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    Clinical Trial Results:
    A Phase 3b, Two-part, Multicenter, One Year Randomized, Double-blind, Placebo-controlled Trial of the Safety, Pharmacokinetics, Tolerability, and Efficacy of Tolvaptan followed by a Two Year Open-label Extension in Children and Adolescent Subjects with Autosomal Dominant Polycystic Kidney Disease (ADPKD)

    Summary
    EudraCT number
    2016-000187-42
    Trial protocol
    GB   DE   IT   BE  
    Global end of trial date
    17 Nov 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    29 May 2022
    First version publication date
    29 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    156-12-298
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02964273
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    Sponsor organisation address
    2440 Research Boulevard, Rockville, United States, 20850
    Public contact
    Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., clinicaltransparency@otsuka-us.com
    Scientific contact
    Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., clinicaltransparency@otsuka-us.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001231-PIP02-13
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Nov 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the long term safety of treatment with tolvaptan in a pediatric and adolescent ADPKD population.
    Protection of trial subjects
    All study subjects were required to read and sign an Assent Form and subject legal guardians read and signed Informed Consent Form. Written informed consent was freely obtained from all subject’s guardian(s) or legally acceptable representative(s), as applicable for local laws.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Sep 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 32
    Country: Number of subjects enrolled
    Belgium: 20
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Italy: 29
    Worldwide total number of subjects
    91
    EEA total number of subjects
    91
    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)
    25
    Adolescents (12-17 years)
    66
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects took part in the study at 18 sites in Belgium, Germany, Italy, and the United Kingdom from 23 September 2016 to 17 November 2021.

    Pre-assignment
    Screening details
    A total of 91 subjects with autosomal dominant polycystic kidney disease (ADPKD) were randomised into 2 groups in a 1:1 ratio to receive tolvaptan or a matching placebo.

    Period 1
    Period 1 title
    Phase A: Double-blind Period (12 Months)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Phase A: Tolvaptan
    Arm description
    Subjects received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), and starting doses based on their weight as per the following specifications: ≥20 to 45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; >75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to <45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; >75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter subjects continued the same dose for 12 months. Doses may be titrated down dependent upon subject tolerability.
    Arm type
    Experimental

    Investigational medicinal product name
    Tolvaptan
    Investigational medicinal product code
    OPC-41061
    Other name
    JINARC®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tolvaptan spray-dried, immediate release tablets

    Arm title
    Phase A: Placebo
    Arm description
    Subjects received matching-placebo tablets, orally as a split-dose (with the first dose taken upon awakening and second dose taken approximately 8 hours later), and starting dose based on their weight as per the following specifications: ≥20 to <45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; >75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to <45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; >75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter subjects continued the same dose for 12 months. Doses may be titrated down dependent upon subject tolerability.
    Arm type
    Placebo

    Investigational medicinal product name
    Tolvaptan Matching-placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tolvaptan matching-placebo tablets

    Number of subjects in period 1
    Phase A: Tolvaptan Phase A: Placebo
    Started
    48
    43
    Dense Pharmacokinetic/dynamic(PK/PD) Set
    12 [1]
    8 [2]
    Completed
    44
    40
    Not completed
    4
    3
         Consent withdrawn by subject
    3
    1
         Physician decision
    -
    2
         Adverse event
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The Dense PK/PD Population included a subset of subjects half on tolvaptan and half on placebo, in the 12 to 17 year old age group who had dense PK sampling after at least 1 month on IMP.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The Dense PK/PD Population included a subset of subjects half on tolvaptan and half on placebo, in the 12 to 17 year old age group who had dense PK sampling after at least 1 month on IMP.
    Period 2
    Period 2 title
    Phase B: Open-label Period (24 Months)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Phase B: Prior Tolvaptan
    Arm description
    Qualified subjects (defined as those who were willing to continue in the trial and who did not have any adverse events [AEs] that would require investigational medicinal product [IMP] discontinuation) who received tolvaptan and completed Phase A were enrolled in Phase B and received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), and starting dose based on their body weight as per following specifications: ≥20 to <45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; >75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to <45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; >75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter subjects continued the same dose for 24 months. Doses may be titrated down dependent upon subject tolerability.
    Arm type
    Experimental

    Investigational medicinal product name
    Tolvaptan
    Investigational medicinal product code
    OPC-41061
    Other name
    JINARC®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tolvaptan spray-dried, immediate release tablets

    Arm title
    Phase B: Prior Placebo
    Arm description
    Qualified subjects (defined as those who were willing to continue in the trial and who did not have any AEs that would require IMP discontinuation) who received matching-placebo and completed Phase A, were enrolled in Phase B and received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), based on their current body weight as per following specifications: ≥20 to <45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; >75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to <45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; >75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter subjects continued the same dose for 24 months. Doses may be titrated down dependent upon subject tolerability.
    Arm type
    Experimental

    Investigational medicinal product name
    Tolvaptan
    Investigational medicinal product code
    OPC-41061
    Other name
    JINARC®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tolvaptan spray-dried, immediate release tablets

    Number of subjects in period 2 [3]
    Phase B: Prior Tolvaptan Phase B: Prior Placebo
    Started
    42
    39
    Completed
    36
    33
    Not completed
    6
    6
         Consent withdrawn by subject
    4
    3
         Reason Not Specified
    2
    1
         Adverse event
    -
    2
    Notes
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 2 Phase A: Tolvaptan completers did not enter Phase B. 1 Phase A: Placebo completer did not enter Phase B.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase A: Tolvaptan
    Reporting group description
    Subjects received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), and starting doses based on their weight as per the following specifications: ≥20 to 45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; >75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to <45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; >75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter subjects continued the same dose for 12 months. Doses may be titrated down dependent upon subject tolerability.

    Reporting group title
    Phase A: Placebo
    Reporting group description
    Subjects received matching-placebo tablets, orally as a split-dose (with the first dose taken upon awakening and second dose taken approximately 8 hours later), and starting dose based on their weight as per the following specifications: ≥20 to <45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; >75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to <45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; >75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter subjects continued the same dose for 12 months. Doses may be titrated down dependent upon subject tolerability.

    Reporting group values
    Phase A: Tolvaptan Phase A: Placebo Total
    Number of subjects
    48 43 91
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    12.9 ( 3.2 ) 12.8 ( 2.8 ) -
    Gender categorical
    Units: Subjects
        Female
    21 23 44
        Male
    27 20 47
    Race
    Units: Subjects
        White
    46 42 88
        Black or African American
    0 1 1
        Asian
    2 0 2
    EthnicityHispanic or Latino
    Units: Subjects
        Hispanic or Latino
    1 1 2
        Not Hispanic or Latino
    47 42 89

    End points

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    End points reporting groups
    Reporting group title
    Phase A: Tolvaptan
    Reporting group description
    Subjects received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), and starting doses based on their weight as per the following specifications: ≥20 to 45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; >75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to <45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; >75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter subjects continued the same dose for 12 months. Doses may be titrated down dependent upon subject tolerability.

    Reporting group title
    Phase A: Placebo
    Reporting group description
    Subjects received matching-placebo tablets, orally as a split-dose (with the first dose taken upon awakening and second dose taken approximately 8 hours later), and starting dose based on their weight as per the following specifications: ≥20 to <45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; >75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to <45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; >75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter subjects continued the same dose for 12 months. Doses may be titrated down dependent upon subject tolerability.
    Reporting group title
    Phase B: Prior Tolvaptan
    Reporting group description
    Qualified subjects (defined as those who were willing to continue in the trial and who did not have any adverse events [AEs] that would require investigational medicinal product [IMP] discontinuation) who received tolvaptan and completed Phase A were enrolled in Phase B and received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), and starting dose based on their body weight as per following specifications: ≥20 to <45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; >75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to <45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; >75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter subjects continued the same dose for 24 months. Doses may be titrated down dependent upon subject tolerability.

    Reporting group title
    Phase B: Prior Placebo
    Reporting group description
    Qualified subjects (defined as those who were willing to continue in the trial and who did not have any AEs that would require IMP discontinuation) who received matching-placebo and completed Phase A, were enrolled in Phase B and received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), based on their current body weight as per following specifications: ≥20 to <45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; >75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to <45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; >75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter subjects continued the same dose for 24 months. Doses may be titrated down dependent upon subject tolerability.

