A Study of CK-1827452 Infusion in Stable Heart Failure

A Phase II, Multi Center, Double-Blind, Randomized, Placebo Controlled, Dose-Escalation, Pharmacokinetic (PK) and Pharmacodynamic (PD) Study of CK-1827452 in Patients With Stable Heart Failure

This study will assess the safety, tolerability, and pharmacodynamics of CK-1827452 infusion in patients with stable heart failure.

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: CK-1827452; Drug: CK-1827452; Drug: CK-1827452; Drug: CK-1827452; Drug: CK-1827452; Drug: CK-1827452; Drug: CK-1827452; Drug: CK-1827452; Drug: Placebo; Drug: Placebo; Drug: CK-1827452; Drug: Placebo; Drug: CK-1827452; Drug: CK-1827452; Drug: CK-1827452; Drug: CK-1827452

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• Georgia
  • Tbilisi, Georgia
    • Diagnostic Services Clinic
• Russian Federation
  • Moscow, Russian Federation, 121552
    • Russian Cardiological Research and Production Complex
  • St. Petersburg, Russian Federation, 192242
    • Dzhanelidze Research Institute for Emergency Medical Care
  • St. Petersburg, Russian Federation, 194156
    • Almazov Federal Heart, Blood and Endocrinology Center
  • St. Petersburg, Russian Federation, 197089
    • St. Petersburg State Medical University
• United Kingdom
  • England
    • Hull, England, United Kingdom, HU16 5JQ
      • Castle Hill Hospital, University of Hull
    • London, England, United Kingdom, SE5 9RS
      • King's College Hospital
    • London, England, United Kingdom, SW17 ORE
      • St. George's Hospital
    • London, England, United Kingdom, W2 1LA
      • St. Mary's Hospital & Imperial College
    • Manchester, England, United Kingdom, M23 9LT
      • Wythenshawe Hospital
    • Manchester, England, United Kingdom, M13 9WL
      • Manchester Heart Centre, Manchester Royal Infirmary
    • Manchester, England, United Kingdom, M15 6SH
      • ICON Development Solutions
    • Middlesex, England, United Kingdom, HA1 3UJ
      • Northwick Park Hospital
  • Scotland
    • Dundee, Scotland, United Kingdom, DD1 9SY
      • Ninewells Hospital and Medical School
    • Glasgow, Scotland, United Kingdom, G12 8TA
      • BHF Cardiovascular Centre
• United States
  • California
    • San Diego, California, United States, 92103
      • University of California, San Diego Medical Center
  • Delaware
    • Newark, Delaware, United States, 19713
      • Christiana Care Health Services, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

1. Patient is male, or female of non-childbearing potential (two years post-menopausal or surgically sterilized)
2. Female patients must have a negative urine pregnancy test prior to entry into the study
3. Patient is 18 years old or greater
4. Patient has given signed informed consent

5. Patient is considered to be in suitable health in the opinion of the investigator, as determined by:

   • A pre-study physical examination with no clinical abnormalities which in the opinion of the investigator would preclude participation in the study other than physical symptoms or signs consistent with stable heart failure
   • An electrocardiogram (ECG) with no abnormalities in the opinion of the investigator that would impair assessment of stopping criteria
6. Patient has pre-study clinical laboratory findings that are within normal range, or if outside of the normal range, should not preclude participation in the study in the opinion of the investigator (see Exclusion Criteria, below, for exceptions)
7. Patient has a documented diagnosis of heart failure with an ejection fraction of less than 40%
8. Patient has been on a stable dose of a beta blocker and an ACE (angiotensin-converting enzyme) inhibitor or an ARB (angiotensin II receptor blocker) for at least 4 weeks. If prescribed, diuretics must have been administered according to a consistent regimen for at least 4 weeks
9. Patient is currently in sinus rhythm
10. Patient has interpretable echocardiographic images on a screening echocardiogram

