A Phase 1, Open-Label Study in Healthy Adults to Evaluate the Safety and Pharmacokinetics of AVYCAZ(R) in Combination With Aztreonam (COMBINE)
Overview
- Phase
- Phase 1
- Intervention
- Ceftazidime-Avibactam
- Conditions
- Bacterial Infection
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Enrollment
- 48
- Locations
- 1
- Primary Endpoint
- Number of Participants With at Least One Grade 2 (Moderate) or Higher Treatment-emergent Adverse Event
- Status
- Completed
- Last Updated
- 3 years ago
Overview
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.
Detailed Description
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 continuous infusion (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. The secondary objectives of this study are to; 1) Characterize the PK profiles of two dosing regimens of AVYCAZ combined with ATM, AVYCAZ alone, and ATM alone at the population level in healthy adult subjects; 2) Characterize the PK profiles of two dosing regimens of AVYCAZ combined with ATM, AVYCAZ alone, and ATM alone following initiation of dosing on day 1 in healthy adult subjects; and 3) Characterize the PK profiles of two dosing regimens of AVYCAZ combined with ATM, AVYCAZ alone, and ATM alone following multiple daily dosing in healthy adult subjects.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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.
Exclusion Criteria
- •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.
Arms & Interventions
Arm 1
2.5g dose of ceftazidime-avibactam (AVYCAZ) administered intravenously as a 2-hour infusion, every 8 hours for 7 days. N=8
Intervention: Ceftazidime-Avibactam
Arm 2
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
Intervention: Ceftazidime-Avibactam
Arm 3
2g dose of aztreonam (ATM) administered intravenously as a 2-hour infusion, every 6 hours for 7 days. N=8
Intervention: AZACTAM
Arm 4
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
Intervention: AZACTAM
Arm 5
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
Intervention: AZACTAM
Arm 5
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
Intervention: Ceftazidime-Avibactam
Arm 6
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
Intervention: AZACTAM
Arm 6
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
Intervention: Ceftazidime-Avibactam
Outcomes
Primary Outcomes
Number of Participants With at Least One Grade 2 (Moderate) or Higher Treatment-emergent Adverse Event
Time Frame: Day 1 through Day 11
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.
Secondary Outcomes
- Accumulation Ratio for AUC (Area Under the Plasma Concentration-time Curve of Study Drug) [RAUC](Day 1 and Day 7)
- Total Body Plasma Clearance of Study Drug (CL)(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)
- Maximum Plasma Concentration of Study Drug After the First Dose (Cmax)(Day 1)
- Maximum Plasma Concentration of Study Drug Following Multiple Daily Dosing (Cmax)(Day 7)
- Renal Clearance of Study Drug (CLR)(Day 1)
- Minimum Plasma Concentration of Study Drug at the End of the Dosing Interval on Day 7 (Cmin)(Day 7)
- Minimum Plasma Concentration of Study Drug Following Multiple Daily Dosing on Day 1 (Cmin)(Day 1)
- Time of Cmax (Maximum Plasma Concentration) of Study Drug After the First Dose (Tmax)(Day 1)
- Concentration of Study Drug at Steady State After Continuous Infusion (Css)(Day 1)
- Volume of Distribution of Study Drug at Steady-state Based on the Last Observed Concentration (Vss)(Day 7)
- Time to Cmax (Maximum Plasma Concentration) of Study Drug Following Multiple Daily Dosing (Tmax)(Day 7)