A Phase I Study to Assess the Safety, Tolerability and PK of Ceftazidime-Avibactam in Healthy Chinese Subjects

Study Overview
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Brief Summary
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Investigate the safety and tolerability, as well as PK profile of ceftazidime-avibactam (CAZ -AVI) administered in single and repeated intravenous (IV) infusions in healthy Chinese subjects.This study data will be used to support CAZ-AVI NDA in China.

Official Title
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A Phase I, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of Ceftazidime-Avibactam Administered as Single and Repeated Intravenous Doses in Healthy Chinese Subjects

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: CAZ-AVI
* Drug: 0.9% Normal Saline


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Provision of signed and dated, written informed consent prior to any study-specific procedures. Healthy male and female (of non-child bearing potential) Chinese subjects, with suitable veins for cannulation or repeated venipuncture BMI 19 to 24 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg. Key Exclusion Criteria: Any clinical condition requiring the regular use of any medication. Consumption of alcohol, drug, tobacco (cigarettes). Sensitive to any food, or any serious reaction to carbapenem, cephalosporin, or other β-lactam antibiotics. Severe medical or psychiatric condition or laboratory abnormality. Blood donation. 12 lead ECG abnormal.

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>IV infusions of 0.9% normal saline | Drug: 0.9% Normal Saline<br>* A single 120 minute IV infusion on Day 1, followed by three times daily (every 8 hours, q8h) as 120 minute IV infusions for 7 days (Day 2 to Day 8), and one single 120 minute IV infusion on Day 9.<br>|
| Experimental: CAZ-AVI<br>IV infusion of AVI 500 mg + CAZ 2000 mg. | Drug: CAZ-AVI<br>* A single 120 minute IV infusion on Day 1, followed by three times daily (every 8 hours, q8h) as 120 minute IV infusions for 7 days (Day 2 to Day 8), and one single 120 minute IV infusion on Day 9.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability:Adverse events, vital signs, ECGs, clinical laboratory measurements, physical examinations, oral body temperature | AE: The onset of an AE relative to treatment will be calculated as the time difference between the onset (date and time) of the AE and the start time of the last dose (date and time) prior to the AE; the duration of a resolved AE will be calculated as the difference between the resolution (date and time) of the AE and the onset (date and time) of the AE. Vital signs and oral temperature:Change in BP, pulse rate and oral temperature at each post treatment time point will be calculated as the post treatment measurement value minus the baseline value observed on Day -1. Physical examination: complete physical examination and brief physical examination. ECG: heart rate, RR, PR, QRS, and QT intervals from the 12-lead ECG and the derived variable QTcF. Safety laboratory (hematology, chemistry and urinalysis): Change in laboratory test value at each post treatment time point will be calculated as the post treatment value minus the baseline value observed on Day -1 . | Routine safety assessments, throughout the period that subjects receive CAZ-AVI/PLACEBO up to 5 days following discontinuation of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma PK parameters for CAZ and AVI of single dose: Cmax, tmax, Clast, tlast, AUC(0-t), AUC, AUC(0-8), λz, t1/2, Vss, Vz, CL, MRT, etc. |  | single IV infusion on Day 1 | 
| Plasma PK parameters for CAZ and AVI of multi dose: the trough concentration Cmin |  | Days 6, 7, 8 | 
| Plasma PK parameters for CAZ and AVI of repeated infusion: Cmax, tmax, Clast, tlast, AUC(0-t), AUC, AUC(0-8), λz, t1/2, Vss, Vz, CL, MRT, etc. |  | After repeated infusion On Day 9 | 
| Urine PK parameters for CAZ and AVI of single and repeated infusion: Cumulated urinary excretion (amount), percentage of cumulated urinary recovery (% dose) and renal clearance (CLr) |  | Day 1 and Day 9 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAZ-AVI China phase I PK study