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    Clinical Trial Results:
    A Multicenter, Single-Arm Study of the Effects of Atrasentan on Spermatogenesis and Testicular Function

    Summary
    EudraCT number
    		 2016-000722-19
    Trial protocol
    		 DE   ES  
    Global end of trial date
    12 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jun 2019
    First version publication date
    22 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M12-919
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02118714
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie Deutschland GmbH & Co. KG
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6-4UB
    Public contact
    Global Medical Services, AbbVie, 001 800-633-9110,
    Scientific contact
    Melissa Wigderson, AbbVie, melissa.wigderson@abbvie.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Jul 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study was conducted to evaluate the effects of Atrasentan on sperm production and testicular function in male subjects with Type 1 or 2 Diabetes and Nephropathy. This study included 2 periods: a Treatment Period (up to 26 weeks) followed by an Observational Period (up to an additional 52 weeks).
    Protection of trial subjects
    Subject read and understood the information provided about the study and gave written permission.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Apr 2015
    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: 11
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    20
    EEA total number of subjects
    11
    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)
    14
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The Safety Analysis Set included all enrolled participants who received >= 1 dose of Atrasentan (N = 20); of these 20, 6 participants entered an Observational Period of up to an additional 52 weeks.

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

    Arms
    Arm title
    		 Atrasentan
    Arm description
    		 Atrasentan 0.75 mg administered orally once daily (QD).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atrasentan
    Investigational medicinal product code
    Other name
    Atrasentan
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Atrasentan 0.75 mg administered orally once daily (QD) for 26 weeks

    Number of subjects in period 1
    		Atrasentan
    Started
    20
    Completed
    17
    Not completed
    3
         Lost to follow-up
    2
         Protocol deviation
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Atrasentan
    Reporting group description
    		 Atrasentan 0.75 mg administered orally once daily (QD).

    Reporting group values
    		 Atrasentan Total
    Number of subjects
    		 20 20
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.1 ± 12.94 -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 20 20

    End points

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    End points reporting groups
    Reporting group title
    Atrasentan
    Reporting group description
    		 Atrasentan 0.75 mg administered orally once daily (QD).

    Subject analysis set title
    Evaluable Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects who met 1 of the following: Study drug compliance ≥ 70%, completed Treatment Period, all planned sperm samples collected; or 2) at least 1 dose study drug, a sperm concentration value that was <15 million/mL observed by the end of the Treatment Period or had a ≥50% reduction from Baseline at the end of the Treatment Period.

    Primary: Percentage of Subjects With a Sperm Concentration < 15 Million Per mL by Treatment Week 26

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    End point title
    		 Percentage of Subjects With a Sperm Concentration < 15 Million Per mL by Treatment Week 26 [1]
    End point description
    Percentage of Subjects with a Sperm Concentration < 15 million per mL by Treatment Week 26. Sperm concentration was calculated as measure of the number sperm per milliliter of semen. Duplicate semen samples were collected. The average of the 2 samples were used as the value for that scheduled collection period.
    End point type
    Primary
    End point timeframe
    Up to 26 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistical analyses were provided based on the point estimate and its 80% and 95% confidence intervals (CI). The percentage of subjects and a 2-sided exact 80% CI was calculated as: 23.5% (10.7 – 41.6 CI). The percentage of subjects and a 2-sided exact 95% CI was calculated as: 23.5% (6.8 – 49.9 CI).
    End point values
    		 Evaluable Set
    Number of subjects analysed
    17
    Units: Percentage of subjects
        number (not applicable)
    23.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Entered the Observation Period and Did Not Return to Within 15% of Baseline Sperm Concentration or Above During the 52-Week Observational Period

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    End point title
    		 Percentage of Participants Who Entered the Observation Period and Did Not Return to Within 15% of Baseline Sperm Concentration or Above During the 52-Week Observational Period
    End point description
    The percentage of participants who entered the Observational Period and did not return to within 15% of Baseline sperm concentration or above during the 52-week Observational Period. Duplicate semen samples were to be collected during the Observational Period. Sperm concentration was calculated as measure of the number sperm per milliliter of semen. Duplicate semen samples were collected. The average of the 2 samples were used as the value for that scheduled collection period.
    End point type
    Secondary
    End point timeframe
    Up to 52 weeks after the Treatment Period
    End point values
    		 Evaluable Set
    Number of subjects analysed
    17
    Units: Percentage of participants
        number (confidence interval 80%)
    11.8 (3.2 to 28.4)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Entered the Observation Period and Did Not Return to within 15% of Baseline Sperm Concentration or Above during the 52-Week Observational Period

