PHASE 1,STUDY TO ASSESS THE PHARMACOKINETICS, SAFETY AND TOLERABILITY OF CEFTAZIDIMEAVIBACTAM (CAZ-AVI) IN CHILDREN FROM 3 MONTHS TO LESS THAN 18 YEARS OF AGE WHO ARE HOSPITALIZED AND RECEIVING SYSTEMIC ANTIBIOTIC THERAPY FOR SUSPECTED OR CONFIRMED NOSOCOMIAL PNEUMONIA, INCLUDING VENTILATOR-ASSOCIATED PNEUMONIA

PHRR200909-002908

C3591025

2020-CT0537

A PHASE 1, OPEN LABEL, SINGLE DOSE STUDY TO ASSESS THE PHARMACOKINETICS, SAFETY AND TOLERABILITY OF CEFTAZIDIME AVIBACTAM (CAZ AVI) IN CHILDREN FROM 3 MONTHS TO LESS THAN 18 YEARS OF AGE WHO ARE HOSPITALIZED AND RECEIVING SYSTEMIC ANTIBIOTIC THERAPY FOR SUSPECTED OR CONFIRMED NOSOCOMIAL PNEUMONIA, INCLUDING VENTILATOR ASSOCIATED PNEUMONIA

This is a multicenter, multinational, open-label single-dose pharmacokinetic (PK) study enrolling at least 32 subjects. The study aims to characterize the PK of CAZ-AVI and assess its safety and tolerability following a single intravenous (IV) infusion. Subjects will be hospitalized pediatric patients who are receiving systemic antibiotic therapy for suspected or confirmed nosocomial pneumonia (NP) defined as pneumonia with onset ≥48 hours after admission or within 7 days of discharge from an inpatient care facility, including ventilator-associated pneumonia (VAP), defined as a parenchymal lung infection arising ≥48 hours after endotracheal intubation and mechanical ventilation. Subjects will be enrolled in 4 cohorts of descending age, each consisting of at least 8 evaluable subjects.

Terminated

The decision to terminate the study is not based on any safety concerns. On 22 October 2020 the European Medicines Agency determined there was sufficient data available from other pediatric and adult studies to grant CAZ-AVI an indication for pediatric Hospital Acquired Pneumonia/Ventilator Associated Pneumonia (HAP/VAP). Pfizer now believes that sufficient PK data accumulated to date in study C3591025, combined with other pediatric data in other infection types and adult data in this indication can support further regulatory approvals of CAZ-AVI for pediatric HAP/VAP.

suspected or confirmed nosocomial pneumonia (NP), also known as hospital-acquired pneumonia (HAP), including the subtype of ventilator-associated pneumonia (VAP)

• CAZ and AVI plasma concentrations by nominal time.
• CAZ and AVI PK parameters calculated by non-compartmental analysis (Cohorts1 and 2 only)

 Safety and tolerability endpoints include adverse events (AEs), serious adverse events (SAEs), deaths, discontinuations due to AEs and laboratory abnormalities.

Terminated

• Australia
• Brazil
• China
• Czech Republic
• Estonia
• Greece
• Hungary
• India
• Italy
• Lithuania
• Netherlands
• Philippines
• Romania
• Slovakia
• Taiwan
• Ukraine
• United Kingdom
• United States

Clinical Trial

20200416141031

2020-08-07

0000-00-00

14

Unspecified

Unspecified

2020-09-30

Inclusion Criteria

1. Evidence of a personally signed and dated informed consent document indicating that the subject’s parent(s), legal guardian, or legally acceptable representative has been informed of all pertinent aspects of the study. As appropriate per local requirements informed assent of subjects must also be documented.
2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Male or female children age ≥3 months to

a. Cohort 1: age 12 years to

b. Cohort 2: age 6 years to

c. Cohort 3: age 2 years to

d. Cohort 4: age 3 months to

4. Hospitalized, receiving systemic antibiotic therapy for the treatment of a suspected or confirmed HAP ,including VAP, meeting the following criteria, and expected to require hospitalization until after the follow-up evaluations are completed on Day3 (48 hours after the end of infusion):

a. Onset of symptoms ≥48 hours after admission or

b. Evidence of new or worsening infiltrate as demonstrated on chest X-ray or other imaging modality that has been performed as part of the subject’s regular medical care;

c. At least 1 of the following systemic signs prior to the initiation of treatment for Nosocomial Pneumonia:

i. Fever (temperature >38°C) or hypothermia (rectal/core temperature <35°C);

ii. White blood cell (WBC) count >10,000 cells/mm3, or WBC count <4,500cells/mm3, or >15% band forms.

