A Study to Investigate the Effect of Administration of Ceftazidime-avibactam (CAZ-AVI) and Ceftaroline Fosamil -Avibactam (CXL) on the Intestinal Flora of Healthy Volunteers

Study Overview
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Brief Summary
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The purpose of this study is to investigate the effect of administration of CAZ-AVI and CXL on the intestinal flora of male and female healthy volunteers after multiple administrations over 7 days. An assessment of the effect on intestinal flora is an important aspect to understand for the safe clinical use of the investigational products and is expected by regulatory agencies.

Official Title
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A Phase 1, Open-label, Multiple-dose, Single Centre Study to Investigate the Effect of Administration of CAZ-AVI and CXL on the Intestinal Flora of Healthy Volunteers.

Conditions
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CXL, Pharmacokinetics, Open Label, CAZ-AVI, Effect on Intestinal Flora, Safety

Intervention / Treatment
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* Drug: CAZ-AVI
* Drug: CXL


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 male and female volunteers aged 18 to 45 years (inclusive) with suitable veins for cannulation or repeated venepuncture. Females: Female healthy volunteers are authorised to participate in this study if both of the following criteria are met: A negative serum pregnancy test BOTH at screening AND at admission to the study centre. Agrees not to attempt pregnancy while receiving investigational product and for a period of 7 days after last investigational product administration, and agrees to the use of acceptable methods of contraception (according to instructions) prior to, during, and for 7 days after the last investigational product administration. Have a body mass index (BMI) between 19 and 30 kg/m2. Exclusion Criteria: History or presence of gastrointestinal, hepatic, or renal disease or any other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs. Any clinically significant abnormalities in physical examination, ECG, clinical chemistry, haematology, coagulation, or urinalysis results, as judged by the investigator. Pregnant or breastfeeding female healthy volunteers. History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the healthy volunteer at risk because of participation in the study, or influence the results or the healthy volunteer's ability to participate in the study. Known history of Clostridium difficile infection in last 3 months.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAZ-AVI or CXL<br>Cohort 1: CAZ-AVI (2000 mg ceftazidime and 500 mg avibactam) by intravenous infusion given over 2 hours, every 8 hours Cohort 2: CXL (600 mg ceftaroline fosamil and 600 mg avibactam) | Drug: CAZ-AVI<br>* IV infusion<br>* Other names: Cohort 1;Drug: CXL<br>* IV infusion<br>* Other names: Cohort 2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the intestinal flora of healthy subjects after administration of ceftazidime-avibactam (CAZ-AVI) and ceftaroline fosamil -avibactam (CXL). | The number and types of microorganisms in faeces. | Change from baseline (Day-1) at Day 2, 5, 7, 10, 14 and 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability | Adverse event, ECG, safety laboratory assessments, physical examinations and vital signs. | Screening up to 12 days after discharge from study site | 
| Pharmacokinetics of CAZ-AVI in healthy volunteers | On Day 7, the following pharmacokinetic parameters will be calculated when applicable: Maximum plasma concentration (Cmax), time of Cmax (tmax), time of last quantifiable plasma concentration (last), area under the plasma concentration-time curve during the dosing interval (AUC(0-τ)), area under the plasma concentration time curve from zero to the time of the last quantifiable concentration (AUC(0-t)), half-life (t½), systemic plasma clearance (CL), apparent plasma clearance (CL/F), volume of distribution at steady state (Vss), and apparent volume of distribution (Vz/F). | Days 1, 2 and 5: Pre-dose and 2 hours post dose. Day 7: pre-dose, 0.5, 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 6, 8, 12, and 24 hours post dose (Day 8) | 
| Pharmacokinetics of CXL in healthy volunteers | On Day 7, the following pharmacokinetic parameters will be calculated when applicable: Maximum plasma concentration (Cmax), time of Cmax (tmax), time of last quantifiable plasma concentration (last), area under the plasma concentration-time curve during the dosing interval (AUC(0-τ)), area under the plasma concentration time curve from zero to the time of the last quantifiable concentration (AUC(0-t)), half-life (t½), systemic plasma clearance (CL), apparent plasma clearance (CL/F), volume of distribution at steady state (Vss), and apparent volume of distribution (Vz/F). | Days 1, 2 and 5: Pre-dose and 1 hour post dose. Day 7: pre-dose, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 5, 7, 8, 12, and 24 hours post dose (Day 8) | 
| To measure CAZ-AVI and CXL plasma and faecal concentrations using bioactivity techniques. | The concentrations of CAZ-AVI and CXL will be determined in plasma and faecal samples. | Day -1, 2, 5, 7, 10, 14 and 21 | 
| To describe the in vitro susceptibility of new colonizing bacteria of the intestinal microflora to CAZ-AVI and CXL during and after CAZ-AVI and CXL administration. | Minimal inhibitory concentration (MIC) for CAZ-AVI and CXL will be determined for new colonizing bacteria from faecal samples. | Day -1, 2, 5, 7, 10, 14 and 21 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase I,, open label,, CAZ-AVI,, CXL,, healthy volunteers,, intestinal flora.