Single-dose PK Study of Ceftazidime-Avibactam In Hospitalized Children Receiving Systemic Antibiotics for Nosocomial Pneumonia

Sponsor
Pfizer (Industry)
Overall Status
Terminated
CT.gov ID
NCT04040621
Collaborator
AbbVie (Industry)
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Study Details

Study Description

Brief Summary

This is a multicenter, multinational, open label single dose pharmacokinetic (PK) study enrolling at least 32 subjects. The study aims to characterize the pharmacokinetics (PK) of a single intravenous dose of CAZ AVI in pediatric subjects aged 3 months to less than 18 years who are receiving systemic antibiotic therapy for suspected or confirmed nosocomial pneumonia, including ventilator associated pneumonia.

Detailed Description

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), including ventilator associated pneumonia (VAP). The study will consist of a Screening visit (Visit 1, Day 1), during which consent will be obtained and subject eligibility will be confirmed, a Baseline/Treatment visit (Visit 2, Day

  1. during which subjects will receive a single IV infusion of CAZ AVI, and then two follow up assessment visits at 24 hours (Visit 3, Day 2) and 48 hours (Visit 4, Day 3). Blood samples for PK analyses (0.5 mL per sample) will be obtained over 22 hours for Cohort 1 (7 samples), over 13 hours for Cohort 2 (6 samples), and over 6 hours for Cohorts 3 and 4 (4 samples). Additionally, for subjects who are undergoing bronchoalveolar lavage (BAL) for clinical purposes and for whom informed consent is obtained specifically for BAL, an epithelial lining fluid (ELF) sample will be collected for estimation of CAZ AVI concentrations.

Study Design

Study Type:
Interventional
Actual Enrollment :
4 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Intervention Model Description:
Non-randomized, single armNon-randomized, single arm
Masking:
None (Open Label)
Primary Purpose:
Basic Science
Official Title:
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
Actual Study Start Date :
Jun 15, 2020
Actual Primary Completion Date :
Apr 9, 2021
Actual Study Completion Date :
May 7, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Ceftazidime-avibactam

This arm includes 4 cohorts

Drug: Ceftazidime-avibactam
Single intravenous infusion of ceftazidime-avibactam over 2 hours. Dosage will vary depending upon age, weight and renal function.

Outcome Measures

Primary Outcome Measures

  1. Area under the plasma concentration curve [time profile from time 0 to 8 hours]

    PK parameters of ceftazidime and avibactam for cohorts 1 and 2

  2. Area under the plasma concentration time profile from time 0 to infinity [Up to 22 hours post infusion for cohort 1, up to 13 hours post infusion for cohort 2]

    PK parameters of ceftazidime and avibactam for cohorts 1 and 2

  3. Area under the plasma concentration time profile from time 0 to the last quantifiable concentration [Up to 22 hours post infusion for cohort 1, up to 13 hours post infusion for cohort 2]

    PK parameters of ceftazidime and avibactam for cohorts 1 and 2

  4. Maximum plasma concentration [Up to 22 hours post infusion for cohort 1, up to 13 hours post infusion for cohort 2]

    PK parameters of ceftazidime and avibactam for cohorts 1 and 2

  5. Time of last quantifiable plasma concentration [Up to 22 hours post infusion for cohort 1, up to 13 hours post infusion for cohort 2]

    PK parameters of ceftazidime and avibactam for cohorts 1 and 2

  6. Time for Cmax [Up to 22 hours post infusion for cohort 1, up to 13 hours post infusion for cohort 2]

    PK parameters of ceftazidime and avibactam for cohorts 1 and 2

  7. Terminal elimination half life [Up to 22 hours post infusion for cohort 1, up to 13 hours post infusion for cohort 2]

    PK parameters of ceftazidime and avibactam for cohorts 1 and 2

  8. Clearance [Up to 22 hours post infusion for cohort 1, up to 13 hours post infusion for cohort 2]

    PK parameters of ceftazidime and avibactam for cohorts 1 and 2

  9. Volume of distribution at steady state [Up to 22 hours post infusion for cohort 1, up to 13 hours post infusion for cohort 2]

    PK parameters of ceftazidime and avibactam for cohorts 1 and 2

  10. Volume of distribution during terminal phase [Up to 22 hours post infusion for cohort 1, up to 13 hours post infusion for cohort 2]

    PK parameters of ceftazidime and avibactam for cohorts 1 and 2

  11. Plasma concentration will be summarized using descriptive statistics, eg, number, mean, SD, minimum, median, maximum, geometric mean, and coefficient of variation. [Up to 22 hours post infusion for cohort 1, up to 13 hours post infusion for cohort 2, and up to up to 6 hours post infusion for cohorts 3 and 4]

    For each cohort 1-4

Secondary Outcome Measures

  1. Number of subjects with adverse Events (AE) and Serious Adverse Events (SAEs) [Screening through 28-35 days post infusion]

    Adverse events will be summarized by preferred term and system organ class using the MedDRA vocabulary (Version 14.0 or higher) by cohort.