Exclusion Criteria

1. Patient has been hospitalized for heart failure, myocardial infarction, coronary revascularization, or another cardiac indication within the last 6 weeks
2. Patient has a current history of alcohol use which in the opinion of the investigator would preclude participation in the study
3. Patient has a current history of drug abuse
4. Patient has donated blood or blood products within 30 days prior to screening
5. Patient has Canadian Cardiovascular Society (CCS) Class III or IV angina
6. Patient has significant obstructive valvular disease or significant congenital heart disease
7. Patient has had a valve replacement
8. Patient is pacemaker dependent
9. Patient is on chronic anti-arrhythmic therapy, with the exception of amiodarone
10. Patient is currently taking, or has taken in the last 7 days, a CYP3A4 inhibitor or inducer medication
11. Patient has a history of hypertrophic obstructive cardiomyopathy
12. Patient weighs > 120 kg
13. Patient has a supine resting systolic blood pressure < 95 mmHg after 3 minutes rest
14. Patient has a supine resting heart rate ≥ 100 beats per minute after 3 minutes rest
15. Patient has an Modification of Diet in Renal Disease (MDRD) estimate of Glomerular Filtration Rate (GFR) ≤ 35 ml/min/1.73 m2
16. Patient has a potassium < 3.5 mEq/L or > 5.5 mEq/L
17. Patient has a sodium ≤ 133 mEq/L
18. Patient has a urea > 15 mmole/L
19. Patient has a troponin I or T at screening that is detectable at the investigative site's clinical laboratory
20. Patient has a hemoglobin < 11 gm/dL in males or < 10 gm/dL in females
21. Patient has an alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALKP) or total bilirubin (TBILI) > 3 times the upper limit of normal
22. Patient is, in the opinion of the investigator, not suitable to participate in the study
23. Patient has participated in any clinical study with an investigational drug within three months prior to the first day of dosing with the exception of coronary stent studies Patient has ever received CK-1827452

