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    Clinical Trial Results:
    A Phase 3b, Multicenter, Open-label, Randomized Withdrawal Trial of the Effects of Titrated Oral SAMSCA® (Tolvaptan) on Serum Sodium, Pharmacokinetics, and Safety in Children and Adolescent Subjects Hospitalized With Euvolemic or Hypervolemic Hyponatremia

    Summary
    EudraCT number
    		 2013-002005-59
    Trial protocol
    		 DE   GB   ES   IT   CZ   BE  
    Global end of trial date
    24 Jul 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Apr 2018
    First version publication date
    25 Apr 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    156-08-276
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02012959
    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 Pharmaceutical Development & Commercialization, Inc., Otsuka Transparency Department, DT-inquiry@otsuka.jp
    Scientific contact
    Otsuka Pharmaceutical Development & Commercialization, Inc., Otsuka Transparency Department, 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jul 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To demonstrate that tolvaptan effectively and safely increases and maintains serum sodium concentrations in children and adolescent subjects with euvolemic or hypervolemic hyponatremia.
    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 had been obtained from them. The informed consent form, protocol, and amendments for this trial were submitted to and approved by the institutional review board or ethics committee at each respective trial center.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Sep 2015
    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: 1
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    United States: 7
    Worldwide total number of subjects
    9
    EEA total number of subjects
    2
    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)
    8
    Adolescents (12-17 years)
    1
    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
    		 A total of 42 sites were activated, 18 in the European Union and 24 in North America. After approximately 32 months of open enrollment, only 14 subjects were screened and 9 subjects were enrolled. The trial was terminated due to low subject enrollment which made the trial highly impracticable to conduct. The trial was not terminated due to safety.

    Pre-assignment
    Screening details
    		 The trial consisted of a screening phase, two treatment phases (Phases A and B), and follow-up Phase C. Overall, in this trial, subjects underwent treatment (2 to 5 days of tolvaptan among 2 treatment phases) and a post-last dose follow-up phase of 14 days.

    Period 1
    Period 1 title
    Treatment Phase A
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Phase A: All participants
    Arm description
    		 During Treatment Phase A, subjects received tolvaptan once daily on Days 1 and 2. If the serum sodium level did not increase at least 4 mEq/L by Day 2, treatment was extended one additional day (to Day 2a). On Day 2a, subjects achieving an increase in serum sodium of ≥ 4 mEq/L were defined as responders, and subjects not achieving a ≥ 4 mEq/L increase in serum sodium were defined as nonresponders.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tolvaptan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Syrup
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received tolvaptan once daily on Days 1 and 2. If the serum sodium level did not increase at least 4 mEq/L by Day 2, treatment was extended one additional day (to Day 2a).

    Number of subjects in period 1
    		Phase A: All participants
    Started
    9
    Completed
    7
    Not completed
    2
         Adverse Events
    2
    Period 2
    Period 2 title
    Treatment Phase B: Responder
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Late Withdrawal
    Arm description
    		 Subjects who were responders (serum sodium increased by ≥ 4 mEq/L) from Phase A continued to Treatment Phase B (Randomization Phase) on Day 3, and were randomized to the Late Withdrawal group (continuing tolvaptan treatment for Days 3 and 4).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tolvaptan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Syrup, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects continued tolvaptan treatment on Days 3 and 4.

    Arm title
    		 Early Withdrawal
    Arm description
    		 Subjects who were responders (serum sodium increased by ≥ 4 mEq/L) from Phase A continued to Treatment Phase B (Randomization Phase) on Day 3, and were randomized to the Early Withdrawal group (not receiving additional tolvaptan on Days 3 or 4). Subjects randomized to Early Withdrawal were monitored for any interventions needed to maintain appropriate serum sodium levels. Where sodium levels declined by ≥ 4 mEq/L, or where the overall clinical condition warranted further intervention to increase serum sodium levels, subjects were treated per the investigator’s preferred standard of care. Any intervention, including fluid restriction, during the first 48 hours of the Early Withdrawal phase was defined as rescue therapy, and subject data was censored thereafter.
    Arm type
    		 Any interventions