    Primary: Phase A: Change From Baseline in Spot Urine Osmolality (Pre-morning Dose)

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    End point title
    Phase A: Change From Baseline in Spot Urine Osmolality (Pre-morning Dose) [1]
    End point description
    Urine osmolality is a measure of urine concentration, measured by osmometer, which evaluates the freezing point depression of a solution and supplies results as milliosmoles per kilogram of water. Spot urine osmolality was determined for urine samples collected immediately prior to morning dosing for Day 1 (Baseline), and Week 1 for all subjects. Sample was taken after the first morning’s void and was provided as a mid-stream, clean catch sample. All subjects were fasting. The Full Analysis Set (FAS) included all subjects who were randomised to a treatment group, received at least 1 dose of the investigational medicinal product (IMP), and had both a Phase A baseline and at least 1 postbaseline efficacy evaluation. n = Number analysed is the number of subjects with data available for analysis at the given time point.
    End point type
    Primary
    End point timeframe
    Baseline, and Week 1 of Phase A
    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: Only descriptive statistics was planned to be reported for this endpoint.
    End point values
    Phase A: Tolvaptan Phase A: Placebo
    Number of subjects analysed
    48
    43
    Units: milliosmoles per kilogram (mOsm/kg)
    arithmetic mean (standard deviation)
        Baseline (n=48, 43)
    635 ( 252 )
    646 ( 250 )
        Change From Baseline at Week 1, Phase A (n =48,42)
    -386 ( 284 )
    -93 ( 332 )
    No statistical analyses for this end point

    Primary: Phase A: Change From Baseline in Specific Gravity (Pre-morning Dose)

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    End point title
    Phase A: Change From Baseline in Specific Gravity (Pre-morning Dose) [2]
    End point description
    Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney’s ability to concentrate urine. Spot urine sample for determination of specific gravity was collected immediately prior to morning dosing for Day 1 (Baseline), and Week 1 for all subjects. Sample was taken after the first morning’s void and was provided as a mid-stream, clean catch sample. All subjects were fasting. The FAS included all subjects who were randomised to a treatment group, received at least 1 dose of the IMP, and had both a Phase A baseline and at least 1 postbaseline efficacy evaluation. n=Number analysed is the number of subjects with data available for analysis at the given time point.
    End point type
    Primary
    End point timeframe
    Baseline, and Week 1 of Phase A
    Notes
    [2] - 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: Only descriptive statistics was planned to be reported for this endpoint.
    End point values
    Phase A: Tolvaptan Phase A: Placebo
    Number of subjects analysed
    48
    43
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n=48, 43)
    1.017 ( 0.006 )
    1.017 ( 0.006 )
        Change From Baseline at Week 1, Phase A (n =48,41)
    -0.009 ( 0.007 )
    -0.002 ( 0.008 )
    No statistical analyses for this end point

    Secondary: Phase A: Percent Change From Phase A Baseline in Height-Adjusted Total Kidney Volume (htTKV) as Measured by Magnetic Resonance Imaging (MRI)

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    End point title
    Phase A: Percent Change From Phase A Baseline in Height-Adjusted Total Kidney Volume (htTKV) as Measured by Magnetic Resonance Imaging (MRI)
    End point description
    htTKV is used in subjects with autosomal dominant polycystic kidney disease to predict the onset of renal insufficiency. The FAS included all subjects who were randomised to a treatment group, received at least 1 dose of the IMP, and had both a Phase A baseline and at least 1 postbaseline efficacy evaluation. Overall number analysed are the number of subjects with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline, and Month 12 of Phase A
    End point values
    Phase A: Tolvaptan Phase A: Placebo
    Number of subjects analysed
    30
    27
    Units: percent change
        arithmetic mean (standard deviation)
    2.28 ( 8.75 )
    6.11 ( 7.48 )
    No statistical analyses for this end point

    Secondary: Phase A and B: Mean 24-hour Fluid Balance Prior to Week 1

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    End point title
    Phase A and B: Mean 24-hour Fluid Balance Prior to Week 1
    End point description
    Subjects were instructed to record all fluid taken and all urine output for the 24-hour period. The FAS for Phase A included all subjects who were randomised to a treatment group, received at least 1 dose of the IMP, and had both a Phase A Baseline and at least 1 postbaseline efficacy evaluation. The FAS for Phase B included all subjects who enrolled to Phase B, received at least 1 dose of the IMP, and had both a baseline and at least 1 postbaseline efficacy evaluation in Phase B. Overall number analysed are the number of subjects with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Prior to Week 1 in Phase A and B
    End point values
    Phase A: Tolvaptan Phase A: Placebo Phase B: Prior Tolvaptan Phase B: Prior Placebo
    Number of subjects analysed
    43
    41
    37
    37
    Units: milliliter (mL)
        arithmetic mean (standard deviation)
    31 ( 1978 )
    241 ( 867 )
    138 ( 1382 )
    207 ( 1355 )
    No statistical analyses for this end point

    Secondary: Phase A: Change From Baseline in Renal Function (Estimated Glomerular Filtration Rate [eGFR] by Schwartz Formula) at Each Clinic Visit in Phase A

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    End point title
    Phase A: Change From Baseline in Renal Function (Estimated Glomerular Filtration Rate [eGFR] by Schwartz Formula) at Each Clinic Visit in Phase A
    End point description
    Renal function was assessed by estimated eGFR calculated by the Schwartz formula (eGFR = 0.413 × height [cm] /serum creatinine mg/dL), expressed as mean change in eGFR at the specified time points. The units for the data reported are milliliter per minute per 1.73 meter square (mL/min/1.73 m^2). The FAS included all subjects who were randomised to a treatment group, received at least 1 dose of the IMP, and had both a Phase A baseline and at least 1 postbaseline efficacy evaluation. n=Number analysed is the number of subjects with data available for analysis at the given time point.
    End point type
    Secondary
    End point timeframe
    Phase A Baseline, Week 1, Months 1, 6, and 12
    End point values
    Phase A: Tolvaptan Phase A: Placebo
    Number of subjects analysed
    48
    43
    Units: mL/min/1.73 m^2
    arithmetic mean (standard deviation)
        Baseline (n=48,43)
    98.8 ( 19.4 )
    99.9 ( 15.0 )
        Change From Baseline at Week 1, Phase A (n=44,42)
    -4.9 ( 10.3 )
    1.5 ( 9.2 )
        Change From Baseline at Month 1, Phase A (n=45,43)
    -2.3 ( 12.2 )
    -0.3 ( 9.2 )
        Change From Baseline at Month 6, Phase A (n=44,41)
    -0.2 ( 13.6 )
    -0.9 ( 9.2 )
        Change From Baseline at Month 12, Phase A(n=43,40)
    -1.4 ( 14.9 )
    -0.9 ( 8.5 )
    No statistical analyses for this end point

    Secondary: Phase B: Change From Phase B Baseline in Renal Function (eGFR by Schwartz Formula) at Each Clinic Visit in Phase B

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    End point title
    Phase B: Change From Phase B Baseline in Renal Function (eGFR by Schwartz Formula) at Each Clinic Visit in Phase B
    End point description
    Renal function was assessed by estimated eGFR calculated by the Schwartz formula (eGFR = 0.413 × height [cm] /serum creatinine mg/dL), expressed as mean change in eGFR at the specified time points. The FAS for Phase B included all subjects who enrolled to Phase B, received at least 1 dose of the IMP, and had both a baseline and at least 1 postbaseline efficacy evaluation in Phase B. n=Number analysed is the number of subjects with data available for analysis at the given time point.
    End point type
    Secondary
    End point timeframe
    Phase B Baseline, Week 1, Months 1, 6, 12, 18, and 24
    End point values
    Phase B: Prior Tolvaptan Phase B: Prior Placebo
    Number of subjects analysed
    42
    39
    Units: mL/min/1.73 m^2
    arithmetic mean (standard deviation)
        Phase B Baseline (n=42,39)
    97.0 ( 17.1 )
    98.5 ( 14.1 )
        Change From Baseline (CFB) at Week 1 (n=40,37)
    -1.7 ( 10.4 )
    -6.7 ( 8.0 )
        CFB at Month 1, Phase B (n=41,38)
    -0.9 ( 10.2 )
    -4.8 ( 9.0 )
        CFB at Month 6, Phase B (n=38,33)
    -4.2 ( 9.6 )
    -6.4 ( 7.9 )
        CFB at Month 12, Phase B (n=36,36)
    -5.6 ( 11.1 )
    -7.2 ( 9.3 )
        CFB at Month 18, Phase B (n=29,27)
    -3.5 ( 9.8 )
    -9.0 ( 10.9 )
        CFB at Month 24, Phase B (n=34,31)
    -5.2 ( 9.4 )
    -10.3 ( 11.0 )
    No statistical analyses for this end point

    Secondary: Phase B: Percent Change From Phase B Baseline in htTKV as Measured by MRI at Month 12 and Month 24

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    End point title
    Phase B: Percent Change From Phase B Baseline in htTKV as Measured by MRI at Month 12 and Month 24
    End point description
    htTKV is used in subjects with autosomal dominant polycystic kidney disease to predict the onset of renal insufficiency. The FAS for Phase B included all subjects who enrolled to Phase B, received at least 1 dose of the IMP, and had both a baseline and at least 1 postbaseline efficacy evaluation in Phase B. n = Number analysed is the number of subjects with data available for analysis at the given time point.
    End point type
    Secondary
    End point timeframe
    Phase B Baseline, Months 12, and 24
    End point values
    Phase B: Prior Tolvaptan Phase B: Prior Placebo
    Number of subjects analysed
    26
    23
    Units: percent change
    arithmetic mean (standard deviation)
        Percent Change From Baseline at Month 12 (n=26,23)
    7.68 ( 9.67 )
    3.09 ( 8.97 )
        Percent Change From Baseline at Month 24 (n=24,21)
    13.55 ( 12.88 )
    7.35 ( 9.57 )
    No statistical analyses for this end point

    Secondary: Phase A: 24-hour Urine Volume

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    End point title
    Phase A: 24-hour Urine Volume
    End point description
    Urine volume refers to the quantity of urine produced per unit of time. The Dense PK/PD Population included a subset of subjects half on tolvaptan and half on placebo, in the 12 to 17 year old age group who had dense PK sampling after at least 1 month on IMP. Overall number analysed are the number of subjects with data available for analyses.
    End point type
    Secondary
    End point timeframe
    24 hours post dose after Month 1 on study medication in Phase A
    End point values
    Phase A: Tolvaptan Phase A: Placebo
    Number of subjects analysed
    12
    8
    Units: milliliter
        arithmetic mean (standard deviation)
    7171 ( 2810 )
    2529 ( 2164 )
    No statistical analyses for this end point

