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    Clinical Trial Results:
    A Phase 3b, Multi-center, Randomized-withdrawal, Placebo-controlled, Double-blind, Parallel-group Trial to Compare the Efficacy and Safety of Tolvaptan (45 to 120 mg/day, Split-dose) in Subjects with Chronic Kidney Disease Between Late Stage 2 to Early Stage 4 Due to Autosomal Dominant Polycystic Kidney Disease

    Summary
    EudraCT number
    2014-000226-38
    Trial protocol
    GB   IT   SE   HU   DK   NL   BE   ES   CZ   PL   FR  
    Global end of trial date
    14 Apr 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    13 May 2018
    First version publication date
    13 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    156-13-210
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02160145
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc
    Sponsor organisation address
    2440 Research Boulevard, Rockville, United States, MD 20850
    Public contact
    Otsuka Transparency Department, Otsuka Pharmaceutical Development & Commercialization, Inc., DT-inquiry@otsuka.jp
    Scientific contact
    Otsuka Transparency Department, Otsuka Pharmaceutical Development & Commercialization, Inc., DT-inquiry@otsuka.jp
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of tolvaptan treatment in reducing the change in estimated glomerular filtration rate (eGFR) from pretreatment baseline to post-treatment follow-up, as compared with placebo, in subjects with late-stage chronic kidney disease (CKD) due to ADPKD who tolerate tolvaptan during an initial run-in period.
    Protection of trial subjects
    This trial was conducted in compliance with Good Clinical Practice guidelines for conducting, recording, and reporting trials, as well as for archiving essential documents. Consistent with ethical principles for the protection of human research subjects, no trial procedures were performed on trial candidates until written consent or assent had been obtained from them and/or their legally acceptable representative. The informed consent form, protocol, and amendments for this trial were submitted to and approved by the Institutional Review Board or Independent Ethics Committee at each respective trial center.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    21 May 2014
    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
    South Africa: 25
    Country: Number of subjects enrolled
    Spain: 61
    Country: Number of subjects enrolled
    Sweden: 26
    Country: Number of subjects enrolled
    United Kingdom: 100
    Country: Number of subjects enrolled
    United States: 637
    Country: Number of subjects enrolled
    Argentina: 24
    Country: Number of subjects enrolled
    Australia: 44
    Country: Number of subjects enrolled
    Belgium: 73
    Country: Number of subjects enrolled
    Canada: 49
    Country: Number of subjects enrolled
    Czech Republic: 34
    Country: Number of subjects enrolled
    Denmark: 28
    Country: Number of subjects enrolled
    France: 72
    Country: Number of subjects enrolled
    Germany: 113
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Israel: 41
    Country: Number of subjects enrolled
    Italy: 82
    Country: Number of subjects enrolled
    Netherlands: 25
    Country: Number of subjects enrolled
    Norway: 6
    Country: Number of subjects enrolled
    Poland: 41
    Country: Number of subjects enrolled
    Romania: 19
    Country: Number of subjects enrolled
    Russian Federation: 4
    Worldwide total number of subjects
    1519
    EEA total number of subjects
    695
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    1504
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial included subjects randomized at 213 sites (screened subjects from 225 sites) in the following 21 countries: Argentina, Australia, Belgium, Canada, Czech Republic, Denmark, France, Germany, Hungary, Israel, Italy, Netherlands, Norway, Poland, Romania, Russia, South Africa, Spain, Sweden, United Kingdom, and United States.

    Pre-assignment
    Screening details
    Subjects who provided informed consent and for whom preliminary eligibility was established entered an 8-week prerandomization period (screening + 3 single-blind periods: placebo run-in, tolvaptan titration and tolvaptan run-in). The screening period (up to Day -43) was typically 1 to 2 weeks.

    Period 1
    Period 1 title
    Placebo Run-in Period
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Subject
    Blinding implementation details
    The subject remained blinded to treatment (matching placebo of tolvaptan).

