Clinical trial NCT03613649: Thorough QT/QTC (TQT) Clinical Trial to Evaluate the Effect of Zoliflodacin on Cardiac Repolarization in Healthy Male and Female Subjects
Official title: A Phase 1, Randomized, Double-blinded, Four-period Crossover, Thorough QT/QTC (TQT) Clinical Trial to Evaluate the Effect of Zoliflodacin on Cardiac Repolarization in Healthy Male and Female Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Electrocardiogram Repolarisation Abnormality
Gonococcal Infection
Keywords: AZD0914
Cardiac
ETX0914
Healthy
Moxifloxacin
Repolarization
Study
TQT
Volunteers
Zoliflodacin
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2018-08-03
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: The Phase I Thorough QT/QTc (TQT) study will be performed in a single center, the Vince \& Associates Clinical Research, Inc., clinical trials unit (CTU), in 72 healthy male or female subjects, aged 18 to 45 years inclusive, to evaluate the effect of zoliflodacin on the corrected QT interval of the electrocardiogram (ECG) using Fridericia's Formula (QTcF) and other ECG parameters; the correlation of the drug concentrations (and pharmacokinetic (PK) profile) with time-matched, placebo-corrected, baseline-adjusted difference in QTcF interval (delta delta QTcF); and the PK and safety profiles of the new zoliflodacin formulation. Each subject will receive one dose of each of four treatments: zoliflodacin 2 g orally, zoliflodacin 4 g orally, placebo for zoliflodacin 4 g orally, and moxifloxacin 400 mg orally. The study will last approximately 12 weeks with a subject participation duration of up to 55 days. The primary hypothesis to be tested is that following administration of zoliflodacin 2 g and 4 g, the upper bound of the one-sided 95% confidence interval (CI) of treatment effect on delta delta QTcF is \> / = 10 msec for at least one of the ECG assessments, against the alternative hypothesis that all mean effects are \< 10 msec. The primary objective is to evaluate the effect of zoliflodacin on the corrected QT interval of the ECG using Fridericia's formula (QTcF).

Detailed description: The Phase I Thorough QT/QTc (TQT) study will be performed in a single center, the Vince \& Associates Clinical Research, Inc., clinical trials unit (CTU), according to a randomized, double-blinded (except for the use of moxifloxacin), placebo-controlled, four-period, four-treatment, crossover design balanced with respect to first-order carryover effect in 72 healthy male or female subjects, aged 18 to 45 years inclusive, to evaluate the effect of zoliflodacin on the corrected QT interval of the electrocardiogram (ECG) using Fridericia's Formula (QTcF) and other ECG parameters; the correlation of the drug concentrations (and pharmacokinetic (PK) profile) with time-matched, placebo-corrected, baseline-adjusted difference in QTcF interval (delta delta QTcF); and the PK and safety profiles of the new zoliflodacin formulation. Each subject will receive one dose of each of four treatments: zoliflodacin 2 g orally, zoliflodacin 4 g orally, placebo for zoliflodacin 4 g orally, and moxifloxacin 400 mg orally. The study will last approximately 12 weeks with a subject participation duration of up to 55 days. The primary hypothesis to be tested is that following administration of zoliflodacin 2 g and 4 g, the upper bound of the one-sided 95% confidence interval (CI) of treatment effect on delta delta QTcF is \> / = 10 msec for at least one of the ECG assessments, against the alternative hypothesis that all mean effects are \< 10 msec. The primary objective is to evaluate the effect of zoliflodacin on the corrected QT interval of the ECG using Fridericia's formula (QTcF). The secondary objectives are: 1) to evaluate the effects of zoliflodacin on other ECG parameters (PR, QRS, and RR intervals, and heart rate (HR)); 2) to evaluate the sensitivity of QTcF measurement using moxifloxacin; 3) to evaluate the effect of zoliflodacin on T-wave morphology; 4) to evaluate the PK of 2 g and 4 g oral zoliflodacin under fasting state; 5) to evaluate the relationship between zoliflodacin PK and time-matched QTcF pharmacodynamics (PD); 6) to evaluate the safety and tolerability of 2 g and 4 g oral zoliflodacin.