    Secondary: Phase A: 24-hour Fluid Intake

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    End point title
    Phase A: 24-hour Fluid Intake
    End point description
    Daily fluid intake (total water) is defined as the amount of water consumed from foods, plain drinking water, and other beverages. The Dense PK/PD Population included a subset of subjects half on tolvaptan and half on placebo, in the 12 to 17 year old age group who had dense PK sampling after at least 1 month on IMP. Overall number analysed are the number of subjects with data available for analyses.
    End point type
    Secondary
    End point timeframe
    24 hours post dose after Month 1 on study medication in Phase A
    End point values
    Phase A: Tolvaptan Phase A: Placebo
    Number of subjects analysed
    11
    5
    Units: milliliter
        arithmetic mean (standard deviation)
    7486 ( 2350 )
    3156 ( 1775 )
    No statistical analyses for this end point

    Secondary: Phase A: 24-hour Fluid Balance

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    End point title
    Phase A: 24-hour Fluid Balance
    End point description
    Fluid balance is a term used to describe the balance of the input and output of fluids in the body to allow metabolic processes to function correctly. The Dense PK/PD Population included a subset of subjects half on tolvaptan and half on placebo, in the 12 to 17 year old age group who had dense PK sampling after at least 1 month on IMP. Overall number analysed are the number of subjects with data available for analyses.
    End point type
    Secondary
    End point timeframe
    24 hours post dose after Month 1 on study medication in Phase A
    End point values
    Phase A: Tolvaptan Phase A: Placebo
    Number of subjects analysed
    11
    5
    Units: milliliter
        arithmetic mean (standard deviation)
    53 ( 1894 )
    230 ( 1254 )
    No statistical analyses for this end point

    Secondary: Phase A: 24-hour Sodium Clearance

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    End point title
    Phase A: 24-hour Sodium Clearance
    End point description
    Data was categorised and reported based on the total daily dose for the given time point of 0-24 hours. The Dense PK/PD Population included a subset of subjects half on tolvaptan and half on placebo, in the 12 to 17 year old age group who had dense PK sampling after at least 1 month on IMP. Overall number analysed are the number of subjects with data available for analyses. n = Number analysed is the number of subjects with data available for analysis at the given time point. 9999 = The mean or standard deviation was not estimable due to lower number of subjects with event.
    End point type
    Secondary
    End point timeframe
    24 hours post dose after Month 1 on study medication in Phase A
    End point values
    Phase A: Tolvaptan Phase A: Placebo
    Number of subjects analysed
    10
    7
    Units: milliliter per minute (mL/min)
    arithmetic mean (standard deviation)
        Total Daily Dose: 37.5 mg (n=3,0)
    0.8 ( 0.3 )
    9999 ( 9999 )
        Total Daily Dose: 45 mg (n=3,0)
    0.7 ( 0.3 )
    9999 ( 9999 )
        Total Daily Dose: 60 mg (n=4,0)
    0.9 ( 0.3 )
    9999 ( 9999 )
        Total Daily Dose: Placebo (n=0,7)
    9999 ( 9999 )
    0.7 ( 0.5 )
    No statistical analyses for this end point

    Secondary: Phase A: 24-hour Creatinine Clearance

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    End point title
    Phase A: 24-hour Creatinine Clearance
    End point description
    Creatinine is produced from the metabolism of protein, when muscles burn energy. Most creatinine is filtered out of the blood by the kidneys and excreted in urine. The creatinine clearance value is determined by measuring the concentration of endogenous creatinine (that which is produced by the body) in both plasma and urine. Data was categorised and reported based on the total daily dose for the given time point of 0-24 hours. The Dense PK/PD Population included a subset of subjects half on tolvaptan and half on placebo, in the 12 to 17 year old age group who had dense PK sampling after at least 1 month on IMP. Overall number analysed are the number of subjects with data available for analyses. n = Number analysed is the number of subjects with data available for analysis for the specified category. 9999 = The mean or standard deviation was not estimable due to lower number of subjects with event.
    End point type
    Secondary
    End point timeframe
    24 hours post dose after Month 1 on study medication in Phase A
    End point values
    Phase A: Tolvaptan Phase A: Placebo
    Number of subjects analysed
    11
    8
    Units: mL/min
    arithmetic mean (standard deviation)
        Total Daily Dose: 22.5 mg (n=1,0)
    124.6 ( 9999 )
    9999 ( 9999 )
        Total Daily Dose: 37.5 mg (n=3,0)
    148.5 ( 23.4 )
    9999 ( 9999 )
        Total Daily Dose: 45 mg (n=3,0)
    95.0 ( 10.1 )
    9999 ( 9999 )
        Total Daily Dose: 60 mg (n=4,0)
    123.7 ( 23.2 )
    9999 ( 9999 )
        Total Daily Dose: Placebo (n=0,8)
    9999 ( 9999 )
    105.1 ( 51.7 )
    No statistical analyses for this end point

    Secondary: Phase A: 24-hour Free Water Clearance

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    End point title
    Phase A: 24-hour Free Water Clearance
    End point description
    Data was categorised and reported based on the total daily dose for the given time point of 0-24 hours. The Dense PK/PD Population included a subset of subjects half on tolvaptan and half on placebo, in the 12 to 17 year old age group who had dense PK sampling after at least 1 month on IMP. Overall number analysed are the number of subjects with data available for analyses. n = Number analysed is the number of subjects with data available for analysis for the specified category. 9999 = The mean or standard deviation was not estimable due to lower number of subjects with event.
    End point type
    Secondary
    End point timeframe
    24 hours post dose after Month 1 on study medication in Phase A
    End point values
    Phase A: Tolvaptan Phase A: Placebo
    Number of subjects analysed
    11
    8
    Units: mL/min
    arithmetic mean (standard deviation)
        Total Daily Dose: 37.5 mg (n=3,0)
    2.3 ( 0.9 )
    9999 ( 9999 )
        Total Daily Dose: 45 mg (n=3,0)
    2.6 ( 0.9 )
    9999 ( 9999 )
        Total Daily Dose: 60 mg (n=5,0)
    3.0 ( 1.2 )
    9999 ( 9999 )
        Total Daily Dose: Placebo (n=0,8)
    9999 ( 9999 )
    0.1 ( 1.2 )
    No statistical analyses for this end point