    Arms
    Arm title
    Placebo Run-in Period - All subjects
    Arm description
    Placebo Run-in Period was from Day -42 to Day -36. In the first week after the screening period, all subjects began the single-blind, placebo run-in period with placebo in a daily split-dose in a form identical to tolvaptan tablets. Subjects unable to tolerate the placebo dose regimen were considered “run-in failures”.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The subjects received placebo orally in a daily split-dose of 0 mg (abbreviated 0/0 mg), in a form identical to tolvaptan tablets at the 15/15 mg dose.

    Number of subjects in period 1
    Placebo Run-in Period - All subjects
    Started
    1519
    Completed
    1496
    Not completed
    23
         Subject Decision
    15
         Other Reasons
    2
         Physician Decision
    5
         Lost to follow-up
    1
    Period 2
    Period 2 title
    Tolvaptan titration and Run-in Period
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Subject
    Blinding implementation details
    Subjects were blinded to treatment.

    Arms
    Arm title
    Tolvaptan titration and Run-in Period: All Subjects
    Arm description
    Tolvaptan Titration Period was from Day -35 to Day -22. During the single-blind, 2-week, tolvaptan titration period, all subjects received 2 boxes of tolvaptan, 1 box containing 2 bottles of 15-mg tablets and the other box containing 2 bottles of 30-mg tablets. Titration was accomplished by increasing the number of tablets/dose and/or switching from 15 mg tablets to 30 mg tablets. Those subjects unable to tolerate at least a 60/30 mg tolvaptan dose regimen were considered “run-in failures". Subjects who tolerated at least 60/30 mg tolvaptan, entered the single-blind, tolvaptan run-in period (3-week duration; Tolvaptan Run-in Period was from Day -21 to Day -1) and continued on a stable 60/30 mg or 90/30 mg tolvaptan dose to confirm tolerability over a longer period and to establish a tolvaptan pre-randomization baseline.
    Arm type
    Experimental

    Investigational medicinal product name
    Tolvaptan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were instructed to take tolvaptan orally at a split-dose of 30/15 mg (as two 15-mg tablets upon waking and one 15-mg tablet approximately 8 to 9 hours later) and to titrate up every 3 to 4 days; first to 45/15, then 60/30, then, up to the maximum dose of 90/30 mg. In tolvaptan run-in period, subjects who tolerated at least 60/30 mg tolvaptan, continued on a stable 60/30 mg or 90/30 mg tolvaptan dose.

    Number of subjects in period 2
    Tolvaptan titration and Run-in Period: All Subjects
    Started
    1496
    Completed
    1370
    Not completed
    126
         Subject Decision
    97
         Other Reasons
    6
         Physician Decision
    19
         Lost to follow-up
    4
    Period 3
    Period 3 title
    Double-blind Randomized Treatment Period
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Except in cases of emergency unblinding, subjects, investigational site personnel, sponsor employees, and all other trial personnel remained blinded to the identity of the treatment assignments until every subject had completed trial treatment and the database had been locked. Once the blind was broken for a given subject, that subject could not reinitiate treatment with IMP.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Tolvaptan
    Arm description
    Treatment Period was from Day 0 to Month 12. Subjects who tolerated the 60/30- or 90/30-mg dose of tolvaptan were randomized to tolvaptan treatment period. Subjects randomized to tolvaptan continued to take the same dose that they received during the tolvaptan run-in period. The treatment duration was for 12 months from the date of randomization.
    Arm type
    Experimental

    Investigational medicinal product name
    Tolvaptan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tolvaptan was administered at 60/30 or 90/30 mg, as split-doses, with down-titrations to 45/15 and 30/15 mg as needed for tolerability. Planned down titration to 30/15 mg was approved by the medical monitor.