Eligibility criteria: Inclusion Criteria:

All must be answered YES for the subject to be eligible for study participation:

1. Informed consent form (ICF) understood and signed before initiating any study procedures
2. Healthy male or female, as assessed by authorized site clinician (listed on FDA Form 1572)
3. Willingness to comply with and be available for all protocol procedures, including inpatient confinement for 3 days in each dosing period and follow-up for the duration of the trial
4. Aged 18 to 45 years inclusive on the day of first dosing
5. Body Mass Index (BMI) \> / = 18.5 and \< / = to 30 kg per m\^2 and weight \> / = 50 kg (110 lbs.) and \< / = 100 kg (220 lbs.)
6. In all female subjects, whether of childbearing potential or post-menopausal by medical history (MH), a negative serum pregnancy test at Screening Visit and on Day -1 of each dosing period

   -Note: A woman is considered of childbearing potential unless post-menopausal (\> / = 1 year without menses without other known or suspected cause and with a FSH level in the menopausal range), or surgically sterilized (hysterectomy, salpingectomy, oophorectomy, or tubal ligation/occlusion).
7. If female, not pregnant, not breast feeding, and not planning to become pregnant during the trial and for 30 days after Final Visit
8. Females of childbearing potential and males agree to use acceptable contraception for the duration of the trial and for 30 days (females) or 90 days (males) after Final Visit

   -Note: A highly effective method of birth control is defined as one with a low failure rate (i.e., less than 1 percent per year) according to CDC criteria. These include progestin implants, intrauterine devices (IUDs), surgical (hysterectomy, salpingectomy, oophorectomy, or tubal ligation/occlusion; vasectomy), or abstinence. Use of methods with higher failure rate (such as progestin injectables, combined oral hormonal contraceptives, condoms, and diaphragms) will not be acceptable when used alone, but they could be considered if used in combination with another method (e.g., a female using combined oral contraceptives if her male partner is sterile, or if she and her non-sterile male partner use a double-barrier method), after consultation with the DMID Medical Officer.
9. Male subjects agree to refrain from sperm donation for the duration of the trial and for 90 days after Final Visit
10. Laboratory tests are in the normal reference range with acceptable exceptions
11. Vital signs (VS) are within the acceptable range
12. Has adequate venous access for blood collection
13. Urine drug screen is negative for tested substances
14. Urine alcohol test is negative
15. Willing to abstain from alcohol consumption for 2 days before Day -1 of Period 1 and for the duration of the trial

Exclusion Criteria:

All must be answered NO for the subject to be eligible for study participation:

