Evaluation of Pharmacokinetics, Safety, and Tolerability of Ceftazidime-avibactam in Neonates and Infants. (NOOR)

A PHASE 2A, 2-PART, OPEN-LABEL, NON-RANDOMIZED, MULTICENTER, SINGLE AND MULTIPLE DOSE TRIAL TO EVALUATE PHARMACOKINETICS, SAFETY AND TOLERABILITY OF CEFTAZIDIME AND AVIBACTAM IN NEONATES AND INFANTS FROM BIRTH TO LESS THAN 3 MONTHS OF AGE WITH SUSPECTED OR CONFIRMED INFECTIONS DUE TO GRAM-NEGATIVE PATHOGENS REQUIRING INTRAVENOUS ANTIBIOTIC TREATMENT

This study will assess the pharmacokinetics, safety, and tolerability of single and multiple doses of intravenous ceftazidime-avibactam in hospitalized infants and neonates from 26 weeks gestation to 3 months of age. In Part A of the study all patients will receive a single dose of ceftazidime-avibactam. In Part B all patients will received multiple doses of ceftazidime-avibactam. Efficacy will be assessed in the infants and neonates receiving multiple doses of ceftazidime-avibactam.

Study Overview

• Status: Terminated
• Conditions: Gram-negative Bacterial Infection
• Intervention / Treatment: Drug: Part A: Single Dose Ceftazidime-Avibactam, Cohorts 1-3; Drug: Part B: Multiple-dose Ceftazidime-Avibactam, Cohorts 1-3

Detailed Description

This is a 2-part, Phase 2a, non-randomized, open-label multicenter, multinational study of intravenous ceftazidime-avibactam in hospitalized neonates and infants with suspected or confirmed bacterial infection. In Part A of the study, patients already receiving intravenous antibacterial therapy with another antibiotic will receive a single intravenous dose of ceftazidime-avibactam followed by observation for 48 hours and a Late Follow-Up assessment 4-5 weeks later. In Part B of the study, patients with suspected or confirmed Gram-negative bacterial infections requiring intravenous antibacterial therapy will receive multiple doses of intravenous ceftazidime-avibactam for up to 14 days. At the discretion of the investigator, patients may also receive other antibiotics if the infection is suspected to include Gram-positive bacteria, multi-drug resistant Gram-negative bacteria, or anaerobic bacteria. At the discretion of the investigator, patients may be switched to oral therapy or outpatient parenteral antimicrobial therapy with an alternative antibiotic after receiving intravenous ceftazidime-avibactam for at least 48 yhours. Clinical outcomes will be assessed at the End of Intravenous (EOIV) treatment with ceftazidime-avibactam, the End-of-Therapy (EOT), the Test-of-Cure (TOC) at 7-14 days after the last study therapy and at a Late Follow-Up (LFU) visit, 28-55 days after the last dose of ceftazidime-avibactam. Safety assessments will occur throughout the study. Ceftazidime-avibactam blood levels will be assessed during the first 12 hours after the single dose of ceftazidime-avibactam in Part A and during 12 hours after at least 3 consecutive doses of ceftazidime-avibactam in Part B.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 2

Contacts and Locations

Study Locations

• Estonia
  • Tallinn, Estonia, 13419
    • Tallinn Children's Hospital
• Greece
  • Thessaloniki, Greece, 546 42
    • "Hippokration" General Hospital of Thessaloniki
  • Ampelokipi
    • Athens, Ampelokipi, Greece, 11 527
      • Athens General Children's Hospital "Panagioti and Aglaias Kyriakou"
  • Athens
    • Chaidari, Athens, Greece, 124 62
      • "ATTIKON" University General Hospital
• Hungary
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem Klinikai Központ
  • Nagykanizsa, Hungary, 8800
    • Kanizsai Dorottya Korhaz
  • Nyíregyháza, Hungary, 4400
    • Szabolcs-Szatmár-Bereg Megyei Kórházak és Oktatókórház, Jósa András Oktatókórház
• India
  • Karnataka
    • Manipal, Karnataka, India, 576104
      • Kasturba Medical College and Hospital
• Italy
  • RM
    • Rome, RM, Italy, 00165
      • Ospedale Pediatrico Bambino Gesù
• Slovakia
  • Martin, Slovakia, 036 59
    • Univerzitna nemocnica Martin
• Taiwan
  • Hsinchu, Taiwan, 30071
    • Hsinchu MacKay Memorial Hospital
  • Taipei, Taiwan, 10041
    • National Taiwan University Hospital
  • R.o.c
    • Hsinchu City, R.o.c, Taiwan, 300
      • Hsinchu Mackay Memorial Hospital, Department of Pharmacy
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Children's Hospital at Tufts Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Durham, North Carolina, United States, 27710
      • Duke University Investigational Drug Services
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Hospital
    • Salt Lake City, Utah, United States, 84108
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 2 months (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria (All Subjects):