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Treatment Phase B: Responder (Overall)
    Arm description
    		 Subjects who were responders (serum sodium increased by ≥ 4 mEq/L) continued to Treatment Phase B (Randomization Phase) on Day 3, and were randomized to either the Early Withdrawal group (not receiving additional tolvaptan on Days 3 or 4) or the Late Withdrawal group (continuing tolvaptan treatment for Days 3 and 4).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tolvaptan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Syrup, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects continued tolvaptan treatment on Days 3 and 4.

    Number of subjects in period 2
    		Late Withdrawal Early Withdrawal Treatment Phase B: Responder (Overall)
    Started
    2
    3
    5
    Completed
    2
    3
    5
    Period 3
    Period 3 title
    Treatment Phase B: Non-responder
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Study Drug
    Arm description
    		 Subjects who were nonresponders during Phase A were not randomized in Phase B but were treated per the investigator’s discretion, and continued tolvaptan for Days 3 and 4.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tolvaptan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Syrup, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects continued tolvaptan treatment on Days 3 and 4.

    Arm title
    		 Standard of Care
    Arm description
    		 Subjects who were nonresponders during Phase A were not randomized in Phase B but were treated per the investigator’s discretion. The subjects in this arm discontinued tolvaptan and received the investigator’s preferred standard of care for Days 3 and 4.
    Arm type
    		 Standard care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		Study Drug Standard of Care
    Started
    1
    1
    Completed
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Phase A
    Reporting group description
    		 -

    Reporting group values
    		 Treatment Phase A Total
    Number of subjects
    		 9 9
    Age categorical
    During Treatment Phase A, subjects received tolvaptan once daily on Days 1 and 2. If the serum sodium level did not increase at least 4 mEq/L by Day 2, treatment was extended one additional day (to Day 2a). On Day 2a, subjects achieving an increase in serum sodium of ≥ 4 mEq/L were defined as responders, and subjects not achieving a ≥ 4 mEq/L increase in serum sodium were defined as nonresponders. Subjects who were responders (serum sodium increased by ≥ 4 mEq/L) continued to Treatment Phase B (Randomization Phase) on Day 3.
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 1 1
        Children (2-11 years)
    		 6 6
        Adolescents (12-17 years)
    		 2 2
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 6.1 ( 5.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 3
        Male
    		 6 6

    End points

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    End points reporting groups
    Reporting group title
    Phase A: All participants
    Reporting group description
    		 During Treatment Phase A, subjects received tolvaptan once daily on Days 1 and 2. If the serum sodium level did not increase at least 4 mEq/L by Day 2, treatment was extended one additional day (to Day 2a). On Day 2a, subjects achieving an increase in serum sodium of ≥ 4 mEq/L were defined as responders, and subjects not achieving a ≥ 4 mEq/L increase in serum sodium were defined as nonresponders.
    Reporting group title
    Late Withdrawal
    Reporting group description
    		 Subjects who were responders (serum sodium increased by ≥ 4 mEq/L) from Phase A continued to Treatment Phase B (Randomization Phase) on Day 3, and were randomized to the Late Withdrawal group (continuing tolvaptan treatment for Days 3 and 4).

    Reporting group title
    Early Withdrawal
    Reporting group description
    		 Subjects who were responders (serum sodium increased by ≥ 4 mEq/L) from Phase A continued to Treatment Phase B (Randomization Phase) on Day 3, and were randomized to the Early Withdrawal group (not receiving additional tolvaptan on Days 3 or 4). Subjects randomized to Early Withdrawal were monitored for any interventions needed to maintain appropriate serum sodium levels. Where sodium levels declined by ≥ 4 mEq/L, or where the overall clinical condition warranted further intervention to increase serum sodium levels, subjects were treated per the investigator’s preferred standard of care. Any intervention, including fluid restriction, during the first 48 hours of the Early Withdrawal phase was defined as rescue therapy, and subject data was censored thereafter.

