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The purpose of this study is to evaluate the pharmacokinetics (PK), safety, and tolerability of omecamtiv mecarbil in healthy volunteers in Japan.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | 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). |
|
| Omecamtiv mecarbil 25 mg / 37.5 mg | Experimental | 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 or a day 8 PK value was not available participants continued to receive 25 mg BID. |
|
| Omecamtiv mecarbil 25 mg / 50 mg | Experimental | 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 or a day 8 PK value was not available participants continued to receive 25 mg BID. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Omecamtiv mecarbil | Drug | Omecamtiv mecarbil tablets for oral administration |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 | Accumulation ratio calculated as the ratio of day 8 AUC(0-12) / day 1 AUC(0-12) | 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 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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:
|
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| MD | Amgen | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | Kagoshima | Kagoshima-ken | 890-0081 | Japan |
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| Label | URL |
|---|---|
| AmgenTrials clinical trials website | View source |
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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.
This study was conducted at a single center in Japan. Participants were enrolled from 13 November 2015 to 24 November 2015.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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). |
| FG001 | Period 1 Group A: Omecamtiv Mecarbil 25 mg | Participants received omecamtiv mecarbil (OM) 25 mg BID in dosing period 1 (days 1 to 8). |
| FG002 | Period 1 Group B: Omecamtiv Mecarbil 25 mg | Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8). |
| FG003 | Period 2 Group A: Omecamtiv Mecarbil 25 mg | Participants who received omecamtiv mecarbil 25 mg BID in dosing period 1 then received omecamtiv mecarbil 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 predose omecamtiv mecarbil plasma concentration (Cpredose). |
| FG004 | Period 2 Group A: Omecamtiv Mecarbil 37.5 mg | Participants who received omecamtiv mecarbil 25 mg BID in dosing period 1 then received omecamtiv mecarbil 37.5 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose. |
| FG005 | Period 2 Group B: Omecamtiv Mecarbil 25 mg | Participants who received omecamtiv mecarbil 25 mg BID in dosing period 1 then received omecamtiv mecarbil 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose. |
| FG006 | Period 2 Group B: Omecamtiv Mecarbil 50 mg | Participants who received omecamtiv mecarbil 25 mg BID in dosing period 1 then received omecamtiv mecarbil 50 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Dosing Period 1 |
| |||||||||||||
| Dosing Period 2 |
|
All randomized participants
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| ID | Title | Description |
|---|---|---|
| BG000 | 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). |
| BG001 | Group A: Omecamtiv Mecarbil 25 mg / 37.5 mg |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Dosing Period 1: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 1 | 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. | Posted | Mean | Standard Deviation | ng/mL | 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. |
|
Period 1: Day 1 to day 19 Period 2: Day 20 to day 35
Serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Period 1: Placebo | Participants received placebo tablets twice a day (BID) in dosing period 1 (days 1 to 8). |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Ventricular tachycardia | Cardiac disorders | MedDRA 18.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Amgen Inc. | 866-572-6436 | medinfo@amgen.com |
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| ID | Term |
|---|---|
| D006333 | Heart Failure |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| C547293 | omecamtiv mecarbil |
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| Placebo | Drug | Matching placebo tablets |
|
| 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 2: Accumulation Ratio | Accumulation ratio calculated as the ratio of day 27 AUC(0-12) / day 20 AUC(0-12). | 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. |
| 35 days |
| 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:
| 35 days |
| 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 | Day 1 predose and day 8 |
| 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 | Day 20 predose and Day 27 |
| COMPLETED | Completed dosing in period 2 |
|
| NOT COMPLETED |
|
|
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.
| BG002 | 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. |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8).