    Secondary: Phase A: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations

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    End point title
    Phase A: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations
    End point description
    Tanner stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). Only those categories with at least one subject with event are reported. The Phase A Safety Set included all subjects who were randomised and received at least 1 dose of IMP in Phase A.
    End point type
    Secondary
    End point timeframe
    At Baseline, Months 6 and 12 of Phase A
    End point values
    Phase A: Tolvaptan Phase A: Placebo
    Number of subjects analysed
    48
    43
    Units: percentage of subjects
    number (not applicable)
        Female (>=4 to <12 Years): Baseline- Stage 1
    6.3
    11.6
        Female (>=4 to <12 Years): Baseline- Stage 3
    0.0
    2.3
        Female (>=4 to <12 Years): Month 6, Phase A-Stage1
    6.3
    9.3
        Female (>=4 to <12 Years): Month 6, Phase A-Stage2
    0.0
    2.3
        Female (>=4 to <12 Years): Month 6, Phase A-Stage4
    0.0
    2.3
        Female (>=4 to <12 Years): Month 12,Phase A-Stage1
    4.2
    7.0
        Female (>=4 to <12 Years): Month 12,Phase A-Stage2
    0.0
    2.3
        Female (>=4 to <12 Years): Month 12,Phase A-Stage4
    0.0
    2.3
        Male (>=4 to <12 Years): Baseline- Stage 1
    16.7
    4.7
        Male (>=4 to <12 Years): Baseline- Stage 2
    0.0
    4.7
        Male (>=4 to <12 Years): Baseline- Stage 3
    2.1
    0.0
        Male (>=4 to <12 Years): Month 6, Phase A- Stage 1
    16.7
    7.0
        Male (>=4 to <12 Years): Month 6, Phase A- Stage 2
    2.1
    0.0
        Male (>=4 to <12 Years): Month 6, Phase A- Stage 3
    2.1
    4.7
        Male (>=4 to <12 Years): Month 12, Phase A- Stage1
    14.6
    4.7
        Male (>=4 to <12 Years): Month 12, Phase A- Stage2
    4.2
    2.3
        Male (>=4 to <12 Years): Month 12, Phase A- Stage3
    0.0
    4.7
        Male (>=4 to <12 Years): Month 12, Phase A- Stage4
    2.1
    0.0
        Female (>=12 to <15 Years): Baseline- Stage 1
    2.1
    0.0
        Female (>=12 to <15 Years): Baseline- Stage 2
    0.0
    4.7
        Female (>=12 to <15 Years): Baseline- Stage 3
    2.1
    2.3
        Female (>=12 to <15 Years): Baseline- Stage 4
    4.2
    0.0
        Female (>=12 to <15 Years): Baseline- Stage 5
    10.4
    7.0
        Female (>=12 to <15 Years): Month 6,Phase A-Stage2
    0.0
    2.3
        Female (>=12 to <15 Years): Month 6,Phase A-Stage3
    0.0
    2.3
        Female (>=12 to <15 Years): Month 6,Phase A-Stage4
    2.1
    0.0
        Female (>=12 to <15 Years): Month 6,Phase A-Stage5
    12.5
    7.0
        Female (>=12 to <15 Years):Month 12,Phase A-Stage2
    0.0
    2.3
        Female (>=12 to <15 Years):Month 12,Phase A-Stage3
    0.0
    2.3
        Female (>=12 to <15 Years):Month 12,Phase A-Stage4
    0.0
    4.7
        Female (>=12 to <15 Years):Month 12,Phase A-Stage5
    14.6
    9.3
        Male (>=12 to <15 Years): Baseline- Stage 2
    6.3
    4.7
        Male (>=12 to <15 Years): Baseline- Stage 3
    4.2
    4.7
        Male (>=12 to <15 Years): Baseline- Stage 4
    2.1
    4.7
        Male (>=12 to <15 Years): Baseline- Stage 5
    2.1
    2.3
        Male (>=12 to <15 Years): Month 6, Phase A-Stage2
    4.2
    2.3
        Male (>=12 to <15 Years): Month 6, Phase A- Stage3
    4.2
    2.3
        Male (>=12 to <15 Years): Month 6, Phase A- Stage4
    4.2
    4.7
        Male (>=12 to <15 Years): Month 6, Phase A- Stage5
    2.1
    2.3
        Male (>=12 to <15 Years): Month 12,Phase A- Stage2
    0.0
    2.3
        Male (>=12 to <15 Years): Month 12,Phase A- Stage3
    2.1
    0.0
        Male (>=12 to <15 Years): Month 12,Phase A- Stage4
    8.3
    7.0
        Male (>=12 to <15 Years): Month 12,Phase A- Stage5
    4.2
    2.3
        Male (>=12 to <15 Years): End of Treatment- Stage5
    2.1
    2.3
        Female (>=15 to <18 Years): Baseline- Stage 4
    2.1
    0.0
        Female (>=15 to <18 Years): Baseline- Stage 5
    12.5
    18.6
        Female (>=15 to <18 Years): Month 6,Phase A-Stage4
    2.1
    0.0
        Female (>=15 to <18 Years): Month 6,Phase A-Stage5
    12.5
    16.3
        Female (>=15 to <18 Years):Month 12,Phase A-Stage4
    2.1
    0.0
        Female (>=15 to <18 Years):Month 12,Phase A-Stage5
    14.6
    16.3
        Female (>=15 to <18 Years):End of Treatment-Stage5
    0.0
    2.3
        Male (>=15 to <18 Years): Baseline- Stage 4
    2.1
    4.7
        Male (>=15 to <18 Years): Baseline- Stage 5
    16.7
    14.0
        Male (>=15 to <18 Years): Month 6, Phase A- Stage4
    2.1
    2.3
        Male (>=15 to <18 Years): Month 6, Phase A- Stage5
    14.6
    16.3
        Male (>=15 to <18 Years): Month 12, Phase A-Stage4
    2.1
    0.0
        Male (>=15 to <18 Years): Month 12, Phase A-Stage5
    14.6
    18.6
        Male (>=15 to <18 Years): End of Treatment- Stage5
    2.1
    0.0
    No statistical analyses for this end point

    Secondary: Phase B: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations

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    End point title
    Phase B: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations
    End point description
    Tanner stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). Only those categories with at least one subject with event are reported. The Phase B Safety Set included all subjects who were enrolled in Phase B and received at least 1 dose of IMP in Phase B. End of Treatment = EOT.
    End point type
    Secondary
    End point timeframe
    At Baseline, Months 6, 12, 18, and 24 of Phase B
    End point values
    Phase B: Prior Tolvaptan Phase B: Prior Placebo
    Number of subjects analysed
    42
    39
    Units: percentage of subjects
    number (not applicable)
        Female (>=4 to <12 Years): Phase B Baseline-Stage1
    7.1
    10.3
        Female (>=4 to <12 Years): Phase B Baseline-Stage2
    0.0
    2.6
        Female (>=4 to <12 Years): Phase B Baseline-Stage4
    0.0
    2.6
        Female (>=4 to <12 Years): Month 6, Phase B-Stage1
    4.8
    7.7
        Female (>=4 to <12 Years): Month 6, Phase B-Stage2
    0.0
    2.6
        Female (>=4 to <12 Years): Month 6, Phase B-Stage4
    0.0
    2.6
        Female (>=4 to <12 Years): Month 12,Phase B-Stage1
    4.8
    7.7
        Female (>=4 to <12 Years): Month 12,Phase B-Stage2
    0.0
    2.6
        Female (>=4 to <12 Years): Month 12,Phase B-Stage3
    0.0
    2.6
        Female (>=4 to <12 Years): Month 12,Phase B-Stage4
    0.0
    2.6
        Female (>=4 to <12 Years): Month 18,Phase B-Stage1
    4.8
    2.6
        Female (>=4 to <12 Years): Month 18,Phase B-Stage2
    0.0
    7.7
        Female (>=4 to <12 Years): Month 18,Phase B-Stage4
    0.0
    2.6
        Female (>=4 to <12 Years): Month 24,Phase B-Stage1
    2.4
    2.6
        Female (>=4 to <12 Years): Month 24,Phase B-Stage2
    2.4
    5.1
        Female (>=4 to <12 Years): Month 24,Phase B-Stage3
    0.0
    2.6
        Female (>=4 to <12 Years): Month 24,Phase B-Stage4
    0.0
    2.6
        Male (>=4 to <12 Years): Phase B Baseline- Stage 1
    11.9
    5.1
        Male (>=4 to <12 Years): Phase B Baseline- Stage 2
    4.8
    2.6
        Male (>=4 to <12 Years): Phase B Baseline- Stage 3
    0.0
    5.1
        Male (>=4 to <12 Years): Phase B Baseline- Stage 4
    2.4
    0.0
        Male (>=4 to <12 Years): Month 6, Phase B- Stage 1
    9.5
    2.6
        Male (>=4 to <12 Years): Month 6, Phase B- Stage 2
    2.4
    2.6
        Male (>=4 to <12 Years): Month 6, Phase B- Stage 3
    2.4
    2.6
        Male (>=4 to <12 Years): Month 6, Phase B- Stage 4
    2.4
    2.6
        Male (>=4 to <12 Years): Month 12, Phase B- Stage1
    9.5
    2.6
        Male (>=4 to <12 Years): Month 12, Phase B- Stage2
    2.4
    0.0
        Male (>=4 to <12 Years): Month 12, Phase B- Stage3
    2.4
    5.1
        Male (>=4 to <12 Years): Month 12, Phase B- Stage4
    2.4
    2.6
        Male (>=4 to <12 Years): Month 18, Phase B- Stage1
    4.8
    2.6
        Male (>=4 to <12 Years): Month 18, Phase B- Stage2
    2.4
    0.0
        Male (>=4 to <12 Years): Month 18, Phase B- Stage3
    0.0
    5.1
        Male (>=4 to <12 Years): Month 18, Phase B- Stage4
    4.8
    0.0
        Male (>=4 to <12 Years): Month 18, Phase B- Stage5
    0.0
    2.6
        Male (>=4 to <12 Years): Month 24, Phase B- Stage1
    4.8
    0.0
        Male (>=4 to <12 Years): Month 24, Phase B- Stage2
    4.8
    0.0
        Male (>=4 to <12 Years): Month 24, Phase B- Stage3
    2.4
    5.1
        Male (>=4 to <12 Years): Month 24, Phase B- Stage4
    2.4
    0.0
        Male (>=4 to <12 Years): Month 24, Phase B- Stage5
    2.4
    2.6
        Female (>=12 to <15 Years):Phase B Baseline-Stage2
    0.0
    2.6
        Female (>=12 to <15 Years):Phase B Baseline-Stage3
    0.0
    2.6
        Female (>=12 to <15 Years):Phase B Baseline-Stage4
    0.0
    5.1
        Female (>=12 to <15 Years):Phase B Baseline-Stage5
    16.7
    10.3
        Female (>=12 to <15 Years): Month 6,Phase B-Stage3
    0.0
    5.1
        Female (>=12 to <15 Years): Month 6,Phase B-Stage4
    0.0
    5.1
        Female (>=12 to <15 Years): Month 6,Phase B-Stage5
    16.7
    10.3
        Female (>=12 to <15 Years):Month 12,Phase B-Stage4
    0.0
    5.1
        Female (>=12 to <15 Years):Month 12,Phase B-Stage5
    14.3
    10.3
        Female (>=12 to <15 Years):Month 18,Phase B-Stage4
    0.0
    2.6
        Female (>=12 to <15 Years):Month 18,Phase B-Stage5
    11.9
    10.3
        Female (>=12 to <15 Years):Month 24,Phase B-Stage4
    0.0
    5.1
        Female (>=12 to <15 Years):Month 24,Phase B-Stage5
    9.5
    10.3
        Female (>=12 to <15 Years): EOT, Phase B, Stage 4
    0.0
    2.6
        Female (>=12 to <15 Years): EOT, Phase B, Stage 5
    7.1
    2.6
        Male (>=12 to <15 Years): Phase B Baseline- Stage2
    0.0
    2.6
        Male (>=12 to <15 Years): Phase B Baseline- Stage3
    2.4
    0.0
        Male (>=12 to <15 Years): Phase B Baseline- Stage4
    9.5
    7.7
        Male (>=12 to <15 Years): Phase B Baseline- Stage5
    4.8
    2.6
        Male (>=12 to <15 Years): Month 6, Phase B- Stage2
    0.0
    2.6
        Male (>=12 to <15 Years): Month 6, Phase B- Stage3
    2.4
    0.0
        Male (>=12 to <15 Years): Month 6, Phase B- Stage4
    4.8
    5.1
        Male (>=12 to <15 Years): Month 6, Phase B- Stage5
    4.8
    2.6
        Male (>=12 to <15 Years): Month 12, Phase B-Stage2
    0.0
    2.6
        Male (>=12 to <15 Years): Month 12, Phase B-Stage4
    7.1
    5.1
        Male (>=12 to <15 Years): Month 12, Phase B-Stage5
    7.1
    5.1
        Male (>=12 to <15 Years): Month 18, Phase B-Stage2
    0.0
    2.6
        Male (>=12 to <15 Years): Month 18, Phase B-Stage4
    4.8
    0.0
        Male (>=12 to <15 Years): Month 18, Phase B-Stage5
    9.5
    7.7
        Male (>=12 to <15 Years): Month 24, Phase B-Stage2
    0.0
    2.6
        Male (>=12 to <15 Years): Month 24, Phase B-Stage4
    4.8
    0.0
        Male (>=12 to <15 Years): Month 24, Phase B-Stage5
    9.5
    10.3
        Male (>=12 to <15 Years): EOT, Phase B- Stage 5
    0.0
    2.6
        Female (>=15 to <18 Years):Phase B Baseline-Stage4
    2.4
    0.0
        Female (>=15 to <18 Years):Phase B Baseline-Stage5
    16.7
    15.4
        Female (>=15 to <18 Years): Month 6,Phase B-Stage4
    2.4
    0.0
        Female (>=15 to <18 Years): Month 6,Phase B-Stage5
    16.7
    12.8
        Female(>=15 to <18 Years):Month 12,Phase B-Stage4
    2.4
    0.0
        Female(>=15 to <18 Years):Month 12,Phase B-Stage5
    16.7
    12.8
        Female(>=15 to <18 Years):Month 18,Phase B-Stage4
    2.4
    0.0
        Female(>=15 to <18 Years):Month 18,Phase B-Stage5
    16.7
    12.8
        Female(>=15 to <18 Years):Month 24,Phase B-Stage4
    2.4
    0.0
        Female(>=15 to <18 Years):Month 24,Phase B-Stage5
    16.7
    12.8
        Female (>=15 to <18 Years): EOT, Phase B- Stage 5
    0.0
    5.1
        Male (>=15 to <18 Years): Phase B Baseline- Stage4
    2.4
    0.0
        Male (>=15 to <18 Years): Phase B Baseline- Stage5
    16.7
    20.5
        Male (>=15 to <18 Years): Month 6, Phase B- Stage5
    19.0
    17.9
        Male (>=15 to <18 Years): Month 12, Phase B-Stage5
    16.7
    17.9
        Male (>=15 to <18 Years): Month 18, Phase B-Stage5
    16.7
    15.4
        Male (>=15 to <18 Years): Month 24, Phase B-Stage5
    16.7
    12.8
        Male (>=15 to <18 Years): EOT, Phase B- Stage 5
    4.8
    7.7
    No statistical analyses for this end point