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; 4 treatment periods with a 2 hour infusion. The 4 treatment periods consist of 3 escalating dose levels of CK-1827452 and 1 placebo treatment randomized into the dose escalation sequence. Treatment periods occur at least 7 days apart.	Drug: CK-1827452; IV infusion for 1 hour at 0.125 mg/kg/h followed by 1 hour at 0.0625 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.25 mg/kg/h followed by 1 hour at 0.125 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.5 mg/kg/h followed by 1 hour at 0.25 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.75 mg/kg/h followed by 1 hour at 0.375 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed by 1 hour at 0.5 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.25 mg/kg/h followed by 1 hour at 0.125 mg/kg/h followed by 22 hours at 0.025 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.5 mg/kg/h followed by 1 hour at 0.25 mg/kg/h followed by 22 hours at 0.05 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed by 1 hour at 0.5 mg/kg/h followed by 22 hours at 0.1 mg/kg/h; Drug: Placebo; IV infusion for 2 hours; Drug: Placebo; IV infusion for 24 hours; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed 1 hour at 0.5 mg/kg/h followed by 70 hours at 0.1 mg/kg/h; Drug: Placebo; IV infusion for 72 hours; Drug: CK-1827452; IV infusion for 1 hour at 0.75 mg/kg/h followed 1 hour at 0.5 mg/kg/h followed by 70 hours at 0.1 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.25 mg/kg/h followed by 23 hours at 0.025 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.5 mg/kg/h followed by 23 hours at 0.05 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed by 23 hours at 0.1 mg/kg/h
Experimental: Cohort 2; 4 treatment periods with a 2 hour infusion. The 4 treatment periods consist of 3 escalating dose levels of CK-1827452 and 1 placebo treatment randomized into the dose escalation sequence. Treatment periods occur at least 7 days apart.	Drug: CK-1827452; IV infusion for 1 hour at 0.125 mg/kg/h followed by 1 hour at 0.0625 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.25 mg/kg/h followed by 1 hour at 0.125 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.5 mg/kg/h followed by 1 hour at 0.25 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.75 mg/kg/h followed by 1 hour at 0.375 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed by 1 hour at 0.5 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.25 mg/kg/h followed by 1 hour at 0.125 mg/kg/h followed by 22 hours at 0.025 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.5 mg/kg/h followed by 1 hour at 0.25 mg/kg/h followed by 22 hours at 0.05 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed by 1 hour at 0.5 mg/kg/h followed by 22 hours at 0.1 mg/kg/h; Drug: Placebo; IV infusion for 2 hours; Drug: Placebo; IV infusion for 24 hours; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed 1 hour at 0.5 mg/kg/h followed by 70 hours at 0.1 mg/kg/h; Drug: Placebo; IV infusion for 72 hours; Drug: CK-1827452; IV infusion for 1 hour at 0.75 mg/kg/h followed 1 hour at 0.5 mg/kg/h followed by 70 hours at 0.1 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.25 mg/kg/h followed by 23 hours at 0.025 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.5 mg/kg/h followed by 23 hours at 0.05 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed by 23 hours at 0.1 mg/kg/h
Experimental: Cohort 3; 4 treatment periods with a 24 hour infusion. The 4 treatment periods consist of 3 escalating dose levels of CK-1827452 and 1 placebo treatment randomized into the dose escalation sequence. Treatment periods occur at least 7 days apart.	Drug: CK-1827452; IV infusion for 1 hour at 0.125 mg/kg/h followed by 1 hour at 0.0625 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.25 mg/kg/h followed by 1 hour at 0.125 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.5 mg/kg/h followed by 1 hour at 0.25 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.75 mg/kg/h followed by 1 hour at 0.375 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed by 1 hour at 0.5 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.25 mg/kg/h followed by 1 hour at 0.125 mg/kg/h followed by 22 hours at 0.025 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.5 mg/kg/h followed by 1 hour at 0.25 mg/kg/h followed by 22 hours at 0.05 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed by 1 hour at 0.5 mg/kg/h followed by 22 hours at 0.1 mg/kg/h; Drug: Placebo; IV infusion for 2 hours; Drug: Placebo; IV infusion for 24 hours; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed 1 hour at 0.5 mg/kg/h followed by 70 hours at 0.1 mg/kg/h; Drug: Placebo; IV infusion for 72 hours; Drug: CK-1827452; IV infusion for 1 hour at 0.75 mg/kg/h followed 1 hour at 0.5 mg/kg/h followed by 70 hours at 0.1 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.25 mg/kg/h followed by 23 hours at 0.025 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.5 mg/kg/h followed by 23 hours at 0.05 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed by 23 hours at 0.1 mg/kg/h
Experimental: Cohort 4; 4 treatment periods with a 24 hour infusion. The 4 treatment periods consist of 3 escalating dose levels of CK-1827452 and 1 placebo treatment randomized into the dose escalation sequence. Treatment periods occur at least 7 days apart.	Drug: CK-1827452; IV infusion for 1 hour at 0.125 mg/kg/h followed by 1 hour at 0.0625 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.25 mg/kg/h followed by 1 hour at 0.125 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.5 mg/kg/h followed by 1 hour at 0.25 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.75 mg/kg/h followed by 1 hour at 0.375 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed by 1 hour at 0.5 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.25 mg/kg/h followed by 1 hour at 0.125 mg/kg/h followed by 22 hours at 0.025 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.5 mg/kg/h followed by 1 hour at 0.25 mg/kg/h followed by 22 hours at 0.05 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed by 1 hour at 0.5 mg/kg/h followed by 22 hours at 0.1 mg/kg/h; Drug: Placebo; IV infusion for 2 hours; Drug: Placebo; IV infusion for 24 hours; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed 1 hour at 0.5 mg/kg/h followed by 70 hours at 0.1 mg/kg/h; Drug: Placebo; IV infusion for 72 hours; Drug: CK-1827452; IV infusion for 1 hour at 0.75 mg/kg/h followed 1 hour at 0.5 mg/kg/h followed by 70 hours at 0.1 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.25 mg/kg/h followed by 23 hours at 0.025 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.5 mg/kg/h followed by 23 hours at 0.05 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed by 23 hours at 0.1 mg/kg/h
Experimental: Cohort 5; 2 treatment periods with a 72 hour infusion. The 2 treatment periods are randomly assigned and consist of 1 dose level of CK-1827452 (with dose de-escalation possible depending on tolerability) and 1 placebo treatment. Treatment period 2 occurs at least 7 days after the conclusion of period 1.	Drug: CK-1827452; IV infusion for 1 hour at 0.125 mg/kg/h followed by 1 hour at 0.0625 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.25 mg/kg/h followed by 1 hour at 0.125 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.5 mg/kg/h followed by 1 hour at 0.25 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.75 mg/kg/h followed by 1 hour at 0.375 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed by 1 hour at 0.5 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.25 mg/kg/h followed by 1 hour at 0.125 mg/kg/h followed by 22 hours at 0.025 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.5 mg/kg/h followed by 1 hour at 0.25 mg/kg/h followed by 22 hours at 0.05 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed by 1 hour at 0.5 mg/kg/h followed by 22 hours at 0.1 mg/kg/h; Drug: Placebo; IV infusion for 2 hours; Drug: Placebo; IV infusion for 24 hours; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed 1 hour at 0.5 mg/kg/h followed by 70 hours at 0.1 mg/kg/h; Drug: Placebo; IV infusion for 72 hours; Drug: CK-1827452; IV infusion for 1 hour at 0.75 mg/kg/h followed 1 hour at 0.5 mg/kg/h followed by 70 hours at 0.1 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.25 mg/kg/h followed by 23 hours at 0.025 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 0.5 mg/kg/h followed by 23 hours at 0.05 mg/kg/h; Drug: CK-1827452; IV infusion for 1 hour at 1.0 mg/kg/h followed by 23 hours at 0.1 mg/kg/h

