Healthy Volunteer
Conditions
Keywords
Heart failure
Brief summary
The purpose of this study is to evaluate the pharmacokinetics (PK), safety, and tolerability of omecamtiv mecarbil in healthy volunteers in Japan.
Detailed description
This study was conducted by Amgen as the IND holder, with Cytokinetics as a collaborator. Due to the termination of the collaboration agreement between Amgen and Cytokinetics in May 2021 and subsequent transfer of the omecamtiv mecarbil IND from Amgen to Cytokinetics, Cytokinetics is now listed as the sponsor.
Interventions
Omecamtiv mecarbil tablets for oral administration
DRUGPlacebo
Matching placebo tablets
Sponsors
Cytokinetics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* No history or evidence of clinically relevant medical disorders as determined by the Investigator, and in good health as determined by a pre-study physical examination and medical history with no clinically significant abnormalities, normal vital signs and no history or presence of a clinically significant abnormal electrocardiogram finding * Subjects' pre-study clinical laboratory findings (including creatine phosphokinase) should be within normal range or if outside of the normal range, are deemed not clinically significant by the Investigator.
Exclusion criteria
* A clinically significant disorder/disease, including gastro intestinal abnormalities that might interfere with absorption * An unstable medical condition, defined as having been hospitalized within 28 days before day 1, major surgery within 6 months before day 1, or otherwise unstable in the judgment of the Investigator * History or evidence of any other clinically significant disorder, condition, or disease that, in the opinion of the Investigator or Medical Monitor would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion * History of malignancy of any type other than surgically excised non-melanomatous skin cancers or in situ cervical cancer within 5 years before the day of dosing * Use of any prescription or over-the-counter medications within 14 days or 5 half-lives (whichever time period is greater), prior to receiving the first dose of omecamtiv mecarbil (acetaminophen up to 2 grams per day for analgesia and hormone replacement therapy (e.g., estrogen) will be allowed * Use of any known inhibitors of CYP3A4/p-glycoprotein (P-gp) or CYP2D6 within 14 days or 5 half-lives, whichever is longer; or use of grapefruit juice or grapefruit containing products within 7 days prior to receiving the first dose of omecamtiv mecarbil * Use of any known CYP3A4 inducers within 30 days or 5 half-lives, whichever is longer, before receiving omecamtiv mecarbil
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dosing Period 2: Accumulation Ratio | Day 20 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 27 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. | Accumulation ratio calculated as the ratio of day 27 AUC(0-12) / day 20 AUC(0-12). |
| Dosing Period 2: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | Day 20 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 27 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after the morning dose. | — |
| Dosing Period 2: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | Day 20 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 27 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after the morning dose. | — |
| Dosing Period 2: AUC(0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 2 | Day 20 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 27 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. | — |
| Dosing Period 2: Predose Omecamtiv Mecarbil Plasma Concentration | Day 27 predose | — |
| Dosing Period 1: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 1 | Day 1 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 8 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after the morning dose. | — |
| Dosing Period 1: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 1 | Day 1 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 8 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after the morning dose. | — |
| Dosing Period 1: Area Under the Concentration-time Curve for a Dosing Interval of 12 Hours (AUC0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 1 | Day 1 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 8 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. | — |
| Dosing Period 1: Predose Omecamtiv Mecarbil Plasma Concentration | Day 8 predose | — |
| Dosing Period 1: Accumulation Ratio | Day 1 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 8 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. | Accumulation ratio calculated as the ratio of day 8 AUC(0-12) / day 1 AUC(0-12) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Grade 3 or Higher Laboratory Toxicities | 35 days | Abnormal laboratory findings were graded for severity according to the NCI CTCAE version 4.0 according to the following guideline: * Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. * Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL). * Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. * Grade 4: Life-threatening consequences; urgent intervention indicated. * Grade 5: Death related to AE. |
| Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1 | Day 1 predose and day 8 | QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle as measured by electrocardiogram (ECG). Maximum increase from Period 1 baseline was categorized as: ≤ 30 milliseconds (ms) \> 30 to 60 ms \> 60 ms |
| Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2 | Day 20 predose and Day 27 | QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle as measured by ECG. Maximum increase from Period 2 baseline was categorized as: ≤ 30 ms \> 30 to 60 ms \> 60 ms |
| Number of Participants With Treatment-emergent Adverse Events | 35 days | An adverse event is defined as any untoward medical occurrence in a clinical trial participant, including worsening of a preexisting medical condition. The event does not necessarily have a causal relationship with study treatment. A serious adverse event is defined as an adverse event that met at least 1 of the following serious criteria: * fatal * life threatening * required in patient hospitalization or prolongation of existing hospitalization * resulted in persistent or significant disability/incapacity * congenital anomaly/birth defect * other medically important serious event. Adverse events were graded for severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. |
Countries
Japan
Participant flow
Recruitment details
This study was conducted at a single center in Japan. Participants were enrolled from 13 November 2015 to 24 November 2015.
