A Single and Multiple Ascending Dose Study of CK-3773274 in Healthy Adult Subjects

A Phase 1, Double-Blind, Randomized, Placebo-Controlled, Multi-Part, Single and Multiple Ascending Dose Study of CK-3773274 in Healthy Adult Subjects

The purposes of this study are to:

1. Learn about the safety of CK-3773274 after a single dose and multiple doses in healthy subjects.
2. Learn how healthy subjects tolerate CK-3773274 after a single dose and multiple doses.
3. Find out how much CK-3773274 is in the blood after a single dose and multiple doses.
4. Determine the effect of doses of CK-3773274 on the pumping function of the heart.
5. Evaluate the effect of cytochrome genetic variants on how the body metabolizes CK-3773274.
6. Evaluate the effect of a meal on how much CK-3773274 is in the blood in healthy adult subjects.
7. Evaluate whether the amount of CK-3773274 in the blood is the similar for both the tablet and granules in capsule forms of the drug.

Study Overview

• Status: Completed
• Conditions: Healthy Subjects; Symptomatic Obstructive Hypertrophic Cardiomyopathy
• Intervention / Treatment: Drug: CK-3773274 - Granules in Capsule; Drug: Placebo - Granules in Capsule; Drug: CK-3773274 - Tablets

• Study Type: Interventional
• Enrollment (Actual): 114
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tempe, Arizona, United States, 85283
      • Clinical Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males and females (of non-childbearing potential) between 18 and 55 years of age, inclusive
2. Body weight > 55.0 kg and body mass index within 18.0 to 32.0 kg/m2, inclusive
3. Normal cardiac structure and function, or if abnormalities are present, they are deemed not clinically significant
4. Normal to high left ventricular ejection fraction.
5. Normal electrocardiogram (ECG) or, if abnormalities are present, they are deemed not clinically significant
6. Clinical laboratory findings within normal range
7. Negative hepatitis panel (including hepatitis B surface antigen and hepatitis C antibody), and negative human immunodeficiency virus antibody screens
8. Willing and able to refrain from strenuous exercise (eg, activity which could be expected to cause muscle soreness)
9. For Arms 5 and 6 only: Subject is a CYP2D6 poor metabolizer

Exclusion Criteria:

1. History of any significant illness or disorder
2. History of stomach or intestinal surgery or resection (appendectomy, hernia repair, and/or cholecystectomy will be allowed)
3. A clinically significant illness within 4 weeks of Check-in
4. Inability to swallow capsules or tablets
5. History of or current substance abuse (drug or alcohol), known drug or alcohol dependence within the last 2 years prior to Screening, or positive test for drugs of abuse during the screening period
6. Use of any tobacco-containing or nicotine-containing products within 3 months prior to Check-in
7. Participation in any other investigational study drug trial in which receipt of an investigational study drug occurred within 30 days prior to Check-in
8. Any blood donation within 60 days of dosing, plasma donation within 30 days of dosing, or receipt of blood products within 2 months prior to Check-in

