Congestive Heart Failure
Conditions
Brief summary
To confirm the non-inferiority of OPC-61815 16-mg injection to tolvaptan 15-mg tablet using as the primary endpoint the change in body weight following 5-day intravenous administration of OPC-61815 16-mg injection or 5-day oral administration of tolvaptan 15-mg tablet to CHF patients with volume overload despite having received diuretics other than vasopressin antagonists
Interventions
DRUGOPC-61815
Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 16 mg
DRUGTolvaptan Tab 15 MG
Once daily for 5 days tolvaptan 15-mg tablet will be orally administered, followed immediately by 1-hour intravenous administration of placebo
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Patients who are currently on treatment with any of the following diuretics 1. Loop diuretics equivalent to furosemide tablet or fine granules at a dose of 40 mg/day or higher 2. Concomitant use of a loop diuretic and a thiazide diuretic (including thiazide analogs) at any dose 3. Concomitant use of a loop diuretic and an aldosterone antagonist or potassium-sparing diuretic agent at any dose * Patients with congestive heart failure in whom lower limb edema, pulmonary congestion, and/or jugular venous distension due to volume overload is present * Patients who are currently hospitalized or who are able to be hospitalized during the trial
Exclusion criteria
* Patients with acute heart failure * Patients who are on a ventricular assist device * Patients who are unable to sense thirst or who have difficulty with fluid intake
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Body Weight | Baseline, Day 6 | Change in body weight from baseline (before investigational medicinal product \[IMP\] administration on Day 1) at time of final IMP administration (day after final IMP administration). A negative change from baseline indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Improvement Rate for Lower Limb Edema and Pulmonary Congestion | Baseline, Day 6 | The improvement rate was defined as the percentage of subjects in whom the symptom was present at baseline and it markedly improved or improved after IMP administration. Improvement category is a 4-point scale below: * Markedly improved * Improved * Unchanged * Deteriorated |
| Change From Baseline in Jugular Venous Distension and Hepatomegaly | Baseline, Day 6 | * Jugular Venous Distension: the presence of Jugular Venous Distension was checked, and if present, the height (in cm) from the sternal angle to the highest point of pulsation in the internal Jugular vein was measured with the subject in a semi-upright position. A negative change from baseline indicates improvement. * Hepatomegaly: the presence of a palpable liver was checked, and if present, the width (distance from the right costal arch of the right chest, in cm) was measured. A negative change from baseline indicates improvement. |
| Percentage of Subjects Who Achieve Resolution of Pulmonary Rales and Third Cardiac Sound | Baseline, Day 6 | Percentage of subjects in whom the symptom was present at baseline and disappeared after IMP administration was provided. * The presence of pulmonary rales was checked by auscultation. * The presence of cardiac third sound was checked by auscultation. |
| Improvement Rate for New York Heart Association (NYHA) Classification | Baseline, Day 6 | NYHA classification assesses the severity of heart failure based on subjective symptoms as follows. Class I: No limitations of physical activity. Ordinary physical activity caused no undue fatigue, palpitation, dyspnea or anginal pain. Class II: Slight limitation of physical activity, comfortable at rest. Ordinary physical activity resulted in fatigue, palpitation, dyspnea or anginal pain. Class III: Marked limitation of physical activity, comfortable at rest. Less than ordinary physical activity caused fatigue, palpitation, dyspnea or anginal pain. Class IV: Inability to carry on any physical activity without discomfort. heart failure or anginal syndrome may have been present even at rest. If any physical activity was undertaken, discomfort was increased. Of the subjects with Class II or higher at baseline, the percentage of subjects whose NYHA classification stage at the time of final IMP administration improved by 1 or more grades was provided. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| OPC-61815 Injection 16 mg Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 16 mg. | 149 |
| Tolvaptan Tablet 15mg Once daily for 5 days tolvaptan 15-mg tablet will be orally administered, followed immediately by 1-hour intravenous administration of placebo. | 145 |
| Total | 294 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 3 |
| Overall Study | Physician Decision | 2 | 3 |
| Overall Study | Protocol Violation | 4 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Tolvaptan Tablet 15mg | Total | OPC-61815 Injection 16 mg |
|---|---|---|---|
| Age, Continuous | 75.4 years STANDARD_DEVIATION 8.2 | 74.7 years STANDARD_DEVIATION 9.3 | 74.0 years STANDARD_DEVIATION 10.2 |
| Race/Ethnicity, Customized Asian | 145 Participants | 294 Participants | 149 Participants |
| Region of Enrollment Japan | 145 Participants | 294 Participants | 149 Participants |
| Sex: Female, Male Female | 47 Participants | 84 Participants | 37 Participants |
| Sex: Female, Male Male | 98 Participants | 210 Participants | 112 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 149 | 0 / 145 |
| other Total, other adverse events | 61 / 149 | 57 / 145 |
| serious Total, serious adverse events | 6 / 149 | 5 / 145 |
Outcome results
Primary
Change From Baseline in Body Weight
Change in body weight from baseline (before investigational medicinal product \[IMP\] administration on Day 1) at time of final IMP administration (day after final IMP administration). A negative change from baseline indicates improvement.
