Pediatric Congestive Heart Failure (CHF) Patients With Volume Overload
Conditions
Brief summary
To determine the efficacy, safety, and dose and regimen of tolvaptan in pediatric CHF patients with volume overload
Interventions
DRUGTolvaptan
Tolvaptan 1% granules or tolvaptan 15 mg tablet with water once daily.
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 14 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentages of Subjects Whose Was Decreased by 1.7% or More Body Weight From Baseline | Day after Day 3 at evaluation dose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change Rate From Baseline in Daily Urine Volume | Baseline, Day1, Day2 and Day3 of administration at evaluation dose | 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 |
| Percent Changes From Baseline in Body Weight (kg) | Day after Day 3 at evaluation dose | 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 |
| Improvement Rates of Lower Limb Edema | Day after Day 3 at evaluation dose | 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 |
| Improvement Rates of Pulmonary Congestion | Day after Day 3 at evaluation dose | 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 |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tolvaptan Tolvaptan 1% granules or tolvaptan 15 mg tablet with water once daily.
Tolvaptan: Tolvaptan 1% granules or tolvaptan 15 mg tablet with water once daily. | 59 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Physician Decision | 3 |
| Overall Study | Serum or blood potassium increased | 4 |
| Overall Study | Serum or blood sodium increased | 4 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Tolvaptan |
|---|---|
| Age, Continuous | 5.44 years STANDARD_DEVIATION 5.03 |
| Age, Customized Age group 2 years to less than 7 years | 16 Participants |
| Age, Customized Age group 6 months to less than 2 years | 20 Participants |
| Age, Customized Age group 7 years to less than 15 years | 23 Participants |
| Race/Ethnicity, Customized Asian | 59 Participants |
| Region of Enrollment Japan | 59 participants |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 60 |
| other Total, other adverse events | 25 / 60 |
| serious Total, serious adverse events | 1 / 60 |
Outcome results
Primary
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.
Time frame: Day after Day 3 at evaluation dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tolvaptan | Percentages of Subjects Whose Was Decreased by 1.7% or More Body Weight From Baseline | 22.8 percentage of participants |
Secondary
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
Time frame: Baseline, Day1, Day2 and Day3 of administration at evaluation dose
Population: The FAS included 59 of 60 subjects (98.3%) who received the IMP. One subject was excluded from the FAS because the subject received the IMP at least once, and discontinued the trial before the daily urine volume data on Day 1 were obtained.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tolvaptan | Change Rate From Baseline in Daily Urine Volume | Day 1 | 53.1 percentage of urine volume (mL) | Standard Deviation 52.9 |
| Tolvaptan | Change Rate From Baseline in Daily Urine Volume | Day 2 | 47.8 percentage of urine volume (mL) | Standard Deviation 43.3 |
| Tolvaptan | Change Rate From Baseline in Daily Urine Volume | Day 3 | 45.8 percentage of urine volume (mL) | Standard Deviation 29.3 |
Secondary
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
Time frame: Day after Day 3 at evaluation dose
Population: The FAS included 59 of 60 subjects (98.3%) who received the IMP. One subject was excluded from the FAS because the subject received the IMP at least once, and discontinued the trial before the daily urine volume data on Day 1 were obtained. Number of subjects with lower libm edema at baseline was 35.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tolvaptan | Improvement Rates of Lower Limb Edema | 68.6 percentage of participants |
Secondary
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
Time frame: Day after Day 3 at evaluation dose
Population: The FAS included 59 of 60 subjects (98.3%) who received the IMP. One subject was excluded from the FAS because the subject received the IMP at least once, and discontinued the trial before the daily urine volume data on Day 1 were obtained. Number of subjects with pulmonary conjestion at baseline was 31.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tolvaptan | Improvement Rates of Pulmonary Congestion | 51.6 percentage of participants |
Secondary
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
Time frame: Day after Day 3 at evaluation dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan | Percent Changes From Baseline in Body Weight (kg) | -0.371 percentage of body weight (kg) | Standard Deviation 2.47 |