To Investigate the Safety and Tolerability of Aztreonam-Avibactam (ATM-AVI)

Study Overview
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Brief Summary
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This is a randomised, double-blind, 3-part study designed to investigate the safety and tolerability of ATM-AVI. The study aims to characterise the pharmacokinetics of ATM-AVI, when both drugs are administered alone (ATM or AVI) and in combination (ATM-AVI), following single administration, and following multiple administrations of ATM-AVI in healthy male and female (females of nonchildbearing potential) volunteers both young and elderly.

Detailed Description
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A Phase I, Randomised, Double-blind, 3-Part Study in Healthy Young and Elderly Subjects to Assess the Safety and Tolerability, and Investigate the Pharmacokinetics of Aztreonam and Avibactam given Alone and in Combination (ATM-AVI)

Official Title
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A Phase I, Randomised, Double-blind, 3-Part Study in Healthy Young and Elderly Subjects to Assess the Safety and Tolerability, and Investigate the Pharmacokinetics of Aztreonam and Avibactam Given Alone and in Combination (ATM-AVI)

Conditions
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Complicated Infection, Bacterial Infections

Intervention / Treatment
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* Drug: Avibactam (AVI)
* Drug: Aztreonam (ATM)
* Drug: combination of Aztreonam - Avibactam (ATM-AVI)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated, written informed consent prior to any study specific procedures Healthy young male and female volunteers aged 18 to 45 years (inclusive) and healthy elderly volunteers aged 65 or older (Part C) with suitable veins for cannulation or repeated venipuncture Have a body mass index (BMI) between 19 and 30 kg/m2 Be able to understand and willing to comply with study procedures, restrictions, and requirements, as judged by the PI Exclusion Criteria: History of any clinically significant disease or disorder which, 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 severe allergy to betalactam and/or L-arginine History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the PI or history of hypersensitivity to drugs with a similar chemical structure or class to ATM or AVI Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks prior to the first administration of IP

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Drug: A<br>Avibactam (AVI) | Drug: Avibactam (AVI)<br>* PART A: AVI IV infusion<br>|
| Experimental: Drug: B<br>Aztreonam (ATM) | Drug: Aztreonam (ATM)<br>* PART A: ATM IV infusion<br>|
| Experimental: Drug: C<br>combination of Aztreonam-Avibactam (ATM-AVI) | Drug: combination of Aztreonam - Avibactam (ATM-AVI)<br>* PART A: ATM-AVI IV infusion. PART B and C: ATM-AVI IV infusions.<br>|
| Placebo Comparator: Drug: D<br>Matching Placebo | Drug: Placebo<br>* PART A, PART B, PART C: matching placebo IV infusions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Profile - Number of Subjects With at Least 1 AE | from screening visit (Day -28) to 3 to 7 days post treatment period 3 (up to Day 22) in Part A, 3 to 7 days after receiving the final dose on Day 11 (days 14 to 18) in Part B, and 3 to 7 days after receiving the final dose on Day 10 (days 13 to 17) in Part C. | Informed consent (up to 28 days before first dose) to follow up period (max of 22 days after first dose for Part A, a max of 28 days after first dose in Part B, max 17 days in Part C) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK- Plasma Pharmacokinetic Parameter AUC (ug*h/mL) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Area under the plasma concentration-time curve from zero extrapolated to infinity (AUC µg*h/mL) or AUC(0-last) in Part A on Day 1 after single infusion, area under the plasma concentration-time curve at steady state after multiple infusion (AUCss µg*h/mL). | 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C | 
| PK- Plasma Pharmacokinetic Parameter t1/2(h) for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Terminal half-life (t1/2), on Day 1 after single infusion and at steady state after multiple infusion. | 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C | 
| PK- Plasma Pharmacokinetic Parameter Tmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) on Day 1 in Parts A, B and C | Time to Cmax (tmax) | Day 1 | 
| PK- Plasma Pharmacokinetic Parameter Cmax for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Maximum plasma concentration (Cmax µg/mL) on Day 1 after single infusion , maximum plasma concentration at steady state (Css,max µg/mL) after multiple infusion. | 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C | 
| PK- Plasma Pharmacokinetic Parameters CL and CLr for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Systemic clearence (CL) and renal clearance (CLr) on Day 1 after single infusion and at steady state after multiple infusion. | 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C | 
| PK- Plasma Pharmacokinetic Parameter Vss for Aztreonam (ATM) and Avibactam (AVI) Alone and in Combination (ATM-AVI) in Parts A, B and C | Volume of distribution at steady state (Vss). | 0 to 24 hours post-dose on Day 1 in Part A. 0 to 24 hours post-dose on Days 1, 2, 4 and 11 in Part B (varied intervals per cohort). 0 to 6 hours post-dose on Days 1, 4, 7 and 10 in Part C. Steady state measure on Day 11 in Part B or Day 10 in Part C | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase I, Safety, tolerability, healthy.