A Trial to Evaluate the Pharmacokinetics and Safety of AVYCAZ(R) in Combination With Aztreonam

NCT03978091 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 17-01075UM1AI104681-09
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase I, open-label, non-randomized, single center study in 48 healthy adult male and female subjects, aged 18 to 45 years. This study is aimed to investigate the safety and pharmacokinetics of ceftazidime-avibactam (AVYCAZ) combined with aztreonam (ATM), AVYCAZ alone, and ATM alone. The study will have 6 arms, arms 1-4 are the single drug administration treatment groups and will include AVYCAZ per label dosing, AVYCAZ as a continuous infusion (CI), ATM per label dosing, and ATM as a CI. Arms 5 and 6 are the two AVYCAZ and ATM combination drug administration treatment groups. The duration of subject participation will be up to 44 days, and the total length of the study will be 15 months. The primary objective of this study is to describe the safety of two dosing regimens of AVYCAZ combined with ATM relative to AVYCAZ alone, and ATM alone in healthy adult subjects.

Conditions

Bacterial Infection

Keywords

Aztreonam; Ceftazidime-Avibactam; Efficacy; Healthy; Pharmacokinetics; Population; Safety

Outcome Measures

Primary Outcomes (1)

• Number of Participants With at Least One Grade 2 (Moderate) or Higher Treatment-emergent Adverse Event

  Adverse events include local and systemic reactions. All Grade 2 (moderate) adverse events were reported, regardless of relationship to study product. Number of participants with an AE are summarized by MedDRA system organ class (SOC). Each participant is only counted once per SOC.

  Day 1 through Day 11

Secondary Outcomes (15)

• Accumulation Ratio for AUC (Area Under the Plasma Concentration-time Curve of Study Drug) [RAUC]

  Day 1 and Day 7

• Accumulation Ratio for Cmax (Maximum Plasma Concentration) (RCmax)

  Day 1 and Day 7

• Area Under the Plasma Concentration-time Curve of Study Drug From Time of Dosing Extrapolated to Infinity [AUC(0-Inf)]

  Day 7

• Area Under the Plasma Concentration-time Curve Data of Study Drug During the Dosing Interval on Day 1 [AUC(0-Tau)]

  Day 1

• Incidence of Treatment-emergent Adverse Events, by System Organ Class (SOC) and Maximum Severity Level

  Day 1 through Day 14

Study Arms (6)

Arm 1

EXPERIMENTAL

2.5g dose of ceftazidime-avibactam (AVYCAZ) administered intravenously as a 2-hour infusion, every 8 hours for 7 days. N=8

Drug: Ceftazidime-Avibactam

Arm 2

EXPERIMENTAL

2.5g dose of AVYCAZ administered intravenously as a 2-hour infusion once, then 0.32g dose per hour daily as a continuous infusion (7.5 g/day) for 7 days. N=8

Drug: Ceftazidime-Avibactam

Arm 3

EXPERIMENTAL

2g dose of aztreonam (ATM) administered intravenously as a 2-hour infusion, every 6 hours for 7 days. N=8

Drug: AZACTAM

Arm 4

EXPERIMENTAL

2g of ATM administered intravenously as a 2-hour infusion once, then 0.33g dose administered intravenously per hour, daily as a continuous infusion (8 g/day) for 7 days. N=8

Drug: AZACTAM

Arm 5

EXPERIMENTAL

2.5g dose of AVYCAZ administered intravenously as a 2-hour infusion, every 8 hours for 7 days, and a 1.5g dose of ATM administered intravenously as a 2-hour infusion, every 6 hours for 7 days. N=8

Drug: AZACTAM; Drug: Ceftazidime-Avibactam

Arm 6

EXPERIMENTAL

2.5 g dose of AVYCAZ administered intravenously as a 2-hour infusion every 8 hours for 7 days, and a 2g dose of ATM as a 2-hour infusion every 6 hours for 7 days. N=8

Drug: AZACTAM; Drug: Ceftazidime-Avibactam

Interventions

AZACTAM DRUG

A synthetic monobactam antibiotic originally isolated from Chromobacterium violaceum

Arm 3; Arm 4; Arm 5; Arm 6

Ceftazidime-Avibactam DRUG

An antibacterial combination product containing ceftazidime and avibactam

Arm 1; Arm 2; Arm 5; Arm 6

Eligibility Criteria

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

You may qualify if:

