A Pharmacokinetic and Pharmacodynamic Study of Omecamtiv Mecarbil in Healthy Volunteers

Study Overview
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Brief Summary
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This study will assess the safety, tolerability, and pharmacodynamics of omecamtiv mecarbil infusion in healthy male volunteers.

Official Title
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A First-in-Man, Phase I, Double-Blind, Randomized, Four-Way Crossover, Placebo-Controlled, Dose-Escalation, Pharmacokinetic and Pharmacodynamic Study of CK-1827452 (Omecamtiv Mecarbil) in Healthy Volunteers

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: placebo
* Drug: omecamtiv mecarbil
* Drug: omecamtiv mecarbil
* Drug: omecamtiv mecarbil
* Drug: omecamtiv mecarbil
* Drug: omecamtiv mecarbil
* Drug: omecamtiv mecarbil
* Drug: omecamtiv mecarbil
* Drug: omecamtiv mecarbil
* Drug: omecamtiv mecarbil
* Drug: omecamtiv mecarbil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is male Subject is aged between 18 and 50 years inclusive. Subject has given signed informed consent. Subject's Body Mass Index (BMI) is between 18 and 30 kg/m2 inclusive. Subject weighs less than 100 kg. Subject is considered to be in good health in the opinion of the investigator, as determined by: A pre-study physical examination with no clinically significant abnormalities. Vital signs within normal ranges (supine after 3 minutes rest - heart rate: 40 to 80 bpm; systolic BP: 100 to 140 mmHg; diastolic BP: 50-90 mmHg; respiration rate: 8 to 18 breaths per minute; oxygen saturation: 96-100%) An ECG with no clinically significant abnormalities. Subject's pre-study clinical laboratory findings are within normal range or if outside of the normal range not deemed clinically significant in the opinion of the investigator. Cardiac troponin I is less than the upper limit of the laboratory reference range. A screening echocardiogram demonstrates normal cardiac function, an ejection fraction of between 40% and 70% with no significant valvular regurgitation (grade 1) and/or stenosis and images are deemed to be of good quality by the sonographer. Exclusion Criteria: Subject has had a clinically significant illness in the four weeks before screening. Use of prescribed mediations in the 3 weeks prior to dosing or over-the-counter preparations (including vitamin supplements and herbal remedies) for 7 days prior to dosing, except paracetamol which will be allowed up to 48 hours prior to dosing. Subject has a significant history of drug/solvent abuse or a positive drugs of abuse test at screening. Subject with a history of alcohol abuse or currently drinks in excess of 28 units per week. Subject smokes more than 5 cigarettes (or equivalent) per day. Subject is not willing to refrain from caffeine/xanthine containing products from 48 hours prior to the screening medical and admission on Day -1 until the post study medical. Subject is in the opinion of the investigator not suitable to participate in the study. Subject who has participated in any clinical study with an investigational drug/device within three months prior to the first day of dosing. Subject who has a positive result of HIV screen, Hepatitis B screen or Hepatitis C screen. Subject has had a serious adverse reaction or significant hypersensitivity to any drug. Subject has donated 500 ml or more of blood within the month prior to screening. Subject has a history of cardiovascular disease or family history of premature cardiovascular disease or death.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose-escalation Cohort 1<br>4 treatment periods consisting of a 2 hour placebo infusion (single blind) followed by a 6 hour infusion of study drug or placebo. Each subject will receive 3 active ascending doses of study drug and 1 dose of placebo randomized into the sequence of escalating doses in a double-blind manner. Treatment periods occur at least 7 days apart. | Drug: placebo<br>* I.V. infusion of placebo for 8 hr<br>Drug: omecamtiv mecarbil<br>* I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.005 mg/kg/hr<br>* Other names: CK-1827452, AMG 423;Drug: omecamtiv mecarbil<br>* I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.015 mg/kg/hr<br>* Other names: CK-1827452, AMG 423;Drug: omecamtiv mecarbil<br>* I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.025 mg/kg/hr<br>* Other names: CK-1827452, AMG 423;|