1. History of acute or chronic cardiovascular disease or surgery

* Note: Conditions include: congestive heart failure; coronary artery disease (myocardial infarction, unstable angina); cerebrovascular disease (cerebrovascular accident or stroke or transient ischemic attack (TIA); chronic hypertension; or coronary revascularization surgery (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) 2. History of cardiac arrhythmia or syncope related to cardiac arrhythmia or unexplained, or use of a cardiac pacemaker
* Note: Conditions include: atrial fibrillation, atrial flutter, or non-sustained or sustained ventricular tachycardia; use of a cardiac pacemaker; personal or family history of LQTS; or family history of sudden death 3. History of any other chronic medical or surgical condition that would interfere with the accurate assessment of the trial's objectives or increase the subject's risk profile
* Note: Chronic medical conditions include: diabetes mellitus; asthma requiring use of medication in the year before screening; autoimmune disorder such as lupus erythematosus, Wegener's, rheumatoid arthritis, thyroid disease; malignancy except low-grade (squamous and basal cell) skin cancer thought to be cured; chronic renal, hepatic, pulmonary, or endocrine disease, myopathy, or neuropathy; gastrointestinal surgery including weight loss surgery or biliary surgery 4. Major surgical interventions are not permitted within 4 weeks of first dosing and during the trial. Minor surgical interventions are not allowed within 2 weeks of first dosing and during the trial 5. History of hypersensitivity or severe allergic reaction of any type to medications, bee stings, food, or environmental factors
* Note: Severe allergic reaction is defined as any of the following: anaphylaxis, urticaria, or angioedema 6. Active allergic symptoms to seasonal and animal allergens that are moderate to severe, affect daily activity, and require continuous treatment 7. A marked baseline prolongation of ECG intervals, or HR less than 45 bpm or greater than 100 bpm on ECG measurements
* Note: The following are considered prolonged ECG intervals: QTc/QTcF \> 449 msec in males and females; PR \> 209 msec; and QRS \> 110 msec 8. Clinically significant abnormal ECG results
* Note: Clinically significant abnormal ECG results include: complete left or right bundle branch block; other ventricular conduction block; 2nd degree or 3rd degree atrioventricular (AV) block; sustained atrial or ventricular arrhythmia; two premature ventricular contractions in a row; pattern of ST elevation felt consistent with cardiac ischemia; evidence of a previous myocardial infarction (MI), left ventricular hypertrophy (LVH), or more than minor non-specific ST-T wave changes; any characteristics that would make QT assessment unreliable, including flat T waves; or any condition deemed clinically significant by a study investigator 9. Abnormal renal function
* Note: Normal renal function is defined as normal creatinine and normal estimated glomerular filtration rate (eGFR) \[i.e., \> 80.0 mL/min\] values according to Cockroft-Gault 10. Positive serology results for HIV, HBsAg, or HCV 11. Febrile illness with temperature \> / = 38.0 degrees Celsius for \< 7 days before dosing in each treatment period 12. Donated whole blood or blood products within 60 days before first dosing, or plans to donate or receive before Final Visit (Day 8 + / - 2 after last dose in dosing period 4)
* Note: Blood products include RBCs, white blood cells (WBCs), platelets, and plasma 13. Known allergic reactions to fluoroquinolones or to components present in the formulation or processing of zoliflodacin and moxifloxacin 14. Treatment with another investigational product within 30 days of first dosing or 5 half-lives or twice the duration of the biological effect of the study drug (whichever is longer)
* Note: Investigational products include a drug, vaccine, biologic, device, or blood product 15. Active drug or alcohol binge consumption, abuse, or dependence within 12 months before Screening Visit that, in the opinion of the investigator, would interfere with adherence to study requirements 16. Use of any prescription medication within 30 days before first dosing or planned use during the trial except as noted below and approved by the designated study clinician
* Note 1: Prohibited medications include moderate or strong CYP3A4 inducers and other drugs with known risk for QT prolongation and TdP; antibiotics; injectable or oral antidiabetic drugs; anti-lipid drugs; immunosuppressive agents; immune modulators; oral corticosteroids; anti-neoplastic agents; any vaccine (licensed or investigational) except licensed influenza vaccine during the flu season, which is allowed up to 7 days before first dosing or 7 days after last dosing
* Note 2: Allowed medications include: oral contraceptives; H1 antihistamines; all medications approved for control of intraocular pressure including topical ophthalmic non-selective beta-blockers, such as betaxolol, carteolol, levobunolol, metipranolol, and timolol; topical/ intranasal corticosteroids; nonsteroidal anti-inflammatory drugs (NSAIDS); licensed influenza vaccine during the flu season, 7 days before first dosing or 7 days after last dosing 17. Use of non-prescription medications, vitamins, herbs, or nutritional supplements within 15 days before first dosing or planned use during the trial unless approved by the study clinician
* Note 1: Intake of nutritional supplements, juice, and herbal preparations or other foods or beverages that may affect the various drug-metabolizing enzymes and transporters (e.g., grapefruit, grapefruit juice, grapefruit-containing beverages, apple or orange juice, vegetables from the mustard green family \[e.g., kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard\], and charbroiled meats) within 7 days before dosing
* Note 2: Exceptions: St. John's wart is not allowed within 30 days of dosing; vitamins and over-the-counter (OTC) medications taken for a brief period (less than 48 h) for the treatment of common symptoms (such as headache, indigestion, muscle pain) may be allowed as approved by the designated study clinician 18. Intake of caffeinated beverages or food within 72 h before first dosing or a history of high caffeine consumption (e.g., in the last 4 months drinking \> 5 cups of coffee/day) 19. Smoking or use of tobacco or nicotine-containing products within 30 days before first dosing 20. Engagement in strenuous exercise within 15 days before first dosing (e.g., marathon running, long-distance cycling, weight lifting) and during the trial 21. Any specific behavioral or clinical condition that, in the judgment of the investigator, precludes participation because it could affect compliance with study procedures or subject safety 22. Plans to enroll or is already enrolled in another clinical trial that could interfere with safety assessment of the study drug at any time during the trial
* Note: Includes trials that have a study intervention such as a drug, biologic, or device 23. Is a CTU employee or staff member who is paid entirely or partially by the Office of Clinical Research Resources (OCRR)/NIAID contract for the DMID-funded trial
* Note: CTU employees or staff include the PIs, sub-investigators, or staff who are supervised by the PI or sub-investigators

