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Study of the Safety and Effectiveness of SAMSCA® (Tolvaptan) in Children and Adolescents With Euvolemic or Hypervolemic Hyponatremia

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ClinicalTrials.gov Identifier: NCT02012959
Recruitment Status : Terminated (Issues with participant recruitment & enrollment which made the trial impossible or highly impracticable. Trial termination was not due to safety reasons.)
First Posted : December 17, 2013
Results First Posted : August 28, 2018
Last Update Posted : September 26, 2018
Sponsor:
Collaborator:
Syneos Health
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Hyponatremia
Intervention Drug: Tolvaptan
Enrollment 9
Recruitment Details  
Pre-assignment Details  
Arm/Group Title 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
Hide Arm/Group Description During Treatment Phase A, participants received tolvaptan once daily on Days 1 and 2. If the serum sodium level did not increase at least 4 milliequivalent (mEq)/liter (L) by Day 2, treatment was extended one additional day (Day 2a). On Day 2a, participants achieving an increase in serum sodium of ≥4 mEq/L were defined as responders, and participants not achieving a ≥4 mEq/L increase in serum sodium were defined as non-responders. Participants 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). Participants 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). Participants 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, participants 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 participant data was censored thereafter. Participants who were non-responders 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. Participants who were non-responders during Phase A were not randomized in Phase B, but were treated per the investigator’s discretion. The participants in this arm discontinued tolvaptan and received the investigator’s preferred standard of care for Days 3 and 4.
Period Title: Treatment Phase A
Started 9 0 [1] 0 [1] 0 [1] 0 [1]
Received At Least 1 Dose of Study Drug [2] 9 0 0 0 0
Completed 7 0 0 0 0
Not Completed 2 0 0 0 0
Reason Not Completed
Adverse Event             2             0             0             0             0
[1]
Zero participants noted because participants did not start Phase B yet
[2]
Phase A Safety Sample
Period Title: Treatment Phase B
Started 0 [1] 2 [2] 3 [3] 1 [4] 1 [5]
Received At Least 1 Dose of Study Drug [6] 0 2 3 1 1
Completed 0 2 3 1 1
Not Completed 0 0 0 0 0
[1]
Zero participants noted because participants had completed Phase A
[2]
Participants in this group continued treatment with the study drug
[3]
Participants in this group did not receive additional study drug after Phase A
[4]
Participants in this group could continue study drug treatment, per the investigator’s discretion
[5]
Participants in this group could receive the investigator's preferred standard of care
[6]
Phase B Safety Sample
Arm/Group Title Treatment Phase A
Hide Arm/Group Description During Treatment Phase A, participants 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 (Day 2a). On Day 2a, participants achieving an increase in serum sodium of ≥4 mEq/L were defined as responders, and participants not achieving a ≥4 mEq/L increase in serum sodium were defined as non-responders. Participants who were responders (serum sodium increased by ≥4 mEq/L) continued to Treatment Phase B (Randomization Phase) on Day 3.
Overall Number of Baseline Participants 9
Hide Baseline Analysis Population Description
Intent-to-treat (ITT) population - Provided following 3 core datasets used for all efficacy analyses: Treatment Phase A; Treatment Phase B responders; Treatment Phase B non-responders.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 9 participants
6.1  (5.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants
Female
3
  33.3%
Male
6
  66.7%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants
Hispanic or Latino
3
  33.3%
Not Hispanic or Latino
5
  55.6%
Unknown or Not Reported
1
  11.1%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants
White
6
  66.7%
Black or African American
1
  11.1%
American Indian or Alaskan Native
0
   0.0%
Asian
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Other
2
  22.2%
1.Primary Outcome
Title Change In Serum Sodium Concentration For Responders
Hide Description Change in serum sodium concentration (mEq/L) for responders from Day 2 (or Day 2a) at the end of Treatment Phase A (where all participants received tolvaptan) to the end of Treatment Phase B for the Early compared to Late Withdrawal groups is reported. Once a participant was randomized to Treatment Phase B, any additional therapies for the purpose of raising serum sodium, including fluid restriction, were considered rescue therapy. Upon receipt of rescue therapy, a participant's endpoint data was collected and then censored from the efficacy analysis thereafter, unless specified.
