Congestive Heart Failure
Conditions
Brief summary
To investigate the effects of intravenous administration of OPC-61815 at 16 and 32 mg on QT/QTc interval in healthy male subjects
Interventions
DRUGOPC-61815 16mg
OPC-61815 16mg will be intravenously administered once a week.
DRUGOPC-61815 32mg
OPC-61815 32mg will be intravenously administered once a week.
DRUGMoxifloxacin
400mg tablet will be administrated once a week.
DRUGPlacebos
Placebo will be intravenously administered once a week.
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
MALE
Age
20 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Body mass index (BMI) \[body weight in kg / (height in m)2\] of at least 18.5 kg/m2 and less than 25.0 kg/m2 as a result of at the screening examination * Judged by the investigator or subinvestigator to be capable of providing written informed consent prior to start of any trial-related procedures and capable of complying with the procedures for this trial
Exclusion criteria
* Subjects with a medical history of convulsive disorder, long QT syndrome (including family history), syncope during swimming, or any other type of syncope or cryptogenic loss of consciousness * Subjects with a serum electrolyte abnormality (hypokalemia, hypomagnesemia, hypocalcemia, etc) * Subjects with a family history of sudden death
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | Baseline, 1h, 1.5h, 2h, 3h, 4h, 6h, 12h, 24h after dosing | For each OPC-61815 dose, the upper limit of the confidence interval (CI) for the time-matched difference in the least squares (LS) mean for the change in QT corrected for heart rate by Fridericia's formula (QTcF) from baseline compared to the placebo data was evaluated to determine if it was lower than 10 msec at all postdose time points. Using a linear mixed effect model with baseline QTcF in each treatment period as a covariate, treatment, sequence, treatment period, time point, and interaction between treatment and time point as fixed effects, and subject as a random effect, point estimates and CIs for the time-matched difference in the LS mean for the change in QTcF from baseline compared to the placebo data were calculated. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sequence 1 (ABDC) Each subject received a single dose of each of the following 4 study treatments in Periods 1 to 4 in the assigned sequence.
A: OPC-6181 16 mg B: OPC-61815 32 mg C: placebo D: moxifloxacin
OPC-61815 and placebo were intravenously administered in a double-blind fashion, and a moxifloxacin 400 mg tablet was orally administered with water in an open-label fashion. A washout period of at least 6 days was set between the days of investigational medicinal product (IMP) administration in a treatment period and the next treatment period. | 6 |
| Sequence 2 (DACB) Each subject received a single dose of each of the following 4 study treatments in Periods 1 to 4 in the assigned sequence.
A: OPC-6181 16 mg B: OPC-61815 32 mg C: placebo D: moxifloxacin
OPC-61815 and placebo were intravenously administered in a double-blind fashion, and a moxifloxacin 400 mg tablet was orally administered with water in an open-label fashion. A washout period of at least 6 days was set between the days of IMP administration in a treatment period and the next treatment period. | 6 |
| Sequence 3 (BCAD) Each subject received a single dose of each of the following 4 study treatments in Periods 1 to 4 in the assigned sequence.
A: OPC-6181 16 mg B: OPC-61815 32 mg C: placebo D: moxifloxacin
OPC-61815 and placebo were intravenously administered in a double-blind fashion, and a moxifloxacin 400 mg tablet was orally administered with water in an open-label fashion. A washout period of at least 6 days was set between the days of IMP administration in a treatment period and the next treatment period. | 6 |
| Sequence 4 (CDBA) Each subject received a single dose of each of the following 4 study treatments in Periods 1 to 4 in the assigned sequence.
A: OPC-6181 16 mg B: OPC-61815 32 mg C: placebo D: moxifloxacin
OPC-61815 and placebo were intravenously administered in a double-blind fashion, and a moxifloxacin 400 mg tablet was orally administered with water in an open-label fashion. A washout period of at least 6 days was set between the days of IMP administration in a treatment period and the next treatment period. | 6 |
| Sequence 5 (ABCD) Each subject received a single dose of each of the following 4 study treatments in Periods 1 to 4 in the assigned sequence.
A: OPC-6181 16 mg B: OPC-61815 32 mg C: placebo D: moxifloxacin
OPC-61815 and placebo were intravenously administered in a double-blind fashion, and a moxifloxacin 400 mg tablet was orally administered with water in an open-label fashion. A washout period of at least 6 days was set between the days of IMP administration in a treatment period and the next treatment period. | 6 |
| Sequence 6 (CADB) Each subject received a single dose of each of the following 4 study treatments in Periods 1 to 4 in the assigned sequence.
