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Hospitalized Children With Suspected or Confirmed Nosocomial PneumoniaPhase 1NCT04040621

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

A Phase 1 study testing Ceftazidime-avibactam in people with Hospitalized Children With Suspected or Confirmed Nosocomial Pneumonia, run by Pfizer at 4 sites in 2 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 3 months to 17 years
What is being tested?
Ceftazidime-avibactam
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
4 participants
Where
4 sitesin 2 countries
Study dates
15 Jun 2020to 7 May 2021
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 3 months to 17 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
  • 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.
  • Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
  • Male or female children age ≥3 months to <18 years at Screening:
  • Cohort 1: age 12 years to <18 years;
  • Cohort 2: age 6 years to <12 years;
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  • Cohort 3: age 2 years to <6 years;
  • Cohort 4: age 3 months to <2 years (must be born ≥37 weeks gestational age).
  • 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):
  • Onset of symptoms ≥48 hours after admission or <7 days after discharge from an inpatient acute or chronic care facility;
  • New or worsening infiltrate on chest X ray;
  • At least 1 of the following systemic signs prior to the initiation of treatment for Nosocomial Pneumonia:
  • 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.
  • 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 (eg, rales, rhonchi, bronchial breath sounds, dullness to percussion, egophony).
  • Dyspnea, tachypnea or hypoxemia (O2 saturation <90% or PaO2 <60 mmHg while breathing room air).
  • 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.
  • Likely to survive the current illness or hospitalization.
  • Sufficient IV access (peripheral or central) to receive study drug and dedicated access for PK sampling.

Who cannot join

  • Subjects with any of the following characteristics/conditions will not be included in the study:
  • 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.
  • Participation in other studies involving investigational drug(s) within 30 days prior to study entry and/or during study participation.
  • 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.
  • Past or current history of epilepsy or seizure disorder (excluding childhood febrile seizures.
  • 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) =
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  • Documented history of any hypersensitivity or allergic reaction to any β lactam antibiotic.
  • 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.
  • 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:
  • Bilirubin >3 × upper limit of normal (ULN), unless isolated hyperbilirubinemia is directly related to the acute infection or due to known Gilbert's disease;
  • 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;
  • 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.
  • 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).
  • 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.
  • 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.
  • 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).
  • Treatment with potent inhibitors of OAT1 and/or OAT3 (eg, probenecid, p aminohippuric acid (PAH), or teriflunomide).

Trial locations and contacts

4 sites in 2 countries.

4 sites in 2 countries

China2 sites
  • Chengdu Women's and Children's Central Hospital

    Chengdu, Sichuan, 610091

  • Wuxi Children's Hospital

    Wuxi, Jiangsu, 214023

Other trials in China

Taiwan2 sites
  • Taipei Municipal Wanfang Hospital

    Taipei, 116

  • Chang Gung Memorial Hospital-Linkou

    Taoyuan City, 333

Other trials in Taiwan

About this study

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

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.

Read the 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.

Being tested
Ceftazidime-avibactam
Keywords
nosocomial pneumonia, NP
Medical subject headings
Healthcare-Associated Pneumonia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Ceftazidime-avibactamDrug

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

Study groups in NCT04040621
Study groupRoleWhat they receive
Ceftazidime-avibactamExperimentalThis arm includes 4 cohorts
Receives: Drug: Ceftazidime-avibactam

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Plasma Concentration Time Summary for Ceftazidime and Avibactam

    Measured: Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose

  2. Area Under the Plasma Concentration-Time Profile From Time 0 to 8 Hours (AUC0-8 Hours)

    Measured: Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8 hours post dose

  3. Area Under the Curve From Time Zero to Extrapolated Infinite Time of CAZ-AVI (AUCinf)

    AUCinf = AUClast + (Clast*/ kel), where Clast* is the estimated concentration at the time of the last quantifiable concentration and kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