Pre-assignment details
Participants were randomly assigned to one of three treatment groups in a 1:2:2 ratio. The study consisted of a screening period, two 8-day treatment periods with an 11-day drug holiday in between, and an end of study (EOS) visit on day 35.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo tablets twice a day (BID) in dosing period 1 (days 1 to 8) and in dosing period 2 (days 20 to 27). | 10 |
| Group A: Omecamtiv Mecarbil 25 mg / 37.5 mg Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg or 37.5 mg BID in dosing period 2 (days 20 to 27) based on their day 8 predose omecamtiv mecarbil plasma concentration (Cpredose): If day 8 Cpredose was \< 200 ng/mL, participants received 37.5 mg BID; if day 8 Cpredose was ≥ 200 ng/mL participants continued to receive 25 mg BID. | 20 |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg or 50 mg BID in dosing period 2 (days 20 to 27) based on their day 8 predose omecamtiv mecarbil plasma concentration (Cpredose): If day 8 Cpredose was \< 200 ng/mL, participants received 50 mg BID; if day 8 Cpredose was ≥ 200 ng/mL participants continued to receive 25 mg BID. | 20 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Dosing Period 2 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Group A: Omecamtiv Mecarbil 25 mg / 37.5 mg | Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 29.2 years STANDARD_DEVIATION 4.2 | 35.5 years STANDARD_DEVIATION 7.6 | 27.3 years STANDARD_DEVIATION 4.6 | 31.0 years STANDARD_DEVIATION 7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 20 Participants | 20 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 10 Participants | 20 Participants | 20 Participants | 50 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 3 Participants | 6 Participants | 6 Participants | 15 Participants |
| Sex: Female, Male Male | 7 Participants | 14 Participants | 14 Participants | 35 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 10 | 5 / 20 | 3 / 20 | 4 / 10 | 3 / 7 | 3 / 13 | 1 / 7 | 3 / 13 |
| serious Total, serious adverse events | 0 / 10 | 0 / 20 | 0 / 20 | 0 / 10 | 0 / 7 | 0 / 13 | 0 / 7 | 0 / 13 |
Outcome results
Primary
Dosing Period 1: Accumulation Ratio
Accumulation ratio calculated as the ratio of day 8 AUC(0-12) / day 1 AUC(0-12)
Time frame: Day 1 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 8 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose.
Population: The PK analysis set with available AUC data at both time points
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Omecamtiv Mecarbil 25 mg | Dosing Period 1: Accumulation Ratio | 3.66 ratio | Standard Deviation 0.89 |
| Group B: Omecamtiv Mecarbil 25 mg | Dosing Period 1: Accumulation Ratio | 3.79 ratio | Standard Deviation 0.77 |
Primary
Dosing Period 1: Area Under the Concentration-time Curve for a Dosing Interval of 12 Hours (AUC0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 1
Time frame: Day 1 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 8 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose.
Population: The PK analysis set with available AUC data at each time point
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A: Omecamtiv Mecarbil 25 mg | Dosing Period 1: Area Under the Concentration-time Curve for a Dosing Interval of 12 Hours (AUC0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 1 | After first dose on day 1 | 687 ng*hr/mL | Standard Deviation 210 |
| Group A: Omecamtiv Mecarbil 25 mg | Dosing Period 1: Area Under the Concentration-time Curve for a Dosing Interval of 12 Hours (AUC0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 1 | After last dose on day 8 | 2570 ng*hr/mL | Standard Deviation 739 |
| Group B: Omecamtiv Mecarbil 25 mg | Dosing Period 1: Area Under the Concentration-time Curve for a Dosing Interval of 12 Hours (AUC0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 1 | After first dose on day 1 | 677 ng*hr/mL | Standard Deviation 163 |
| Group B: Omecamtiv Mecarbil 25 mg | Dosing Period 1: Area Under the Concentration-time Curve for a Dosing Interval of 12 Hours (AUC0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 1 | After last dose on day 8 | 2670 ng*hr/mL | Standard Deviation 699 |
Primary
Dosing Period 1: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 1
Time frame: Day 1 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 8 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after the morning dose.