|
|
| Primary | Dosing Period 1: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 1 | PK analysis set | Posted | Median | Full Range | hours | 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. |
|
|
|
| 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 | The PK analysis set with available AUC data at each time point | Posted | Mean | Standard Deviation | ng*hr/mL | 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. |
|
|
|
| Primary | Dosing Period 1: Predose Omecamtiv Mecarbil Plasma Concentration | PK analysis set | Posted | Mean | Standard Deviation | ng/mL | Day 8 predose |
|
|
|
| Primary | Dosing Period 1: Accumulation Ratio | Accumulation ratio calculated as the ratio of day 8 AUC(0-12) / day 1 AUC(0-12) | The PK analysis set with available AUC data at both time points | Posted | Mean | Standard Deviation | 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. |
|
|
|
| Primary | Dosing Period 2: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | Pharmacokinetic analysis set with available data at each time point | Posted | Mean | Standard Deviation | ng/mL | 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. |
|
|
|
| Primary | Dosing Period 2: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 | Pharmacokinetic analysis set with available data at each time point | Posted | Median | Full Range | hours | 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. |
|
|
|
| Primary | Dosing Period 2: AUC(0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 2 | Pharmacokinetic analysis set with available AUC data at each time point | Posted | Mean | Standard Deviation | ng*hr/mL | 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. |
|
|
|
| Primary | Dosing Period 2: Predose Omecamtiv Mecarbil Plasma Concentration | PK analysis set | Posted | Mean | Standard Deviation | ng/mL | Day 27 predose |
|
|
|
| Primary | Dosing Period 2: Accumulation Ratio | Accumulation ratio calculated as the ratio of day 27 AUC(0-12) / day 20 AUC(0-12). | Pharmacokinetic analysis set with available AUC data at both time points | Posted | Mean | Standard Deviation | 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. |
|
|
|
| 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:
| All randomized participants who received at least one dose of study treatment (omecamtiv mecarbil or placebo). | Posted | Count of Participants | Participants | 35 days |
|
|
|
| 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:
| All randomized participants who received at least one dose of study treatment (omecamtiv mecarbil or placebo). | Posted | Count of Participants | Participants | 35 days |
|
|
|
| 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 | All randomized participants who received at least one dose of study treatment (omecamtiv mecarbil or placebo). | Posted | Count of Participants | Participants | Day 1 predose and day 8 |
|
|
|
| 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 | Randomized participants who received at least one dose of study treatment (omecamtiv mecarbil or placebo), with available data. | Posted | Count of Participants | Participants | Day 20 predose and Day 27 |
|
|
|
| 0 |
| 10 |
| 2 |
| 10 |
| EG001 | Period 1 Group A: OM 25 mg BID | Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8). | 0 | 20 | 5 | 20 |
| EG002 | Period 1 Group B: OM 25 mg BID | Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8). | 0 | 20 | 3 | 20 |
| EG003 | Period 2: Placebo | Participants received placebo tablets BID in dosing period 2 (days 20 to 27). | 0 | 10 | 4 | 10 |
| EG004 | Period 2 Group A: OM 25 mg BID | Participants received omecamtiv mecarbil 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose. | 0 | 7 | 3 | 7 |
| EG005 | Period 2 Group A: OM 37.5 mg BID | Participants received omecamtiv mecarbil 37.5 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose. | 0 | 13 | 3 | 13 |
| EG006 | Period 2 Group B: OM 25 mg BID | Participants received omecamtiv mecarbil 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose. | 0 | 7 | 1 | 7 |
| EG007 | Period 2 Group B: OM 50 mg BID | Participants received omecamtiv mecarbil 50 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose. | 0 | 13 | 3 | 13 |
| Nausea | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Chest pain | General disorders | MedDRA 18.1 | Systematic Assessment |
|
| Injection site nerve damage | General disorders | MedDRA 18.1 | Systematic Assessment |
|
| Chronic tonsillitis | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
|
| Herpes zoster | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
|
| Pharyngitis | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA 18.1 | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA 18.1 | Systematic Assessment |
|
| Blood bilirubin increased | Investigations | MedDRA 18.1 | Systematic Assessment |
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| Protein urine present | Investigations | MedDRA 18.1 | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 18.1 | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 18.1 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 18.1 | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Upper respiratory tract inflammation | Respiratory, thoracic and mediastinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Dermatitis contact | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Systematic Assessment |
|
| Orthostatic hypotension | Vascular disorders | MedDRA 18.1 | Systematic Assessment |
|
The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
| After last dose on day 8 |
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| After last dose on day 27 |
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| After last dose on day 27 |
|
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| After last dose on day 27 |
|
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| Serious adverse events |
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| TEAE leading to discontinuation of study drug |
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| Severe adverse events |
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| Life-threatening adverse events |
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| Fatal adverse events |
|
| > 30 to 60 ms |
|
| > 60 ms |
|
| > 30 to 60 ms |
|
| > 60 ms |
|