Clinical Trial Results:
A Phase 3b, Multicenter, Extension Follow-up Trial to Evaluate the Long-term Safety of Children and Adolescent Subjects With Euvolemic or Hypervolemic Hyponatremia Who Have Previously Participated in a Trial of Titrated Oral SAMSCA® (Tolvaptan)
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Summary
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EudraCT number |
2013-002810-11 |
Trial protocol |
DE GB BE IT CZ RO ES |
Global end of trial date |
23 Oct 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
17 Sep 2021
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First version publication date |
17 Sep 2021
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
156-11-294
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02020278 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Otsuka Pharmaceutical Development & Commercialization, Inc
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Sponsor organisation address |
2440 Research Boulevard, Rockville, MD, United States, 20850
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Public contact |
Otsuka Pharmaceutical Development & Commercialization, Inc., Global Clinical Development, +1 844-687-8522, OtsukaRMReconciliation@rmpdc.org
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Scientific contact |
Otsuka Pharmaceutical Development & Commercialization, Inc., Global Clinical Development, +1 844-687-8522, OtsukaRMReconciliation@rmpdc.org
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001231-PIP02-13 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
23 Oct 2017
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
23 Oct 2017
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The objective of this trial was to provide 6 months of safety follow-up for children and adolescents with dilutional (euvolemic or hypervolemic) hyponatremia who had previously participated in a tolvaptan hyponatremia trial and to assess the efficacy of tolvaptan in increasing serum sodium for those participants who received optional continuing tolvaptan treatment of variable duration (up to 6 months).
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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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
22 Apr 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 3
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Worldwide total number of subjects |
3
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
1
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Children (2-11 years) |
1
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Adolescents (12-17 years) |
1
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Eligible participants included those enrolled in a previous tolvaptan pediatric trial for hyponatremia (NCT02012959); who provided written informed consent at baseline and were able to understand that he/she could withdraw at any time; with the ability to comply with all requirements of the trial; ready to be followed up for 6 months. | ||||||
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Pre-assignment
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Screening details |
There was no screening phase. Approximately 100 male or female participants were planned to be enrolled in this trial. A total of 3 participants were enrolled in this trial, but no participant received optional investigational medicinal product during this trial. | ||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||
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Arms
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Arm title
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Tolvaptan | ||||||
Arm description |
All participants enrolled first entered a 6-month follow-up trial that evaluated post-treatment safety after participation in a tolvaptan hyponatremia trial. Participants were then eligible to receive open-label tolvaptan if they had a clinical need as determined by the investigator and met the eligibility criteria for optional tolvaptan treatment during the 6-month follow-up period. In this trial, no participants qualified for treatment during the 6- month follow-up period. Daily dose levels would have included 3.75 milligrams (mg), 7.5 mg, 15 mg, 30 mg, and 60 mg. However, no subjects received IMP during this trial. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Tolvaptan
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Investigational medicinal product code |
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Other name |
SAMSCA®
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Tolvaptan was planned to be supplied as 3.75-, 7.5-, 15-, and 30 mg spray-dried tablets and administered orally once daily (QD), preferably in the morning hours, with a dose-proportional amount of water. However, no subjects received IMP during this trial.
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
- | ||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Tolvaptan
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Reporting group description |
All participants enrolled first entered a 6-month follow-up trial that evaluated post-treatment safety after participation in a tolvaptan hyponatremia trial. Participants were then eligible to receive open-label tolvaptan if they had a clinical need as determined by the investigator and met the eligibility criteria for optional tolvaptan treatment during the 6-month follow-up period. In this trial, no participants qualified for treatment during the 6- month follow-up period. Daily dose levels would have included 3.75 milligrams (mg), 7.5 mg, 15 mg, 30 mg, and 60 mg. However, no subjects received IMP during this trial. | ||
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End point title |
Change From Baseline At Month 6 In Serum Sodium While Tolvaptan Was Being Administered [1] | ||||||||
End point description |
No enrolled participant received any investigational medicinal product during the study. Due to early study termination, efficacy data were not collected for this outcome measure.
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End point type |
Primary
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End point timeframe |
Baseline, Month 6
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| 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: Due to early study termination, efficacy data were not collected. |
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| Notes [2] - Due to early study termination, efficacy data were not collected for this outcome measure. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage Of Participants Who Required Rescue Therapy While On Tolvaptan Treatment | ||||||||
End point description |
No enrolled participant received any investigational medicinal product during the study. Due to early study termination, efficacy data were not collected for this outcome measure.
