A Pharmacokinetic and Pharmacodynamic Study of Omecamtiv Mecarbil in Healthy Volunteers

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

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

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: 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

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • England
    • Manchester, England, United Kingdom, United Kingdom
      • ICON Development Solutions

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Subject is male
2. Subject is aged between 18 and 50 years inclusive.
3. Subject has given signed informed consent.
4. Subject's Body Mass Index (BMI) is between 18 and 30 kg/m2 inclusive.
5. Subject weighs less than 100 kg.

6. Subject is considered to be in good health in the opinion of the investigator, as determined by:

   1. A pre-study physical examination with no clinically significant abnormalities.
   2. 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%)
   3. An ECG with no clinically significant abnormalities.
7. 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.
8. Cardiac troponin I is less than the upper limit of the laboratory reference range.
9. 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:

1. Subject has had a clinically significant illness in the four weeks before screening.
2. 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.
3. Subject has a significant history of drug/solvent abuse or a positive drugs of abuse test at screening.
4. Subject with a history of alcohol abuse or currently drinks in excess of 28 units per week.
5. Subject smokes more than 5 cigarettes (or equivalent) per day.
6. 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.
7. Subject is in the opinion of the investigator not suitable to participate in the study.
8. Subject who has participated in any clinical study with an investigational drug/device within three months prior to the first day of dosing.
9. Subject who has a positive result of HIV screen, Hepatitis B screen or Hepatitis C screen.
10. Subject has had a serious adverse reaction or significant hypersensitivity to any drug.
11. Subject has donated 500 ml or more of blood within the month prior to screening.
12. Subject has a history of cardiovascular disease or family history of premature cardiovascular disease or death.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose-escalation Cohort 1; 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; I.V. infusion of placebo for 8 hr; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.005 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.015 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.025 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.0625 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.125 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.25 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.5 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 1.0 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.75 mg/kg/hr (dose reduced); Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.625 mg/kg/hr (dose reduced); Other Names: CK-1827452, AMG 423
Experimental: Dose-escalation Cohort 2; 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; I.V. infusion of placebo for 8 hr; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.005 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.015 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.025 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.0625 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.125 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.25 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.5 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 1.0 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.75 mg/kg/hr (dose reduced); Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.625 mg/kg/hr (dose reduced); Other Names: CK-1827452, AMG 423
Experimental: Dose-escalation Cohort 3; 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; I.V. infusion of placebo for 8 hr; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.005 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.015 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.025 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.0625 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.125 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.25 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.5 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 1.0 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.75 mg/kg/hr (dose reduced); Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.625 mg/kg/hr (dose reduced); Other Names: CK-1827452, AMG 423
Experimental: Dose-escalation Cohort 4; 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; I.V. infusion of placebo for 8 hr; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.005 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.015 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.025 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.0625 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.125 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.25 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.5 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 1.0 mg/kg/hr; Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.75 mg/kg/hr (dose reduced); Other Names: CK-1827452, AMG 423; Drug: omecamtiv mecarbil; I.V. infusion of placebo for 2 hr followed by 6 hr infusion of omecamtiv mecarbil at 0.625 mg/kg/hr (dose reduced); Other Names: CK-1827452, AMG 423

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Cytokinetics

Publications and helpful links

General Publications

• Vu T, Ma P, Xiao JJ, Wang YM, Malik FI, Chow AT. Population pharmacokinetic-pharmacodynamic modeling of omecamtiv mecarbil, a cardiac myosin activator, in healthy volunteers and patients with stable heart failure. J Clin Pharmacol. 2015 Nov;55(11):1236-47. doi: 10.1002/jcph.538. Epub 2015 Jul 14.
• Teerlink JR, Clarke CP, Saikali KG, Lee JH, Chen MM, Escandon RD, Elliott L, Bee R, Habibzadeh MR, Goldman JH, Schiller NB, Malik FI, Wolff AA. Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study. Lancet. 2011 Aug 20;378(9792):667-75. doi: 10.1016/S0140-6736(11)61219-1.

Study record dates

Study Major Dates

• Study Start: August 1, 2005
• Primary Completion (Actual): April 1, 2006
• Study Completion (Actual): April 1, 2006

Study Registration Dates

• First Submitted: June 22, 2011
• First Submitted That Met QC Criteria: June 22, 2011
• First Posted (Estimate): June 27, 2011

Study Record Updates

• Last Update Posted (Estimate): October 14, 2015
• Last Update Submitted That Met QC Criteria: October 9, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: CY 1111; 2005-001886-32 (EudraCT Number)