Population: The pharmacokinetic (PK) analysis set included all randomized participants who received at least 1 dose of omecamtiv mecarbil and had at least 1 evaluable omecamtiv mecarbil PK parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A: Omecamtiv Mecarbil 25 mg | Dosing Period 1: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 1 | After first dose on day 1 | 77.4 ng/mL | Standard Deviation 21.6 |
| Group A: Omecamtiv Mecarbil 25 mg | Dosing Period 1: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 1 | After last dose on day 8 | 256 ng/mL | Standard Deviation 71.2 |
| Group B: Omecamtiv Mecarbil 25 mg | Dosing Period 1: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 1 | After first dose on day 1 | 79.5 ng/mL | Standard Deviation 18.9 |
| Group B: Omecamtiv Mecarbil 25 mg | Dosing Period 1: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 1 | After last dose on day 8 | 259 ng/mL | Standard Deviation 59.2 |
Primary
Dosing Period 1: Predose Omecamtiv Mecarbil Plasma Concentration
Time frame: Day 8 predose
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Omecamtiv Mecarbil 25 mg | Dosing Period 1: Predose Omecamtiv Mecarbil Plasma Concentration | 190 ng/mL | Standard Deviation 58.5 |
| Group B: Omecamtiv Mecarbil 25 mg | Dosing Period 1: Predose Omecamtiv Mecarbil Plasma Concentration | 192 ng/mL | Standard Deviation 55.1 |
Primary
Dosing Period 1: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 1
Time frame: Day 1 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 8 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after the morning dose.
Population: PK analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group A: Omecamtiv Mecarbil 25 mg | Dosing Period 1: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 1 | After first dose on day 1 | 4.0 hours |
| Group A: Omecamtiv Mecarbil 25 mg | Dosing Period 1: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 1 | After last dose on day 8 | 2.0 hours |
| Group B: Omecamtiv Mecarbil 25 mg | Dosing Period 1: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 1 | After first dose on day 1 | 3.0 hours |
| Group B: Omecamtiv Mecarbil 25 mg | Dosing Period 1: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 1 | After last dose on day 8 | 2.0 hours |
Primary
Dosing Period 2: Accumulation Ratio
Accumulation ratio calculated as the ratio of day 27 AUC(0-12) / day 20 AUC(0-12).
Time frame: Day 20 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 27 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose.
Population: Pharmacokinetic analysis set with available AUC data at both time points
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Omecamtiv Mecarbil 25 mg | Dosing Period 2: Accumulation Ratio | 4.12 ratio | Standard Deviation 1.28 |
| Group B: Omecamtiv Mecarbil 25 mg | Dosing Period 2: Accumulation Ratio | 3.81 ratio | Standard Deviation 0.83 |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Dosing Period 2: Accumulation Ratio | 4.53 ratio | Standard Deviation 1.19 |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Dosing Period 2: Accumulation Ratio | 4.11 ratio | Standard Deviation 1.15 |
Primary
Dosing Period 2: AUC(0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 2
Time frame: Day 20 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 27 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose.
Population: Pharmacokinetic analysis set with available AUC data at each time point
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A: Omecamtiv Mecarbil 25 mg | Dosing Period 2: AUC(0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 2 | After first dose on day 20 | 902 ng*hr/mL | Standard Deviation 220 |
| Group A: Omecamtiv Mecarbil 25 mg | Dosing Period 2: AUC(0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 2 | After last dose on day 27 | 3520 ng*hr/mL | Standard Deviation 505 |
| Group B: Omecamtiv Mecarbil 25 mg | Dosing Period 2: AUC(0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 2 | After last dose on day 27 | 3500 ng*hr/mL | Standard Deviation 519 |
| Group B: Omecamtiv Mecarbil 25 mg | Dosing Period 2: AUC(0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 2 | After first dose on day 20 | 950 ng*hr/mL | Standard Deviation 228 |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Dosing Period 2: AUC(0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 2 | After first dose on day 20 | 841 ng*hr/mL | Standard Deviation 403 |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Dosing Period 2: AUC(0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 2 | After last dose on day 27 | 3290 ng*hr/mL | Standard Deviation 662 |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Dosing Period 2: AUC(0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 2 | After first dose on day 20 | 1330 ng*hr/mL | Standard Deviation 217 |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Dosing Period 2: AUC(0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 2 | After last dose on day 27 | 5490 ng*hr/mL | Standard Deviation 1000 |
Primary
Dosing Period 2: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2
Time frame: Day 20 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 27 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after the morning dose.