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End point type |
Secondary
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End point timeframe |
Month 6
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| Notes [3] - Due to early study termination, efficacy data were not collected. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage Of Participants Who Had Recurrence Of Hyponatremia While On Tolvaptan | ||||||||
End point description |
No enrolled participant received any investigational medicinal product during the study. Due to early study termination, efficacy data were not collected for this outcome measure.
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End point type |
Secondary
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End point timeframe |
Month 6
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| Notes [4] - Due to early study termination, efficacy data were not collected. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage Of Participants Requiring Continuation Of Tolvaptan Following 30 Days Of Treatment | ||||||||
End point description |
No enrolled participant received any investigational medicinal product during the study. Due to early study termination, efficacy data were not collected for this outcome measure.
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End point type |
Secondary
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End point timeframe |
Month 6
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| Notes [5] - Due to early study termination, efficacy data were not collected. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline In Pediatric Quality of Life Inventory (PedsQL) Generic Core Scale (GCS) Total Score At Month 6 | ||||||||
End point description |
The PedsQL GCS was used for quality of life assessment. It is appropriate for at least 2 years of age, however availability may be limited for certain ages and languages. It encompasses 4 dimensions of functioning (physical, emotional, social, school). The age groups covered are: Toddler (2-4 years), Young child (5-7 years), Child (8-12 years), and Adolescent (13-18 years). Depending on the participant's age, the questionnaire may be completed by either the participant or the parent/caregiver, as appropriate. For the Toddler group, the PedsQL GCS consists of 21 items, using a 5-point Likert scale (0 to 4); for all other groups, the PedsQL GCS consists of 23 items, with a 3-point Likert scale (0, 2, 4) for the Young Child, and a 5-point Likert scale for the Child and Adolescent groups. Scores are transformed on a scale from 0 to 100 and averaged. Higher scores indicate improved quality of life. The change from baseline in the GCS total score is presented.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 6
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| Notes [6] - All enrolled participants with analyzable data at specified timepoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline In PedsQL GCS Physical Health Summary Score At Month 6 | ||||||||
End point description |
The PedsQL GCS was used for quality of life assessment. It is appropriate for at least 2 years of age, however availability may be limited for certain ages and languages. It encompasses 4 dimensions of functioning (physical, emotional, social, school). The age groups covered are: Toddler (2-4 years), Young child (5-7 years), Child (8-12 years), and Adolescent (13-18 years). Depending on the participant's age, the questionnaire may be completed by either the participant or the parent/caregiver, as appropriate. For the Toddler group, the PedsQL GCS consists of 21 items, using a 5-point Likert scale (0 to 4); for all other groups, the PedsQL GCS consists of 23 items, with a 3-point Likert scale (0, 2, 4) for the Young Child, and a 5-point Likert scale for the Child and Adolescent groups. Scores are transformed on a scale from 0 to 100 and averaged. Higher scores indicate improved quality of life. The change from baseline in the physical health dimension is presented.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 6
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| Notes [7] - All enrolled participants with analyzable data at specified timepoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline In PedsQL GCS Psychosocial Health Summary Score At Month 6 | ||||||||
End point description |
The PedsQL GCS was used for quality of life assessment. It is appropriate for at least 2 years of age, however availability may be limited for certain ages and languages. It encompasses 4 dimensions of functioning (physical, emotional, social, school). The age groups covered are: Toddler (2-4 years), Young child (5-7 years), Child (8-12 years), and Adolescent (13-18 years). Depending on the participant's age, the questionnaire may be completed by either the participant or the parent/caregiver, as appropriate. For the Toddler group, the PedsQL GCS consists of 21 items, using a 5-point Likert scale (0 to 4); for all other groups, the PedsQL GCS consists of 23 items, with a 3-point Likert scale (0, 2, 4) for the Young Child, and a 5-point Likert scale for the Child and Adolescent groups. Scores are transformed on a scale from 0 to 100 and averaged. Higher scores indicate improved quality of life. The change from baseline in summed emotional, social, and school dimensions is presented.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 6
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| Notes [8] - All enrolled participants with analyzable data at specified timepoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline In PedsQL Multidimensional Fatigue Scale (MFS) Total Score At Month 6 | ||||||||
End point description |
The PedsQL MFS was used for quality-of-life assessment. It is appropriate for at least 2 years of age; however, availability may be limited for certain ages and languages. The PedsQL MFS consists of 18 items in 3 subscales: general fatigue, sleep/rest fatigue, and cognitive fatigue. The instrument focuses on the domains of processing speed, attention/vigilance, visual and working memory. The age groups covered by these assessments are Toddler (2–4 years), Young child (5–7 years), Child (8–12 years), and Adolescent (13–18 years). Depending on the subject’s age, the questionnaire may be completed by either the subject or the parent/caregiver, as appropriate. A 5-point Likert scale is used (0 = never a problem; 1 = almost never a problem; 2 = sometimes a problem; 3 = often a problem; 4 = almost always a problem). Items are reverse-scored and transformed to a 0–100 scale so that higher PedsQL MFS scores indicate better quality of life.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 6