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline of Systolic Ejection Time at Various CK-1827452 Plasma Concentrations	Pooled analysis of the echocardiographic measure systolic ejection time from echocardiograms taken at all timepoints. 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 and 5 (564 echocardiograms) were binned into either placebo group or 1 of 6 groups based on plasma concentration of CK-1827452.	4 days
Change From Baseline of Fractional Shortening at Various CK-1827452 Plasma Concentrations	Pooled analysis of the echocardiographic measure fractional shortening from echocardiograms taken at all timepoints. Fractional shortening is the percentage of change from baseline in the left ventricular cavity dimension with systole. Echocardiograms from cohorts 1,2,3,4 and 5 (564 echocardiograms) were binned into either placebo group or 1 of 6 groups based on plasma concentration of CK-1827452.	4 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CK-1827452 Maximum Observed Plasma Concentration (Cmax)	Determined by evaluation of plasma concentrations from blood samples collected prior to dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 12, 24 and 48 hours after initiation of study drug infusion	2 days
CK-1827452 Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUClast)	Determined by evaluation of plasma concentrations from blood samples collected prior to dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 12, 24 and 48 hours after initiation of study drug infusion	2 days

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.
• Cleland JG, Teerlink JR, Senior R, Nifontov EM, Mc Murray JJ, Lang CC, Tsyrlin VA, Greenberg BH, Mayet J, Francis DP, Shaburishvili T, Monaghan M, Saltzberg M, Neyses L, Wasserman SM, Lee JH, Saikali KG, Clarke CP, Goldman JH, Wolff AA, Malik FI. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet. 2011 Aug 20;378(9792):676-83. doi: 10.1016/S0140-6736(11)61126-4.

Study record dates

Study Major Dates

• Study Start: April 1, 2007
• Primary Completion (Actual): February 1, 2009
• Study Completion (Actual): February 1, 2009

Study Registration Dates

• First Submitted: December 21, 2007
• First Submitted That Met QC Criteria: February 19, 2008
• First Posted (Estimate): February 27, 2008

Study Record Updates

• Last Update Posted (Actual): May 14, 2021
• Last Update Submitted That Met QC Criteria: April 20, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: CY 1121