Heart Failure
Conditions
Keywords
omecamtiv mecarbil
Brief summary
This study is designed to understand the pharmacokinetics of different oral formulations of CK-1827452 being considered for future studies in patients with heart failure. This study will compare the pharmacokinetics and safety and tolerability of both modified-release (MR) and immediate-release (IR) oral formulations of CK-1827452.
Interventions
DRUGCK-1827452
50 mg MR CK-1827452 BID for 10 days
Sponsors
Cytokinetics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. The patient has signed an Informed Consent Form/Patient Information Sheet for this study approved by the governing Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 2. The patient is at least 18 years old at the time of consent 3. Left ventricular ejection fraction (LVEF) ≤ 35% as determined by the Investigator within 3 weeks prior to enrollment 4. Treated for at least 4 weeks with a beta blocker and an ACE inhibitor (and/or an ARB) unless not tolerated. If prescribed, diuretics must have been administered according to a consistent regimen for at least 4 weeks. 5. Diagnosed with heart failure for ≥ 3 months prior to enrollment 6. Patient is considered to be an appropriate candidate for study enrollment as determined by the patient's clinical laboratory findings, vital signs and ECGs within normal range, or if outside of the normal range not deemed clinically significant in the opinion of the Investigator 7. For female patients only: The patient is post-menopausal (≥ 1 year) or sterilized, or if she is of childbearing potential, she is not breastfeeding, her pregnancy test is negative, she has no intention to become pregnant during the course of the study, and she is using contraceptive drugs or devices. For male patients only: Male patients agree for the duration of the study and 10 weeks after the end of the study to use a condom during sexual intercourse with female partners who are of reproductive potential and to have female partners use an additional effective means of contraception (eg, diaphragm plus spermicide, or oral contraceptives) or the male subject must agree to abstain from sexual intercourse for 10 weeks after the end of the study.
Exclusion criteria
1. Patient has been hospitalised for heart failure, acute coronary syndrome, myocardial infarction, coronary revascularisation, transient ischemic attack or stroke, cardiac arrhythmia, or major surgery within 6 weeks prior to enrollment 2. Poorly controlled hypertension defined as blood pressure \> 150/95 mmHg, documented on at least 2 separate occasions prior to enrollment 3. The patient has a supine heart rate ≥ 100 beats per minute after 10 minutes of rest 4. Patient has a troponin I at screening that is above the upper limit of normal 5. The patient has severe aortic or mitral stenosis 6. The patient has active myocarditis; clinically significant restrictive, constrictive, or hypertrophic obstructive cardiomyopathy; clinically significant congenital heart disease; history of major organ transplantation 7. The patient has Canadian Cardiovascular Society Class IV angina 8. Patient is on chronic anti-arrhythmic therapy, with the exception of amiodarone 9. Patient has impaired renal function defined as an estimated GFR ≤ 30 ml/min/1.73 m2 calculated by the Modification of Diet in Renal Disease (MDRD) equation 10. Patient is currently taking, or has taken within 14 days prior to enrollment, a potent CYP3A4 inhibitor (medication or food). Patient is currently taking, or has taken within 28 days prior to enrollment, a potent CYP3A4 inducer (medication or food). 11. The patient has hepatic impairment defined as a total bilirubin \> 3 mg/dL, or an ALT or AST \> 2 times the upper limit of normal 12. Concomitant non-cardiovascular disease that is expected to reduce life expectancy to less than 1 year 13. The patient has received an investigational drug or device within 30 days or 5 half-lives, whichever is greater, of enrollment 14. Patient has, in the opinion of the Investigator, a condition that compromises the ability of the subject to give written informed consent or to comply with study procedures, including scheduled self-administration of oral CK-1827452 15. The patient has had any prior treatment with CK-1827452
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC (Day 1, Dose 1) | 1 day | Area under the curve (AUC) measured in hours \* nanograms per milliliter (hr\*ng/mL) post first dose and pre second dose on day 1. Doses are approximately 12 hours apart in cohort 1 and 3 and 8 hours apart in cohort 2. |
| C Max (Day 1, Dose 1) | 1 day | Maximum plasma concentration (C max) measured in nanograms per milliliter (ng/mL) post first dose and pre second dose on day 1. Doses are approximately 12 hours apart in cohort 1 and 3 and 8 hours apart in cohort 2. |
| T Max (Day 1, Dose 1) | 1 day | Time of observed maximum plasma concentration (T max) measured in hours (hr) post first dose and pre second dose on day 1. Doses are approximately 12 hours apart in cohort 1 and 3 and 8 hours apart in cohort 2. |
| AUC (Day 10) | 1 day | Area under the curve (AUC) measured in hours \* nanograms per milliliter (hr\*ng/mL) post dose on day 10. Only one dose was administered on day 10 (final dose of study). |
| C Max (Day 10) | 1 day | Maximum plasma concentration (C max) measured in nanograms per milliliter (ng/mL) post dose on day 10. Only one dose was administered on day 10 (final dose of study). |
| T Max (Day 10) | 1 day | Time of observed maximum plasma concentration (T max) measured in hours (hr) post dose on day 10. Only one dose was administered on day 10 (final dose of study). |
Secondary
| Measure | Time frame |
|---|---|
| Evaluate the Safety and Tolerability of Oral Formulations of CK-1827452 When Dosed to Steady-state in Patients With Stable Heart Failure. | 1 week |
Countries
Georgia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: MR 50 mg BID Modified-release (MR) 50 mg dose of CK-1827452 twice a day (BID) for 10 days. | 12 |
| Cohort 2: IR 37.5 mg TID Immediate-release (IR) 37.5 mg dose of CK-1827452 three times a day (TID) for 10 days. | 11 |
| Cohort 3: MR 100 mg BID Modified-release (MR) 100 mg dose of CK-1827452 twice a day (BID) for 10 days | 12 |
| Total | 35 |
Baseline characteristics
| Characteristic | Cohort 2: IR 37.5 mg TID | Cohort 3: MR 100 mg BID | Cohort 1: MR 50 mg BID | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 6 Participants | 5 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 6 Participants | 7 Participants | 21 Participants |
| Age Continuous | 61.1 years STANDARD_DEVIATION 7.97 | 62.4 years STANDARD_DEVIATION 11.51 | 64.1 years STANDARD_DEVIATION 7.74 | 62.6 years STANDARD_DEVIATION 9.08 |
| Region of Enrollment Georgia | 11 participants | 12 participants | 12 participants | 35 participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 8 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 12 | 0 / 11 | 2 / 12 |
| serious Total, serious adverse events | 0 / 12 | 1 / 11 | 0 / 12 |
Outcome results
Primary
AUC (Day 10)
Area under the curve (AUC) measured in hours \* nanograms per milliliter (hr\*ng/mL) post dose on day 10. Only one dose was administered on day 10 (final dose of study).