Time Frame Day 2/2a, Day 4
Hide Outcome Measure Data
Hide Analysis Population Description
Treatment Phase B Responders: full analysis dataset comprised of all participants in the Phase B Safety Sample with both baseline and at least 1 postrandomization serum sodium evaluation in Phase B.
Arm/Group Title Responder - Late Withdrawal Responder - Early Withdrawal
Hide Arm/Group Description:
Participants 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).
Participants 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). Participants 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, participants 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 participant data was censored thereafter.
Overall Number of Participants Analyzed 2 3
Mean (Standard Deviation)
Unit of Measure: mEq/L
-4.0  (4.2) -1.0  (1.0)
2.Secondary Outcome
Title Change In Serum Sodium Concentration During Treatment Phase A
Hide Description Change in serum sodium concentration (mEq/L) from baseline to the end of Day 2 (or 2a) during Treatment Phase A for all participants (responders and non-responders) is reported.
Time Frame Baseline, Day 2/2a
Hide Outcome Measure Data
Hide Analysis Population Description
Treatment Phase A: all participants in the Phase A Safety Sample and who had baseline and at least 1 postbaseline serum sodium evaluation in Phase A.
Arm/Group Title Phase A: All Participants
Hide Arm/Group Description:
During Treatment Phase A, participants 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 (Day 2a). On Day 2a, participants achieving an increase in serum sodium of ≥4 mEq/L were defined as responders, and participants not achieving a ≥4 mEq/L increase in serum sodium were defined as non-responders.
Overall Number of Participants Analyzed 9
Mean (Standard Deviation)
Unit of Measure: mEq/L
Day 1: 24 hours Post Dose Number Analyzed 8 participants
1  (3)
Day 2: 24 hours Post Dose Number Analyzed 7 participants
3.4  (4.8)
Day 2a: 24 hours Post Dose Number Analyzed 3 participants
2.3  (2.1)
3.Secondary Outcome
Title Fluid Balance (Intake Minus Output) During Treatment Phase A
Hide Description Every 6 hours and for the 24-hour daily interval on Days 1 and 2 during Treatment Phase A, fluid balance (milliliters [mL]) was determined by fluid intake (oral and intravenous) minus urine output. Improved fluid balance would be indicated through the induction of increased urine volume. Fluid balance was monitored per institutional guidelines.
Time Frame Every 6 hours on Days 1 and 2
Hide Outcome Measure Data
Hide Analysis Population Description
Treatment Phase A: all participants in the Phase A Safety Sample and who had baseline and at least 1 postbaseline serum sodium evaluation in Phase A.
Arm/Group Title Phase A: All Participants
Hide Arm/Group Description:
During Treatment Phase A, participants 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 (Day 2a). On Day 2a, participants achieving an increase in serum sodium of ≥4 mEq/L were defined as responders, and participants not achieving a ≥4 mEq/L increase in serum sodium were defined as non-responders.
Overall Number of Participants Analyzed 9
Mean (Standard Deviation)
Unit of Measure: mL
Day 1: 0-6 hours Number Analyzed 9 participants
-1  (505)
Day 1: 6-12 hours Number Analyzed 9 participants
-261  (533)
Day 1: 12-18 hours Number Analyzed 9 participants
-36  (253)
Day 1: 18-24 hours Number Analyzed 9 participants
31  (344)
Day 1: 0-24 hours Number Analyzed 9 participants
-268  (849)
Day 2: 0-6 hours Number Analyzed 8 participants
-101  (376)
Day 2: 6-12 hours Number Analyzed 8 participants
6  (513)
Day 2: 12-18 hours Number Analyzed 8 participants
-45  (400)
Day 2: 18-24 hours Number Analyzed 8 participants
-21  (191)
Day 2: 0-24 hours Number Analyzed 8 participants
-160  (733)
Time Frame From screening through early termination or follow-up phase (14 days postrandomization).
