A Study to Evaluate the Safety, Tolerability and Plasma PK of a Single Oral Dose of Zoliflodacin in Healthy Male and Female Volunteers

NCT03404167 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 16-0118HHSN272201500005I
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

The trial is to evaluate the pharmacokinetics and safety profiles of the single-dose of zoliflodacin in eight healthy male or female subjects ages 18 to 45 years inclusive. All subjects will be dosed in the morning of Day 1 in a staggered fashion with a minimum of several minutes apart. Each subject will receive a single 4g dose of zoliflodacin (2 x 2 g sachets of zoliflodacin) after at least an 8-h fast, which will continue for at least 4 h after dosing. Consumption of water will be permitted during the fasting period. Subjects will be monitored as inpatients in the Clinical Trial Unit (CTU) up to Day 4 and at the Final Visit (Day 8 ± 2). Study duration is approximately 4 weeks with subject participation duration up to 10 days (from dosing to final visit). The primary objective of this study is to evaluate the plasma PK of zoliflodacin after administration of a single 4-g oral dose under fasting conditions.

Conditions

Gonorrhoea

Keywords

ETX0914; Plasma Pharmacokinetic; Safety; Tolerability; Zoliflodacin

Outcome Measures

Primary Outcomes (8)

• Maximum Observed Concentration (Cmax) of Zoliflodacin

  Cmax is defined as the maximum observed drug concentration observed in plasma over all PK sample concentrations computed from concentrations that were measured using a validated HPLC-MS/MS method.

  From Day 1 to Day 4

• Time of Maximum Observed Concentration (Tmax) of Zoliflodacin

  Tmax was defined as the time at which the maximum concentration (Cmax) occurs in plasma computed from concentrations that were measured using a validated HPLC-MS/MS method.

  From Day 1 to Day 4

• Area Under the Concentration Time-curve From Time Zero to Infinity (AUC(0-infinity)) for Zoliflodacin

  AUC(0-8) was defined as the total area under the concentration-time curve from dosing (time 0) taken to the limit as the end time becomes arbitrarily large. AUC(0-8) and was calculated by adding AUC(0-last) to an extrapolated value equal to the last measured concentration greater than the lower limit of quantification of the bioanalytical assay divided by the terminal phase elimination rate constant (Ke) computed from concentrations that were measured using a validated HPLC-MS/MS method.

  From Day 1 to Day 4

• Area Under the Concentration Time-curve From Time Zero to the Last Concentration Above the Lower Limit of Quantitation (AUC(0-last)) for Zoliflodacin

  AUC(0-last) was defined as the area under the concentration-time curve from dosing (time 0) to the time of the last measured concentration computed from concentrations that were measured using a validated HPLC-MS/MS method.

  From Day 1 to Day 4

• Apparent Volume of Distribution (Vz/F) of Zoliflodacin

  Apparent volume of distribution during terminal phase (Vz/F) after non-intravenous administration was calculated as (CL/F)/ Ke computed from concentrations that were measured using a validated HPLC-MS/MS method.

  From Day 1 to Day 4

• Apparent Oral Clearance (CL/F) of Zoliflodacin

  Apparent oral clearance (CL/F) computed as Dose/Area under the curve (AUC) from time zero to infinity (0-8) computed from concentrations that were measured using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method.

  Day 1 to Day 4

• Elimination Rate Constant (Ke) of Zoliflodacin

  The terminal phase elimination rate constant (Ke) was defined as the first-order rate constant describing the rate of decrease of drug concentration in the terminal phase (defined as the terminal region of the PK curve where drug concentration follows first-order elimination kinetics) computed from concentrations that were measured using a validated HPLC-MS/MS method.

  From Day 1 to Day 4

• Terminal Elimination Half-life (t1/2) of Zoliflodacin

  The apparent terminal elimination half-life (t1/2) was defined as the time required for the drug concentration to decrease by a factor of one-half in the terminal phase computed from concentrations that were measured using a validated HPLC-MS/MS method.

  From Day 1 to Day 4

Secondary Outcomes (24)

• Changes From Baseline for White Blood Cells With Differentials and Platelets

  From Day -1 through Day 4

• Changes From Baseline Hematocrit

  From Day -1 through Day 4

• Changes From Baseline Hemoglobin

  From Day -1 through Day 4

• Changes From Baseline Red Blood Cell Count

  From Day -1 through Day 4

• Changes From Baseline for Albumin and Total Protein

  From Day -1 through Day 4

Study Arms (1)

Zoliflodacin

EXPERIMENTAL

4 g (2 sachets of 2 g) of zoliflodacin orally in the morning of Day 1 after 8 hours of fasting, n=8