Time frame: 1 day
Population: PK population (4 patients excluded from cohort 3 analysis due to improper dosing and 1 patient excluded from cohort 2 due to sudden death).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: MR 50 mg BID | AUC (Day 10) | 1886 hr*ng/mL | Standard Deviation 1002 |
| Cohort 2: IR 37.5 mg TID | AUC (Day 10) | 2118 hr*ng/mL | Standard Deviation 623 |
| Cohort 3: MR 100 mg BID | AUC (Day 10) | 6457 hr*ng/mL | Standard Deviation 5147 |
Primary
AUC (Day 1, Dose 1)
Area under the curve (AUC) measured in hours \* nanograms per milliliter (hr\*ng/mL) post first dose and pre second dose on day 1. Doses are approximately 12 hours apart in cohort 1 and 3 and 8 hours apart in cohort 2.
Time frame: 1 day
Population: PK population (4 patients excluded from cohort 3 analysis due to improper dosing).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: MR 50 mg BID | AUC (Day 1, Dose 1) | 446 hr*ng/mL | Standard Deviation 206 |
| Cohort 2: IR 37.5 mg TID | AUC (Day 1, Dose 1) | 1003 hr*ng/mL | Standard Deviation 387 |
| Cohort 3: MR 100 mg BID | AUC (Day 1, Dose 1) | 1650 hr*ng/mL | Standard Deviation 1354 |
Primary
C Max (Day 10)
Maximum plasma concentration (C max) measured in nanograms per milliliter (ng/mL) post dose on day 10. Only one dose was administered on day 10 (final dose of study).
Time frame: 1 day
Population: PK population (4 patients excluded from cohort 3 analysis due to improper dosing and 1 patient excluded from cohort 2 due to sudden death).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: MR 50 mg BID | C Max (Day 10) | 205 ng/mL | Standard Deviation 111 |
| Cohort 2: IR 37.5 mg TID | C Max (Day 10) | 420 ng/mL | Standard Deviation 158 |
| Cohort 3: MR 100 mg BID | C Max (Day 10) | 704 ng/mL | Standard Deviation 494 |
Primary
C Max (Day 1, Dose 1)
Maximum plasma concentration (C max) measured in nanograms per milliliter (ng/mL) post first dose and pre second dose on day 1. Doses are approximately 12 hours apart in cohort 1 and 3 and 8 hours apart in cohort 2.
Time frame: 1 day
Population: PK population (4 patients excluded from cohort 3 analysis due to improper dosing).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: MR 50 mg BID | C Max (Day 1, Dose 1) | 58 ng/mL | Standard Deviation 27 |
| Cohort 2: IR 37.5 mg TID | C Max (Day 1, Dose 1) | 243 ng/mL | Standard Deviation 148 |
| Cohort 3: MR 100 mg BID | C Max (Day 1, Dose 1) | 209 ng/mL | Standard Deviation 164 |
Primary
T Max (Day 10)
Time of observed maximum plasma concentration (T max) measured in hours (hr) post dose on day 10. Only one dose was administered on day 10 (final dose of study).
Time frame: 1 day
Population: PK population (4 patients excluded from cohort 3 analysis due to improper dosing and 1 patient excluded from cohort 2 due to sudden death).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: MR 50 mg BID | T Max (Day 10) | 1.8 hr | Standard Deviation 0.9 |
| Cohort 2: IR 37.5 mg TID | T Max (Day 10) | 1.8 hr | Standard Deviation 1.1 |
| Cohort 3: MR 100 mg BID | T Max (Day 10) | 2.7 hr | Standard Deviation 1.6 |
Primary
T Max (Day 1, Dose 1)
Time of observed maximum plasma concentration (T max) measured in hours (hr) post first dose and pre second dose on day 1. Doses are approximately 12 hours apart in cohort 1 and 3 and 8 hours apart in cohort 2.
Time frame: 1 day
Population: PK population (4 patients excluded from cohort 3 analysis due to improper dosing).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: MR 50 mg BID | T Max (Day 1, Dose 1) | 3.5 hr | Standard Deviation 2.9 |
| Cohort 2: IR 37.5 mg TID | T Max (Day 1, Dose 1) | 3.7 hr | Standard Deviation 3.7 |
| Cohort 3: MR 100 mg BID | T Max (Day 1, Dose 1) | 3.5 hr | Standard Deviation 3.9 |
Secondary
Evaluate the Safety and Tolerability of Oral Formulations of CK-1827452 When Dosed to Steady-state in Patients With Stable Heart Failure.
Time frame: 1 week