A Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Ziresovir in Healthy Subjects

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled, dose escalation study to evaluate the safety, tolerability, and pharmacokinetics (PK) of ziresovir following a single ascending oral dose administration in healthy adult subjects under fasted conditions.

Detailed Description
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Up to 3 dose cohorts are planned. The ziresovir dose level of each cohort is determined based on the collective clinical and nonclinical data of ziresovir. The proposed dose levels of Cohorts 1, 2 and 3 are 300 mg and up to 600 mg and up to 900 mg, respectively. A total of up to 24 subjects will be randomized with 18 subjects to receive active drug and 6 subjects to receive placebo in a double-blind fashion. Eight subjects will be randomized in each dose cohort, with 6 subjects to receive active drug and 2 subjects o receive placebo.

Official Title
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A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Sequential Parallel Group, Single Ascending Dose Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Ziresovir in Healthy Subjects

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: Ziresovir
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of giving written informed consent and complying with study procedures; Between the ages of 18 and 55 years, inclusive; Body mass index (BMI) of 18.0 to 32.0 kg/m2 inclusive and body weight not less than 50 kg; Female subjects must have a negative pregnancy test result at screening; Considered healthy by the Investigator, based on subject's reported medical history, full physical examination, 12-lead ECG, and vital signs; Willing and being able to adhere to study restrictions and to be confined at the Clinical Research Unit. Exclusion Criteria: Clinically significant reported history of gastrointestinal, cardiovascular, musculoskeletal, endocrine, hematologic, psychiatric, renal, hepatic, bronchopulmonary, neurologic, immunologic, lipid metabolism disorders, or drug hypersensitivity as determined by the Investigator; Poor venous access; Taken an investigational drug or participated in a clinical trial evaluating an investigational drug or device within 30 days (or 5 half-lives) prior to the study drug dose, whichever is longer; Taken any prescription medications within 14 days or 5 half-lives (whichever is longer) of the study drug dose; Major surgery or hospitalization within 6 months prior to screening that in the Investigator's opinion would put the subject or study conduct at risk, or have any scheduled surgery or hospitalization during the study period; Any condition or finding that in the Investigator's opinion would put the subject or study conduct at risk if the subject were to participate in the study.

