Phase 1
N=72
Thorough QT/QTC (TQT) Clinical Trial to Evaluate the Effect of Zoliflodacin on Cardiac Repolarization in Healthy Male and Female Subjects
Electrocardiogram Repolarisation Abnormality · Gonococcal Infection
Bottom Line
View on ClinicalTrials.gov: NCT03613649 ↗Enrolled (actual)
72
Serious AEs
0.0%
Results posted
Mar 2020
Primary outcome: Primary: 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 — -3.2; -1.0; -2.1; -1.9 milliseconds (msec)
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 1
- Interventions
- AZD0914 (Drug); Moxifloxacin (Drug); Placebo (Other)
- Age
- Adult · 18+ yrs
- Sex
- All
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Primary completion
- Jan 2019
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY 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 |
-3.2; -1.0; -2.1; -1.9; 0.1; -2.3 | — |
| SECONDARY Time-matched, Placebo-corrected, Baseline-adjusted Heart Rate (HR) Following Administration of Zoliflodacin |
0.4; 2.2; 0.1; 1.6; 2.3; -0.6 | — |
| SECONDARY 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 |
-0.7; -1.1; -0.3; -0.9; -2.3; 0.2 | — |
| SECONDARY Time-matched, Placebo-corrected, Baseline-adjusted the Time Elapsed Between Two Successive R Waves of the QRS (RR Interval) Following Administration of Zoliflodacin |
-5.8; -33.5; -1.2; -22.6; -35.0; 9.7 | — |
| SECONDARY Time-matched, Placebo-corrected, Baseline-adjusted QRS Duration Following Administration of Zoliflodacin |
-0.3; -0.1; -0.3; -0.5; 0.1; 0.0 | — |
| SECONDARY 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 |
7.9; -2.3; 8.5; -2.2; 8.0; -2.6 | — |
| SECONDARY Incidence of Abnormal T-wave Morphology Following Administration of Zoliflodacin |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY Maximum Observed Concentration (Cmax) of Zoliflodacin |
12120; 20350 | — |
| SECONDARY Time of Maximum Observed Concentration (Tmax) of Zoliflodacin |
2.90; 3.03 | — |
| SECONDARY Area Under the Concentration Time-curve From Time Zero to Infinity (AUC(0 - Infinity)) for Zoliflodacin |
108300; 181400 | — |
| SECONDARY Area Under the Concentration Time-curve From Time Zero to the Last Concentration Above the Lower Limit of Quantitation (AUC(0-last)) for Zoliflodacin |
102700; 177300 | — |
| SECONDARY Apparent Volume of Distribution (Vz/F) of Zoliflodacin |
160.55; 204.29 | — |
| SECONDARY Apparent Oral Clearance (CL/F) of Zoliflodacin |
20.08; 23.77 | — |
| SECONDARY Elimination Rate Constant (Ke) of Zoliflodacin |
0.1267; 0.1174 | — |
| SECONDARY Terminal Elimination Half-life (t1/2) of Zoliflodacin |
5.55; 5.99 | — |
| SECONDARY Relationship Between Plasma Concentrations of Zoliflodacin and Time-matched, Placebo-corrected, Baseline-adjusted Mean QTcF Interval (Delta Delta QTcF) Following Administration of Zoliflodacin |
1.5; 3.0 | — |
| SECONDARY Number of Participants With Treatment-emergent Serious Adverse Events Following Administration of Zoliflodacin and Moxifloxacin |
0; 0; 0; 0 | — |
| SECONDARY Number of Participants With Treatment-emergent Adverse Events Following Administration of Study Product |
38; 46; 35; 41 | — |
| SECONDARY Changes From Baseline for Blood Pressure - Systolic |
0.8; 1.3; 0.8; 0.4; 0.4; -0.3 | — |
| SECONDARY Changes From Baseline for Blood Pressure - Diastolic |
0.3; 0.3; 0.8; 1.5; -0.4; -0.9 | — |
| SECONDARY Changes From Baseline for Pulse Rate |
5.2; 5.7; 2.8; 6.9; 3.9; 6.5 | — |
| SECONDARY Changes From Baseline for Respiratory Rate |
0.8; 1.1; 1.0; 0.4; 0.4; 0.7 | — |
| SECONDARY Changes From Baseline for Temperature |
0.08; 0.03; 0.03; 0.05; 0.10; 0.06 | — |
| SECONDARY Changes From Baseline for White Blood Cells With Differentials |
-246.4; -129.9; -64.3; -282.9; -273.5; 140.3 | — |
| SECONDARY Changes From Baseline for Hemoglobin |
0.15; 0.01; 0.04; -0.06; -0.01; -0.23 | — |
| SECONDARY Changes From Baseline for Hematocrit |
0.39; -0.10; 0.08; -0.26; -0.03; -0.69 | — |
| SECONDARY Changes From Baseline for Erythrocytes |
0.050; -0.008; -0.002; -0.031; -0.005; -0.088 | — |
| SECONDARY Changes From Baseline for Platelets |
-8.2; -10.3; -10.5; -15.4; 1.7; 2.9 | — |
| SECONDARY Changes From Baseline for Sodium, Potassium, Chloride and Bicarbonate |
0.2; -0.1; 0.6; 0.7; 0.1; -0.3 | — |
| SECONDARY Changes From Baseline for Magnesium, Glucose (Fasting), Blood Urea Nitrogen (BUN), Creatinine, Total Bilirubin, Direct Bilirubin |
0.05; 0.03; 0.02; 0.01; 0.04; 0.00 | — |
| SECONDARY Changes From Baseline for Total Protein and Albumin |
-0.42; -0.42; -0.45; -0.45; -0.01; -0.06 | — |
| SECONDARY Changes From Baseline for Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) and Alkaline Phosphatase (AP) |
-2.9; -2.7; -2.7; -2.8; 0.1; 0.0 | — |
| SECONDARY Changes From Baseline for Glomerular Filtration Rate (GFR) - Estimated |
-10.4; -9.5; -0.1; -6.2; -5.3; 1.8 | — |
| SECONDARY Occurrence of Urinalysis Adverse Events Following Administration of Study Product |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY Changes From Baseline in ECG Measures: PR Interval, QRS Duration, QT Interval, QTcF Interval and RR Interval |
1.2; 0.0; 1.3; 1.3; 1.2; -0.7 | — |
| SECONDARY Changes From Baseline in ECG Measures: Ventricular Rate |
2.4; 3.3; 0.9; 4.7; 2.9; 4.6 | — |
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:
- Informed consent form (ICF) understood and signed before initiating any study procedures
- Healthy male or female, as assessed by authorized site clinician (listed on FDA Form 1572)
- 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
- Aged 18 to 45 years inclusive on the day of first dosing
- Body Mass Index (BMI) > / = 18.5 and / = 50 kg (110 lbs.) and / = 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).
- If female, not pregnant, not breast feeding, and not planning to become pregnant during the trial and for 30 days after Final Visit
- 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.
- Male subjects agree to refrain from sperm donation for the duration of the trial and for 90 days after Final Visit
- Laboratory tests are in the normal reference range with acceptable exceptions
- Vital signs (VS) are within the acceptable range
- Has adequate venous access for blood collection
- Urine drug screen is negative for tested substances
- Urine alcohol test is negative
- 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:
- 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
Data sourced from ClinicalTrials.gov (NCT03613649). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.