Population: Pharmacokinetic analysis set with available data at each time point
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A: Omecamtiv Mecarbil 25 mg | Dosing Period 2: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | After first dose on day 20 | 96.5 ng/mL | Standard Deviation 27.2 |
| Group A: Omecamtiv Mecarbil 25 mg | Dosing Period 2: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | After last dose on day 27 | 335 ng/mL | Standard Deviation 32 |
| Group B: Omecamtiv Mecarbil 25 mg | Dosing Period 2: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | After last dose on day 27 | 341 ng/mL | Standard Deviation 48.8 |
| Group B: Omecamtiv Mecarbil 25 mg | Dosing Period 2: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | After first dose on day 20 | 107 ng/mL | Standard Deviation 30.4 |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Dosing Period 2: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | After first dose on day 20 | 84.9 ng/mL | Standard Deviation 30 |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Dosing Period 2: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | After last dose on day 27 | 311 ng/mL | Standard Deviation 54.2 |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Dosing Period 2: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | After first dose on day 20 | 154 ng/mL | Standard Deviation 22 |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Dosing Period 2: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | After last dose on day 27 | 537 ng/mL | Standard Deviation 91.7 |
Primary
Dosing Period 2: Predose Omecamtiv Mecarbil Plasma Concentration
Time frame: Day 27 predose
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Omecamtiv Mecarbil 25 mg | Dosing Period 2: Predose Omecamtiv Mecarbil Plasma Concentration | 271 ng/mL | Standard Deviation 44.8 |
| Group B: Omecamtiv Mecarbil 25 mg | Dosing Period 2: Predose Omecamtiv Mecarbil Plasma Concentration | 256 ng/mL | Standard Deviation 42.1 |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Dosing Period 2: Predose Omecamtiv Mecarbil Plasma Concentration | 245 ng/mL | Standard Deviation 43.3 |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Dosing Period 2: Predose Omecamtiv Mecarbil Plasma Concentration | 401 ng/mL | Standard Deviation 77.8 |
Primary
Dosing Period 2: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2
Time frame: Day 20 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 27 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after the morning dose.
Population: Pharmacokinetic analysis set with available data at each time point
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group A: Omecamtiv Mecarbil 25 mg | Dosing Period 2: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | After first dose on day 20 | 4.0 hours |
| Group A: Omecamtiv Mecarbil 25 mg | Dosing Period 2: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | After last dose on day 27 | 2.0 hours |
| Group B: Omecamtiv Mecarbil 25 mg | Dosing Period 2: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | After last dose on day 27 | 3.0 hours |
| Group B: Omecamtiv Mecarbil 25 mg | Dosing Period 2: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | After first dose on day 20 | 2.0 hours |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Dosing Period 2: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | After first dose on day 20 | 4.0 hours |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Dosing Period 2: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | After last dose on day 27 | 4.0 hours |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Dosing Period 2: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | After first dose on day 20 | 3.0 hours |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Dosing Period 2: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | After last dose on day 27 | 3.0 hours |
Secondary
Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1
QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle as measured by electrocardiogram (ECG). Maximum increase from Period 1 baseline was categorized as: ≤ 30 milliseconds (ms) \> 30 to 60 ms \> 60 ms
Time frame: Day 1 predose and day 8
Population: All randomized participants who received at least one dose of study treatment (omecamtiv mecarbil or placebo).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A: Omecamtiv Mecarbil 25 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1 | > 60 ms | 0 Participants |
| Group A: Omecamtiv Mecarbil 25 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1 | ≤ 30 ms | 10 Participants |
| Group A: Omecamtiv Mecarbil 25 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1 | > 30 to 60 ms | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1 | > 60 ms | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1 | ≤ 30 ms | 7 Participants |
| Group B: Omecamtiv Mecarbil 25 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1 | > 30 to 60 ms | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1 | > 60 ms | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1 | ≤ 30 ms | 13 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1 | > 30 to 60 ms | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1 | ≤ 30 ms | 7 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1 | > 30 to 60 ms | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1 | > 60 ms | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1 | ≤ 30 ms | 13 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1 | > 30 to 60 ms | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1 | > 60 ms | 0 Participants |
Secondary
Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2
QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle as measured by ECG. Maximum increase from Period 2 baseline was categorized as: ≤ 30 ms \> 30 to 60 ms \> 60 ms
Time frame: Day 20 predose and Day 27
Population: Randomized participants who received at least one dose of study treatment (omecamtiv mecarbil or placebo), with available data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A: Omecamtiv Mecarbil 25 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2 | ≤ 30 ms | 10 Participants |
| Group A: Omecamtiv Mecarbil 25 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2 | > 60 ms | 0 Participants |
| Group A: Omecamtiv Mecarbil 25 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2 | > 30 to 60 ms | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2 | > 30 to 60 ms | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2 | ≤ 30 ms | 7 Participants |
| Group B: Omecamtiv Mecarbil 25 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2 | > 60 ms | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2 | > 30 to 60 ms | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2 | ≤ 30 ms | 13 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2 | > 60 ms | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2 | ≤ 30 ms | 7 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2 | > 60 ms | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2 | > 30 to 60 ms | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2 | > 30 to 60 ms | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2 | ≤ 30 ms | 12 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2 | > 60 ms | 0 Participants |
Secondary
Number of Participants With Grade 3 or Higher Laboratory Toxicities
Abnormal laboratory findings were graded for severity according to the NCI CTCAE version 4.0 according to the following guideline: * Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. * Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL). * Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. * Grade 4: Life-threatening consequences; urgent intervention indicated. * Grade 5: Death related to AE.