  2. Number of subjects with clinically significant abnormal laboratory results [Screening through 28-35 days post infusion]

  3. Number of subjects with clinically significant abnormal vital signs [Screening through 28-35 days post infusion]

  4. Number of deaths reported for study subjects [Screening through 28-35 days post infusion]

  5. Number of subjects discontinued due to AEs [Screening through 28-35 days post-infusion]

  6. Number of subjects with abnormal findings from physical examinations performed [Screening visit and 48 hour assessment]

Eligibility Criteria

Criteria

Ages Eligible for Study:
3 Months to 17 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:

Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:

  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 <18 years at Screening:

  4. Cohort 1: age 12 years to <18 years;

  5. Cohort 2: age 6 years to <12 years;

  6. Cohort 3: age 2 years to <6 years;

  7. Cohort 4: age 3 months to <2 years (must be born ≥37 weeks gestational age).

  8. Hospitalized, receiving systemic antibiotic therapy for the treatment of a suspected or confirmed HAP or VAP meeting the following criteria, and expected to require hospitalization until after the follow up evaluations are completed on Day 3 (48 hours after the end of infusion):

  9. Onset of symptoms ≥48 hours after admission or <7 days after discharge from an inpatient acute or chronic care facility;

  10. New or worsening infiltrate on chest X ray;

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

  1. Fever (temperature >38°C) or hypothermia (rectal/core temperature <35°C); ii. White blood cell (WBC) count >10,000 cells/mm3, or WBC count <4,500 cells/mm3, or >15% band forms.

  2. 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.

  1. Auscultatory findings consistent with pneumonia/pulmonary consolidation (eg, rales, rhonchi, bronchial breath sounds, dullness to percussion, egophony).

  2. Dyspnea, tachypnea or hypoxemia (O2 saturation <90% or PaO2 <60 mmHg while breathing room air).

  3. 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.

  1. Likely to survive the current illness or hospitalization.

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

Exclusion Criteria:

Subjects with any of the following characteristics/conditions will not be included in the study:

  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) within 30 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/1.73 m2 calculated using the child's measured height (length) and serum creatinine with the Bedside Schwartz equation (Schwartz, Munoz, et al., 2009):3 CrCL (mL/min/1.73 m2) =

  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 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:

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

  10. ALT or AST >3 × ULN values used by the laboratory performing the test. Subjects with values >3 × ULN and <5 × ULN are eligible if this value is acute and directly related to the infectious process being treated. This must be documented;

  11. ALP >3 × ULN. Subjects with values >3 × ULN and <5 × ULN are eligible if this value is acute and directly related to the infectious process being treated. This must be documented.

  12. Any condition (eg, 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 (eg, would place a patient at risk; compromise the quality of the data; or interfere with the absorption, distribution, metabolism, or excretion of CAZ AVI).

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

  14. Body mass index (BMI) below the 5th percentile or above the 95th percentile for height, age, and weight except for children <2 years of age as BMI is not considered a screening tool for healthy weight in children under 2 years of age.

  15. 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).

  16. Treatment with potent inhibitors of OAT1 and/or OAT3 (eg, probenecid, p aminohippuric acid (PAH), or teriflunomide).

Contacts and Locations

Locations

Site City State Country Postal Code
1 Wuxi Children's Hospital Wuxi Jiangsu China 214023
2 Chengdu Women's and Children's Central Hospital Chengdu Sichuan China 610091
3 Taipei Municipal Wanfang Hospital Taipei Taiwan 116
4 Chang Gung Memorial Hospital-Linkou Taoyuan City Taiwan 333

Sponsors and Collaborators

  • Pfizer
  • AbbVie

Investigators

  • Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT04040621
Other Study ID Numbers:
  • C3591025
  • 2018-002841-12
  • EMBA
First Posted:
Aug 1, 2019
Last Update Posted:
Nov 19, 2021
Last Verified:
Nov 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Pfizer
Additional relevant MeSH terms:

Study Results

No Results Posted as of Nov 19, 2021