Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics Study of Tolvaptan in Pediatric Congestive Heart Failure (CHF) Patients With Volume Overload

A Multicenter, Open-labeled, Dose-defining Trial to Investigate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Tolvaptan in Pediatric Congestive Heart Failure (CHF) Patients With Volume Overload

To determine the efficacy, safety, and dose and regimen of tolvaptan in pediatric CHF patients with volume overload

Study Overview

• Status: Completed
• Conditions: Pediatric Congestive Heart Failure (CHF) Patients With Volume Overload
• Intervention / Treatment: Drug: Tolvaptan

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Kanto Region, Japan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 14 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with volume overload despite having received any of the following diuretic therapies in whom sufficient effects cannot be expected even if the dose of the diuretics is increased or in whom the investigator or subinvestigator judges that increasing the dose of the diuretics is difficult due to concerns regarding electrolyte abnormalities or other side effects

  • Furosemide (oral administration) ≥0.5 mg/kg/day. Azosemide 30 mg and torasemide 4 mg will be calculated as equivalent to furosemide 20 mg.
  • Hydrochlorothiazide ≥2 mg/kg/day
  • Trichlormethiazide ≥0.05 mg/kg/day
  • Spironolactone ≥ 1 mg/kg/day
• Patients capable of complaining of thirst. Patients unable to complain of thirst due to their young age can also be enrolled in the trial if strict management of fluid intake and excretion is conducted. However, even if such fluid management is possible, the patients in whom the investigator or subinvestigator judges that tolvaptan cannot be safely administered are to be excluded
• Patients who can be hospitalized from at least 3 days before start of tolvaptan administration until 2 days after the final administration.

others

Exclusion Criteria:

• Patients whose volume overload status shows improvement during the screening period or pretreatment observation period
• Patients who are unable to drink fluid (including patients who are unable to sense thirst)
• Patients whose circulatory blood flow is suspected to be decreased
• Patients with an assisted circulation apparatus
• Patients with hypernatremia (serum or blood sodium concentration exceeding 145 mEq/L) others

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tolvaptan; Tolvaptan 1% granules or tolvaptan 15 mg tablet with water once daily.	Drug: Tolvaptan; Tolvaptan 1% granules or tolvaptan 15 mg tablet with water once daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentages of Subjects Whose Was Decreased by 1.7% or More Body Weight From Baseline	The primary endpoint of this trial was the percentage of subjects whose body weight on the day after the third day of treatment with tolvaptan at the evaluation dose (the third day of administration at the evaluation dose) was decreased by 1.7% or more from the weight measured before breakfast (baseline) on the first day of the treatment period (the initial tolvaptan administration day), under the condition that the mean daily urine volume for the 3 days of treatment with tolvaptan at the evaluation dose was higher than the daily urine volume for the pretreatment observation period. The percentage of subjects as well as the exact 95% confidence interval (CI) based on binomial distribution were calculated.	Day after Day 3 at evaluation dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change Rate From Baseline in Daily Urine Volume	Daily urine volume was measured for the time interval starting at urination (an instruction to urinate) after breakfast and ending at complete urination immediately before administration on the following day. Baseline was 100% and the change rate was calculated like this. Percent change (%) = ([daily urine volume on the Day1, Day2 and Day3 of the tolvaptan at the evaluation dose] - [daily urine volume on baseline] ) / [daily urine volume on baseline] ×100	Baseline, Day1, Day2 and Day3 of administration at evaluation dose
Percent Changes From Baseline in Body Weight (kg)	Percent change from baseline in body weight (kg) on the day after the third day of treatment with tolvaptan at the evaluation dose was evaluated. For body weight measured on the day after the third day of administration at the evaluation dose, their percent changes from baseline (before the start of tolvaptan administration on the first day of the treatment period) mean and standard deviation (SD) were calculated. Baseline was 100% and the change rate was alculated like this. Percent change (%) = ([body weight on the day after the third day of treatment with tolvaptan at the evaluation dose] - [body weight on baseline] ) / [body weight on baseline] ×100	Day after Day 3 at evaluation dose
Improvement Rates of Lower Limb Edema	The improvement rate was defined as the percentage of subjects in whom a symptom was present at baseline and then markedly improved or improved after IMP administration. Improvement category is a 4-point scale below: Markedly improved; Improved; Unchanged; Deteriorated	Day after Day 3 at evaluation dose
Improvement Rates of Pulmonary Congestion	The improvement rate was defined as the percentage of subjects in whom a symptom was present at baseline and then markedly improved or improved after IMP administration. Improvement category is a 4-point scale below: Markedly improved; Improved; Unchanged; Deteriorated	Day after Day 3 at evaluation dose

Collaborators and Investigators

• Sponsor: Otsuka Pharmaceutical Co., Ltd.
• Investigators: Study Director: Takehisa Matsumaru, Mr, Otsuka Pharmaceutical Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2018
• Primary Completion (Actual): July 11, 2021
• Study Completion (Actual): July 15, 2021

Study Registration Dates

• First Submitted: August 18, 2017
• First Submitted That Met QC Criteria: August 18, 2017
• First Posted (Actual): August 21, 2017

Study Record Updates

• Last Update Posted (Actual): August 23, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Antidiuretic Hormone Receptor Antagonists; Tolvaptan
• Other Study ID Numbers: 156-102-00123; JapicCTI-173674 (Other Identifier: Japic)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal.
• IPD Sharing Time Frame: Data will be available after marketing approval in global markets, or beginning 1-3 years following article Publication. There is no end date to the availability of the data.
• IPD Sharing Access Criteria: Otsuka will share data on an Otsuka-owned remotely accessible data sharing platform with Python and R analytical software. Research requests should be directed to clinicaltransparency@Otsuka-us.com.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No