    Arm title
    Placebo
    Arm description
    Subjects randomized to placebo received placebo tablets matching their tolerated tolvaptan dose during the tolvaptan run-in period. The treatment duration was for 12 months from the date of randomization.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablets (15 or 30 mg) were self-administered orally as split-dose regimens, once upon awakening and another approximately 8 to 9 hours later.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: This study consisted of pre-randomization period which comprised of a screening period, a placebo run-in period and a tolvaptan run-in period. Since the actual randomization of subjects occurred after this pre-randomization period, Period 3 was considered as the "Baseline period". Only the randomized subjects were taken into account for the efficacy and safety analysis
    Number of subjects in period 3 [2]
    Tolvaptan Placebo
    Started
    683
    687
    Completed
    654
    659
    Not completed
    29
    28
         Subject Decision
    21
    20
         Physician Decision
    7
    5
         Lost to follow-up
    1
    3
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: In order to achieve 90% power with the assumption of 10% dropout rate in the trial, a total sample size of approximately 1300 subjects were planned. But in the trial, 1370 subjects were randomized and were considered as the baseline population count.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tolvaptan
    Reporting group description
    Treatment Period was from Day 0 to Month 12. Subjects who tolerated the 60/30- or 90/30-mg dose of tolvaptan were randomized to tolvaptan treatment period. Subjects randomized to tolvaptan continued to take the same dose that they received during the tolvaptan run-in period. The treatment duration was for 12 months from the date of randomization.

    Reporting group title
    Placebo
    Reporting group description
    Subjects randomized to placebo received placebo tablets matching their tolerated tolvaptan dose during the tolvaptan run-in period. The treatment duration was for 12 months from the date of randomization.

    Reporting group values
    Tolvaptan Placebo Total
    Number of subjects
    683 687 1370
    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)
    47.3 ± 8.2 47.2 ± 8.2 -
    Gender categorical
    Units: Subjects
        Female
    336 354 690
        Male
    347 333 680

    End points

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    End points reporting groups
    Reporting group title
    Placebo Run-in Period - All subjects
    Reporting group description
    Placebo Run-in Period was from Day -42 to Day -36. In the first week after the screening period, all subjects began the single-blind, placebo run-in period with placebo in a daily split-dose in a form identical to tolvaptan tablets. Subjects unable to tolerate the placebo dose regimen were considered “run-in failures”.
    Reporting group title
    Tolvaptan titration and Run-in Period: All Subjects
    Reporting group description
    Tolvaptan Titration Period was from Day -35 to Day -22. During the single-blind, 2-week, tolvaptan titration period, all subjects received 2 boxes of tolvaptan, 1 box containing 2 bottles of 15-mg tablets and the other box containing 2 bottles of 30-mg tablets. Titration was accomplished by increasing the number of tablets/dose and/or switching from 15 mg tablets to 30 mg tablets. Those subjects unable to tolerate at least a 60/30 mg tolvaptan dose regimen were considered “run-in failures". Subjects who tolerated at least 60/30 mg tolvaptan, entered the single-blind, tolvaptan run-in period (3-week duration; Tolvaptan Run-in Period was from Day -21 to Day -1) and continued on a stable 60/30 mg or 90/30 mg tolvaptan dose to confirm tolerability over a longer period and to establish a tolvaptan pre-randomization baseline.
    Reporting group title
    Tolvaptan
    Reporting group description
    Treatment Period was from Day 0 to Month 12. Subjects who tolerated the 60/30- or 90/30-mg dose of tolvaptan were randomized to tolvaptan treatment period. Subjects randomized to tolvaptan continued to take the same dose that they received during the tolvaptan run-in period. The treatment duration was for 12 months from the date of randomization.

    Reporting group title
    Placebo
    Reporting group description
    Subjects randomized to placebo received placebo tablets matching their tolerated tolvaptan dose during the tolvaptan run-in period. The treatment duration was for 12 months from the date of randomization.

