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

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02012959
• Collaborator: Syneos Health (Other)
• Enrollment: 9
• Locations: 7
• Arms: 2
• Actual Duration (Months): 22
• Patients Per Site: 1.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this trial was to demonstrate that tolvaptan effectively and safely increases and maintains serum sodium concentrations in children and adolescent participants with euvolemic or hypervolemic hyponatremia.

Condition or Disease	Intervention/Treatment	Phase
Hyponatremia	Drug: Tolvaptan	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Sep 22, 2015
• Actual Primary Completion Date: Jul 24, 2017
• Actual Study Completion Date: Jul 24, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tolvaptan Early Withdrawal All participants initially received tolvaptan once daily for the first 2 days. A third day of treatment was permitted if a participant had not reached the desired sodium target improvement per the investigator's judgment. At the end of Day 2 (or Day 3), responders (participants who achieved an increase in serum sodium by ≥4 millimoles/liter [mmol/L]) were randomized to either the Early or Late Withdrawal Group. Non-responders could continue treatment with tolvaptan for an additional 2 days. Discontinued tolvaptan treatment immediately after randomization. All participants were observed up to 14 days post randomization.	Drug: Tolvaptan; Other Names: SAMSCA®
Experimental: Tolvaptan Late Withdrawal All participants initially received tolvaptan once daily for the first 2 days. A third day of treatment was permitted if a participant had not reached the desired sodium target improvement per the investigator's judgment. At the end of Day 2 (or Day 3), responders (participants who achieved an increase in serum sodium by ≥4 mmol/L) were randomized to either the Early or Late Withdrawal Group in Treatment Phase B. Non-responders could continue treatment with tolvaptan for an additional 2 days. Continued treatment for 2 additional days. All participants were observed up to 14 days post randomization.	Drug: Tolvaptan; Other Names: SAMSCA®

Outcome Measures

Primary Outcome Measures

1. Change In Serum Sodium Concentration For Responders [Day 2/2a, Day 4]

   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.

Secondary Outcome Measures

1. Change In Serum Sodium Concentration During Treatment Phase A [Baseline, Day 2/2a]

   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.

2. Fluid Balance (Intake Minus Output) During Treatment Phase A [Every 6 hours on Days 1 and 2]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Weeks to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion:

• Male and female participants ≥4 weeks (or ≥44 weeks adjusted gestational age) to <18 years old

• Participants hospitalized with euvolemic or hypervolemic hyponatremia resistant to initial standard background therapy

• Persistent euvolemic or hypervolemic hyponatremia defined as being documented as <130 milliequivalent (mEq)/L and present for at least 48 hours, evidenced by at least 2 serum sodium assessments (12 hours apart)

• Ability to maintain adequate fluid intake (orally or intravenously)

• Ability to take oral medications

• Ability to comply with all requirements of the trial

• Completion of the trial-specific informed consent/assent as age appropriate

• Ability to commit to remain fully abstinent or practice double-barrier birth control as required by the trial

Exclusion:

• Evidence of hypovolemia or intravascular volume depletion

• Serum sodium <120 mEq/L

• Use of potent cytochrome P450 3A4 (CYP3A4) inhibitors in participants <12 kilogram (kg) or moderate CYP3A4 inhibitors in participants <6 kg

• Lacks free access to water (inability to respond to thirst) or without intensive care unit level fluid monitoring and management

• History or current diagnosis of nephrotic syndrome

• Transient hyponatremia likely to resolve

• Hyperkalemia

• Estimated glomerular filtration rate <30 milliliters/minute/1.73 meters squared

• Acute kidney injury

• Severe or acute neurological symptoms requiring other intervention

• Prior treatment for hyponatremia with hypertonic saline within 8 hours of qualifying serum sodium assessments; urea, lithium, demeclocycline, conivaptan, or tolvaptan within 4 days of qualifying serum sodium assessments; any other treatments for the purpose of increasing serum sodium concurrent with dosing of trial medication

• Anuria or urinary outflow obstruction, unless participant is/can be catheterized

• History of hypersensitivity and/or idiosyncratic reaction to benzazepine or benzazepine derivatives

• Psychogenic polydipsia

• Uncontrolled diabetes mellitus (defined as fasting glucose >300 milligrams/deciliter)

• Screening liver function values >3 times the upper limit of normal

• Participants who have cirrhosis and meet any of the following conditions: a major GI bleed within the past 6 months, evidence of active bleeding, platelet count <50,000/microliter, or use of concomitant medications known to increase bleeding risk

• Hyponatremia due to the result of any medication that can safely be withdrawn or that is most appropriately corrected by alternative therapies

• History of drug or medication abuse within 3 months prior to screening or current alcohol abuse

• Participants who require suspension formulation and have a Hereditary Fructose Intolerance

• Has hyponatremia that is more appropriately corrected by alternative therapies

• Is pregnant or currently breastfeeding

• Has any medical condition that could interfere with evaluation of trial objectives or participant safety

• Has participated in another investigational drug trial in the last 30 days

• Weighs <3 kg

• Unable to swallow tablets, if suspension unavailable

• Is deemed unsuitable for trial participation in the opinion of the investigator

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Aurora	Colorado	United States	80045
2		Washington	District of Columbia	United States	20010
3		New York	New York	United States	10032
4		Richmond	Virginia	United States	23298-0270
5		Seattle	Washington	United States	98105
6		Rome		Italy	00165
7		London		United Kingdom	WC1N 3JH

Sponsors and Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.
• Syneos Health

Investigators

• Study Director: Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Documents (Full-Text)