    Secondary: Phase A: Change From Baseline in Growth Percentile by Gender and Age

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    End point title
    Phase A: Change From Baseline in Growth Percentile by Gender and Age
    End point description
    The growth percentile was based on the assessment of height and weight. The Phase A Safety Set included all subjects who were randomised and received at least 1 dose of IMP in Phase A. Number analysed is the number of subjects with data available for analysis at the given time point. Change From Baseline = CFB, End of Treatment = EOT. 9999 = The mean or standard deviation was not estimable due to lower number of subjects with event. n = Number analysed is the number of subjects with data available for analysis at the given time point.
    End point type
    Secondary
    End point timeframe
    At Baseline, Months 6 and 12 of Phase A
    End point values
    Phase A: Tolvaptan Phase A: Placebo
    Number of subjects analysed
    48
    43
    Units: growth percentile
    arithmetic mean (standard deviation)
        Females: Age 15-18 Years - Baseline (n=9,8)
    62 ( 28 )
    60 ( 34 )
        CFB in Females: Age 15-18 Years - Month 6 (n=9,6)
    2 ( 18 )
    -2 ( 12 )
        CFB in Females: Age 15-18 Years - Month 12 (n=9,7)
    7 ( 10 )
    -5 ( 11 )
        Males: Age 15-18 Years - Baseline(n=9,8)
    56 ( 29 )
    73 ( 18 )
        CFB in Males: Age 15-18 Years - Month 6(n=8,8)
    12 ( 16 )
    -1 ( 30 )
        CFB in Males: Age 15-18 Years - Month 12(n=8,8)
    2 ( 37 )
    -3 ( 25 )
        Females: Age 12-15 Years - Baseline (n=9,8)
    71 ( 20 )
    72 ( 29 )
        CFB in Females: Age 12-15 Years - Month 6(n=7,8)
    -2 ( 12 )
    -20 ( 21 )
        CFB in Females: Age 12-15 Years - Month 12 (n=7,8)
    -11 ( 9 )
    -18 ( 27 )
        Males: Age 12-15 Years - Baseline(n=8,7)
    70 ( 21 )
    76 ( 24 )
        CFB in Males: Age 12-15 Years - Month 6(n=7,7)
    -7 ( 13 )
    -13 ( 38 )
        CFB in Males: Age 12-15 Years - Month 12(n=7,5)
    0 ( 20 )
    8 ( 17 )
        Females: Age 4-11 Years - Baseline(n=3,7)
    71 ( 25 )
    57 ( 14 )
        CFB in Females: Age 4-11 Years - Month 6(n=3,7)
    -1 ( 3 )
    4 ( 16 )
        CFB in Females: Age 4-11 Years - Month 12(n=3,7)
    7 ( 15 )
    2 ( 18 )
        Males: Age 4-11 Years - Baseline(n=10,5)
    57 ( 31 )
    63 ( 19 )
        CFB in Males: Age 4-11 Years - Month 6 (n=10,5)
    4 ( 16 )
    0 ( 0 )
        CFB in Males: Age 4-11 Years - Month 12 (n=10,5)
    1 ( 3 )
    1 ( 4 )
    No statistical analyses for this end point

    Secondary: Phase B: Change From Baseline in Growth Percentile by Gender and Age

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    End point title
    Phase B: Change From Baseline in Growth Percentile by Gender and Age
    End point description
    The growth percentile was based on the assessment of height and weight. The Phase B Safety Set included all subjects who were enrolled in Phase B and received at least 1 dose of IMP in Phase B. n = Number analysed is the number of subjects with data available for analysis at the given time point. Change from Baseline = CFB, End of Treatment = EOT. 9999 = The mean or standard deviation was not estimable due to lower number of subjects with event.
    End point type
    Secondary
    End point timeframe
    At Baseline, Months 6, 12, 18, 24 of Phase B
    End point values
    Phase B: Prior Tolvaptan Phase B: Prior Placebo
    Number of subjects analysed
    42
    39
    Units: growth percentile
    arithmetic mean (standard deviation)
        Females: Age 15-18 Years - Baseline(n=9,6)
    69 ( 32 )
    46 ( 28 )
        CFB in Females: Age 15-18 Years - Month 6(n=7,5)
    -7 ( 17 )
    12 ( 21 )
        CFB in Females: Age 15-18 Years - Month 12(n=8,5)
    0 ( 7 )
    20 ( 18 )
        CFB in Females: Age 15-18 Years - Month 18(n=6,3)
    -2 ( 2 )
    10 ( 9 )
        CFB in Females: Age 15-18 Years - Month 24(n=8,5)
    6 ( 16 )
    16 ( 20 )
        Males: Age 15-18 Years - Baseline(n=8,8)
    60 ( 34 )
    69 ( 18 )
        CFB in Males: Age 15-18 Years - Month 6(n=8,7)
    -13 ( 53 )
    1 ( 2 )
        CFB in Males: Age 15-18 Years - Month 12(n=6,6)
    -8 ( 47 )
    8 ( 11 )
        CFB in Males: Age 15-18 Years - Month 18(n=5,6)
    16 ( 65 )
    -4 ( 25 )
        CFB in Males: Age 15-18 Years - Month 24(n=6,5)
    -2 ( 50 )
    -11 ( 25 )
        Females: Age 12-15 Years - Baseline(n=7,8)
    62 ( 24 )
    54 ( 34 )
        CFB in Females: Age 12-15 Years - Month 6(n=7,8)
    3 ( 6 )
    13 ( 18 )
        CFB in Females: Age 12-15 Years - Month 12(n=6,8)
    12 ( 20 )
    12 ( 23 )
        CFB in Females: Age 12-15 Years - Month 18(n=5,5)
    5 ( 9 )
    10 ( 22 )
        CFB in Females: Age 12-15 Years - Month 24(n=4,7)
    1 ( 3 )
    13 ( 18 )
        Males: Age 12-15 Years - Baseline(n=7,5)
    67 ( 26 )
    77 ( 23 )
        CFB in Males: Age 12-15 Years - Month 6(n=5,5)
    1 ( 10 )
    -15 ( 38 )
        CFB in Males: Age 12-15 Years - Month 12(n=7,5)
    4 ( 16 )
    -23 ( 37 )
        CFB in Males: Age 12-15 Years - Month 18 (n=5,4)
    -4 ( 14 )
    -22 ( 40 )
        CFB in Males: Age 12-15 Years - Month 24(n=6,5)
    -8 ( 15 )
    -18 ( 36 )
        Females: Age 4-11 Years - Baseline(n=3,7)
    78 ( 19 )
    59 ( 22 )
        CFB in Females: Age 4-11 Years - Month 6(n=3,6)
    -2 ( 2 )
    2 ( 12 )
        CFB in Females: Age 4-11 Years - Month 12(n=3,7)
    5 ( 8 )
    1 ( 12 )
        CFB in Females: Age 4-11 Years - Month 18(n=3,7)
    -5 ( 6 )
    2 ( 23 )
        CFB in Females: Age 4-11 Years - Month 24(n=3,7)
    -4 ( 5 )
    10 ( 21 )
        Males: Age 4-11 Years -Baseline (n=8,5)
    65 ( 30 )
    64 ( 21 )
        CFB in Males: Age 4-11 Years - Month 6(n=8,4)
    0 ( 13 )
    1 ( 2 )
        CFB in Males: Age 4-11 Years - Month 12(n=8,5)
    3 ( 20 )
    4 ( 8 )
        CFB in Males: Age 4-11 Years - Month 18(n=5,4)
    -4 ( 12 )
    2 ( 9 )
        CFB in Males: Age 4-11 Years - Month 24(n=7,4)
    0 ( 18 )
    21 ( 23 )
    No statistical analyses for this end point