Primary outcomes:
measure: The One-sided 95% Confidence Interval (CI) for the Largest Time-matched, Placebo-corrected, Baseline-adjusted Mean QTcF Interval (Delta Delta QTcF) Following Administration of Zoliflodacin
timeFrame: Baseline, 0.5 hour (h), 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h post-dose after 2 and 4 g zolifloadacin
Secondary outcomes:
measure: Time-matched, Placebo-corrected, Baseline-adjusted Heart Rate (HR) Following Administration of Zoliflodacin
timeFrame: Baseline, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h post-dose
measure: Time-matched, Placebo-corrected, Baseline-adjusted, the Time From the Onset of the P Wave to the Start of the QRS Complex (PR Interval) Following Administration of Zoliflodacin
timeFrame: Baseline, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h post-dose
measure: Time-matched, Placebo-corrected, Baseline-adjusted the Time Elapsed Between Two Successive R Waves of the QRS (RR Interval) Following Administration of Zoliflodacin
timeFrame: Baseline, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h post-dose
measure: Time-matched, Placebo-corrected, Baseline-adjusted QRS Duration Following Administration of Zoliflodacin
timeFrame: Baseline, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h post-dose
measure: The One-sided 95% Confidence Interval (CI) of the Time-matched, Placebo-corrected, Baseline-adjusted Mean QTcF Interval (Delta Delta QTcF) After a Single Dose of Moxifloxacin
timeFrame: Baseline, 1 h, 2 h, 3 h, and 4 h post-dose
measure: Incidence of Abnormal T-wave Morphology Following Administration of Zoliflodacin
timeFrame: Baseline, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h post-dose
measure: Maximum Observed Concentration (Cmax) of Zoliflodacin
timeFrame: Baseline, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h post-dose
measure: Time of Maximum Observed Concentration (Tmax) of Zoliflodacin
timeFrame: Baseline, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h post-dose
measure: Area Under the Concentration Time-curve From Time Zero to Infinity (AUC(0 - Infinity)) for Zoliflodacin
timeFrame: Baseline, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h post-dose
measure: Area Under the Concentration Time-curve From Time Zero to the Last Concentration Above the Lower Limit of Quantitation (AUC(0-last)) for Zoliflodacin
timeFrame: Baseline, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h post-dose
measure: Apparent Volume of Distribution (Vz/F) of Zoliflodacin
timeFrame: Baseline, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h post-dose
measure: Apparent Oral Clearance (CL/F) of Zoliflodacin
timeFrame: Baseline, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h post-dose
measure: Elimination Rate Constant (Ke) of Zoliflodacin
timeFrame: Baseline, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h post-dose
measure: Terminal Elimination Half-life (t1/2) of Zoliflodacin
timeFrame: Baseline, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h post-dose
measure: Relationship Between Plasma Concentrations of Zoliflodacin and Time-matched, Placebo-corrected, Baseline-adjusted Mean QTcF Interval (Delta Delta QTcF) Following Administration of Zoliflodacin
timeFrame: Baseline, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h post-dose
measure: Number of Participants With Treatment-emergent Serious Adverse Events Following Administration of Zoliflodacin and Moxifloxacin
timeFrame: From study product administration (Day 1) through prior to the next dose (Day 8 or Final visit).
measure: Number of Participants With Treatment-emergent Adverse Events Following Administration of Study Product