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: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ziresovir<br>The study drugs will be administered to subjects by CRU staff at approximately 8:00 a.m. (± 1 hour), following an overnight fast. Immediately following administration of the assigned dose of the study drugs, subjects will be given water such that their water consumption is approximately 240 mL as follows: If administered 60 mL as the study drug dose, follow with approximately 180 mL water. If administered 120 mL as the study drug dose, follow with approximately 120 mL water. If administered 180 mL as the study drug dose, follow with approximately 60 mL water. | Drug: Ziresovir<br>* Planned treatments are: Cohort 1: 300 mg of ziresovir Cohort 2: up to 600 mg of ziresovir Cohort 3: up to 900 mg of ziresovir<br>* Other names: AK0529;|
| Placebo Comparator: placebo<br>The study drugs will be administered to subjects by CRU staff at approximately 8:00 a.m. (± 1 hour), following an overnight fast. Immediately following administration of the assigned dose of the study drugs, subjects will be given water such that their water consumption is approximately 240 mL as follows: If administered 60 mL as the study drug dose, follow with approximately 180 mL water. If administered 120 mL as the study drug dose, follow with approximately 120 mL water. If administered 180 mL as the study drug dose, follow with approximately 60 mL water. | Other: Placebo<br>* Planned treatments are: Cohort 1: 300 mg of placebo Cohort 2: up to 600 mg of placebo Cohort 3: up to 900 mg of placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| numbers of all AEs | The Common Terminology Criteria for Adverse Events (CTCAE) Version 5 will be used to grade AEs | through study completion, an average of 22 days | 
| percentages of all AEs | The Common Terminology Criteria for Adverse Events (CTCAE) Version 5 will be used to grade AEs | through study completion, an average of 22 days | 
| change from baseline in systolic and diastolic blood pressure | blood pressure in millimeter of mercury | screen/day -1/day 1/day 2/day 3/day4 | 
| change from baseline in pulse rate | pulse rate in times per minute | screen/day -1/day 1/day 2/day 3/day4 | 
| change from baseline in respiratory rate | respiratory rate in times per minute | screen/day -1/day 1/day 2/day 3/day4 | 
| change from baseline in oral temperature | oral temperature in degree | screen/day -1/day 1/day 2/day 3/day4 | 
| change from baseline in Prothrombin time/International Normalized Ratio | INR is calculated from the PT and allows for worldwide standardization of results. | screen/day -1/day 2/day4 | 
| change from baseline in Thrombin time | Thrombin time in seconds | screen/day -1/day 2/day4 | 
| change from baseline in activated Partial Thromboplastin time | activated Partial Thromboplastin time in seconds | screen/day -1/day 2/day4 | 
| change from baseline in Hemoglobin (Hgb) count | Hemoglobin (Hgb) in gram per liter | screen/day -1/day 2/day4 | 
| change from baseline in Hematocrit (Hct) |  | screen/day -1/day 2/day4 | 
| change from baseline in Platelet count | Platelet count per liter | screen/day -1/day 2/day4 | 
| change from baseline in Red blood cell (RBC) count |  | screen/day -1/day 2/day4 | 
| change from baseline in White blood cell (WBC) count with differential |  | screen/day -1/day 2/day4 | 
| change from baseline in Specific gravity from urinalysis |  | screen/day -1/day 2/day4 | 
| change from baseline in pH from urinalysis |  | screen/day -1/day 2/day4 | 
| change from baseline in Protein from urinalysis |  | screen/day -1/day 2/day4 | 
| change from baseline in Glucose from urinalysis |  | screen/day -1/day 2/day4 | 
| change from baseline in Ketones from urinalysis |  | screen/day -1/day 2/day4 | 
| change from baseline in Bilirubin from urinalysis |  | screen/day -1/day 2/day4 | 
| change from baseline in Blood from urinalysis |  | screen/day -1/day 2/day4 | 
| change from baseline in Nitrites from urinalysis |  | screen/day -1/day 2/day4 | 
| change from baseline in Leukocytes from urinalysis |  | screen/day -1/day 2/day4 | 
| change from baseline in Urobilinogen from urinalysis |  | screen/day -1/day 2/day4 | 
| Incidence of abnormal Microscopic urine analysis |  | screen/day -1/day 2/day4 | 
| change from baseline in heart rate-corrected QT interval from resting 12-lead ECGs | ECGs will be performed after the subject has been supine for at least 5 minutes | screen/day -1/day1/day2/day4 | 
| change from baseline in heart rate from resting 12-lead ECGs | ECGs will be performed after the subject has been supine for at least 5 minutes | screen/day -1/day1/day2/day4 | 
| change from baseline in QRS intervals from resting 12-lead ECGs | ECGs will be performed after the subject has been supine for at least 5 minutes | screen/day -1/day1/day2/day4 | 
| change from baseline in treatment-emergent T-wave morphology from resting 12-lead ECGs | ECGs will be performed after the subject has been supine for at least 5 minutes | screen/day -1/day1/day2/day4 | 
| change from baseline in appearance of U-waves from resting 12-lead ECGs | ECGs will be performed after the subject has been supine for at least 5 minutes | screen/day -1/day1/day2/day4 | 
| Incidence of abnormal physical findings | full physical examination will be conducted at screening and an abbreviated physical exam will be conducted on Day -1 and Day 2. A symptom-directed physical exam will be conducted on Day 3 and Day 4. | screen/day -1/day2/day3/day4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the drug concentration of ziresovir following single ascending doses by oral administration in healthy adult male and female subjects |  | 0 (within 90 minutes prior to dosing) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, and 72 hours post-dose |