    Secondary: Phase A: Change From Baseline in Creatinine Value

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    End point title
    Phase A: Change From Baseline in Creatinine Value
    End point description
    Phase A Baseline is the last pre-dose evaluation. The Last Visit is the last available post-baseline evaluation including early term. The Phase A Safety Set included all subjects who were randomised and received at least 1 dose of IMP in Phase A. n = Number analysed is the number of subjects with data available for analysis at the given time point. 9999 = The mean or standard deviation was not estimable due to lower number of subjects with event. As prespecified in the protocol, data for safety is reported by the treatment group (Phase A: Tolvaptan and Phase A: Placebo)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, Follow Up Day 7, End of Treatment, and Last Visit
    End point values
    Phase A: Tolvaptan Phase A: Placebo
    Number of subjects analysed
    48
    43
    Units: milligrams per deciliter (mg/dL)
    arithmetic mean (standard deviation)
        Baseline (n=48,43)
    0.70 ( 0.16 )
    0.67 ( 0.12 )
        Change From Baseline at Week 1(n=47,42)
    0.04 ( 0.09 )
    -0.01 ( 0.06 )
        Change From Baseline at Month 1(n=48,43)
    0.01 ( 0.08 )
    0.01 ( 0.06 )
        Change From Baseline at Month 2(n=44,42)
    0.01 ( 0.09 )
    0.00 ( 0.07 )
        Change From Baseline at Month 3(n=45,43)
    0.00 ( 0.11 )
    0.01 ( 0.06 )
        Change From Baseline at Month 4(n=45,40)
    0.00 ( 0.09 )
    -0.01 ( 0.07 )
        Change From Baseline at Month 5(n=45,39)
    0.01 ( 0.09 )
    0.01 ( 0.06 )
        Change From Baseline at Month 6(n=44,41)
    0.01 ( 0.10 )
    0.02 ( 0.07 )
        Change From Baseline at Month 7(n=44,39)
    0.01 ( 0.10 )
    0.02 ( 0.06 )
        Change From Baseline at Month 8(n=43,39)
    0.01 ( 0.11 )
    0.02 ( 0.07 )
        Change From Baseline at Month 9(n=44,39)
    0.04 ( 0.11 )
    0.01 ( 0.07 )
        Change From Baseline at Month 10(n=40,34)
    0.01 ( 0.10 )
    0.03 ( 0.07 )
        Change From Baseline at Month 11(n=41,38)
    0.02 ( 0.11 )
    0.04 ( 0.08 )
        Change From Baseline at Month 12(n=43,40)
    0.02 ( 0.09 )
    0.02 ( 0.06 )
        Change From Baseline at Follow Up Day 7(n=1,1)
    0.09 ( 9999 )
    -0.02 ( 9999 )
        Change From Baseline at End of Treatment(n=2,3)
    0.03 ( 0.10 )
    0.03 ( 0.04 )
        Change From Baseline at Last Visit(n=48,43)
    0.03 ( 0.09 )
    0.02 ( 0.06 )
    No statistical analyses for this end point

    Secondary: Phase B: Change From Baseline in Creatinine Value

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    End point title
    Phase B: Change From Baseline in Creatinine Value
    End point description
    Phase B Baseline is the last evaluation prior to the first dose in Phase B. The Last Visit is the last available post-baseline evaluation including early term. The Phase B Safety Set included all subjects who were enrolled in Phase B and received at least 1 dose of IMP in Phase B. n = Number analysed is the number of subjects with data available for analysis at the given time point. 9999 = The mean or standard deviation was not estimable due to lower number of subjects with event. As prespecified in the protocol, data for safety is reported by the treatment group (Phase A: Tolvaptan and Phase A: Placebo)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, Follow Up Day 7, End of Treatment, and Last Visit
    End point values
    Phase B: Prior Tolvaptan Phase B: Prior Placebo
    Number of subjects analysed
    42
    39
    Units: mg/dL
    arithmetic mean (standard deviation)
        Baseline (n=42,39)
    0.73 ( 0.17 )
    0.69 ( 0.13 )
        Change From Baseline at Week 1(n=42,38)
    0.01 ( 0.06 )
    0.04 ( 0.06 )
        Change From Baseline at Month 1(n=41,38)
    0.01 ( 0.07 )
    0.04 ( 0.06 )
        Change From Baseline at Month 2(n=41,37)
    0.02 ( 0.07 )
    0.04 ( 0.07 )
        Change From Baseline at Month 3(n=41,37)
    0.02 ( 0.07 )
    0.04 ( 0.07 )
        Change From Baseline at Month 4(n=40,36)
    0.04 ( 0.06 )
    0.05 ( 0.07 )
        Change From Baseline at Month 5(n=38,30)
    0.03 ( 0.06 )
    0.07 ( 0.07 )
        Change From Baseline at Month 6(n=38,33)
    0.03 ( 0.07 )
    0.06 ( 0.07 )
        Change From Baseline at Month 7(n=38,32)
    0.04 ( 0.07 )
    0.06 ( 0.07 )
        Change From Baseline at Month 8(n=38,34)
    0.05 ( 0.08 )
    0.07 ( 0.07 )
        Change From Baseline at Month 9(n=38,35)
    0.07 ( 0.11 )
    0.09 ( 0.13 )
        Change From Baseline at Month 10(n=37,34)
    0.06 ( 0.07 )
    0.06 ( 0.07 )
        Change From Baseline at Month 11(n=38,32)
    0.05 ( 0.07 )
    0.08 ( 0.08 )
        Change From Baseline at Month 12(n=36,36)
    0.06 ( 0.12 )
    0.07 ( 0.08 )
        Change From Baseline at Month 13(n=34,34)
    0.04 ( 0.08 )
    0.08 ( 0.08 )
        Change From Baseline at Month 14(n=33,31)
    0.08 ( 0.07 )
    0.08 ( 0.08 )
        Change From Baseline at Month 15(n=37,30)
    0.06 ( 0.07 )
    0.06 ( 0.08 )
        Change From Baseline at Month 16(n=36,29)
    0.05 ( 0.08 )
    0.08 ( 0.09 )
        Change From Baseline at Month 17(n=33,27)
    0.07 ( 0.08 )
    0.08 ( 0.09 )
        Change From Baseline at Month 18(n=30,27)
    0.05 ( 0.09 )
    0.09 ( 0.07 )
        Change From Baseline at Month 19(n=29,25)
    0.06 ( 0.10 )
    0.09 ( 0.10 )
        Change From Baseline at Month 20(n=27,20)
    0.04 ( 0.08 )
    0.11 ( 0.08 )
        Change From Baseline at Month 21(n=27,23)
    0.09 ( 0.12 )
    0.09 ( 0.10 )
        Change From Baseline at Month 22(n=29,23)
    0.06 ( 0.08 )
    0.09 ( 0.10 )
        Change From Baseline at Month 23(n=25,24)
    0.07 ( 0.06 )
    0.12 ( 0.08 )
        Change From Baseline at Month 24(n=34,31)
    0.07 ( 0.08 )
    0.12 ( 0.10 )
        Change From Baseline at Follow Up Day 7(n=2,7)
    -0.01 ( 0.02 )
    0.14 ( 0.08 )
        Change From Baseline at End of Treatment(n=5,7)
    -0.01 ( 0.11 )
    0.02 ( 0.08 )
        Change From Baseline at Last Visit(n=42,39)
    0.05 ( 0.09 )
    0.10 ( 0.08 )
    No statistical analyses for this end point

    Secondary: Phase A and B: Percentage of Subjects With Potentially Clinically Significant Abnormalities in Vital Signs