timeFrame: From study product administration (Day 1) through prior to the next dose (Day 8 or Final visit).
measure: Changes From Baseline for Blood Pressure - Systolic
timeFrame: From study product administration (Day 1) through prior to the next dose (Day 8 or Final visit).
measure: Changes From Baseline for Blood Pressure - Diastolic
timeFrame: From study product administration (Day 1) through prior to the next dose (Day 8 or Final visit).
measure: Changes From Baseline for Pulse Rate
timeFrame: From study product administration (Day 1) through prior to the next dose (Day 8 or Final visit).
measure: Changes From Baseline for Respiratory Rate
timeFrame: From study product administration (Day 1) through prior to the next dose (Day 8 or Final visit).
measure: Changes From Baseline for Temperature
timeFrame: From study product administration (Day 1) through prior to the next dose (Day 8 or Final visit).
measure: Changes From Baseline for White Blood Cells With Differentials
timeFrame: Prior to dosing, 24 hour post dose through prior to the next dose (Day 8 or Final visit).
measure: Changes From Baseline for Hemoglobin
timeFrame: Prior to dosing, 24 hour post dose through prior to the next dose (Day 8 or Final visit).
measure: Changes From Baseline for Hematocrit
timeFrame: Prior to dosing, 24 hour post dose through prior to the next dose (Day 8 or Final visit).
measure: Changes From Baseline for Erythrocytes
timeFrame: Prior to dosing, 24 hour post dose through prior to the next dose (Day 8 or Final visit).
measure: Changes From Baseline for Platelets
timeFrame: Prior to dosing, 24 hour post dose through prior to the next dose (Day 8 or Final visit).
measure: Changes From Baseline for Sodium, Potassium, Chloride and Bicarbonate
timeFrame: Prior to dosing, 24 hour post dose through prior to the next dose (Day 8 or Final visit).
measure: Changes From Baseline for Magnesium, Glucose (Fasting), Blood Urea Nitrogen (BUN), Creatinine, Total Bilirubin, Direct Bilirubin
timeFrame: Prior to dosing, 24 hour post dose through prior to the next dose (Day 8 or Final visit).
measure: Changes From Baseline for Total Protein and Albumin
timeFrame: Prior to dosing, 24 hour post dose through prior to the next dose (Day 8 or Final visit).
measure: Changes From Baseline for Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) and Alkaline Phosphatase (AP)
timeFrame: Prior to dosing, 24 hour post dose through prior to the next dose (Day 8 or Final visit).
measure: Changes From Baseline for Glomerular Filtration Rate (GFR) - Estimated
timeFrame: Prior to dosing, 24 hour post dose through prior to the next dose (Day 8 or Final visit).
measure: Occurrence of Urinalysis Adverse Events Following Administration of Study Product
timeFrame: From study product administration (Day 1) through prior to the next dose (Day 8 or Final visit).
measure: Changes From Baseline in ECG Measures: PR Interval, QRS Duration, QT Interval, QTcF Interval and RR Interval
timeFrame: Baseline, 1 h, 2 h, 4h, 24 h post-dose and follow up
measure: Changes From Baseline in ECG Measures: Ventricular Rate
timeFrame: Baseline, 1 h, 2 h, 4h, 24 h post-dose and follow up
Other outcomes:
Locations:
city: Overland Park
country: United States
facility: Vince and Associates Clinical Research
state: Kansas
Study officials:
References:
citation: Newman LM, Kankam M, Nakamura A, Conrad T, Mueller J, O'Donnell J, Osborn BL, Gu K, Saviolakis GA. Thorough QT Study To Evaluate the Effect of Zoliflodacin, a Novel Therapeutic for Gonorrhea, on Cardiac Repolarization in Healthy Adults. Antimicrob Agents Chemother. 2021 Nov 17;65(12):e0129221. doi: 10.1128/AAC.01292-21. Epub 2021 Oct 4.