    Primary: Treatment difference in the change of eGFR (Estimated glomerular filtration rate), from pre-treatment baseline to post-treatment follow-up, annualized (divided) by each subject’s trial duration

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    End point title
    Treatment difference in the change of eGFR (Estimated glomerular filtration rate), from pre-treatment baseline to post-treatment follow-up, annualized (divided) by each subject’s trial duration
    End point description
    Treatment difference in the change of eGFR was calculated using Chronic Kidney Disease-Epidemiology (CKD-EPI) formula. To reduce the variation in this primary endpoint, 3 observations of eGFR were obtained at baseline during a 3-week interval (screening and placebo run-in periods) and another 3 observations were obtained post-treatment during a 2-week interval that began 1 week after the end of treatment (3-week post-treatment follow-up). The average of the 3 eGFR values observed during the baseline period was set as the baseline and the average of the 3 eGFR values observed during the post-treatment follow-up period was set as the renal function measurement post-treatment.
    End point type
    Primary
    End point timeframe
    From prior to randomization to follow-up (3 weeks post-treatment)
    End point values
    Tolvaptan Placebo
    Number of subjects analysed
    668
    663
    Units: mL/min/1.73 m2/yr
        arithmetic mean (standard deviation)
    -2.961 ± 4.590
    -4.249 ± 4.009
    Statistical analysis title
    Treatment difference in Change in eGFR
    Comparison groups
    Placebo v Tolvaptan
    Number of subjects included in analysis
    1331
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001 [1]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.271
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.859
         upper limit
    1.684
    Notes
    [1] - Derived from weighted ANCOVA with effects of treatment and randomization stratification factors and covariate baseline.

    Secondary: Number of subjects with adverse events (AEs)

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    End point title
    Number of subjects with adverse events (AEs)
    End point description
    An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A suspected adverse reaction means any AE for which there is a reasonable possibility that the drug caused the AE.
    End point type
    Secondary
    End point timeframe
    From Day 0 until the follow-up visit (3 weeks post-treatment)
    End point values
    Tolvaptan Placebo
    Number of subjects analysed
    681
    685
    Units: Participants
    number (not applicable)
        Subjects with AEs
    581
    564
        Subjects with treatment-emergent AEs
    581
    564
        Subjects with serious treatment-emergent AEs
    85
    60
        Subjects with non-serious treatment-emergent AEs
    569
    556
        Subjects with severe treatment-emergent AEs
    70
    50
        Subjects discontinued drug due to AEs
    65
    15
        Number of subjects who died
    0
    1
    No statistical analyses for this end point

    Secondary: Treatment difference in annualized slope of eGFR calculated for individual subjects using eGFR data observed in the placebo run-in, tolvaptan run-in (not including tolvaptan titration), double-blind treatment, and post-treatment follow-up periods

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    End point title
    Treatment difference in annualized slope of eGFR calculated for individual subjects using eGFR data observed in the placebo run-in, tolvaptan run-in (not including tolvaptan titration), double-blind treatment, and post-treatment follow-up periods
    End point description
    The key secondary endpoint of the trial was the annualized rate of eGFR change, which was derived from each individual subject’s eGFR slope using the CKD-EPI formula. The analysis of the key secondary endpoint was formally conducted, once the primary endpoint was significant at a 2-sided alpha of 0.05. Then a 2-sided alpha of 0.05 was applied to the primary analysis of the key secondary endpoint. In this analysis, all eGFR observations from placebo run-in, tolvaptan run-in (not including tolvaptan titration), double-blind treatment, and post-treatment follow-up (not including data collected in the first week after the last IMP dose) periods were included in the analysis, with the data of tolvaptan run-in and tolvaptan subjects in the double-blind treatment period were flagged (yes = 1 and no = 0) with a tolvaptan acute hemodynamic effect.
    End point type
    Secondary
    End point timeframe
    Prior to and post 13 1/2 months of treatment
    End point values
    Tolvaptan Placebo
    Number of subjects analysed
    680
    682
    Units: mL/min/1.73 m2/yr
        arithmetic mean (standard deviation)
    -2.552 ± 7.911
    -3.238 ± 5.757
    Statistical analysis title
    Treatment difference in annualized slope of eGFR
    Comparison groups
    Placebo v Tolvaptan
    Number of subjects included in analysis
    1362
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001 [2]
    Method
    Linear Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    1.011
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.618
         upper limit
    1.403
    Notes
    [2] - Derived from linear mixed model with effects of treatment, time, treatment time interaction, acute hemodynamic effect, pre-treatment baseline, and randomization stratification factors.