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    End point title
    Phase A and B: Percentage of Subjects With Potentially Clinically Significant Abnormalities in Vital Signs
    End point description
    Vital signs=measurements of respiratory rate, blood pressure, body temperature and pulse. Any value outside the normal range was flagged for the attention of the investigator who assessed whether or not a flagged value is of clinical significance. Only those categories with at least one subject with event are reported. The Phase A Safety Set included all subjects who were randomized and received at least 1 dose of IMP in Phase A. The Phase B Safety Set included all subjects who were enrolled in Phase B and received at least 1 dose of IMP in Phase B. n=Number analysed is the number of subjects with at least one post-baseline numeric result for the given vital sign parameter. Pulse rate(PR) is measured in beats per minute(BPM), Systolic and Diastolic Blood Pressure (BP) is measured in millimetre of mercury (mmHg). As prespecified in the protocol, data for safety is reported by the treatment group (Phase A: Tolvaptan, Phase A: Placebo, Phase B: Prior Tolvaptan).
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to 14 days post last dose (up to approximately 37 months)
    End point values
    Phase A: Tolvaptan Phase A: Placebo Phase B: Prior Tolvaptan Phase B: Prior Placebo
    Number of subjects analysed
    48
    43
    42
    39
    Units: percentage of subjects
    number (not applicable)
        PR <=50 and Baseline Decrease >=15(n=48,43,42,38)
    0.0
    2.3
    0.0
    5.3
        SystolicBP>=130&BaselineIncrease>=20;n=48,43,42,39
    2.1
    0.0
    0.0
    0.0
        SystolicBP<=120&BaselineDecrease>=20;n=48,43,42,39
    4.2
    7.0
    9.5
    10.3
        SystolicBP>=144&BaselineIncrease>=20;n=48,43,42,39
    2.1
    2.3
    0.0
    2.6
        DiastolicBP<=50&BaselineDecrease>=15;n=48,43,42,39
    4.2
    7.0
    9.5
    0.0
        DiastolicBP>=86&BaselineIncrease>=15;n=48,43,42,39
    0.0
    0.0
    7.1
    0.0
        DiastolicBP<=80&BaselineDecrease>=15;n=48,43,42,39
    12.5
    18.6
    16.7
    12.8
        DiastolicBP>=92&BaselineIncrease>=15;n=48,43,42,39
    0.0
    4.7
    4.8
    2.6
    No statistical analyses for this end point

    Secondary: Phase A and B: Percentage of Subjects With Potentially Clinically Significant Abnormalities in Laboratory Test Results Including Liver Function Tests (LFTs)

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    End point title
    Phase A and B: Percentage of Subjects With Potentially Clinically Significant Abnormalities in Laboratory Test Results Including Liver Function Tests (LFTs)
    End point description
    Parameters=haematology,chemistry,urinalysis,&LFTs.Criteria=Increased(INC)creatinine level: Baseline(BSL):Grade 0,>BSL-1.5xBSL:1,>1.5-3xBSL:2,>3-6xBSL:3,>6xBSL:4.Decreased(DEC) glucose level: <30:-4,30-<40:-3, 40-<55:-2, 55-<65:-1,>=65:0; INC:<=115:0,>115-160:1,>160-250:2,>250-500:3,>500:4.DEC potassium: <2.5:-4,2.5-<3:-3,3-<lower limit of normal(LLN):-1,LLN:0; INC: upper limit of normal(ULN):0,>ULN-5.5:1,>5.5-6:2,>6-7:3,>7:4.DEC sodium: <120:-4,120-124:-3,125-129:-2,130-135:-1,>=136:0; INC:<=145:0,146-150:1,151-155:2,156-160:3,>160:4. INC triglyceride:ULN:0,>ULN-2.5xULN:1,>2.5-5xULN:2,>5-6xULN:3,>6xULN:4. DEC Neutrophils:<0.5:-4,0.5-<1:-3,1-<1.5:-2,1.5-<LLN:-1,LLN:0. Potentially clinically significant INC/DEC=BSL grade 0,1,-1 and post-BSL grade >1,<-1 or BSL grade >1,<-1 and post-BSL grade >or<BSL grade. Only those categories with atleast 1 subject with event are reported. Phase A and B Safety Set; n=number of subjects with≥1 post-baseline result. milliequivalents per deciliter=mEq/dL
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to 14 days post last dose (up to approximately 37 months)
    End point values
    Phase A: Tolvaptan Phase A: Placebo Phase B: Prior Tolvaptan Phase B: Prior Placebo
    Number of subjects analysed
    48
    43
    42
    39
    Units: percentage of subjects
    number (not applicable)
        Increase in Creatinine Level(mg/dL)(n=48,43,42,39)
    8.3
    0.0
    7.1
    7.7
        Decrease in Glucose Level(mg/dL)(n=36,39,32,34)
    0.0
    2.6
    0.0
    2.9
        Increase in Potassium Level(mEq/dL)(n=47,43,40,38)
    2.1
    0.0
    0.0
    2.6
        Increase in Sodium Level (mEq/dL)(n=48,43,42,39)
    0.0
    0.0
    0.0
    2.6
        Increased TriglycerideLevel(mg/dL)(n=36,39,32,34)
    0.0
    0.0
    3.1
    0.0
        Decrease in Neutrophils (10^9/L)(n=46,41,40,38)
    0.0
    4.9
    5.0
    2.6
    No statistical analyses for this end point

    Secondary: Phase A and B: Percentage of Subjects With Aquaretic Adverse Events (AEs)

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    End point title
    Phase A and B: Percentage of Subjects With Aquaretic Adverse Events (AEs)
    End point description
    An AE was defined as any untoward medical occurrence in a subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Aquaretic AEs included Medical Dictionary for Regulatory Activities [MedDRA] preferred terms of thirst, polyuria (production of large volumes of dilute urine), nocturia (need to wake up to urinate at night), pollakiuria (abnormally frequent urination), and polydipsia (excessive thirst). The Phase A Safety Set included all subjects who were randomised and received at least 1 dose of IMP in Phase A. The Phase B Safety Set included all subjects who were enrolled in Phase B and received at least 1 dose of IMP in Phase B. As prespecified in the protocol, data for safety is reported by the treatment group (Phase A: Tolvaptan, Phase A: Placebo, Phase B: Prior Tolvaptan and Phase B: Prior Placebo).
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to 14 days post last dose (up to approximately 37 months)
    End point values
    Phase A: Tolvaptan Phase A: Placebo Phase B: Prior Tolvaptan Phase B: Prior Placebo
    Number of subjects analysed
    48
    43
    42
    39
    Units: percentage of subjects
        number (not applicable)
    64.6
    16.3
    14.3
    48.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of the study drug up to 14 days post last dose (up to approximately 37 months)
    Adverse event reporting additional description
    Phase A Safety Set=all subjects randomised and received atleast 1 dose of IMP in Phase A.Phase B Safety Set=all subjects enrolled in Phase B and received atleast 1 dose of IMP in Phase B. As prespecified in protocol, data for safety is reported by treatment group(PhaseA:Tolvaptan, PhaseA:Placebo, PhaseB:Prior Tolvaptan and PhaseB:Prior Placebo).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Phase A: Tolvaptan
    Reporting group description
    Subjects received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), and starting doses based on their weight as per the following specifications: ≥20 to 45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; >75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to <45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; >75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter subjects continued the same dose for 12 months. Doses may be titrated down dependent upon subject tolerability.

    Reporting group title
    Phase A: Placebo
    Reporting group description
    Subjects received matching-placebo tablets, orally as a split-dose (with the first dose taken upon awakening and second dose taken approximately 8 hours later), and starting dose based on their weight as per the following specifications: ≥20 to <45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; >75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to <45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; >75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter subjects continued the same dose for 12 months. Doses may be titrated down dependent upon subject tolerability.

    Reporting group title
    Phase B: Prior Tolvaptan
    Reporting group description
    Qualified subjects (defined as those who were willing to continue in the trial and who did not have any adverse events [AEs] that would require investigational medicinal product [IMP] discontinuation) who received tolvaptan and completed Phase A were enrolled in Phase B and received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), and starting dose based on their body weight as per following specifications: ≥20 to <45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; >75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to <45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; >75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter subjects continued the same dose for 24 months. Doses may be titrated down dependent upon subject tolerability.

    Reporting group title
    Phase B: Prior Placebo
    Reporting group description
    Qualified subjects (defined as those who were willing to continue in the trial and who did not have any AEs that would require IMP discontinuation) who received matching-placebo and completed Phase A, were enrolled in Phase B and received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), based on their current body weight as per following specifications: ≥20 to <45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; >75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to <45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; >75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter subjects continued the same dose for 24 months. Doses may be titrated down dependent upon subject tolerability.