    Reporting group title
    Treatment Phase B: Responder (Overall)
    Reporting group description
    		 Subjects who were responders (serum sodium increased by ≥ 4 mEq/L) continued to Treatment Phase B (Randomization Phase) on Day 3, and were randomized to either the Early Withdrawal group (not receiving additional tolvaptan on Days 3 or 4) or the Late Withdrawal group (continuing tolvaptan treatment for Days 3 and 4).
    Reporting group title
    Study Drug
    Reporting group description
    		 Subjects who were nonresponders during Phase A were not randomized in Phase B but were treated per the investigator’s discretion, and continued tolvaptan for Days 3 and 4.

    Reporting group title
    Standard of Care
    Reporting group description
    		 Subjects who were nonresponders during Phase A were not randomized in Phase B but were treated per the investigator’s discretion. The subjects in this arm discontinued tolvaptan and received the investigator’s preferred standard of care for Days 3 and 4.

    Primary: Mean Change from Baseline in Serum Sodium Concentration (mEq/L) for Responders

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    End point title
    		 Mean Change from Baseline in Serum Sodium Concentration (mEq/L) for Responders [1]
    End point description
    To assess the change in serum sodium level for responders from Day 2 (or 2a) at the end of Treatment Phase A (where all subjects received tolvaptan) to the end of Treatment Phase B for the Early compared to Late Withdrawal groups. Once a subject was randomized to Treatment Phase B, any additional therapies for the purpose of raising serum sodium, including fluid restriction, was considered rescue therapy. Upon receipt of rescue therapy, a subject’s endpoint data was collected and then censored from the efficacy analysis thereafter unless specified.
    End point type
    Primary
    End point timeframe
    Day 2/2a/3, Day 4/5
    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: The trial was terminated due to low subject recruitment and enrollment which made the trial highly impracticable or impossible to conduct. No statistical analysis was done for the primary endpoint.
    End point values
    		 Late Withdrawal Early Withdrawal
    Number of subjects analysed
    2
    3
    Units: mEq/L
        arithmetic mean (standard deviation)
    -4.0 ( 4.2 )
    -1.0 ( 1.0 )
    No statistical analyses for this end point

    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 was defined as any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which did not necessarily have a causal relationship with this treatment. AEs would not include information recorded as medical history at screening for pre planned procedures for which the underlying condition was known and no worsening occurred. An adverse reaction was any untoward and unintended response to an investigational medicinal product (IMP) related to any dose administered.
    End point type
    Secondary
    End point timeframe
    Adverse events were recorded from the time of the informed consent was signed until the follow-up visit 14 (+ 2) days post-last dose.
    End point values
    		 Phase A: All participants Late Withdrawal Early Withdrawal Study Drug Standard of Care
    Number of subjects analysed
    9
    2
    3
    1
    1
    Units: Subjects
    number (not applicable)
        Subjects with Adverse Events
    5
    2
    2
    1
    1
        Subjects with Treatment-Emergent Adverse Events
    4
    2
    2
    1
    1
        Subjects with Serious Treatment-Emergent AEs
    2
    1
    0
    1
    0
        Subjects with Severe Treatment-Emergent AEs
    0
    0
    0
    1
    0
        Subjects Discontinued Due to AEs
    2
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Mean change from baseline in serum sodium concentration (mEq/L) in Treatment Phase A

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    End point title
    		 Mean change from baseline in serum sodium concentration (mEq/L) in Treatment Phase A
    End point description
    To assess the change from baseline in serum sodium concentration at the end of Day 2 (or 2a) at the end of Treatment Phase A. A hierarchical testing procedure was used to maintain the overall experiment-wise type I error rate at 0.05. Thus, if the primary efficacy analysis yielded a statistically significant result at an alpha level of 0.05 (2-sided), then the paired t-test was performed at an alpha level of 0.05 for the key secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Day 2/2a
    End point values
    		 Phase A: All participants
    Number of subjects analysed
    9
    Units: mEq/L
    arithmetic mean (standard deviation)
        Phase A Day 1 : 24 hour Post-Dose (N = 8)
    1 ( 3 )
        Phase A Day 2 : 24 hour Post-Dose (N = 7)
    3.4 ( 4.8 )
        Phase A Day 2a : 24 hour Post-Dose (N = 3)
    2.3 ( 2.1 )
    No statistical analyses for this end point

