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

• ClinicalTrials.gov Identifier: NCT03767855
• Recruitment Status: Active, not recruiting
• First Posted: December 7, 2018
• Last Update Posted: November 13, 2019
• Sponsor: Cytokinetics
• Information provided by (Responsible Party): Cytokinetics

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Symptomatic Obstructive Hypertrophic Cardiomyopathy; Healthy Subjects	Drug: CK-3773274 - Granules in Capsule; Drug: Placebo - Granules in Capsule; Drug: CK-3773274 - Tablets	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: A Phase 1, Double-Blind, Randomized, Placebo-Controlled, Multi-Part, Single and Multiple Ascending Dose Study of CK-3773274 in Healthy Adult Subjects
• Actual Study Start Date: December 4, 2018
• Estimated Primary Completion Date: December 2019
• Estimated Study Completion Date: December 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Incidence of Adverse events and Safety Signals observed during single and multiple ascending doses of CK-3773274 administered orally to healthy adult subjects. [ Time Frame: 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 ]
   Subject incidence of AEs, SAEs, and reduced LVEF

Secondary Outcome Measures :

1. Cmax of CK-3773274 after single and multiple ascending doses [ Time Frame: 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 ]
   Maximum concentration after dosing (Cmax) following single and multiple doses of CK-3773274 administered to healthy subjects
2. Change in absolute reduction in ejection fraction relative to baseline with doses of CK-3773274 [ Time Frame: 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 ]
   Changes from baseline in LVEF as measured by echocardiography with doses of CK-3773274
3. Assess the effect of CYP2D6 genetic variants on the PK of CK-3773274 [ Time Frame: Day -1 - Day 24 ]
   Maximum concentration after dosing (Cmax) following a single dose administered to CYP2D6 poor metabolizers
4. Assess the effect of a meal on how much CK-3773274 is in the blood in healthy subjects [ Time Frame: Day -1 - Day 24 ]
   Maximum concentration after dosing (Cmax) following single and multiple doses of CK-3773274 administered to healthy subjects in fed and fasted states
5. Relative bioavailability of CK-3773274 formulated as granules in capsule versus a tablet in healthy adult subjects [ Time Frame: Time Frame for Bioavailability Cohort: Day -1 - Day 29 ]
   PK parameters such as AUC calculated using plasma concentrations of CK-3773274

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

United States, Arizona

Clinical Site

Tempe, Arizona, United States, 85283

Sponsors and Collaborators

Cytokinetics

Investigators

• Study Director: Study Director MD; Cytokinetics

More Information

• Responsible Party: Cytokinetics
• ClinicalTrials.gov Identifier: NCT03767855
• Other Study ID Numbers: CY 6011
• First Posted: December 7, 2018
• Last Update Posted: November 13, 2019
• Last Verified: November 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Cytokinetics:

CK-3773274; CK-274; obstructive hypertrophic cardiomyopathy; oHCM

Additional relevant MeSH terms:

Cardiomyopathies; Cardiomyopathy, Hypertrophic; Hypertrophy; Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Heart Valve Diseases