| Experimental: Dose-escalation Cohort 2<br>4 treatment periods consisting of a 2 hour placebo infusion (single blind) followed by a 6 hour infusion of study drug or placebo. Each subject will receive 3 active ascending doses of study drug and 1 dose of placebo randomized into the sequence of escalating doses in a double-blind manner. Treatment periods occur at least 7 days apart. | Drug: placebo<br>* I.V. infusion of placebo for 8 hr<br>Drug: omecamtiv mecarbil<br>* I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.025 mg/kg/hr<br>* Other names: CK-1827452, AMG 423;Drug: omecamtiv mecarbil<br>* I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.0625 mg/kg/hr<br>* Other names: CK-1827452, AMG 423;Drug: omecamtiv mecarbil<br>* I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.125 mg/kg/hr<br>* Other names: CK-1827452, AMG 423;|
| Experimental: Dose-escalation Cohort 3<br>4 treatment periods consisting of a 2 hour placebo infusion (single blind) followed by a 6 hour infusion of study drug or placebo. Each subject will receive 3 active ascending doses of study drug and 1 dose of placebo randomized into the sequence of escalating doses in a double-blind manner. Treatment periods occur at least 7 days apart. | Drug: placebo<br>* I.V. infusion of placebo for 8 hr<br>Drug: omecamtiv mecarbil<br>* I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.125 mg/kg/hr<br>* Other names: CK-1827452, AMG 423;Drug: omecamtiv mecarbil<br>* I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.25 mg/kg/hr<br>* Other names: CK-1827452, AMG 423;Drug: omecamtiv mecarbil<br>* I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.5 mg/kg/hr<br>* Other names: CK-1827452, AMG 423;|
| Experimental: Dose-escalation Cohort 4<br>4 treatment periods consisting of a 2 hour placebo infusion (single blind) followed by a 6 hour infusion of study drug or placebo. Each subject will receive 3 active ascending doses of study drug and 1 dose of placebo randomized into the sequence of escalating doses in a double-blind manner. Treatment periods occur at least 7 days apart. | Drug: placebo<br>* I.V. infusion of placebo for 8 hr<br>Drug: omecamtiv mecarbil<br>* I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.5 mg/kg/hr<br>* Other names: CK-1827452, AMG 423;Drug: omecamtiv mecarbil<br>* I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 1.0 mg/kg/hr<br>* Other names: CK-1827452, AMG 423;Drug: omecamtiv mecarbil<br>* I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.75 mg/kg/hr (dose reduced)<br>* Other names: CK-1827452, AMG 423;Drug: omecamtiv mecarbil<br>* I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.625 mg/kg/hr (dose reduced)<br>* Other names: CK-1827452, AMG 423;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Omecamtiv Mecarbil in Healthy Volunteers | The highest infusion rate tolerated by at least eight subjects. A dose was intolerable if: 1) the pattern of intolerance clearly distinguished active drug from placebo, or 2) the number of subjects intolerant of the dose level in question was at least 3 more than the number of subjects intolerant of placebo. | 2 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline of Systolic Ejection Time at Various Omecamtiv Mecarbil Infusion Rates | Pooled analysis of the echocardiographic measure systolic ejection time. The systolic ejection time is the period during which the aortic valve is open and blood is flowing across the valve. Echocardiograms from cohorts 1,2,3,4 were binned into either placebo group or groups based on infusion rate of omecamtiv mecarbil. | 1 day | 
| Change From Baseline of Fractional Shortening at Various Omecamtiv Mecarbil Infusion Rates | Pooled analysis of the echocardiographic measure fractional shortening. Fractional shortening is the percentage of change from baseline in the left ventricular cavity dimension with systole. Echocardiograms from cohorts 1,2,3,4 were binned into either placebo group or groups based on infusion rate of omecamtiv mecarbil. | 1 day |