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    End point title
    		 Percentage of Participants Who Entered the Observation Period and Did Not Return to within 15% of Baseline Sperm Concentration or Above during the 52-Week Observational Period
    End point description
    The percentage of participants who entered the Observational Period and did not return to within 15% of Baseline sperm concentration or above during the 52-week Observational Period. Duplicate semen samples were to be collected during the Observational Period. Sperm concentration was calculated as measure of the number sperm per milliliter of semen. Duplicate semen samples were collected. The average of the 2 samples were used as the value for that scheduled collection period.
    End point type
    Secondary
    End point timeframe
    Up to 52 weeks after the Treatment Period
    End point values
    		 Evaluable Set
    Number of subjects analysed
    17
    Units: Percentage of Subjects
        number (confidence interval 95%)
    11.8 (1.5 to 36.4)
    No statistical analyses for this end point

    Secondary: Change From Baseline up to Treatment Period Week 26 and Observation Period Week 52 in Sperm Concentration

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    End point title
    		 Change From Baseline up to Treatment Period Week 26 and Observation Period Week 52 in Sperm Concentration
    End point description
    Duplicate semen samples will be collected during the Treatment and Observational Periods. The average of the 2 samples were used as the value for that scheduled collection period. A negative change from baseline indicated a decrease in sperm concentration.
    End point type
    Secondary
    End point timeframe
    Change from Week 0 up to Treatment Period Week 26 and Observation Period Week 52 in Sperm Concentration
    End point values
    		 Atrasentan
    Number of subjects analysed
    18 [2]
    Units: sperm * million per milliliter(X10^6/mL)
    arithmetic mean (standard deviation)
        Treatment Period Week 13 (n = 18)
    2.2 ± 42.21
        Treatment Period Week 26 (n = 17)
    -10.6 ± 53.44
        Observation Period Week 13 (n = 6)
    35.8 ± 113.60
        Observation Period Week 26 (n = 2)
    -16.5 ± 0.00
        Observation Period Week 39 (n = 2)
    -27.5 ± 19.09
        Observation Period Week 52 (n = 2)
    -25.8 ± 1.06
    Notes
    [2] - Subjects in the Safety Analysis Set with evaluable data at both baseline and the given time point.
    No statistical analyses for this end point

    Secondary: Change From Baseline up to Treatment Period Week 26 and Observation Period Week 52 in Sperm Motility

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    End point title
    		 Change From Baseline up to Treatment Period Week 26 and Observation Period Week 52 in Sperm Motility
    End point description
    Duplicate semen samples will be collected during the Treatment and Observation Periods. The average of the 2 samples were used as the value for that scheduled collection period. A negative change from baseline indicated a lower sperm motility (worsening).
    End point type
    Secondary
    End point timeframe
    From Week 0 up to Treatment Period Week 26 and Observation Observation Week 52
    End point values
    		 Atrasentan
    Number of subjects analysed
    18 [3]
    Units: Percent motility
    arithmetic mean (standard deviation)
        Treatment Period Week 13 (n = 18)
    -5.8 ± 13.65
        Treatment Period Week 26 (n = 17)
    -7.4 ± 15.77
        Observation Period Week 13 (n = 6)
    -0.3 ± 19.20
        Observation Period Week 26 (n = 2)
    -6.3 ± 5.30
        Observation Period Week 39 (n = 2)
    10.8 ± 15.20
        Observation Period Week 52 (n = 2)
    1.8 ± 16.62
    Notes
    [3] - Subjects in the Safety Analysis Set with evaluable data at both baseline and the given time point.
    No statistical analyses for this end point

    Secondary: Change From Baseline up to Treatment Period Week 26 and Observation Period Week 52 in Sperm Morphology