A: OPC-6181 16 mg B: OPC-61815 32 mg C: placebo D: moxifloxacin
OPC-61815 and placebo were intravenously administered in a double-blind fashion, and a moxifloxacin 400 mg tablet was orally administered with water in an open-label fashion. A washout period of at least 6 days was set between the days of IMP administration in a treatment period and the next treatment period. | 6 |
| Sequence 7 (BDAC) Each subject received a single dose of each of the following 4 study treatments in Periods 1 to 4 in the assigned sequence.
A: OPC-6181 16 mg B: OPC-61815 32 mg C: placebo D: moxifloxacin
OPC-61815 and placebo were intravenously administered in a double-blind fashion, and a moxifloxacin 400 mg tablet was orally administered with water in an open-label fashion. A washout period of at least 6 days was set between the days of IMP administration in a treatment period and the next treatment period. | 6 |
| Sequence 8 (DCBA) Each subject received a single dose of each of the following 4 study treatments in Periods 1 to 4 in the assigned sequence.
A: OPC-6181 16 mg B: OPC-61815 32 mg C: placebo D: moxifloxacin
OPC-61815 and placebo were intravenously administered in a double-blind fashion, and a moxifloxacin 400 mg tablet was orally administered with water in an open-label fashion. A washout period of at least 6 days was set between the days of IMP administration in a treatment period and the next treatment period. | 6 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Sequence 8 (DCBA) | Total | Sequence 1 (ABDC) | Sequence 4 (CDBA) | Sequence 5 (ABCD) | Sequence 2 (DACB) | Sequence 3 (BCAD) | Sequence 6 (CADB) | Sequence 7 (BDAC) |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 26.2 years STANDARD_DEVIATION 6.4 | 28.5 years STANDARD_DEVIATION 7.3 | 31.7 years STANDARD_DEVIATION 11.4 | 26.5 years STANDARD_DEVIATION 9.1 | 28.3 years STANDARD_DEVIATION 8.4 | 27.3 years STANDARD_DEVIATION 7.4 | 30.2 years STANDARD_DEVIATION 7.7 | 30.3 years STANDARD_DEVIATION 4.4 | 27.5 years STANDARD_DEVIATION 4.1 |
| Race/Ethnicity, Customized Japanese | 6 Participants | 48 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants |
| Region of Enrollment Japan | 6 Participants | 48 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 48 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 47 | 0 / 47 | 0 / 48 | 0 / 47 |
| other Total, other adverse events | 3 / 47 | 5 / 47 | 1 / 48 | 2 / 47 |
| serious Total, serious adverse events | 0 / 47 | 0 / 47 | 0 / 48 | 0 / 47 |
Outcome results
Primary
Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG)
For each OPC-61815 dose, the upper limit of the confidence interval (CI) for the time-matched difference in the least squares (LS) mean for the change in QT corrected for heart rate by Fridericia's formula (QTcF) from baseline compared to the placebo data was evaluated to determine if it was lower than 10 msec at all postdose time points. Using a linear mixed effect model with baseline QTcF in each treatment period as a covariate, treatment, sequence, treatment period, time point, and interaction between treatment and time point as fixed effects, and subject as a random effect, point estimates and CIs for the time-matched difference in the LS mean for the change in QTcF from baseline compared to the placebo data were calculated.