    Secondary: Pharmacodynamic endpoint: Mean change from baseline in Urinalysis - Urine osmolality (Uosm)

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    End point title
    Pharmacodynamic endpoint: Mean change from baseline in Urinalysis - Urine osmolality (Uosm)
    End point description
    Uosm was one of the pharmacodynamic endpoints. Urine osmolality was summarized by treatment (tolvaptan or placebo) and time point using descriptive statistics. Baseline values were from the sample obtained at the end of the tolvaptan run-in period.
    End point type
    Secondary
    End point timeframe
    From Day -1 through Month 12/end of treatment (EoTx) visit, and the last follow-up visit (3 weeks post-treatment).
    End point values
    Tolvaptan Placebo
    Number of subjects analysed
    681
    685
    Units: mOsm/kg
    arithmetic mean (standard deviation)
        Month 3 ( N = 655, 664)
    10.2 ± 80.3
    177.7 ± 124.5
        Month 6 (N = 637, 652)
    22.9 ± 84.3
    179.1 ± 126.2
        Month 9 (N = 625, 646)
    30.4 ± 92.1
    179.9 ± 125.1
        Month 12 (N = 629, 651)
    36.9 ± 96.0
    180.3 ± 121.1
        Follow-up Day 21 (N = 624, 650)
    162.4 ± 114.0
    179.5 ± 128.9
    No statistical analyses for this end point

    Secondary: Pharmacodynamic endpoint: Mean change from baseline in Urinalysis - urine specific gravity

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    End point title
    Pharmacodynamic endpoint: Mean change from baseline in Urinalysis - urine specific gravity
    End point description
    Urine specific gravity was one of the pharmacodynamic endpoints. Urine specific gravity was summarized by treatment (tolvaptan or placebo) and time point using descriptive statistics. Baseline values were from the sample obtained at the end of the tolvaptan run-in period.
    End point type
    Secondary
    End point timeframe
    From Day -1 through Month 12/end of treatment (EoTx) visit, and the last follow-up visit (3 weeks post-treatment).
    End point values
    Tolvaptan Placebo
    Number of subjects analysed
    681
    685
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Month 3 (N = 654, 662)
    0.0001 ± 0.0022
    0.0041 ± 0.0033
        Month 6 (N = 638, 649 )
    0.0003 ± 0.0024
    0.0042 ± 0.0033
        Month 9 (N = 623, 641)
    0.0004 ± 0.0025
    0.0040 ± 0.0032
        Month 12 (N = 635, 648)
    0.0006 ± 0.0027
    0.0040 ± 0.0033
        Follow-up Day 21 (N = 620, 653)
    0.0037 ± 0.0031
    0.0040 ± 0.0034
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening until the follow-up visit (3 weeks post-treatment)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Tolvaptan
    Reporting group description
    Subjects who reached the end of the tolvaptan run-in period and who tolerated the 60/30- or 90/30-mg dose of tolvaptan were randomized to tolvaptan treatment period. Subjects randomized to tolvaptan continued to take the same dose that they received during the tolvaptan run-in period. Treatment Period was from Day 0 to Month 12.

    Reporting group title
    Placebo
    Reporting group description
    Subjects randomized to placebo received placebo tablets matching their tolerated tolvaptan dose during the tolvaptan run-in period. The treatment duration was for 12 months from the date of randomization.