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    End point title
    		 Change From Baseline up to Treatment Period Week 26 and Observation Period Week 52 in Sperm Morphology
    End point description
    Duplicate semen samples will be collected during the Treatment and Observational Periods. The percentage of sperm with normal versus abnormal morphology will be determined via microscopic analysis. A positive change from baseline indicates an improved sperm morphology.
    End point type
    Secondary
    End point timeframe
    From Week 0 up to Treatment Period Week 26 and Observation Period Week 52
    End point values
    		 Atrasentan
    Number of subjects analysed
    18 [4]
    Units: percentagle of normal
    arithmetic mean (standard deviation)
        Treatment Period Week 13 (n = 18)
    -1.1 ± 4.78
        Treatment Period Week 26 (n = 17)
    -2.2 ± 7.54
        Observation Period Week 13 (n = 6)
    -0.8 ± 7.53
        Observation Period Week 26 (n = 2)
    -6.8 ± 0.35
        Observation Period Week 39 (n = 2)
    -2.3 ± 1.77
        Observation Period Week 52 (n = 2)
    1.8 ± 0.35
    Notes
    [4] - Subjects in the Safety Analysis Set with evaluable data at both baseline and the given time point.
    No statistical analyses for this end point

    Secondary: Change From Baseline up to Treatment Period Week 26 and Observation Period Week 52 in Semen Volume

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    End point title
    		 Change From Baseline up to Treatment Period Week 26 and Observation Period Week 52 in Semen Volume
    End point description
    Duplicate semen samples will be collected during the Treatment and Observation Periods. The average of the 2 samples were used as the value for that scheduled collection period. A negative change from baseline indicated a decrease in semen volume.
    End point type
    Secondary
    End point timeframe
    From Week 0 to up to Treatment Period Week 26 and Observation Period Week 52
    End point values
    		 Atrasentan
    Number of subjects analysed
    18 [5]
    Units: milliliter (mL)
    arithmetic mean (standard deviation)
        Treatment Period Week 13 (n = 18)
    0.0 ± 0.65
        Treatment Period Week 26 (n = 17)
    -0.3 ± 0.75
        Observation Period Week 13 (n = 6)
    0.0 ± 1.39
        Observation Period Week 26 (n = 2)
    0.0 ± 0.35
        Observation Period Week 39 (n = 2)
    0.1 ± 0.42
        Observation Period Week 52 (n = 2)
    -0.4 ± 0.14
    Notes
    [5] - Subjects in the Safety Analysis Set with evaluable data at both baseline and the given time point.
    No statistical analyses for this end point

    Secondary: Change From Baseline up to Treatment Period Week 26 and Observation Period Week 52 in Serum Testosterone

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    End point title
    		 Change From Baseline up to Treatment Period Week 26 and Observation Period Week 52 in Serum Testosterone
    End point description
    Serum hormones levels will be tested during the Treatment and Observational Periods. A negative change from baseline indicated a decrease in serum testosterone.
    End point type
    Secondary
    End point timeframe
    From Week 0 up to Treatment Period Week 26 and Observation Period Week 52
    End point values
    		 Atrasentan
    Number of subjects analysed
    18 [6]
    Units: nanomole/liter (nmol/L)
    arithmetic mean (standard deviation)
        Treatment Period Week 13 (n = 18)
    0.2 ± 2.18
        Treatment Period Week 26 (n = 18)
    0.8 ± 2.33
        Observation Period Week 13 (n = 5)
    0.6 ± 2.08
        Observation Period Week 26 (n = 3)
    -0.3 ± 0.85
        Observation Period Week 39 (n = 2)
    -1.6 ± 1.37
        Observation Period Week 52 (n = 2)
    -1.1 ± 1.68
    Notes
    [6] - Subjects in the Safety Analysis Set with evaluable data at both baseline and the given time point.
    No statistical analyses for this end point

    Secondary: Change From Baseline up to Treatment Period Week 26 and Observation Period Week 52 in Estradiol

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    End point title
    		 Change From Baseline up to Treatment Period Week 26 and Observation Period Week 52 in Estradiol
    End point description
    Serum hormones levels were tested during the Treatment and Observational Periods. A negative change from baseline indicated a decrease in serum estradiol.
    End point type
    Secondary
    End point timeframe
    From Week 0 up to Treatment Period Week 26 and Observation Period Week 52
    End point values
    		 Atrasentan
    Number of subjects analysed
    18 [7]
    Units: Picmoles per litre (pmol/L)
    arithmetic mean (standard deviation)
        Treatment Period Week 13 (n = 18)
    -11.7 ± 44.57
        Treatment Period Week 26 (n = 18)
    -18.6 ± 42.04
        Observation Period Week 13 (n = 6)
    -17.8 ± 62.78
        Observation Period Week 26 (n = 3)
    -47.3 ± 39.97
        Observation Period Week 39 (n = 2)
    20.3 ± 4.78
        Observation Period Week 52 (n = 2)
    10.5 ± 45.54
    Notes
    [7] - Subjects in the Safety Analysis Set with evaluable data at both baseline and the given time point.
    No statistical analyses for this end point