    Secondary: Mean change in serum sodium from 24 hours post-last dose to 7 days post-last dose in Phase B for Responders

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    End point title
    		 Mean change in serum sodium from 24 hours post-last dose to 7 days post-last dose in Phase B for Responders
    End point description
    To assess the change in serum sodium concentration from 24 hours post-last dose to 7 days post-last dose. This analysis used a paired Student’s t-test, descriptive statistics, and/or 2-sided 95% Confidence Intervels (CIs).
    End point type
    Secondary
    End point timeframe
    7 Days
    End point values
    		 Treatment Phase B: Responder (Overall)
    Number of subjects analysed
    5
    Units: mEq/L
    arithmetic mean (standard deviation)
        72h Post-last Dose
    -0.8 ( 0.8 )
        7 Days Post-last Dose
    3.6 ( 3.9 )
    No statistical analyses for this end point

    Secondary: Fluid intake in Treatment Phase A

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    End point title
    		 Fluid intake in Treatment Phase A
    End point description
    To assess the fluid intake (both oral and intravenous [IV]) every 6 hours on Days 1 and 2 in Treatment Phase A. Fluid intake is one of the pharmacodynamic [PD] endpoints. The fluid content of foods with significant water content (eg, soup) was added to the total fluid intake. Fluid intake was monitored per institutional guidelines.
    End point type
    Secondary
    End point timeframe
    Every 6 hours on Days 1 and 2
    End point values
    		 Phase A: All participants
    Number of subjects analysed
    9
    Units: mL
    arithmetic mean (standard deviation)
        Day 1: 0-6 hours
    555 ( 402 )
        Day 1 : 6-12 hours
    396 ( 282 )
        Day 1 : 12-18 hours
    435 ( 496 )
        Day 1 : 18-24 hours
    387 ( 308 )
        Day 1 : 0-24 hours
    1774 ( 1242 )
        Day 2 : 0-6 hours (N=8)
    411 ( 134 )
        Day 2 : 6-12 hours (N=8)
    461 ( 522 )
        Day 2 : 12-18 hours (N=8)
    307 ( 221 )
        Day 2 : 18-24 hours (N=8)
    424 ( 299 )
        Day 2 : 0-24 hours (N=8)
    1603 ( 1099 )
    No statistical analyses for this end point

    Secondary: Urine output in Treatment Phase A

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    End point title
    		 Urine output in Treatment Phase A
    End point description
    To assess the urine output 6 hours on Days 1 and 2 in Treatment Phase A. Urine output is one of the PD endpoints.
    End point type
    Secondary
    End point timeframe
    Every 6 hours on Days 1 and 2
    End point values
    		 Phase A: All participants
    Number of subjects analysed
    9
    Units: mL
    arithmetic mean (standard deviation)
        Day 1 : 0-6 hours
    557 ( 293 )
        Day 1 : 6-12 hours
    658 ( 595 )
        Day 1 : 12-18 hours
    472 ( 498 )
        Day 1 : 18-24 hours
    355 ( 329 )
        Day 1 : 0-24 hours
    2041 ( 1127 )
        Day 2 : 0-6 hours (N=8)
    512 ( 398 )
        Day 2 : 6-12 hours (N=8)
    455 ( 485 )
        Day 2 : 12-18 hours (N=8)
    352 ( 482 )
        Day 2 : 18-24 hours (N=8)
    444 ( 442 )
        Day 2 : 0-24 hours (N=8)
    1763 ( 1358 )
    No statistical analyses for this end point