Time frame: 35 days
Population: All randomized participants who received at least one dose of study treatment (omecamtiv mecarbil or placebo).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A: Omecamtiv Mecarbil 25 mg | Number of Participants With Grade 3 or Higher Laboratory Toxicities | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg | Number of Participants With Grade 3 or Higher Laboratory Toxicities | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Number of Participants With Grade 3 or Higher Laboratory Toxicities | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Number of Participants With Grade 3 or Higher Laboratory Toxicities | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Number of Participants With Grade 3 or Higher Laboratory Toxicities | 0 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events
An adverse event is defined as any untoward medical occurrence in a clinical trial participant, including worsening of a preexisting medical condition. The event does not necessarily have a causal relationship with study treatment. A serious adverse event is defined as an adverse event that met at least 1 of the following serious criteria: * fatal * life threatening * required in patient hospitalization or prolongation of existing hospitalization * resulted in persistent or significant disability/incapacity * congenital anomaly/birth defect * other medically important serious event. Adverse events were graded for severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Time frame: 35 days
Population: All randomized participants who received at least one dose of study treatment (omecamtiv mecarbil or placebo).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A: Omecamtiv Mecarbil 25 mg | Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event | 6 Participants |
| Group A: Omecamtiv Mecarbil 25 mg | Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group A: Omecamtiv Mecarbil 25 mg | Number of Participants With Treatment-emergent Adverse Events | Fatal adverse events | 0 Participants |
| Group A: Omecamtiv Mecarbil 25 mg | Number of Participants With Treatment-emergent Adverse Events | Life-threatening adverse events | 0 Participants |
| Group A: Omecamtiv Mecarbil 25 mg | Number of Participants With Treatment-emergent Adverse Events | Severe adverse events | 0 Participants |
| Group A: Omecamtiv Mecarbil 25 mg | Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of study drug | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg | Number of Participants With Treatment-emergent Adverse Events | Fatal adverse events | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg | Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event | 4 Participants |
| Group B: Omecamtiv Mecarbil 25 mg | Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg | Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of study drug | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg | Number of Participants With Treatment-emergent Adverse Events | Severe adverse events | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg | Number of Participants With Treatment-emergent Adverse Events | Life-threatening adverse events | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of study drug | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Number of Participants With Treatment-emergent Adverse Events | Life-threatening adverse events | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Number of Participants With Treatment-emergent Adverse Events | Severe adverse events | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Number of Participants With Treatment-emergent Adverse Events | Fatal adverse events | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 25 mg | Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event | 7 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of study drug | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Number of Participants With Treatment-emergent Adverse Events | Fatal adverse events | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event | 4 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Number of Participants With Treatment-emergent Adverse Events | Severe adverse events | 1 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Number of Participants With Treatment-emergent Adverse Events | Life-threatening adverse events | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Number of Participants With Treatment-emergent Adverse Events | TEAE leading to discontinuation of study drug | 1 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Number of Participants With Treatment-emergent Adverse Events | Fatal adverse events | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Number of Participants With Treatment-emergent Adverse Events | Life-threatening adverse events | 0 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event | 3 Participants |
| Group B: Omecamtiv Mecarbil 25 mg / 50 mg | Number of Participants With Treatment-emergent Adverse Events | Severe adverse events | 1 Participants |