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

Study Overview
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Brief Summary
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The purposes of this study are to: Learn about the safety of CK-3773274 after a single dose and multiple doses in healthy subjects. Learn how healthy subjects tolerate CK-3773274 after a single dose and multiple doses. Find out how much CK-3773274 is in the blood after a single dose and multiple doses. Determine the effect of doses of CK-3773274 on the pumping function of the heart. Evaluate the effect of cytochrome genetic variants on how the body metabolizes CK-3773274. Evaluate the effect of a meal on how much CK-3773274 is in the blood in healthy adult subjects. 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.

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

Conditions
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Symptomatic Obstructive Hypertrophic Cardiomyopathy, Healthy Subjects

Intervention / Treatment
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* Drug: CK-3773274 - Granules in Capsule
* Drug: Placebo - Granules in Capsule
* Drug: CK-3773274 - Tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females (of non-childbearing potential) between 18 and 55 years of age, inclusive Body weight > 55.0 kg and body mass index within 18.0 to 32.0 kg/m2, inclusive Normal cardiac structure and function, or if abnormalities are present, they are deemed not clinically significant Normal to high left ventricular ejection fraction. Normal electrocardiogram (ECG) or, if abnormalities are present, they are deemed not clinically significant Clinical laboratory findings within normal range Negative hepatitis panel (including hepatitis B surface antigen and hepatitis C antibody), and negative human immunodeficiency virus antibody screens Willing and able to refrain from strenuous exercise (eg, activity which could be expected to cause muscle soreness) For Arms 5 and 6 only: Subject is a CYP2D6 poor metabolizer Exclusion Criteria: History of any significant illness or disorder History of stomach or intestinal surgery or resection (appendectomy, hernia repair, and/or cholecystectomy will be allowed) A clinically significant illness within 4 weeks of Check-in Inability to swallow capsules or tablets 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 Use of any tobacco-containing or nicotine-containing products within 3 months prior to Check-in Participation in any other investigational study drug trial in which receipt of an investigational study drug occurred within 30 days prior to Check-in 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

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: Basic Science
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CK-3773274, CK-274, obstructive hypertrophic cardiomyopathy, oHCM