• Provide a signed and dated written informed consent.
• Be able to understand and willing to comply with study procedures, restrictions, and requirements, as determined by the Principal Investigator (PI).
• Male and female volunteers aged 18 to 45 years inclusive.
• Suitable veins for cannulation or repeated venipuncture.
• Subject must be in good general health as judged by the investigator as determined by medical history, vital signs\*, body mass index (BMI) and body weight\*\*, clinical laboratory values\*\*\*, and physical examination (PE).
• \*Oral temp \<38.0 degrees Celsius/100.4 degrees Fahrenheit; pulse 50 to 100 bpm; systolic blood pressure 90 to 140 mm Hg, and diastolic blood pressure 55 to 90 mmHg.
• \*\*BMI between 19-33 kg/m\^2 and body weight \> / = 50 kg
• \*\*\*Clinical chemistry, hematology, coagulation and urinalysis results within the clinical laboratory reference ranges; clinical laboratory values outside these ranges, if considered by the site investigator to be clinically insignificant, are also acceptable
• Sexually active female subjects must be of non-childbearing potential\*\*\*\* or must use a highly effective method of birth control\*\*\*\*\*.
• \*\*\*\*Non-childbearing potential is defined as being post-menopausal for at least 18 months or surgically sterile via hysterectomy, bilateral oophorectomy, or tubal sterilization.
• \*\*\*\*\*Sexually active female subjects of childbearing potential must avoid becoming pregnant by using one of the following acceptable methods of birth control for 30 days prior to study product dosing and must be maintained for 30 days after last dose of study product: Intrauterine contraceptive device; OR Approved hormonal contraceptives (such as birth control pills, skin patches, Implanon(R), Nexplanon(R), DepoProvera(R) or NuvaRing(R)); OR Birth control must be captured on the appropriate data collection form.
• Sexually active male subjects must be vasectomized or agree to use barrier contraception (condom with spermicide) from first dose of study product until 30 days following the last dose of study product.
• Nonsmokers defined as abstinence from cigarette smoking or use of nicotine-containing products for 6 months prior to enrollment into the study.

You may not qualify if:

• History of any clinically significant (CS) disease or disorder, medical/surgical procedure, or trauma within 4 weeks prior to the first administration of study product(s)\*.
• \*In the opinion of the PI, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer's ability to participate in the study
• History or presence of gastrointestinal, hepatic, or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• Known history of a clinically important allergy/hypersensitivity to AVI, any monobactam, any beta-lactam and/or L-arginine.
• Receipt of probenecid or furosemide within 14 days prior to study enrollment.
• Receipt of any antibiotics within 14 days prior to study enrollment.
• Receipt of prescription medications (except birth control pills or hormone replacement in females) within 14 days prior to study enrollment, unless in the opinion of site investigator the medication will not interfere with the study procedures or impact subject safety.
• Receipt of non-antibiotic medications that interacts with OAT3\*\* within 14 days prior to study enrollment.
• \*\*Adefovir, Anagliptin, Baricitinib, Cefaclor, Cimetidine, Ciprofloxacin (Systemic), Clofarabine, Eluxadoline, Empagliflozin, Furosemide, Ketoprofen, Methotrexate, Mycophenolate, PEMEtrexed, Penicillin G (Parenteral/Aqueous), Penicillin G Benzathine, Penicillin G Procaine, Penicillin V Benzathine, Penicillin V Potassium, Zidovudine
• Receipt of herbal and dietary supplements (including St. John's Wort) within 14 days prior to study enrollment.
• ALT or AST laboratory value above the ULN as defined in the toxicity table.
• Prolonged QTcF (\> 450 msec) or shortened QTcF (\< 340 msec) or family history of long QT syndrome. Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG\*\*\*.
• \*\*\*Abnormalities that may interfere with interpretation of QTc interval changes per the medical judgment of the PI.
• Any positive result on screening for human immunodeficiency virus (HIV) serum hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV) antibody.
• Creatinine clearance equal or less than 80 mL/minute (measured by Cockcroft-Gault method).

Sponsors & Collaborators

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

Study Sites (1)

Duke University School of Medicine - Duke Clinical Research Institute - Duke Clinical Research Unit

Durham, North Carolina, 27710-4000, United States

Location

MeSH Terms

Conditions

Bacterial Infections

Interventions

Aztreonam; avibactam, ceftazidime drug combination

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Monobactams; beta-Lactams; Lactams; Amides; Organic Chemicals; Sulfur Compounds; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Thomas Lodise, PharmD, PhD
• Organization: ARLG - Albany College of Pharmacy and Health Sciences

Thomas.Lodise@acphs.edu

1 (518) 694-7292

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: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 23, 2019
• First Posted: June 6, 2019
• Study Start: July 9, 2019
• Primary Completion: November 23, 2020
• Study Completion: November 23, 2020
• Last Updated: June 7, 2022
• Results First Posted: December 23, 2021

Record last verified: 2020-02-07

Locations

US (1)