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| Notes [9] - All enrolled participants with analyzable data at specified timepoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage Of Participants With Overly Rapid Correction In Serum Sodium 24 Hours After The First Dose At Introduction Or Reintroduction Of Tolvaptan | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Month 6
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| Notes [10] - Due to early study termination, efficacy data were not collected. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Plasma Concentrations Of Tolvaptan And Metabolites In Participants Who Had Continued Tolvaptan Therapy For Eight Consecutive Weeks | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
8 Weeks
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| Notes [11] - Due to early study termination, no pharmacokinetic analyses were performed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Participants With A Tanner Staging Score Of 1 At Month 6 | ||||||||
End point description |
Tanner Staging assessment consists of 2 domains (pubic hair and breast development) for girls and 3 domains (pubic hair, penis development, and testes development) for boys. Staging was based on a single score summarizing the domains (not individual domain scores). Stages range from 1-5, with 1 indicating preadolescent and 5 adult. Participants with a Tanner staging score of 1 (preadolescent) at Month 6 are reported.
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End point type |
Secondary
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End point timeframe |
Month 6
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| Notes [12] - All enrolled participants with analyzable data at specified timepoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline In Growth Percentiles For Body Height And Weight At Month 6 | ||||||||||||
End point description |
Changes from baseline in growth percentiles for body height and weight were calculated and are reported.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 6
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| Notes [13] - All enrolled participants with analyzable data at specified timepoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline In Alanine Aminotransferase (ALT) And Aspartate Aminotransferase (AST) For Participants On Tolvaptan At Month 2 | ||||||||||||
End point description |
No enrolled participant received any investigational medicinal product during the study. Due to early study termination, efficacy data were not collected. Data reported only include assessments made for ALT and AST during the Core Safety Follow-up Component of the trial. Results are reported in units/liter (U/L).
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End point type |
Secondary
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End point timeframe |
Baseline, Month 2
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| Notes [14] - All enrolled participants with analyzable data at specified timepoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline In Bilirubin For Participants On Tolvaptan At Month 2 | ||||||||
End point description |
No enrolled participant received any investigational medicinal product during the study. Due to early study termination, efficacy data were not collected. Data reported only include assessments made for bilirubin during the Core Safety Follow-up Component of the trial. Results are reported in micromoles (umol)/L.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 2
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| Notes [15] - All enrolled participants with analyzable data at specified timepoint. |
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Baseline to Month 6
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
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Reporting groups
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Reporting group title |
Tolvaptan
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Reporting group description |
All participants enrolled first entered a 6-month follow-up trial that evaluated post-treatment safety after participation in a tolvaptan hyponatremia trial. Participants were then eligible to receive open-label tolvaptan if they had a clinical need as determined by the investigator and met the eligibility criteria for optional tolvaptan treatment during the 6-month follow-up period. In this trial, no participants qualified for treatment during the 6-month follow-up period. Daily dose levels would have included 3.75 milligrams (mg), 7.5 mg, 15 mg, 30 mg, and 60 mg. | ||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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05 Sep 2013 |
• To increase the consistency of this protocol with other tolvaptan pediatric hyponatremia protocols
• To revise trial endpoints in accordance with the Pediatric Investigation Plan
• To clarify study design, procedures, and assessments
• To incorporate revised definitions of IMP causality
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26 Feb 2015 |
• Implementation of additional serum sodium testing during drug titration to align with the current EU label (SmPC) for the adult indication of hyponatremia. We are adding safety testing for serum sodium 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.
• Additional background data from non-clinical juvenile toxicity studies.
• Updates to clarify prohibition of hypertonic saline.
• Clarify roll-over into extension study 156-11-294.
• Clarification of scheduled treatment interruption after 30 days of treatment and close clinical monitoring with the addition of visits.
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09 Nov 2015 |
The main intent of the amendment is to streamline text within the protocol by providing administrative clarifications, removing duplicative language, and ensuring consistency across sections. Efficiencies have been established in the Schedule of Assessments between the core safety and optional tolvaptan treatment components. This amendment is also intended to reduce burden on the subject, including the replacement of Months 2 and 4 in-clinic visits with telephone assessments. Therefore assessments required for in clinic visits on these months have been removed. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| None reported | |||||||