Drug: AZD0914

Interventions

AZD0914 DRUG

Zoliflodacin (also known as AZD0914 and ETX0914), is a spiropyrimidinetrione antibacterial agent

Zoliflodacin

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Informed consent form (ICF) understood and signed before initiating any study procedures
• Healthy male or female, as assessed by the authorized site clinician (listed on FDA Form 1572)
• Willingness to comply with and be available for all protocol procedures including inpatient confinement for about 4 days and availability for follow-up for the duration of the trial
• Aged 18 to 45 years inclusive on the day of study drug dosing
• Body Mass Index (BMI) \> / = 18.5 and \< / = 30 kg/m\^2 and weight \> / = 50 kg (110 lbs.) and \< / = 100 kg (220 lbs.)
• In female subjects of childbearing potential, a negative serum pregnancy test at Screening Visit and on Day -1
• \- 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)
• If female, not pregnant, not breast feeding, and not planning on becoming pregnant during the trial and for 30 days after study participation
• 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 study 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 the 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 must 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 are within the acceptable range
• Has adequate venous access for blood collection
• Urine drug screen is negative for tested substances

You may not qualify if:

• \) History of a 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; cardiovascular disease, including coronary artery disease or cerebrovascular disease, or surgery; syncope related to cardiac arrhythmia or unexplained; chronic hypertension; 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 or biliary surgery.
• \) 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 3) Active allergic symptoms to seasonal and animal allergens that require treatment 4) A marked baseline prolongation of ECG intervals, or HR \< 45 bpm or \> 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 5) 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; or any condition deemed clinically significant by a study investigator 6) 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 7) Positive serology results for HIV, HBsAg, or HCV 8) Febrile illness with temperature \> 37.6°C for \< 7 days before dosing 9) Donated whole blood or blood products within 60 days before dosing, or plans to donate before Final Visit (Day 8 ± 2)
• Note: Blood products include RBCs, WBCs, platelets, and plasma 10) Known allergic reactions to any of the study drug components present in the formulation or in its processing, as listed in the IB 11) Treatment with another investigational product within 30 days of 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 12) Active drug or alcohol use, abuse, or dependence within 12 months before Screening Visit that, in the opinion of the investigator, would interfere with adherence to study requirements 13) Use of any prescription medication within 30 days before dosing or planned use during the study period except as noted below and approved by the designated study clinician
• Note 1: Prohibited medications include moderate or strong CYP3A4 inducers; 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 7 days before or after dosing
• Note 2: Allowed medications include: oral contraceptives; H1 antihistamines; topical/ intranasal corticosteroids; nonsteroidal anti-inflammatory drugs \[NSAIDS\]; licensed influenza vaccine during the flu season, 7 days before or after dosing.
• \) Use of any non-prescription medication, herbal preparation, or nutritional supplement within 15 days before dosing or planned use during the study unless approved by the study clinician
• Note: Exceptions: St. John's wart is not allowed within 30 days of dosing, vitamins and OTC medications taken for a brief period (\<48 h) for the treatment of common symptoms (such as headache, indigestion, muscle pain) may be allowed as approved by the designated study clinician 15) Intake of caffeinated beverages or food within 72 h before dosing or a history of high caffeine consumption (e.g., in the last 4 months drinking \> 5 cups of coffee/day) 16) Smoking or use of tobacco or nicotine-containing products within 15 days before dosing 17) Engagement in strenuous exercise within 15 days before dosing (e.g., marathon running, long distance cycling, weight lifting) and during the study period 18) 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 19) 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 study period
• Note: Includes trials that have a study intervention such as a drug, biologic, or device 20) Is a study site employee or staff member who is paid entirely or partially by the OCRR/NIAID contract for the DMID-funded trial
• Note: Site employees or staff include the PIs, sub-investigators, or staff who are supervised by the PI or sub-investigators

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

Quintiles Phase I Services - Overland Park

Overland Park, Kansas, 66211-1553, United States

Location

MeSH Terms

Conditions

Gonorrhea

Interventions

zoliflodacin

Condition Hierarchy (Ancestors)

Neisseriaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Sexually Transmitted Diseases, Bacterial; Sexually Transmitted Diseases; Communicable Diseases; Genital Diseases; Urogenital Diseases

Results Point of Contact

• Title: George A. Saviolakis, MD, PhD, Medical Director
• Organization: DynPort Vaccine Company LLC, a GDIT Company

George.Saviolakis@gdit.com

1-240-651-8116

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 4, 2018
• First Posted: January 19, 2018
• Study Start: February 2, 2018
• Primary Completion: March 2, 2018
• Study Completion: March 2, 2018
• Last Updated: March 18, 2019
• Results First Posted: March 18, 2019

Record last verified: 2018-01-11

Locations

US (1)