Time frame: Baseline, Day 6
Population: Full Analysis Set: subjects who received at least one dose of IMP and had at least one postbaseline weight measurement
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| OPC-61815 Injection 16 mg | Change From Baseline in Body Weight | -1.67 kg |
| Tolvaptan Tablet 15mg | Change From Baseline in Body Weight | -1.36 kg |
Secondary
Change From Baseline in Jugular Venous Distension and Hepatomegaly
* Jugular Venous Distension: the presence of Jugular Venous Distension was checked, and if present, the height (in cm) from the sternal angle to the highest point of pulsation in the internal Jugular vein was measured with the subject in a semi-upright position. A negative change from baseline indicates improvement. * Hepatomegaly: the presence of a palpable liver was checked, and if present, the width (distance from the right costal arch of the right chest, in cm) was measured. A negative change from baseline indicates improvement.
Time frame: Baseline, Day 6
Population: Subjects with baseline values in the Full Analysis Set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| OPC-61815 Injection 16 mg | Change From Baseline in Jugular Venous Distension and Hepatomegaly | Jugular Venous Distension | -2.89 cm |
| OPC-61815 Injection 16 mg | Change From Baseline in Jugular Venous Distension and Hepatomegaly | Hepatomegaly | -0.93 cm |
| Tolvaptan Tablet 15mg | Change From Baseline in Jugular Venous Distension and Hepatomegaly | Jugular Venous Distension | -3.15 cm |
| Tolvaptan Tablet 15mg | Change From Baseline in Jugular Venous Distension and Hepatomegaly | Hepatomegaly | -0.88 cm |
Secondary
Improvement Rate for Lower Limb Edema and Pulmonary Congestion
The improvement rate was defined as the percentage of subjects in whom the symptom was present at baseline and it markedly improved or improved after IMP administration. Improvement category is a 4-point scale below: * Markedly improved * Improved * Unchanged * Deteriorated
Time frame: Baseline, Day 6
Population: Full Analysis Set: subjects who received at least one dose of IMP and had at least one postbaseline weight measurement were included in the full analysis. Number Analyzed = number of subjects with baseline symptoms.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OPC-61815 Injection 16 mg | Improvement Rate for Lower Limb Edema and Pulmonary Congestion | Lower Limb Edema | 68.9 percentage of participants |
| OPC-61815 Injection 16 mg | Improvement Rate for Lower Limb Edema and Pulmonary Congestion | Pulmonary Congestion | 56.1 percentage of participants |
| Tolvaptan Tablet 15mg | Improvement Rate for Lower Limb Edema and Pulmonary Congestion | Lower Limb Edema | 75.7 percentage of participants |
| Tolvaptan Tablet 15mg | Improvement Rate for Lower Limb Edema and Pulmonary Congestion | Pulmonary Congestion | 64.7 percentage of participants |
Secondary
Improvement Rate for New York Heart Association (NYHA) Classification
NYHA classification assesses the severity of heart failure based on subjective symptoms as follows. Class I: No limitations of physical activity. Ordinary physical activity caused no undue fatigue, palpitation, dyspnea or anginal pain. Class II: Slight limitation of physical activity, comfortable at rest. Ordinary physical activity resulted in fatigue, palpitation, dyspnea or anginal pain. Class III: Marked limitation of physical activity, comfortable at rest. Less than ordinary physical activity caused fatigue, palpitation, dyspnea or anginal pain. Class IV: Inability to carry on any physical activity without discomfort. heart failure or anginal syndrome may have been present even at rest. If any physical activity was undertaken, discomfort was increased. Of the subjects with Class II or higher at baseline, the percentage of subjects whose NYHA classification stage at the time of final IMP administration improved by 1 or more grades was provided.
Time frame: Baseline, Day 6
Population: Full Analysis Set: subjects who received at least one dose of IMP and had at least one postbaseline weight measurement were included in the full analysis. Overall Number of Participants Analyzed = number of subjects with a baseline of class II or more.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OPC-61815 Injection 16 mg | Improvement Rate for New York Heart Association (NYHA) Classification | 44.9 percentage of participants |
| Tolvaptan Tablet 15mg | Improvement Rate for New York Heart Association (NYHA) Classification | 42.5 percentage of participants |
Secondary
Percentage of Subjects Who Achieve Resolution of Pulmonary Rales and Third Cardiac Sound
Percentage of subjects in whom the symptom was present at baseline and disappeared after IMP administration was provided. * The presence of pulmonary rales was checked by auscultation. * The presence of cardiac third sound was checked by auscultation.
Time frame: Baseline, Day 6
Population: Full Analysis Set: subjects who received at least one dose of IMP and had at least one postbaseline weight measurement were included in the full analysis. Number Analyzed = number of subjects with baseline symptoms.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OPC-61815 Injection 16 mg | Percentage of Subjects Who Achieve Resolution of Pulmonary Rales and Third Cardiac Sound | Pulmonary Rales | 74.3 percentage of participants |
| OPC-61815 Injection 16 mg | Percentage of Subjects Who Achieve Resolution of Pulmonary Rales and Third Cardiac Sound | Third Cardiac Sound | 31.7 percentage of participants |
| Tolvaptan Tablet 15mg | Percentage of Subjects Who Achieve Resolution of Pulmonary Rales and Third Cardiac Sound | Pulmonary Rales | 78.9 percentage of participants |
| Tolvaptan Tablet 15mg | Percentage of Subjects Who Achieve Resolution of Pulmonary Rales and Third Cardiac Sound | Third Cardiac Sound | 31.0 percentage of participants |