d. At least 2 of the following respiratory signs or symptoms:

i. A new onset of cough (or worsening of cough);

ii. Production of purulent sputum or endotracheal secretions;

iii. Auscultatory findings consistent with pneumonia/pulmonary consolidation (e.g., rales, rhonchi, bronchial breath sounds, dullness to percussion, egophony);

iv. Dyspnea, tachypnea or hypoxemia (O2 saturation <90% or PaO2

v. A need for mechanical ventilation or, for already ventilated subjects, acute changes made in the ventilator support system to enhance oxygenation, as determined by, for example arterial blood gas or worsening PaO2/FiO2.

5. Likely to survive the current illness or hospitalization.

 6. Sufficient IV access (peripheral or central) to receive study drug and dedicated access for PK sampling.

Exclusion Criteria

1. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study.

2. Participation in other studies involving investigational drug(s) within30 days prior to study entry and/or during study participation.

3. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study.

4. Past or current history of epilepsy or seizure disorder (excluding childhood febrile seizures.

5. Severe renal impairment defined as creatinine clearance (CrCL) ≤30 mL/min/1.73m2 calculated using the child’s measured height (length) and serum creatinine with the Bedside Schwartz equation

6. Documented history of any hypersensitivity or allergic reaction to any β-lactam antibiotic.

7. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and female subjects of childbearing potential who are sexually active and unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after the last dose of CAZ-AVI.

8. Acute hepatitis in the prior 6 months, a prior history of cirrhosis, acute hepatic failure, or acute decompensation of chronic hepatic failure; and/or any of the following blood test results, for any individual, when assessed for eligibility:

a. Bilirubin >3 × upper limit of normal (ULN), unless isolated hyperbilirubinemia is directly related to the acute infection or due to known Gilbert’s disease;

b. ALT or AST >3 × ULN values used by the laboratory performing the test. Subjects with values >3 × ULN and

c. ALP >3 × ULN. Subjects with values >3 × ULN and

9. Any condition (e.g., septic shock, burns, cystic fibrosis, acute hemodynamic instability, including those conditions not responding to pressor support) that would make the patient, in the opinion of the Investigator, unsuitable for the study (e.g., would place a patient at risk; compromise the quality of the data; or interfere with the absorption, distribution, metabolism, or excretion of CAZ-AVI).

10.Receipt of a blood or blood component or scheduled for transfusion within the PK sampling period (e.g., red blood cells, fresh frozen plasma, platelets) transfusion during the 24-hour period before enrollment.

11.Body mass index (BMI)below the 5th percentile or above the 95th percentile for height, age, and weight except for children

12.Treatment with ceftazidime within 12 hours of CAZ-AVI administration or treatment with ceftazidime within 24 hours of CAZ-AVI administration in subjects with renal impairment (CrCL ≤50 mL/min/1.73 m2).

13.Treatment with potent inhibitors of OAT1 and/or OAT3 (e.g., probenecid, p-aminohippuric acid (PAH), or teriflunomide).

Interventional

Zavicefta (Ceftazidime-Avibactam)

The investigational product, Zavicefta (ceftazidime 2 g/avibactam 0.5 g), will be supplied by Pfizer as a white to yellow powder for concentrate for solution for infusion in a 20 mL glass vial. Each vial contains a fixed dose combination of ceftazidime pentahydrate equivalent to 2 g ceftazidime and avibactam sodium equivalent to 0.5 g avibactam.

None

Non-Randomized

Open Label

Unspecified

Single

Primary Objective:

To characterize the pharmacokinetics (PK) of a single intravenous dose of CAZ-AVI in pediatric subjects aged 3months to less than 18 years who are receiving systemic antibiotic therapy for suspected or confirmed nosocomial pneumonia, including ventilator-associated pneumonia.

Secondary Objective:

To evaluate the safety and tolerability of a single intravenous dose of CAZ-AVI in pediatric subjects aged 3months to less than 18 years with nosocomial pneumonia, including ventilator-associated pneumonia.

Exploratory Objective:

To determine CAZ-AVI concentrations in bronchial epithelial lining fluid (ELF) by bronchoalveolar lavage (BAL) from subjects undergoing bronchoscopy for their clinical management if bronchoscopy with BAL is performed within the PK sampling interval after CAZ-AVI infusion.

Phase I