    Secondary: Fluid balance (intake minus output) in Treatment Phase A

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    End point title
    		 Fluid balance (intake minus output) in Treatment Phase A
    End point description
    To assess the fluid balance every 6 hours and for the 24-hour daily interval on Days 1 and 2 in Treatment Phase A. Fluid balance is one of the PD endpoints. Fluid balance was monitored per institutional guidelines.
    End point type
    Secondary
    End point timeframe
    Every 6 hours on Days 1 and 2
    End point values
    		 Phase A: All participants
    Number of subjects analysed
    9
    Units: mL
    arithmetic mean (standard deviation)
        Day 1 : 0-6 hours
    -1 ( 505 )
        Day 1 : 6-12 hours
    -261 ( 533 )
        Day 1 : 12-18 hours
    -36 ( 253 )
        Day 1 : 18-24 hours
    31 ( 344 )
        Day 1 : 0-24 hours
    -268 ( 849 )
        Day 2 : 0-6 hours (N=8)
    -101 ( 376 )
        Day 2 : 6-12 hours (N=8)
    6 ( 513 )
        Day 2 : 12-18 hours (N=8)
    -45 ( 400 )
        Day 2 : 18-24 hours (N=8)
    -21 ( 191 )
        Day 2 : 0-24 hours (N=8)
    -160 ( 733 )
    No statistical analyses for this end point

    Secondary: Incidence of Laboratory Values of Potential Clinical Relevance

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    End point title
    		 Incidence of Laboratory Values of Potential Clinical Relevance
    End point description
    The laboratory values were one of the variables to measure the safety of individual participants. Incidence of treatment emergent adverse events (TEAEs) of potential clinical relevance include abnormal values in hematology, coagulation, chemistry and urinalysis that were identified based on pre-defined criteria. Abnormal laboratory values in participants were reported as serious adverse event/adverse events (SAE/AEs) and are reported in the SAE/other AE section of this report.
    End point type
    Secondary
    End point timeframe
    From baseline to end of study
    End point values
    		 Phase A: All participants Late Withdrawal Early Withdrawal Study Drug Standard of Care
    Number of subjects analysed
    9
    2
    3
    1
    1
    Units: Participants
    number (not applicable)
        Chemistry- Potassium
    1
    0
    0
    0
    0
        Hematology - Hemoglobin
    0
    0
    1
    0
    0
        Hematology - Lymphocytes
    0
    1
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Vital sign (blood pressure) of potential clinical relevance - mean change from baseline to study for Phase B (Responders)

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    End point title
    		 Vital sign (blood pressure) of potential clinical relevance - mean change from baseline to study for Phase B (Responders)
    End point description
    Vital sign (blood pressure) was assessed after the subject had been supine for greater than or equal to 3 minutes. Vital signs were assessed prior to any blood draws.
    End point type
    Secondary
    End point timeframe
    7 days post last dose
    End point values
    		 Late Withdrawal Early Withdrawal
    Number of subjects analysed
    2
    3
    Units: mmHg
    arithmetic mean (standard deviation)
        Supine systolic blood pressure
    6.0 ( 2.8 )
    1.3 ( 20.3 )
        Supine diastolic blood pressure
    8.0 ( 0 )
    3.0 ( 8.7 )
    No statistical analyses for this end point

    Secondary: Vital sign (supine heart rate) of potential clinical relevance - mean change from baseline to study for Phase B (Responders)

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    End point title
    		 Vital sign (supine heart rate) of potential clinical relevance - mean change from baseline to study for Phase B (Responders)
    End point description
    Vital sign (supine heart rate) was assessed after the subject had been supine for greater than or equal to 3 minutes. Vital signs were assessed prior to any blood draws.
    End point type
    Secondary
    End point timeframe
    7 days post last dose
    End point values
    		 Late Withdrawal Early Withdrawal
    Number of subjects analysed
    2
    3
    Units: beats/min
        arithmetic mean (standard deviation)
    10.5 ( 2.1 )
    -2.3 ( 4.2 )
    No statistical analyses for this end point

