Thorough QT/QTC (TQT) Clinical Trial to Evaluate the Effect of Zoliflodacin on Cardiac Repolarization in Healthy Male and Female Subjects
Condition: Electrocardiogram Repolarisation Abnormality; Gonococcal Infection
MeSH terms: Gonorrhea
Intervention: AZD0914; Moxifloxacin; Placebo
Intervention description: Spiropyrimidinetrione antibacterial drug, which inhibits bacterial DNA synthesis by a novel mechanism. Powder will be reconstituted in 60 mL of tap water and dosed orally after an overnight fast. After the cup containing 60 mL of zoliflodacin is taken, approximately 60 mL of tap water will be added to the cup and consumed by the subject to chase the initial dose.; Broad-spectrum 8-methoxy fluoroquinolone with activity against both Gram-positive and Gram-negative bacteria, including anaerobes. A single, commercially-available, film-coated, 400-mg tablet of moxifloxacin hydrochloride will be administered orally with 120 mL of tap water.; Composed of 4 g of the same excipients found in zoliflodacin. Powder will be reconstituted in 60 mL of tap water and dosed orally after an overnight fast. After the cup containing 60 mL of placebo is taken, approximately 60 mL of tap water will be added to the cup and consumed by the subject to chase the initial dose.
Intervention MeSH terms: Moxifloxacin; Zoliflodacin
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 72.0
Sex: All
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: AZD0914; Cardiac; ETX0914; Healthy; Moxifloxacin; Repolarization; Study; TQT; Volunteers; Zoliflodacin

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).
    

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