Time frame: Baseline, 1h, 1.5h, 2h, 3h, 4h, 6h, 12h, 24h after dosing
Population: Central tendency analysis for OPC-61815 was performed for subjects in the Pharmacodynamic Analysis Set who appropriately completed all IMP treatments and for whom predose and postdose QT data are available for all 4 treatment periods. One subject was excluded from the central tendency analysis due to lack of QT data following OPC-61815 16 mg, OPC-61815 32 mg, and placebo administration.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| OPC-61815 16 mg | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 6 hours postdose | -11.9 msec | Standard Error 1.1 |
| OPC-61815 16 mg | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 2 hours postdose | 1.7 msec | Standard Error 1.1 |
| OPC-61815 16 mg | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 4 hours postdose | -2.6 msec | Standard Error 1.1 |
| OPC-61815 16 mg | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 12 hours postdose | -9.6 msec | Standard Error 1.1 |
| OPC-61815 16 mg | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 24 hours postdose | -3.6 msec | Standard Error 1.1 |
| OPC-61815 16 mg | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 1 hour postdose | 0.9 msec | Standard Error 1.1 |
| OPC-61815 16 mg | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 3 hours postdose | -1.2 msec | Standard Error 1.1 |
| OPC-61815 16 mg | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 1.5 hours postdose | 2.0 msec | Standard Error 1.1 |
| OPC-61815 32 mg | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 1 hour postdose | 0.0 msec | Standard Error 1.1 |
| OPC-61815 32 mg | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 1.5 hours postdose | 1.3 msec | Standard Error 1.1 |
| OPC-61815 32 mg | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 12 hours postdose | -9.8 msec | Standard Error 1.1 |
| OPC-61815 32 mg | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 2 hours postdose | 0.4 msec | Standard Error 1.1 |
| OPC-61815 32 mg | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 24 hours postdose | -2.8 msec | Standard Error 1.1 |
| OPC-61815 32 mg | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 3 hours postdose | -2.2 msec | Standard Error 1.1 |
| OPC-61815 32 mg | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 4 hours postdose | -2.2 msec | Standard Error 1.1 |
| OPC-61815 32 mg | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 6 hours postdose | -10.8 msec | Standard Error 1.1 |
| Moxifloxacin | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 12 hours postdose | 2.6 msec | Standard Error 1.1 |
| Moxifloxacin | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 3 hours postdose | 10.9 msec | Standard Error 1.1 |
| Moxifloxacin | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 24 hours postdose | 4.3 msec | Standard Error 1.1 |
| Moxifloxacin | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 1 hour postdose | 9.9 msec | Standard Error 1.1 |
| Moxifloxacin | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 1.5 hours postdose | 9.5 msec | Standard Error 1.1 |
| Moxifloxacin | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 2 hours postdose | 10.8 msec | Standard Error 1.1 |
| Moxifloxacin | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 4 hours postdose | 11.1 msec | Standard Error 1.1 |
| Moxifloxacin | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 6 hours postdose | 1.9 msec | Standard Error 1.1 |
| Placebo | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 4 hours postdose | 1.5 msec | Standard Error 1.1 |
| Placebo | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 1 hour postdose | -0.9 msec | Standard Error 1.1 |
| Placebo | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 24 hours postdose | -2.7 msec | Standard Error 1.1 |
| Placebo | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 2 hours postdose | -0.4 msec | Standard Error 1.1 |
| Placebo | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 6 hours postdose | -8.5 msec | Standard Error 1.1 |
| Placebo | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 1.5 hours postdose | -0.7 msec | Standard Error 1.1 |
| Placebo | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 12 hours postdose | -4.7 msec | Standard Error 1.1 |
| Placebo | Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG) | 3 hours postdose | -0.6 msec | Standard Error 1.1 |
Comparison: 1 hour postdose90% CI: [-0.4, 4.1]
Comparison: 1.5 hours postdose90% CI: [0.4, 4.9]
Comparison: 2 hours postdose90% CI: [-0.1, 4.4]
Comparison: 3 hours postdose90% CI: [-2.8, 1.7]
Comparison: 4 hours postdose90% CI: [-6.3, -1.8]
Comparison: 6 hours postdose90% CI: [-5.7, -1.2]
Comparison: 12 hours postdose90% CI: [-7.1, -2.6]
Comparison: 24 hours postdose90% CI: [-3.1, 1.4]
Comparison: 1 hour postdose90% CI: [-1.4, 3.1]
Comparison: 1.5 hours postdose90% CI: [-0.2, 4.2]
Comparison: 2 hours postdose90% CI: [-1.4, 3.1]
Comparison: 3 hours postdose90% CI: [-3.8, 0.7]
Comparison: 4 hours postdose90% CI: [-5.9, -1.5]
Comparison: 6 hours postdose90% CI: [-4.6, -0.1]
Comparison: 12 hours postdose90% CI: [-7.3, -2.8]
Comparison: 24 hours postdose90% CI: [-2.4, 2.1]
Comparison: 1 hour postdose98% CI: [7.6, 14]
Comparison: 1.5 hours postdose98% CI: [7, 13.4]
Comparison: 2 hours postdose98% CI: [8, 14.4]
Comparison: 3 hours postdose98% CI: [8.3, 14.7]
Comparison: 4 hours postdose98% CI: [6.5, 12.8]
Comparison: 6 hours postdose98% CI: [7.2, 13.5]
Comparison: 12 hours postdose98% CI: [4.1, 10.4]
Comparison: 24 hours postdose98% CI: [3.8, 10.2]