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CK-3773274 for SAD Cohorts; Subjects will be assigned to one of 8 planned dose cohorts and receive single doses of CK-3773274	Drug: CK-3773274 - Granules in Capsule; CK-3773274 formulated as granules in capsule
Placebo Comparator: Placebo for SAD Cohorts; Subjects will be assigned to one of 8 planned dose cohorts and receive single doses of placebo	Drug: Placebo - Granules in Capsule; Placebo formulated as granules in capsule
Experimental: CK-3773274 for MAD Cohorts; Subjects will be assigned to one of 3 planned dose cohorts and receive multiple doses of CK-3773274	Drug: CK-3773274 - Granules in Capsule; CK-3773274 formulated as granules in capsule
Placebo Comparator: Placebo for MAD Cohorts; Subjects will be assigned to one of 3 planned dose cohorts and receive multiple doses of placebo	Drug: Placebo - Granules in Capsule; Placebo formulated as granules in capsule
Experimental: CK-3773274 for CYP2D6 Cohort; Subjects with CYP2D6 poor metabolizer phenotype will be assigned to receive a single dose of CK-3773274	Drug: CK-3773274 - Granules in Capsule; CK-3773274 formulated as granules in capsule
Placebo Comparator: Placebo for CYP2D6 Cohort; Subjects with CYP2D6 poor metabolizer phenotype will be assigned to receive a single dose of placebo	Drug: Placebo - Granules in Capsule; Placebo formulated as granules in capsule
Experimental: Food Effect; Subjects will be administered CK-3773274 with and without food in a randomized cross-over fashion	Drug: CK-3773274 - Granules in Capsule; CK-3773274 formulated as granules in capsule
Experimental: Relative Bioavailability; Subjects will be administered CK-3773274 as granules in a capsule and as a tablet in a randomized cross-over fashion.	Drug: CK-3773274 - Granules in Capsule; CK-3773274 formulated as granules in capsule; Drug: CK-3773274 - Tablets; CK-3773274 formulated as tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse events and Safety Signals observed during single and multiple ascending doses of CK-3773274 administered orally to healthy adult subjects.	Subject incidence of AEs, SAEs, and reduced LVEF	SAD Cohorts: Day -1 - Day 10; CYP2D6 Cohort: Day -1 - Day - 24; MAD Cohorts: Day -1 - Day 27; Food Effect Cohort: Day -1 - Day 24; relative Bioavailability Cohort: Day -1 - Day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of CK-3773274 after single and multiple ascending doses	Maximum concentration after dosing (Cmax) following single and multiple doses of CK-3773274 administered to healthy subjects	SAD Cohorts: Day 1; CYP2D6 Cohort: Day 1; MAD Cohorts: Day 14 or Day 17; Food Effect Cohort: Day 15; Relative Bioavailability Cohort: Day 15
Change in absolute reduction in ejection fraction relative to baseline with doses of CK-3773274	Changes from baseline in LVEF as measured by echocardiography with doses of CK-3773274	Time Frame for SAD Cohorts: Day -1 - Day 10; Time Frame for CYP2D6 Cohort: Day -1 - Day 24; Time Frame for MAD Cohorts: Day -1 - Day 27
Assess the effect of CYP2D6 genetic variants on the PK of CK-3773274	Maximum concentration after dosing (Cmax) following a single dose administered to CYP2D6 poor metabolizers	Day -1 - Day 24
Assess the effect of a meal on how much CK-3773274 is in the blood in healthy subjects	Maximum concentration after dosing (Cmax) following single and multiple doses of CK-3773274 administered to healthy subjects in fed and fasted states	Day -1 - Day 24
Relative bioavailability of CK-3773274 formulated as granules in capsule versus a tablet in healthy adult subjects	PK parameters such as AUC calculated using plasma concentrations of CK-3773274	Time Frame for Bioavailability Cohort: Day -1 - Day 29

Collaborators and Investigators

• Sponsor: Cytokinetics
• Investigators: Study Director: Study Director MD, Cytokinetics

Publications and helpful links

General Publications

• Malik FI, Robertson LA, Armas DR, Robbie EP, Osmukhina A, Xu D, Li H, Solomon SD. A Phase 1 Dose-Escalation Study of the Cardiac Myosin Inhibitor Aficamten in Healthy Participants. JACC Basic Transl Sci. 2022 Aug 10;7(8):763-775. doi: 10.1016/j.jacbts.2022.04.008. eCollection 2022 Aug.

Study record dates

Study Major Dates

• Study Start (Actual): December 4, 2018
• Primary Completion (Actual): January 3, 2020
• Study Completion (Actual): January 3, 2020

Study Registration Dates

• First Submitted: December 3, 2018
• First Submitted That Met QC Criteria: December 5, 2018
• First Posted (Actual): December 7, 2018

Study Record Updates

• Last Update Posted (Actual): January 29, 2020
• Last Update Submitted That Met QC Criteria: January 28, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: oHCM; CK-3773274; CK-274; obstructive hypertrophic cardiomyopathy
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Hypertrophy; Cardiomyopathies; Cardiomyopathy, Hypertrophic
• Other Study ID Numbers: CY 6011

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No