A Single Ascending Dose Study of AV-006 in Healthy Subjects

A Placebo Controlled, Double Blind, Single Ascending Dose Study of AV-006 in Healthy Subjects

Characterization of the single dose pharmacokinetics of AV-006 in healthy male and female subjects. Description of safety and tolerability of AV-006 in healthy subjects

Study Overview

• Status: Unknown
• Conditions: Bacterial Infections
• Intervention / Treatment: Drug: Placebos; Drug: AV-006

Detailed Description

The present study is a first in human study of an avibactam prodrug to be administered orally. Avibactam is the β-lactamase inhibitor (BLI) component of the intravenous antibiotic AVYCAZQR (ceftazidime avibactam), approved in the US in 2015 to treat resistant Gram-negative infections. Avibactam is a non-β-lactam BLI without intrinsic antibacterial activity. Avibactam binds covalently with bacterial β-lactamases thereby preventing hydrolysis and inactivation of the partner β-lactam antibiotic.

Arixa and others have shown that that avibactam (the product of AV-006) restores the susceptibility of many oral β-lactam antibiotics against broad panels of clinical Enterobacteriaceae isolates that produce β-lactamases.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Nucleus Network

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female subjects age 18-55 (inclusive).
2. Good general health, with no significant medical history. Subjects must have no clinically significant abnormalities on physical examination at screening, and/or before administration of study drug
3. Body weight ≥ 50 kg at the screening visit
4. Body Mass Index (BMI) between 18 and 32 kg/m2 inclusive.
5. Has laboratory values (clinical chemistry and hematology) within the normal reference range. Deviations from this range may be acceptable if they are considered not clinically significant' (NCS) by the PI

6. Women of childbearing potential may be enrolled if one of the following criteria applies:

   1. Must be using two methods of contraception, consisting of (1) a highly-effective method associated with a < 1% failure rate when used correctly and consistently (e.g. hormonal contraception methods associated with suppression of ovulation or an IUD) and (2) partner use of a condom. Contraception should have been used for at least one month prior to study entry, the subject must have maintained a normal menstrual pattern for the three months prior to study entry and have a negative pregnancy test (urine) at the time of admission to the unit. Women must be willing to continue this contraception for 45 days following administration of study drug
   2. Is abstinent from heterosexual intercourse where this is consistent with the participant's usual and preferred lifestyle
   3. Is monogamous with a vasectomized partner (>3 months prior)
   4. Is postmenopausal (i.e., no cycle for at least the previous 12 months, is of menopausal age (> 45 years) and has a negative pregnancy test (urine) both at Screening and Day -1)
   5. Is surgically sterilized (confirmed by medical record review)
   6. Has had a total hysterectomy a minimum of 3 months prior to dosing on Day 1 (confirmed by medical record review)

7. Males who are sexually abstinent may be enrolled or, if sexually active, may be enrolled if one of the following criteria applies:

   1. Has had a vasectomy (>3 months prior to study entry, confirmed by medical record review)
   2. Using condoms and whose partner is using an acceptable form of contraception (IUD, oral contraceptives, birth control patch or vaginal ring, injectable or implanted contraceptives, or tubal ligation [surgical sterilization]) from Day -1 to 90 days after study drug administration
8. Understands the study procedures and agrees to participate in the study by giving written informed consent
9. Is a non-smoker (i.e. fewer than 4 cigarettes in 12 weeks prior to screening) Able and willing to attend the necessary visits to the study center

Exclusion Criteria:

1. Blood donation or recipient of blood transfusion in previous 30 days.
2. History of clinically significant endocrine, neurological, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases.
3. History of neoplastic disease (except adequately-treated non-melanomatous skin carcinoma)
4. Mentally or legally incapacitated, ie has significant emotional problems at the time of Screening Visit or expected during the conduct of the study, or has a history of a clinically significant psychiatric disorder within the last 5 years
5. Fever (body temperature >38◦C) or symptomatic viral/bacterial infection or use of antibiotics within 2 weeks prior to Screening
6. Resting blood pressure (BP) >140/90 mmHg or heart rate (HR) >100 beats per minute at Screening or at Day -1 (vital signs to be taken with subject in semi- recumbent position)
7. Clinically significant abnormality on ECG performed at the Screening Visit or prior to administration of the initial dose of study drug. (Screening and predose ECG conduction intervals (corrected for heart rate) must be within the normal range).
8. Clinically significant laboratory abnormalities. Impaired renal function (which should be determined on the Screening day only) to be estimated using creatinine clearance (CrCl) of <80 mL/minute based on the appropriate formula for calculation of CrCL [calculation to be performed by laboratory responsible]
9. Positive test for hepatitis C antibody, hepatitis B surface antigen, or human immunodeficiency virus (HIV) antibody at Screening
10. Participants with a positive toxicology screening panel (urine test including qualitative identification of barbiturates, tetrahydrocannabinol, amphetamines, benzodiazepines, opiates and cocaine)
11. Participants with a history of substance abuse or dependency or history of recreational IV drug use (by self-declaration)
12. Alcohol consumption >14 alcohol units per week. (One unit of alcohol is 10 ml, in- formation on calculation the content of drinks is provided at: http://www.alcohol.gov.au/internet/alcohol/publishing.nsf/Content/standard)
13. Unable to refrain from or anticipates the use of any medications, including prescription and non-prescription drugs and herbal remedies (such as St. John's Wort [Hypericum perforatum]), beginning 14 days (or 5 half-lives, whichever is longer) before administration of the initial dose of study drug and continuing throughout the study until the final study visit. There may be certain medications that are permitted at the discretion of the Investigator and Sponsor (including paracetamol/acetaminophen, medications for the treatment of AEs following administration of study drug
14. Subjects who are unlikely to comply with the study protocol or, in the opinion of the investigator, would not be a suitable candidate for participation in the study.
15. Have participated in any other investigational drug trial within 30 days of dosing in the present stud
16. Known intolerance of or sensitivity to avibactam

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; placebo	Drug: Placebos; Single ascending dose administration
ACTIVE_COMPARATOR: Active; AV-006	Drug: AV-006; Single ascending dose administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of treatment related adverse events, vital signs data, ECGs, clinical laboratory tests of AV-006 following oral administration	7 days

Collaborators and Investigators

• Sponsor: Arixa Pharmaceuticals
• Investigators: Principal Investigator: Jason Lickliter, PhD, Nucleus Network

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): June 24, 2019
• Primary Completion (ANTICIPATED): September 1, 2019
• Study Completion (ANTICIPATED): November 1, 2019

Study Registration Dates

• First Submitted: April 25, 2019
• First Submitted That Met QC Criteria: April 26, 2019
• First Posted (ACTUAL): April 30, 2019

Study Record Updates

• Last Update Posted (ACTUAL): May 1, 2019
• Last Update Submitted That Met QC Criteria: April 29, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Bacterial Infections
• Other Study ID Numbers: Arixa-AV-006-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No