    Serious adverse events
    Phase A: Tolvaptan Phase A: Placebo Phase B: Prior Tolvaptan Phase B: Prior Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 48 (2.08%)
    6 / 43 (13.95%)
    7 / 42 (16.67%)
    8 / 39 (20.51%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Heart rate increased
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hand fracture
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Expired product administered
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Petit mal epilepsy
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Intentional self-injury
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eating disorder
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal pain
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Viral pericarditis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    2 / 42 (4.76%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Phase A: Tolvaptan Phase A: Placebo Phase B: Prior Tolvaptan Phase B: Prior Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 48 (93.75%)
    42 / 43 (97.67%)
    38 / 42 (90.48%)
    39 / 39 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 43 (2.33%)
    4 / 42 (9.52%)
    2 / 39 (5.13%)
         occurrences all number
    4
    1
    5
    2
    Hypotension
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    2 / 42 (4.76%)
    3 / 39 (7.69%)
         occurrences all number
    0
    0
    2
    3
    Orthostatic hypotension
         subjects affected / exposed
    5 / 48 (10.42%)
    0 / 43 (0.00%)
    3 / 42 (7.14%)
    3 / 39 (7.69%)
         occurrences all number
    5
    0
    3
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 48 (0.00%)
    3 / 43 (6.98%)
    3 / 42 (7.14%)
    2 / 39 (5.13%)
         occurrences all number
    0
    3
    3
    2
    Fatigue
         subjects affected / exposed
    4 / 48 (8.33%)
    3 / 43 (6.98%)
    3 / 42 (7.14%)
    3 / 39 (7.69%)
         occurrences all number
    5
    4
    3
    4
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    3 / 42 (7.14%)
    0 / 39 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Pyrexia
         subjects affected / exposed
    4 / 48 (8.33%)
    3 / 43 (6.98%)
    8 / 42 (19.05%)
    7 / 39 (17.95%)
         occurrences all number
    5
    6
    10
    11
    Thirst
         subjects affected / exposed
    7 / 48 (14.58%)
    2 / 43 (4.65%)
    1 / 42 (2.38%)
    3 / 39 (7.69%)
         occurrences all number
    8
    2
    1
    3
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 43 (2.33%)
    0 / 42 (0.00%)
    3 / 39 (7.69%)
         occurrences all number
    4
    1
    0
    3
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    3 / 39 (7.69%)
         occurrences all number
    0
    0
    0
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 48 (14.58%)
    5 / 43 (11.63%)
    7 / 42 (16.67%)
    8 / 39 (20.51%)
         occurrences all number
    10
    8
    9
    10
    Epistaxis
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    7 / 39 (17.95%)
         occurrences all number
    3
    0
    3
    7
    Oropharyngeal pain
         subjects affected / exposed
    4 / 48 (8.33%)
    6 / 43 (13.95%)
    9 / 42 (21.43%)
    7 / 39 (17.95%)
         occurrences all number
    5
    6
    11
    8
    Psychiatric disorders
    Enuresis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    2 / 42 (4.76%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    4
    3
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    1
    2
    Blood creatinine increased
         subjects affected / exposed
    9 / 48 (18.75%)
    2 / 43 (4.65%)
    7 / 42 (16.67%)
    5 / 39 (12.82%)
         occurrences all number
    12
    2
    9
    11
    Liver function test increased
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    0
    2
    Vitamin D decreased
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    4 / 42 (9.52%)
    1 / 39 (2.56%)
         occurrences all number
    0
    0
    5
    1
    Weight decreased
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    5 / 39 (12.82%)
         occurrences all number
    0
    0
    1
    5
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    2 / 42 (4.76%)
    3 / 39 (7.69%)
         occurrences all number
    0
    0
    2
    5
    Hand fracture
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    0
    2
    Head injury
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    3 / 39 (7.69%)
         occurrences all number
    0
    0
    0
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 48 (6.25%)
    5 / 43 (11.63%)
    4 / 42 (9.52%)
    4 / 39 (10.26%)
         occurrences all number
    3
    6
    5
    6
    Headache
         subjects affected / exposed
    16 / 48 (33.33%)
    21 / 43 (48.84%)
    15 / 42 (35.71%)
    17 / 39 (43.59%)
         occurrences all number
    23
    37
    22
    66
    Migraine
         subjects affected / exposed
    2 / 48 (4.17%)
    3 / 43 (6.98%)
    1 / 42 (2.38%)
    2 / 39 (5.13%)
         occurrences all number
    2
    3
    1
    2
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    3 / 48 (6.25%)
    2 / 43 (4.65%)
    2 / 42 (4.76%)
    2 / 39 (5.13%)
         occurrences all number
    6
    4
    6
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 48 (12.50%)
    3 / 43 (6.98%)
    4 / 42 (9.52%)
    12 / 39 (30.77%)
         occurrences all number
    7
    3
    4
    16
    Abdominal pain upper
         subjects affected / exposed
    5 / 48 (10.42%)
    4 / 43 (9.30%)
    5 / 42 (11.90%)
    4 / 39 (10.26%)
         occurrences all number
    8
    6
    6
    8
    Constipation
         subjects affected / exposed
    5 / 48 (10.42%)
    1 / 43 (2.33%)
    4 / 42 (9.52%)
    2 / 39 (5.13%)
         occurrences all number
    5
    1
    4
    2
    Diarrhoea
         subjects affected / exposed
    3 / 48 (6.25%)
    7 / 43 (16.28%)
    3 / 42 (7.14%)
    5 / 39 (12.82%)
         occurrences all number
    3
    8
    3
    6
    Enteritis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    0
    2
    Nausea
         subjects affected / exposed
    3 / 48 (6.25%)
    7 / 43 (16.28%)
    7 / 42 (16.67%)
    5 / 39 (12.82%)
         occurrences all number
    4
    7
    16
    9
    Toothache
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    1
    2
    Vomiting
         subjects affected / exposed
    7 / 48 (14.58%)
    10 / 43 (23.26%)
    5 / 42 (11.90%)
    7 / 39 (17.95%)
         occurrences all number
    9
    17
    9
    17
    Renal and urinary disorders
    Nocturia
         subjects affected / exposed
    7 / 48 (14.58%)
    3 / 43 (6.98%)
    1 / 42 (2.38%)
    6 / 39 (15.38%)
         occurrences all number
    8
    3
    1
    9
    Pollakiuria
         subjects affected / exposed
    9 / 48 (18.75%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    2 / 39 (5.13%)
         occurrences all number
    9
    0
    2
    2
    Polyuria
         subjects affected / exposed
    13 / 48 (27.08%)
    2 / 43 (4.65%)
    2 / 42 (4.76%)
    13 / 39 (33.33%)
         occurrences all number
    13
    2
    2
    13
    Renal impairment
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    3 / 39 (7.69%)
         occurrences all number
    0
    0
    1
    9
    Renal pain
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    4 / 42 (9.52%)
    3 / 39 (7.69%)
         occurrences all number
    0
    0
    5
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    5 / 39 (12.82%)
         occurrences all number
    0
    0
    0
    5
    Back pain
         subjects affected / exposed
    4 / 48 (8.33%)
    5 / 43 (11.63%)
    5 / 42 (11.90%)
    2 / 39 (5.13%)
         occurrences all number
    5
    5
    7
    2
    Flank pain
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    3 / 42 (7.14%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    3
    3
    Pain in extremity
         subjects affected / exposed
    0 / 48 (0.00%)
    6 / 43 (13.95%)
    1 / 42 (2.38%)
    3 / 39 (7.69%)
         occurrences all number
    0
    6
    2
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 43 (2.33%)
    2 / 42 (4.76%)
    2 / 39 (5.13%)
         occurrences all number
    4
    1
    2
    2
    Cystitis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    3 / 42 (7.14%)
    0 / 39 (0.00%)
         occurrences all number
    0
    0
    6
    0
    Ear infection
         subjects affected / exposed
    1 / 48 (2.08%)
    4 / 43 (9.30%)
    3 / 42 (7.14%)
    2 / 39 (5.13%)
         occurrences all number
    1
    4
    3
    2
    Gastoenteritis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    3 / 42 (7.14%)
    5 / 39 (12.82%)
         occurrences all number
    0
    0
    5
    6
    Nasopharyngitis
         subjects affected / exposed
    10 / 48 (20.83%)
    14 / 43 (32.56%)
    11 / 42 (26.19%)
    13 / 39 (33.33%)
         occurrences all number
    14
    24
    18
    19
    Pharyngitis
         subjects affected / exposed
    4 / 48 (8.33%)
    0 / 43 (0.00%)
    3 / 42 (7.14%)
    2 / 39 (5.13%)
         occurrences all number
    4
    0
    3
    2
    Rhinitis
         subjects affected / exposed
    3 / 48 (6.25%)
    3 / 43 (6.98%)
    11 / 42 (26.19%)
    4 / 39 (10.26%)
         occurrences all number
    3
    3
    14
    5
    Sinusitis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    3 / 42 (7.14%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    3
    2
    Tonsillitis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    4 / 42 (9.52%)
    3 / 39 (7.69%)
         occurrences all number
    0
    0
    4
    3
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 48 (8.33%)
    2 / 43 (4.65%)
    2 / 42 (4.76%)
    5 / 39 (12.82%)
         occurrences all number
    6
    2
    3
    6
    Urinary tract infection
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    1 / 42 (2.38%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    1
    4
    Viral infection
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 43 (2.33%)
    5 / 42 (11.90%)
    3 / 39 (7.69%)
         occurrences all number
    5
    1
    5
    5
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 43 (0.00%)
    0 / 42 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    0
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 48 (8.33%)
    2 / 43 (4.65%)
    1 / 42 (2.38%)
    5 / 39 (12.82%)
         occurrences all number
    4
    2
    2
    5
    Polydipsia
         subjects affected / exposed
    5 / 48 (10.42%)
    1 / 43 (2.33%)
    1 / 42 (2.38%)
    2 / 39 (5.13%)
         occurrences all number
    5
    1
    1
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Aug 2016
    The following changes were implemented with Amendment 1: -Exclusion of subjects who had a known lactose intolerance. -Removed ADPKD Teen Scale.
    29 Jul 2020
    The following changes were implemented with Amendment 2: Added trial conduct information to introduce the Coronavirus 2019 (COVID-19) Addendum. Updated text for secondary endpoints.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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