    Measured: Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose

  4. Area Under the Concentration-Time Profile From Time 0 to Time to Last Quantifiable Concentration (AUClast) of CAZ-AVI

    Measured: Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose

  5. Maximum Observed Plasma Concentration (Cmax) of CAZ-AVI

    Measured: Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose

  6. Time to Last Quantifiable Plasma Concentration (Tlast) of CAZ-AVI

    Measured: Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose

  7. Time to Reach Maximum Observed Plasma Concentration (Tmax) of CAZ-AVI

    Measured: Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose

  8. Termination Elimination Half-Life (t1/2) of CAZ-AVI

    Measured: Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose

  9. Clearance (CL) of CAZ-AVI

    Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood (rate at which a drug is metabolized or eliminated by normal biological processes). Clearance obtained after intravenous infusion dose (apparent clearance) is influenced by the fraction of the dose absorbed. CL = Dose/AUCinf.

    Measured: Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose

  10. Volume of Distribution of CAZ-AVI

    Volume of distribution at steady state (Vss) = Clearance (CL) × Mean Residence Time (MRT), MRT = Area under the first moment curve from 0 time to infinity (AUMCinf)/AUCinf - (infusion time/2), AUMCinf = AUMClast + (t × Cest1*/kel) +(Cest1*/kel2), 1Cest = e(-KEL × Tlast) × KELC0 , where C0 is the back-extrapolated concentration at time zero.

    Measured: Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose

  11. Volume of Distribution During Terminal Phase (Vz) of CAZ-AVI

    Vz = Dose/(AUCinf × kel).

    Measured: Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose

Secondary outcomes (4)
  1. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

    Measured: Day 1 up to maximum of 35 days after last dose of study treatment (maximum of 36 days)

  2. Number of Participants With Death and Discontinuations Due to Adverse Events (AEs)

    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.

    Measured: Day 1 up to maximum of 35 days after last dose of study treatment (maximum of 36 days)

  3. Number of Participants With Clinically Significant Abnormal Laboratory Values

    Following parameters were analyzed for laboratory examination: Clinical Chemistry-sodium, potassium, chloride, bicarbonate, creatinine, blood urea nitrogen, glucose-non fasting, calcium, phosphorus, magnesium, alkaline phosphatase, gamma glutamyl transferase, aspartate transaminase, alanine transaminase, creatinine kinase, lactate dehydrogenase, indirect bilirubin, total bilirubin; Hematology- hematocrit, hemoglobin, red blood cells (RBC), white blood cells (WBC), neutrophils, lymphocytes, monocytes, eosinophils, basophils, neutrophils immature, platelets, mean cell volume, mean cell hemoglobin, β- human chorionic gonadotropin (hCG) pregnancy test (blood or urine) for females; Urinalysis- appearance (color, clarity), bilirubin, glucose, ketones leukocyte esterase, nitrite, pH, protein, specific gravity, urobilinogen, microscopic (RBC, WBC, casts, crystals, bacteria, yeast, parasites).

    Measured: Baseline up to Day 3

  4. Number of Participants With Clinically Significant Physical Examination Abnormalities

    Parameters assessed for physical examination included: body weight and height. Abnormality was judged by investigator.

    Measured: Baseline up to Day 3

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Aug 2019
  2. Study start15 Jun 2020
  3. Primary completion9 Apr 2021
  4. Study completion7 May 2021

Why it stopped: Following regulatory consultation, the Sponsor has decided to terminate the study and analyze the current dataset. The decision to terminate was solely based on a business decision, not due to safety concerns.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Basic science
Allocation
Not applicable
Intervention model
Single group
Model description
Non-randomized, single arm
Masking
None (open label)
Enrolment
4 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04040621
Sponsor's protocol ID
C3591025
Other IDs
2018-002841-12, EMBA, 2018
Status last verified
Mar 2022
First submitted
26 Jul 2019
Last updated
9 Sep 2022
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical\_trials/trial\_data\_and\_results/data\_requests.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Ceftazidime-avibactam in people with Hospitalized Children With Suspected or Confirmed Nosocomial Pneumonia, run by Pfizer at 4 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 9 Sep 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in China, Taiwan. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 9 Sep 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Plasma Concentration Time Summary for Ceftazidime and Avibactam (time frame: Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose). The study lists 11 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Sep 2022.

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