A Single-Center, Randomized, Partially Double-Blind, Placebo- and Active-Controlled, Four-period Crossover, Thorough QT/QTc (TQT) Clinical Study to Evaluate the Effects of Ziresovir on Cardiac Repolarization in Healthy Subjects
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Enrollment
- 34
- Locations
- 1
- Primary Endpoint
- Change from baseline QTcF (ΔQTcF)
Study Overview
Brief Summary
This is a single-center, randomized, partially double-blind, placebo and active-controlled, 4-period crossover design thorough QT/QTc (TQT) clinical study to evaluate the effects of ziresovir on cardiac repolarization in healthy subjects.
Detailed Description
This clinical study is a single-center, randomized, partially double-blind, placebo- and active-controlled, four-period crossover design, with healthy subjects comprising the enrolled population. Ziresovir and placebo will be administered in a double-blind manner, while moxifloxacin hydrochloride tablets will be administered in as open-label.
Thirty-two subjects meeting all inclusion criteria and none of the exclusion criteria will be randomized into 1 of 12 dosing sequences, each consisting of 4 periods with an 8-day washout period in-between.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- Single (Participant)
Masking Description
Partially Double-Blind
Eligibility Criteria
- Ages
- 18 Years to 50 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •The subject voluntarily signed a written informed consent form.
- •Male or female; between 18 and 50 years old (inclusive).
- •Male subjects weighing ≥50 kg, female subjects weighing ≥45 kg, body mass index (BMI) between 19.0 and 30.0 kg/m2 (inclusive), BMI= weight (kg)/height2 (m2).
- •Healthy, as defined by no clinically significant or relevant abnormalities identified by vital signs, physical examination, laboratory examination items, ECG, and other trial-related examinations at screening, admission or baseline day of each period as assessed by the investigator.
- •The subject can communicate well with the investigator and is able to complete the study in compliance with the protocol.
Exclusion Criteria
- •History of or evidence of clinically significant disorder, condition or disease not otherwise excluded that, in the opinion of the investigator, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.
- •History of cardiovascular disease or risk factors for Torsade de Pointes (TdP) at screening, including but not limited to: unexplained syncope; heart failure; cardiomyopathy; hypertension; angina pectoris; myocardial infarction; hypokalemia; bradycardia or sick sinus syndrome; cardiac conduction abnormalities; personal or family history of long QT syndrome (LQTS); or family history of sudden death.
- •Known or suspected malignancy.
- •Known allergic reactions to study intervention (e.g., ziresovir or its drug excipients, moxifloxacin, fluoroquinolone antibiotics) or history of clinically significant multiple or severe drug allergies, food allergies.
- •Subjects who have donated blood or have had a blood loss ≥500 ml within 3 months prior to screening.
- •Subjects who have participated in a clinical trial evaluating an investigational drug or device within 30 days or 5 half-lives (whichever is longer) prior to screening.
- •History of substance abuse (e.g., alcohol, licit or illicit drugs) within 1 year prior to screening.
- •12-lead ECG at screening or admission exceeding criteria: PR>220 ms, QRS>120 ms, HR< 50 bpm or >100 bpm, QTcF >450 ms (male and female) (The mean of 3 triplicate ECGs timepoint measurement); or ECG abnormalities that are considered by the investigator to be abnormal and clinically significant.
- •Systolic blood pressure (BP) > 140 mmHg or < 90 mmHg, or diastolic BP > 90 mmHg at screening or admission.
- •Serum potassium, calcium, or magnesium levels outside the normal range at screening or admission.
- •Positive blood alcohol test, positive urine cotinine test or positive urine drug abuse screening at screening or admission.
- •Engaged in strenuous exercise within 48 hours before randomization (e.g., marathon running, long-distance cycling, weightlifting).
- •Intake of caffeinated beverages or food within 48 hours before randomization or a history of high caffeine consumption (e.g., in the last 3 months drinking >5 cups of coffee/day).
- •History of alcoholism or regular alcohol consumption within 1 year prior to screening, defined as more than 14 units (male) or 7 units (female) of alcohol per week (1 unit =360 mL of beer or 45 mL of spirits containing 40% alcohol or 150 mL of wine).
- •Smoking or use of tobacco or nicotine-containing products within 6 months before screening.
- •Pregnant or lactating women or those with positive blood pregnancy test results.
Arms & Interventions
Treatment PC (positive control)
The subjects will receive a moxifloxacin hydrochloride tablet 400 mg as single dose on Day 1 (Period 1) or Day 9 (Period 2) or Day 17 (Period 3) or Day 25 (Period 4)
Intervention: Moxifloxacin hydrochloride tablet 400 mg (Drug)
Treatment P (Placebo)
The subjects will receive a placebo as single dose on Day 1 (Period 1) or Day 9 (Period 2) or Day 17 (Period 3) or Day 25 (Period 4)
Intervention: Placebo (Drug)
Treatment T (Therapeutic dose)
The subjects will receive a ziresovir 125 mg as single dose on Day 1 (Period 1) or Day 9 (Period 2) or Day 17 (Period 3) or Day 25 (Period 4)
Intervention: Ziresovir 125 mg (Drug)
Treatment ST (Supratherapeutic dose)
The subjects will receive a ziresovir 500 mg as single dose on Day 1 (Period 1) or Day 9 (Period 2) or Day 17 (Period 3) or Day 25 (Period 4)
Intervention: Ziresovir 500 mg (Drug)
Outcomes
Primary Outcomes
Change from baseline QTcF (ΔQTcF)
Time Frame: Before dosing (Baseline) through 48 hours after the dose on Day 1 in each treatment period
The primary ECG endpoint is the change from baseline in the QT interval corrected for heart rate (HR) using the Fridericia method (ΔQTcF).
Secondary Outcomes
- Change from baseline in QTc(Before dosing (Baseline) through 48 hours after the dose on Day 1 in each treatment period)
- Change from baseline in HR, PR, and QRS(Before dosing (Baseline) through 48 hours after the dose on Day 1 in each treatment period)
- Incidence of treatment-emergent adverse events (TEAEs) and changes in laboratory safety tests, vital signs, and ECGs.(Up to Day 8 of each treatment period (up to 31 days))
- Treatment-emergent changes in ECG Morphology(Before dosing (Baseline) through 48 hours after the dose on Day 1 in each treatment period)
- Categorical outliers for QTcF/QTcI/QTcS, HR, PR, and QRS.(Before dosing (Baseline) through 48 hours after the dose on Day 1 in each treatment period)
- Maximum observed plasma concentration (Cmax) of ziresovir(Pre-dose within 1 hour and at 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 hours, and 72 hours post-dose during each period)
- Terminal elimination half-life (t1/2) of ziresovir.(Pre-dose within 1 hour and at 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 hours, and 72 hours post-dose during each period.)
- Area under the curve (AUC) of ziresovir.(Pre-dose within 1 hour and at 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 hours, and 72 hours post-dose during each period.)