    Secondary: Change From Baseline up to Treatment Period Week 26 and Observation Period Week 52 in Lutenizing Hormone (LH)

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    End point title
    		 Change From Baseline up to Treatment Period Week 26 and Observation Period Week 52 in Lutenizing Hormone (LH)
    End point description
    Serum hormones levels will be tested during the Treatment and Observational Periods. A positive change from baseline indicated an increase in serum lutenizing hormone.
    End point type
    Secondary
    End point timeframe
    From Week 0 to up to Treatment Period Week 26 and Observation Period Week 52
    End point values
    		 Atrasentan
    Number of subjects analysed
    18 [8]
    Units: International Units/Liter (IU/L)
    arithmetic mean (standard deviation)
        Treatment Period Week 13 (n = 18)
    1.0 ± 2.60
        Treatment Period Week 26 (n = 18)
    0.7 ± 2.44
        Observation Period Week 13 (n = 6)
    1.3 ± 1.33
        Observation Period Week 26 (n = 3)
    1.9 ± 2.35
        Observation Period Week 39 (n = 2)
    0.5 ± 0.07
        Observation Period Week 52 (n = 2)
    1.8 ± 3.46
    Notes
    [8] - Subjects in the Safety Analysis Set with evaluable data at both baseline and the given time point.
    No statistical analyses for this end point

    Secondary: Change From Baseline up to Treatment Period Week 26 and Observation Period Week 52 in in Follicle Stimulating Hormone (FSH)

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    End point title
    		 Change From Baseline up to Treatment Period Week 26 and Observation Period Week 52 in in Follicle Stimulating Hormone (FSH)
    End point description
    Serum hormones levels will be tested during the Treatment and Observational Periods. A positive change from baseline indicated an increase in serum follicle stimulating hormone.
    End point type
    Secondary
    End point timeframe
    From Week 0 to Treatment Week 26 and Observation Week 52
    End point values
    		 Atrasentan
    Number of subjects analysed
    18 [9]
    Units: International Units/Liter (IU/L)
    arithmetic mean (standard deviation)
        Treatment Period Week 13 (n = 18)
    1.1 ± 2.43
        Treatment Period Week 26 (n = 18)
    0.8 ± 1.91
        Observation Period Week 13 (n = 6)
    0.4 ± 1.60
        Observation Period Week 26 (n = 3)
    0.7 ± 1.49
        Observation Period Week 39 (n = 2)
    0.4 ± 1.57
        Observation Period Week 52 (n = 2)
    0.8 ± 0.59
    Notes
    [9] - Subjects in the Safety Analysis Set with evaluable data at both baseline and the given time point.
    No statistical analyses for this end point

    Secondary: Change From Baseline up to Treatment Period Week 26 and Observation Period Week 52 in Inhibin B

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    End point title
    		 Change From Baseline up to Treatment Period Week 26 and Observation Period Week 52 in Inhibin B
    End point description
    Serum hormones levels will be tested during the Treatment and Observational Periods. A negative change from baseline indicated a decrease in serum Inhibin B.
    End point type
    Secondary
    End point timeframe
    From Week 0 up to Treatment Period Week 26 and Observation Period Week 52
    End point values
    		 Atrasentan
    Number of subjects analysed
    18 [10]
    Units: Picogram per milliliter (pg/mL)
    arithmetic mean (standard deviation)
        Treatment Period Week 13 (n = 18)
    -2.7 ± 24.19
        Treatment Period Week 26 (n = 18)
    -8.8 ± 34.73
        Observation Period Week 13 (n = 6)
    -7.2 ± 20.77
        Observation Period Week 26 (n = 3)
    -22.7 ± 27.10
        Observation Period Week 39 (n = 2)
    -21.0 ± 16.97
        Observation Period Week 52 (n = 2)
    -5.5 ± 2.12
    Notes
    [10] - Subjects in the Safety Analysis Set with evaluable data at both baseline and the given time point.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) were collected from first dose of study drug until 30 days after the last dose of study drug (up to approximately 30 weeks).
    Adverse event reporting additional description
    TEAEs and SAEs are defined as any AE or SAE with onset or worsening reported by a participant from the time that the first dose of atrasentan is administered until 30 days have elapsed following discontinuation of atrasentan administration. TEAEs were collected whether elicited or spontaneously reported by the participant.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Atrasentan
    Reporting group description
    		 -

