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

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.

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.

Study Overview

• Status: Completed
• Conditions: Pharmacokinetics; Safety; Open Label; CAZ-AVI; CXL; Effect on Intestinal Flora
• Intervention / Treatment: Drug: CAZ-AVI; Drug: CXL

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Stockholm, Sweden
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Provision of signed and dated, written informed consent prior to any study specific procedures

2. 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:

   1. A negative serum pregnancy test BOTH at screening AND at admission to the study centre.
   2. 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.
3. Have a body mass index (BMI) between 19 and 30 kg/m2.

Exclusion Criteria:

1. 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.
2. Any clinically significant abnormalities in physical examination, ECG, clinical chemistry, haematology, coagulation, or urinalysis results, as judged by the investigator.
3. Pregnant or breastfeeding female healthy volunteers.
4. 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.
5. Known history of Clostridium difficile infection in last 3 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: CAZ-AVI or CXL; 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; IV infusion; Other Names: Cohort 1; Drug: CXL; IV infusion; Other Names: Cohort 2

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Study Director: Paul Newell, MD, AstraZeneca R&D, Alderly Park, Mereside, SK 104TG, Macclesfield, Cheshire, United Kingdom; Study Chair: Sandhia Ponnarambil, MD, AstraZeneca R&D Alderly Park, Parklands, SK 104TF, Macclesfield, Cheshire, United Kingdom; Principal Investigator: Georgios Panagiotidis, MD, Clinical Pharmacology Trial Unit, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden

Study record dates

Study Major Dates

• Study Start: August 1, 2013
• Primary Completion (ACTUAL): March 1, 2014
• Study Completion (ACTUAL): March 1, 2014

Study Registration Dates

• First Submitted: February 4, 2013
• First Submitted That Met QC Criteria: February 11, 2013
• First Posted (ESTIMATE): February 12, 2013

Study Record Updates

• Last Update Posted (ACTUAL): September 5, 2017
• Last Update Submitted That Met QC Criteria: September 1, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: Phase I,; healthy volunteers,; open label,; CAZ-AVI,; CXL,; intestinal flora.
• Other Study ID Numbers: D4280C00023