    Secondary: Vital sign (supine respiratory rate) of potential clinical relevance - mean change from baseline to study for Phase B (Responders)

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    End point title
    		 Vital sign (supine respiratory rate) of potential clinical relevance - mean change from baseline to study for Phase B (Responders)
    End point description
    Vital sign (supine respiratory rate) was assessed after the subject had been supine for greater than or equal to 3 minutes. Vital signs were assessed prior to any blood draws.
    End point type
    Secondary
    End point timeframe
    7 days post last dose
    End point values
    		 Late Withdrawal Early Withdrawal
    Number of subjects analysed
    2
    2
    Units: breaths/min
        arithmetic mean (standard deviation)
    4.5 ( 3.5 )
    -6.0 ( 9.9 )
    No statistical analyses for this end point

    Secondary: Vital sign (supine temperature) of potential clinical relevance - mean change from baseline to study for Phase B (Responders)

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    End point title
    		 Vital sign (supine temperature) of potential clinical relevance - mean change from baseline to study for Phase B (Responders)
    End point description
    Vital sign (blood pressure) was assessed after the subject had been supine for greater than or equal to 3 minutes. Vital signs were assessed prior to any blood draws.
    End point type
    Secondary
    End point timeframe
    7 days post last dose
    End point values
    		 Late Withdrawal Early Withdrawal
    Number of subjects analysed
    2
    2
    Units: Degree Centigrade
        arithmetic mean (standard deviation)
    0.5 ( 0.1 )
    0.2 ( 0.4 )
    No statistical analyses for this end point

    Secondary: Body weight of potential clinical relevance - mean change from baseline to study for Phase B (Responders)

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    End point title
    		 Body weight of potential clinical relevance - mean change from baseline to study for Phase B (Responders)
    End point description
    Body weight was measured predose each day throughout Treatment Phase B. Effort was made to ensure that body weight measurements were performed in a reproducible and consistent manner. Body weight measurements were performed using the same scale.
    End point type
    Secondary
    End point timeframe
    7 days post last dose
    End point values
    		 Late Withdrawal Early Withdrawal
    Number of subjects analysed
    2
    3
    Units: kg
        arithmetic mean (standard deviation)
    -0.4 ( 0.8 )
    1.1 ( 0.9 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening till follow-up Phase C/early termination (ET)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Treatment Phase A
    Reporting group description
    		 During Treatment Phase A, subjects received tolvaptan once daily on Days 1 and 2. If the serum sodium level did not increase at least 4 mEq/L by Day 2, treatment was extended one additional day (to Day 2a). On Day 2a, subjects achieving an increase in serum sodium of ≥ 4 mEq/L were defined as responders, and subjects not achieving a ≥ 4 mEq/L increase in serum sodium were defined as nonresponders.

    Reporting group title
    Treatment Phase B: Responder - Late Withdrawal
    Reporting group description
    		 Subjects who were responders (serum sodium increased by ≥ 4 mEq/L) from Phase A continued to Treatment Phase B (Randomization Phase) on Day 3, and were randomized to the Late Withdrawal group (continuing tolvaptan treatment for Days 3 and 4).

    Reporting group title
    Treatment Phase B: Responder - Early Withdrawal
    Reporting group description
    		 Subjects who were responders (serum sodium increased by ≥ 4 mEq/L) from Phase A continued to Treatment Phase B (Randomization Phase) on Day 3, and were randomized to the Early Withdrawal group (not receiving additional tolvaptan on Days 3 or 4). Subjects randomized to Early Withdrawal were monitored for any interventions needed to maintain appropriate serum sodium levels. Where sodium levels declined by ≥ 4 mEq/L, or where the overall clinical condition warranted further intervention to increase serum sodium levels, subjects were treated per the investigator’s preferred standard of care. Any intervention, including fluid restriction, during the first 48 hours of the Early Withdrawal phase was defined as rescue therapy, and subject data was censored thereafter.

    Reporting group title
    Treatment Phase B: Non-responder - Study Drug
    Reporting group description
    		 Subjects who were nonresponders during Phase A were not randomized in Phase B but were treated per the investigator’s discretion, and continued tolvaptan for Days 3 and 4.