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title 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
Hide Arm/Group Description During Treatment Phase A, participants 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, participants achieving an increase in serum sodium of ≥4 mEq/L were defined as responders, and participants not achieving a ≥4 mEq/L increase in serum sodium were defined as non-responders. Participants 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). Participants 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). Participants 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, participants 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 participant data was censored thereafter. Participants who were non-responders 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. Participants who were non-responders during Phase A were not randomized in Phase B, but were treated per the investigator’s discretion. The participants in this arm discontinued tolvaptan and received the investigator’s preferred standard of care for Days 3 and 4.
All-Cause Mortality
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
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/9 (0.00%)   0/2 (0.00%)   0/3 (0.00%)   0/1 (0.00%)   0/1 (0.00%) 
Show Serious Adverse Events Hide 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
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/9 (22.22%)   1/2 (50.00%)   0/3 (0.00%)   1/1 (100.00%)   0/1 (0.00%) 
Gastrointestinal disorders           
Diarrhoea * 1  0/9 (0.00%)  1/2 (50.00%)  0/3 (0.00%)  0/1 (0.00%)  0/1 (0.00%) 
Faecal volume increased * 1  1/9 (11.11%)  0/2 (0.00%)  0/3 (0.00%)  0/1 (0.00%)  0/1 (0.00%) 
General disorders           
Catheter site extravasation * 1  0/9 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  1/1 (100.00%)  0/1 (0.00%) 
Medical device site haemorrhage * 1  1/9 (11.11%)  0/2 (0.00%)  0/3 (0.00%)  0/1 (0.00%)  0/1 (0.00%) 
1
Term from vocabulary, MedDRA 19.0
*
Indicates events were collected by non-systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
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
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/9 (33.33%)   1/2 (50.00%)   2/3 (66.67%)   1/1 (100.00%)   1/1 (100.00%) 
Cardiac disorders           
Bradycardia * 1  0/9 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/1 (0.00%)  0/1 (0.00%) 
Gastrointestinal disorders           
Diarrhoea * 1  3/9 (33.33%)  0/2 (0.00%)  0/3 (0.00%)  0/1 (0.00%)  0/1 (0.00%) 
Vomiting * 1  0/9 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/1 (0.00%)  0/1 (0.00%) 
General disorders           
Pyrexia * 1  0/9 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/1 (0.00%)  0/1 (0.00%) 
Infections and infestations           
Upper respiratory tract infection * 1  0/9 (0.00%)  1/2 (50.00%)  0/3 (0.00%)  0/1 (0.00%)  0/1 (0.00%) 
Investigations           
Blood sodium decreased * 1  0/9 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/1 (0.00%)  1/1 (100.00%) 
Metabolism and nutrition disorders           
Fluid overload * 1  0/9 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  1/1 (100.00%)  0/1 (0.00%) 
Hyperkalaemia * 1  0/9 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  1/1 (100.00%)  0/1 (0.00%) 
Hyponatraemia * 1  0/9 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  1/1 (100.00%)  0/1 (0.00%) 
Respiratory, thoracic and mediastinal disorders           
Cough * 1  0/9 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/1 (0.00%)  0/1 (0.00%) 
Dyspnoea * 1  0/9 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  1/1 (100.00%)  0/1 (0.00%) 
Hypoxia * 1  0/9 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  1/1 (100.00%)  0/1 (0.00%) 
Nasal congestion * 1  0/9 (0.00%)  1/2 (50.00%)  0/3 (0.00%)  0/1 (0.00%)  0/1 (0.00%) 
Nasal inflammation * 1  0/9 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/1 (0.00%)  1/1 (100.00%) 
1
Term from vocabulary, MedDRA 19.0
*
Indicates events were collected by non-systematic assessment
Issues with recruitment and enrollment made trial execution highly impracticable. This ultimately led to termination of the trial. The study was not terminated due to safety reasons.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Sponsor reserves the right to review, edit, and authorize publications.
Results Point of Contact
Name/Title: Global Clinical Development
Organization: Otsuka Pharmaceutical Development & Commercialization, Inc.
Phone: +1-609-524-6788
Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT02012959     History of Changes
Other Study ID Numbers: 156-08-276
2013-002005-59 ( EudraCT Number )
First Submitted: December 11, 2013
First Posted: December 17, 2013
Results First Submitted: July 31, 2018
Results First Posted: August 28, 2018
Last Update Posted: September 26, 2018