Congestive Heart Failure
Conditions
Brief summary
The dose for intravenous administration of OPC-61815 achieving tolvaptan exposure equivalent to that for oral administration of tolvaptan 15-mg tablet will be investigated by administering OPC-61815 injection 2 to 16mg or tolvaptan 15-mg oral tablet to subjects with congestive heart failure.
Interventions
DRUGOPC-61815 injection 2mg
Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 2 mg.
DRUGOPC-61815 injection 4mg
Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 4 mg.
DRUGOPC-61815 injection 8mg
Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 8 mg.
DRUGOPC-61815 injection 16mg
Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 16 mg.
DRUGTolvaptan tablet 15mg
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
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Subjects who are currently on treatment with any of the following diuretics * Loop diuretics equivalent to furosemide tablet or fine granules at a dose of 40 mg/day or higher * Concomitant use of a loop diuretic and a thiazide diuretic (including thiazide analogs) at any dose * Concomitant use of a loop diuretic and an aldosterone antagonist or potassium-sparing diuretic agent at any dose 2. Subjects with congestive heart failure in whom lower limb edema, pulmonary congestion, and/or jugular venous distension due to volume overload is present 3. Subjects who are currently hospitalized or who are able to be hospitalized during the trial
Exclusion criteria
1. Subjects with acute heart failure 2. Subjects with a history of hypersensitivity to any of ingredients of OPC-61815 or tolvaptan 3. Subjects who are unable to sense thirst or who have difficulty with fluid intake
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Maximum Plasma Concentration (Cmax) of OPC-41061 on Day 1 | Baseline, 1, 1.5, 2, 4, 6, 12 24 hours after the start of administration of investigational drug |
| Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC24h) on Day 1 | Baseline, 1, 1.5, 2, 4, 6, 12 24 hours after the start of administration of investigational drug |
Countries
Japan
Participant flow
Pre-assignment details
A total of 74 subjects were screened for this trial, 13 were screen failures, and 61 were randomly assigned to one of the treatment groups. One subject assigned to the OPC-61815 16-mg group was withdrawn due to dehydration before initiation of the trial drug administration; therefore, 60 subjects received at least 1 dosing of the trial drug.
Participants by arm
| Arm | Count |
|---|---|
| OPC-61815 Injection 2mg Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 2 mg. | 13 |
| OPC-61815 Injection 4mg Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 4 mg. | 12 |
| OPC-61815 Injection 8mg Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 8 mg. | 12 |
| OPC-61815 Injection 16mg Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 16 mg. | 11 |
| 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. | 12 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 0 | 1 | 1 |
| Overall Study | AST/ALT is increased to 3 times upper limit of normal or higher | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | OPC-61815 Injection 2mg | OPC-61815 Injection 4mg | OPC-61815 Injection 8mg | OPC-61815 Injection 16mg | Tolvaptan Tablet 15mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 73.7 years STANDARD_DEVIATION 9.5 | 74.5 years STANDARD_DEVIATION 11.9 | 72.2 years STANDARD_DEVIATION 9.9 | 77.9 years STANDARD_DEVIATION 3.8 | 74.8 years STANDARD_DEVIATION 8.9 | 74.6 years STANDARD_DEVIATION 9.1 |
| Race/Ethnicity, Customized Asian | 13 Participants | 12 Participants | 12 Participants | 11 Participants | 12 Participants | 60 Participants |
| Region of Enrollment Japan | 13 Participants | 12 Participants | 12 Participants | 11 Participants | 12 Participants | 60 Participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 5 Participants | 3 Participants | 2 Participants | 19 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 7 Participants | 8 Participants | 10 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 12 | 0 / 12 | 0 / 11 | 0 / 12 |
| other Total, other adverse events | 7 / 13 | 7 / 12 | 4 / 12 | 8 / 11 | 10 / 12 |
| serious Total, serious adverse events | 0 / 13 | 1 / 12 | 0 / 12 | 0 / 11 | 0 / 12 |
Outcome results
Primary
Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC24h) on Day 1
Time frame: Baseline, 1, 1.5, 2, 4, 6, 12 24 hours after the start of administration of investigational drug
Population: Subjects treated with the IMP at least once and had at least 1 data of primary endpoint after IMP administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OPC-61815 Injection 2mg | Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC24h) on Day 1 | 356 ng*h/mL | Standard Deviation 157 |
| OPC-61815 Injection 4mg | Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC24h) on Day 1 | 983 ng*h/mL | Standard Deviation 563 |
| OPC-61815 Injection 8mg | Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC24h) on Day 1 | 1340 ng*h/mL | Standard Deviation 522 |
| OPC-61815 Injection 16mg | Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC24h) on Day 1 | 2400 ng*h/mL | Standard Deviation 1030 |
| Tolvaptan Tablet 15mg | Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC24h) on Day 1 | 2850 ng*h/mL | Standard Deviation 1580 |
Primary
Maximum Plasma Concentration (Cmax) of OPC-41061 on Day 1
Time frame: Baseline, 1, 1.5, 2, 4, 6, 12 24 hours after the start of administration of investigational drug
Population: Subjects treated with the IMP at least once and had at least 1 data of primary endpoint after IMP administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OPC-61815 Injection 2mg | Maximum Plasma Concentration (Cmax) of OPC-41061 on Day 1 | 41.4 ng/mL | Standard Deviation 11.4 |
| OPC-61815 Injection 4mg | Maximum Plasma Concentration (Cmax) of OPC-41061 on Day 1 | 98.6 ng/mL | Standard Deviation 43.7 |
| OPC-61815 Injection 8mg | Maximum Plasma Concentration (Cmax) of OPC-41061 on Day 1 | 149 ng/mL | Standard Deviation 61.7 |
| OPC-61815 Injection 16mg | Maximum Plasma Concentration (Cmax) of OPC-41061 on Day 1 | 282 ng/mL | Standard Deviation 96 |
| Tolvaptan Tablet 15mg | Maximum Plasma Concentration (Cmax) of OPC-41061 on Day 1 | 325 ng/mL | Standard Deviation 194 |