    Reporting group title
    Treatment Phase B: Non-responder - Standard of Care
    Reporting group description
    		 Subjects who were nonresponders during Phase A were not randomized in Phase B but were treated per the investigator’s discretion. The subjects in this arm discontinued tolvaptan and received the investigator’s preferred standard of care for Days 3 and 4.

    Serious adverse events
    		 Treatment Phase A Treatment Phase B: Responder - Late Withdrawal Treatment Phase B: Responder - Early Withdrawal Treatment Phase B: Non-responder - Study Drug Treatment Phase B: Non-responder - Standard of Care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Catheter site extravasation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medical device site haemorrhage
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecal volume increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment Phase A Treatment Phase B: Responder - Late Withdrawal Treatment Phase B: Responder - Early Withdrawal Treatment Phase B: Non-responder - Study Drug Treatment Phase B: Non-responder - Standard of Care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 2 (50.00%)
    2 / 3 (66.67%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    Investigations
    Blood sodium decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 9 (33.33%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hypoxia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nasal inflammation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Nov 2013
    Amendment 1: To update the clinical management representative for this trial  To remove the serum chemistry assessment at 7 (plus/minus 1) days post-randomization  To change the sample size from 80 to 70 responders  To clarify that subjects who cannot safely swallow the tablet are excluded until a liquid formulation is available  To add neurological exam as an exploratory variable  To update the dosing rationale based on starting doses (mg/kg) used for hyponatremia trials of tolvaptan in adults  To change early termination from the 7-day Follow-up Visit to Day 5/6  To clarify that Phase B (Randomization Phase) applies to all subjects  To correct the definition of a rapid correction of serum sodium  To update the interim analysis  To update the contact list for reporting an IRE
    19 May 2014
    Amendment 2:  To increase the consistency of this protocol with other tolvaptan pediatric hyponatremia protocols  To add neurocognitive and quality-of-life assessments as exploratory endpoints  To clarify study design, procedures, and assessments  To better define study phases and associated visits  To provide greater detail about clinical laboratory tests  To add Tanner staging to the assessments performed during the physical examination  To better define completers and stopping rules  To incorporate newly revised definitions of IMP causality
    26 Feb 2015
    Amendment 3:  Implementation of additional serum sodium testing during drug titration to align with the current EU label (SmPC) for the adult indication of hyponatremia. Safety testing for serum sodium was added at interim time points during titration with the option of using a point of care device to minimize impact on total blood volume required for the trial.  Clarification of the “baseline” assessment for trial qualification.  Additional background data from non-clinical juvenile toxicity studies.  Updates to clarify the titration and rescue therapy schematic.  Clarify roll-over into extension study 156-11-294.  Implementation of a suspension formulation for short-term use in hospitalized subjects.  Implementation of an optional swallow test for the tablet formulation.
    07 May 2015
    Amendment 4:  Correction of typographical errors in the dosing table for the suspension for subjects taking a CYP3A inhibitor.  Removed the word “Tablet” from the title of Table 2.1.1-2 as the table includes dosing information for tolvaptan tablets and for the suspension formulation of tolvaptan.  Updated the Clinical Management contact information on the title page and in Appendix 1.  Correction of typographical error in Section 2.1.1 Dosing Rationale.
    17 Nov 2015
    Amendment 5 : The main intent was to clarify administrative sections, align with current protocol templates, and incorporate recent requests from Regulatory Authorities (Food and Drug Administration [FDA]).

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    24 Jul 2017
    The trial was terminated 24 Jul 2017 due to low subject recruitment and enrollment which made the trial highly impracticable or impossible to conduct. The trial was not terminated due to safety reasons. The Food and Drug Administration (FDA) granted Otsuka release/Pediatric Research Equity Act (PREA) waiver on 19 Jul 2017 and rescinded the pediatric written request (WR) on 19 Jul 2017.
    -

    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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