    Serious adverse events
    Tolvaptan Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    85 / 681 (12.48%)
    60 / 685 (8.76%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 681 (0.00%)
    2 / 685 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm benign
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phaeochromocytoma
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cyst rupture
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 681 (0.15%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 681 (0.15%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural intestinal perforation
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 681 (0.15%)
    3 / 685 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    2 / 681 (0.29%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 681 (1.17%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    7 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 681 (0.44%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 681 (0.00%)
    2 / 685 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    11 / 681 (1.62%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    10 / 12
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    3 / 681 (0.44%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    4 / 681 (0.59%)
    2 / 685 (0.29%)
         occurrences causally related to treatment / all
    7 / 7
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic specific antigen increased
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    2 / 681 (0.29%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 681 (0.00%)
    2 / 685 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 681 (0.15%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve prolapse
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital hepatic fibrosis
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 681 (0.29%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery aneurysm
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral artery thrombosis
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 681 (0.15%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    1 / 681 (0.15%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 681 (0.29%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal incarcerated hernia
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 681 (0.15%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Swollen tongue
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 681 (0.29%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 681 (0.15%)
    2 / 685 (0.29%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst haemorrhage
         subjects affected / exposed
    3 / 681 (0.44%)
    2 / 685 (0.29%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal haemorrhage
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    2 / 681 (0.29%)
    3 / 685 (0.44%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal pain
         subjects affected / exposed
    1 / 681 (0.15%)
    3 / 685 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic hepatic cyst
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cyst
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 681 (0.15%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash pruritic
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 681 (0.29%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 681 (0.00%)
    2 / 685 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitamin B complex deficiency
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter bacteraemia
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 681 (0.15%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cyst infection
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 681 (0.15%)
    3 / 685 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst infection
         subjects affected / exposed
    2 / 681 (0.29%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 681 (0.15%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 681 (0.15%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 681 (0.44%)
    0 / 685 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 681 (0.00%)
    1 / 685 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Tolvaptan Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    569 / 681 (83.55%)
    556 / 685 (81.17%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    73 / 681 (10.72%)
    79 / 685 (11.53%)
         occurrences all number
    88
    95
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    46 / 681 (6.75%)
    44 / 685 (6.42%)
         occurrences all number
    58
    54
    Nervous system disorders
    Headache
         subjects affected / exposed
    55 / 681 (8.08%)
    59 / 685 (8.61%)
         occurrences all number
    66
    65
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    45 / 681 (6.61%)
    24 / 685 (3.50%)
         occurrences all number
    48
    26
    Oedema peripheral
         subjects affected / exposed
    30 / 681 (4.41%)
    45 / 685 (6.57%)
         occurrences all number
    37
    50
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    47 / 681 (6.90%)
    23 / 685 (3.36%)
         occurrences all number
    54
    25
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    37 / 681 (5.43%)
    35 / 685 (5.11%)
         occurrences all number
    51
    40
    Polyuria
         subjects affected / exposed
    36 / 681 (5.29%)
    11 / 685 (1.61%)
         occurrences all number
    38
    11
    Renal pain
         subjects affected / exposed
    112 / 681 (16.45%)
    127 / 685 (18.54%)
         occurrences all number
    157
    171
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    33 / 681 (4.85%)
    41 / 685 (5.99%)
         occurrences all number
    35
    45
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    58 / 681 (8.52%)
    58 / 685 (8.47%)
         occurrences all number
    69
    71
    Urinary tract infection
         subjects affected / exposed
    38 / 681 (5.58%)
    55 / 685 (8.03%)
         occurrences all number
    44
    65
    Viral upper respiratory tract infection
         subjects affected / exposed
    72 / 681 (10.57%)
    84 / 685 (12.26%)
         occurrences all number
    98
    111

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Feb 2014
    Administrative Change 1: Corrected typographical errors and added additional clarifying information to Figure 3.1-1 (Trial Design Schematic).
    31 Mar 2014
    Amendment 1: The primary purpose of this amendment was to increase the sample size and period of enrollment to increase power for the primary and secondary endpoints. In addition, information associated with a potential interim analysis was added, the number of creatinine blood draws was reduced, an inclusion criterion was added, and an exclusion criterion was modified. Minor revisions were also made to the protocol for clarity.
    25 Jun 2014
    Administrative Change 2: Aligned the Statistical Analysis Plan with the protocol. In addition, an administrative change to Home Nursing Services was made and several clarifications to the protocol were added.
    26 Mar 2015
    Amendment 2: The primary purpose of this amendment is to clarify the inclusion criterion for older subjects, and to correct a misstatement regarding SUSAR reporting for procedures. Other clarifications were added for consistency between the Schedule of Assessments table and text or to clarify sample collection process or timing. The DNA sample collection time was changed from the second screening visit only to any visit from the second screening visit onwards.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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