Thorough QT/QTc (TQT) Clinical Study to Evaluate the Effects of Ziresovir on Cardiac Repolarization in Healthy Subjects
- Conditions
- Healthy Volunteers
- Interventions
- Registration Number
- NCT06591845
- Lead Sponsor
- Shanghai Ark Biopharmaceutical Co., Ltd.
- 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.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 32
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Treatment T (Therapeutic dose) Ziresovir 125 mg 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) Treatment ST (Supratherapeutic dose) Ziresovir 500 mg 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) Treatment P (Placebo) 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) Treatment PC (positive control) Moxifloxacin hydrochloride tablet 400 mg 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)
- Primary Outcome Measures
Name Time Method Change from baseline QTcF (ΔQTcF) 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 Outcome Measures
Name Time Method 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 QTc using correction methods not chosen as the primary correction method if a substantial HR effect is observed
Change from baseline in HR, PR, and QRS Before dosing (Baseline) through 48 hours after the dose on Day 1 in each treatment period Change-from-baseline in HR, PR and QRS (ΔHR, ΔPR and ΔQRS).
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) Incidence of treatment-emergent adverse events (TEAEs) and changes in laboratory safety tests, vital signs, and ECGs.
Treatment-emergent changes in ECG Morphology Before dosing (Baseline) through 48 hours after the dose on Day 1 in each treatment period Treatment-emergent changes in ECG Morphology
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 Categorical outliers for QTcF/QTcI/QTcS, HR, PR, and QRS.
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 PK parameters of ziresovir and its metabolites including maximum observed plasma concentration (Cmax).
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. PK parameters of ziresovir and its metabolites including terminal elimination half-life (t1/2).
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. PK parameters of ziresovir and its metabolites including area under the curve (AUC).