• Study Protocol - Nov 17, 2015
• Statistical Analysis Plan - Nov 17, 2015

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT02012959
• Other Study ID Numbers: 156-08-276; 2013-002005-59
• First Posted: Dec 17, 2013
• Last Update Posted: Sep 26, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.: Hyponatremia; Euvolemic; Hypervolemic; Serum sodium; Dilutional hyponatremia; Electrolyte abnormality; Electrolyte imbalance; Metabolic disease
• Additional relevant MeSH terms: Hyponatremia; Tolvaptan

Study Results

Participant Flow

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
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	0	0	0
Received At Least 1 Dose of Study Drug	9	0	0	0	0
COMPLETED	7	0	0	0	0
NOT COMPLETED	2	0	0	0	0
Period Title: Treatment Phase A
STARTED	0	2	3	1	1
Received At Least 1 Dose of Study Drug	0	2	3	1	1
COMPLETED	0	2	3	1	1
NOT COMPLETED	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Treatment Phase A
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 Participants	9
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	6.1 (5.1)
Sex: Female, Male (Count of Participants)
Female	3 33.3%
Male	6 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 33.3%
Not Hispanic or Latino	5 55.6%
Unknown or Not Reported	1 11.1%
Race/Ethnicity, Customized (Count of Participants)
White	6 66.7%
Black or African American	1 11.1%
American Indian or Alaskan Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Other	2 22.2%

Outcome Measures

1. Primary Outcome

Title	Change In Serum Sodium Concentration For Responders
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

Outcome Measure Data

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
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.
Measure Participants	2	3
Mean (Standard Deviation) [mEq/L]	-4.0 (4.2)	-1.0 (1.0)

2. Secondary Outcome

Title	Change In Serum Sodium Concentration During Treatment Phase A
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

Outcome Measure Data

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
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.
Measure Participants	9
Day 1: 24 hours Post Dose	1 (3)
Day 2: 24 hours Post Dose	3.4 (4.8)
Day 2a: 24 hours Post Dose	2.3 (2.1)

3. Secondary Outcome

Title	Fluid Balance (Intake Minus Output) During Treatment Phase A
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

Outcome Measure Data

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
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.
Measure Participants	9
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	-101 (376)
Day 2: 6-12 hours	6 (513)
Day 2: 12-18 hours	-45 (400)
Day 2: 18-24 hours	-21 (191)
Day 2: 0-24 hours	-160 (733)

Adverse Events

Time Frame	From screening through early termination or follow-up phase (14 days postrandomization).
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
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/2 (0%)		0/3 (0%)		0/1 (0%)		0/1 (0%)
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/9 (22.2%)		1/2 (50%)		0/3 (0%)		1/1 (100%)		0/1 (0%)
Gastrointestinal disorders
Diarrhoea	0/9 (0%)		1/2 (50%)		0/3 (0%)		0/1 (0%)		0/1 (0%)
Faecal volume increased	1/9 (11.1%)		0/2 (0%)		0/3 (0%)		0/1 (0%)		0/1 (0%)
General disorders
Catheter site extravasation	0/9 (0%)		0/2 (0%)		0/3 (0%)		1/1 (100%)		0/1 (0%)
Medical device site haemorrhage	1/9 (11.1%)		0/2 (0%)		0/3 (0%)		0/1 (0%)		0/1 (0%)
Other (Not Including 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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/9 (33.3%)		1/2 (50%)		2/3 (66.7%)		1/1 (100%)		1/1 (100%)
Cardiac disorders
Bradycardia	0/9 (0%)		0/2 (0%)		1/3 (33.3%)		0/1 (0%)		0/1 (0%)
Gastrointestinal disorders
Diarrhoea	3/9 (33.3%)		0/2 (0%)		0/3 (0%)		0/1 (0%)		0/1 (0%)
Vomiting	0/9 (0%)		0/2 (0%)		1/3 (33.3%)		0/1 (0%)		0/1 (0%)
General disorders
Pyrexia	0/9 (0%)		0/2 (0%)		1/3 (33.3%)		0/1 (0%)		0/1 (0%)
Infections and infestations
Upper respiratory tract infection	0/9 (0%)		1/2 (50%)		0/3 (0%)		0/1 (0%)		0/1 (0%)
Investigations
Blood sodium decreased	0/9 (0%)		0/2 (0%)		0/3 (0%)		0/1 (0%)		1/1 (100%)
Metabolism and nutrition disorders
Fluid overload	0/9 (0%)		0/2 (0%)		0/3 (0%)		1/1 (100%)		0/1 (0%)
Hyperkalaemia	0/9 (0%)		0/2 (0%)		0/3 (0%)		1/1 (100%)		0/1 (0%)
Hyponatraemia	0/9 (0%)		0/2 (0%)		0/3 (0%)		1/1 (100%)		0/1 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/9 (0%)		0/2 (0%)		1/3 (33.3%)		0/1 (0%)		0/1 (0%)
Dyspnoea	0/9 (0%)		0/2 (0%)		0/3 (0%)		1/1 (100%)		0/1 (0%)
Hypoxia	0/9 (0%)		0/2 (0%)		0/3 (0%)		1/1 (100%)		0/1 (0%)
Nasal congestion	0/9 (0%)		1/2 (50%)		0/3 (0%)		0/1 (0%)		0/1 (0%)
Nasal inflammation	0/9 (0%)		0/2 (0%)		0/3 (0%)		0/1 (0%)		1/1 (100%)

Limitations/Caveats

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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor reserves the right to review, edit, and authorize publications.