    Serious adverse events
    		 Atrasentan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 20 (15.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    POSTOPERATIVE RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    AORTIC DISSECTION
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    CARDIOGENIC SHOCK
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    RESPIRATORY DISTRESS
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    OSTEOMYELITIS
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    DIABETIC KETOACIDOSIS
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Atrasentan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 20 (60.00%)
    Vascular disorders
    AORTIC ANEURYSM
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    HAEMATOMA
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    HYPERTENSION
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    HYPERTENSIVE CRISIS
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    ORTHOSTATIC HYPERTENSION
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    PERIPHERAL ARTERIAL OCCLUSIVE DISEASE
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    OEDEMA PERIPHERAL
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    4
    Social circumstances
    DENTAL PROSTHESIS USER
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    PULMONARY OEDEMA
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Psychiatric disorders
    DELIRIUM TREMENS
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    DEPRESSION
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    PANIC ATTACK
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Investigations
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    BLOOD PRESSURE INCREASED
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    WEIGHT INCREASED
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    WHITE BLOOD CELL COUNT INCREASED
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    CHEST INJURY
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    POST PROCEDURAL INFLAMMATION
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    TOOTH FRACTURE
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Cardiac disorders
    ANGINA PECTORIS
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    LEFT VENTRICULAR HYPERTROPHY
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    HAEMORRHAGIC ANAEMIA
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ear and labyrinth disorders
    EUSTACHIAN TUBE DYSFUNCTION
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    GASTRITIS
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    NAUSEA
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    TOOTH DISORDER
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    UPPER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    VOMITING
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    HAEMATURIA
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    POLLAKIURIA
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    FLANK PAIN
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    PAIN IN EXTREMITY
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    LOCALISED INFECTION
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    NASOPHARYNGITIS
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    5
    PNEUMONIA
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    TINEA CRURIS
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    TOOTH INFECTION
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    DIABETES MELLITUS
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    FLUID OVERLOAD
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    HYPERTRIGLYCERIDAEMIA
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    HYPOGLYCAEMIA
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    HYPOKALAEMIA
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    HYPOMAGNESAEMIA
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Apr 2014
    The protocol was amended to remove an exclusion criterion for hypogonadism to exclude subjects with evidence or history of hypogonadism. Also included in this amendment was guidance for managing weight gain and edema during the study.
    15 Oct 2014
    The protocol was amended to revise an exclusion criterion to allow subjects with treated retrograde ejaculation to be enrolled on the study with the approval of the Study Designated Physician. Also included in this amendment was the addition of a study requirement to address retrograde ejaculation during the course of the study and allowed the investigator discretion in obtaining replacement semen samples for potentially confounding conditions.
    06 May 2015
    The protocol was amended to revise inclusion criteria and exclusion criteria that included the following: to clarify that subjects must be on an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) (renin angiotensin system [RAS] inhibitor); to allow up to a serum brain natriuretic peptide (BNP) level of 200 ng/L at Screening; to clarify to include total abstinence as an allowed birth control method; and to remove an exclusion that excluded subjects with a history of occupational exposure to environmental toxins within the past 6 months.
    08 Apr 2016
    The protocol was amended to remove collection of duplicate semen samples at Treatment Week 4 (T4)/Week 6 visit and to remove collection of duplicate semen samples at T6/EOT visit if subject prematurely discontinued study drug as a result of entering the Observational Period. In addition, the inclusion criteria were amended and changes included the following: removed the requirement for being on a stable dose of ACEi or angiotensin II receptor blocker prior to the Screening Period, lowered the estimated glomerular filtration rate criterion to ≥ 35 mL/min/1.73 m^2, and increased the upper limit of systolic blood pressure to 180 mmHg and increased the serum potassium upper limit to 6.0 mEq/L. Exclusion criteria changes included removing the exclusion of subjects with moderate edema and pulmonary edema.

    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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