occurrences all number
    47
    38
    42
    Nervous system disorders
    Nervous system disorder
         subjects affected / exposed
    53 / 206 (25.73%)
    43 / 189 (22.75%)
    50 / 192 (26.04%)
         occurrences all number
    67
    57
    66
    Blood and lymphatic system disorders
    Lymphatic disorder
         subjects affected / exposed
    72 / 206 (34.95%)
    86 / 189 (45.50%)
    94 / 192 (48.96%)
         occurrences all number
    104
    115
    156
    All blood systems
         subjects affected / exposed
    196 / 206 (95.15%)
    185 / 189 (97.88%)
    183 / 192 (95.31%)
         occurrences all number
    1838
    1834
    5371
    Eye disorders
    Eye disorder
         subjects affected / exposed
    10 / 206 (4.85%)
    11 / 189 (5.82%)
    8 / 192 (4.17%)
         occurrences all number
    10
    12
    8
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    104 / 206 (50.49%)
    113 / 189 (59.79%)
    100 / 192 (52.08%)
         occurrences all number
    245
    244
    228
    Skin and subcutaneous tissue disorders
    Skin disorder
         subjects affected / exposed
    31 / 206 (15.05%)
    40 / 189 (21.16%)
    21 / 192 (10.94%)
         occurrences all number
    40
    56
    30
    Renal and urinary disorders
    Renal disorder
         subjects affected / exposed
    87 / 206 (42.23%)
    65 / 189 (34.39%)
    68 / 192 (35.42%)
         occurrences all number
    167
    131
    111
    Musculoskeletal and connective tissue disorders
    Musculoskeletal disorder
         subjects affected / exposed
    38 / 206 (18.45%)
    48 / 189 (25.40%)
    43 / 192 (22.40%)
         occurrences all number
    62
    66
    58
    Infections and infestations
    Infection
         subjects affected / exposed
    98 / 206 (47.57%)
    82 / 189 (43.39%)
    78 / 192 (40.63%)
         occurrences all number
    148
    130
    115
    Metabolism and nutrition disorders
    Metabolic disorder
         subjects affected / exposed
    110 / 206 (53.40%)
    103 / 189 (54.50%)
    95 / 192 (49.48%)
         occurrences all number
    248
    252
    237

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Sep 2008
    Amendment No. 3 (D3), Version 1.0, dated 30 Sep 2008 Additional sites
    25 Aug 2011
    Study Protocol, Version 4.0, dated 25 Aug 2011 Change of Sponsor

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27871759
    For support, Contact us.
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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