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.
2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Male or female neonates and infants with age at Screening:

Cohort 1: Full term infants (gestational age ≥ 37 weeks) with chronological age >28 days to <3 months (<89 days) or pre-term infants with corrected age >28 days to <3 months (<89 days). A maximum of 3 pre-term corrected age infants may be enrolled in each part (A and B) of Cohort 1. Sites will be notified in writing if this limit is reached.

Cohort 2: Full term neonates (gestational age ≥ 37 weeks) from birth to ≤ 28 days.

Cohort 3: Pre-term neonates (gestational age ≥ 26 to <37 weeks) from birth to ≤ 28 days.

Corrected age = Subtract the number of weeks born before 40 weeks of gestation from the chronological age.

Inclusion Criteria for Part A Subjects Only:

1. Hospitalized and receiving intravenous antibacterial therapy for the treatment of a suspected or confirmed bacterial infection.

Inclusion Criteria for Part B Subjects Only:

1. Hospitalized with suspected or confirmed aerobic Gram-negative bacterial infection requiring intravenous antibacterial therapy.
2. Subjects must meet at least 1 clinical and 1 laboratory criterion or meet at least 2 of the clinical criteria:

Clinical Criteria:

1. Hypothermia (<36ºC) OR fever (>38.5ºC);
2. Bradycardia OR tachycardia OR rhythm instability;
3. Urine output 0.5 to 1 mL/kg/h OR hypotension OR mottled skin OR impaired peripheral perfusion;
4. Petechial rash OR sclerema neonatorum;
5. New onset or worsening of apnea episodes OR tachypnea episodes OR increased oxygen requirements OR requirement for ventilation support;
6. Feeding intolerance OR poor suckling OR abdominal distension;
7. Irritability;
8. Lethargy;
9. Hypotonia.

Laboratory Criteria:

1. White blood cell count ≤ 4.0 × 10^9/L OR ≥ 20.0 × 10^9/L;
2. Immature to total neutrophil ratio >0.2;
3. Platelet count ≤ 100 × 10^9/L;
4. C reactive protein (CRP) >15 mg/L OR procalcitonin ≥ 2 ng/mL;
5. Hyperglycemia OR Hypoglycemia;
6. Metabolic acidosis.

Exclusion Criteria (All Subjects):

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 another clinical study involving investigational drug(s) within 30 days prior to study entry and/or during this study participation or have previously participated in the current study or in another study of CAZ-AVI (in which an active agent was received).
3. Use of potent inhibitors of organic anion transporters OAT1 and/or OAT3 (eg, probenecid, p-aminohippuric acid (PAH), or teriflunomide) are prohibited. This prohibition of OAT1 and/or OAT3 inhibitors also applies to the mothers of any neonates or infants who are breast feeding during the trial.
4. Other acute or chronic medical 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.
5. Documented history of any hypersensitivity or allergic reaction to any beta-lactam antibiotic.
6. Refractory septic shock within 24 hours before screening that does not resolve after 60 minutes of vasopressor therapy.
7. Moderate or severe renal impairment defined as serum creatinine ≥ 2 times the upper limit of normal (ULN) for age OR urine output <0.5 mL/kg/h (measured over at least 8 hours) OR requirement for dialysis. Deterioration of renal function after enrollment during Part B of the study will be handled on a case-by-case basis in discussion with the Medical Monitor.
8. Evidence of progressively fatal underlying disease, or life expectancy of ≤ 60 days.
9. Documented history of seizure.
10. Active acute viral hepatitis or acute hepatic failure.
11. Known Clostridium difficile associated diarrhea.
12. Requiring or currently taking antiretroviral therapy for human immunodeficiency virus (HIV) or known HIV positive mother.
13. Any condition (eg, cystic fibrosis, urea cycle disorders), antepartum/peripartum factors, or procedures that would, in the opinion of the Investigator, make the subject unsuitable for the study, place a subject at risk, or compromise the quality of data.
14. Treatment with ceftazidime within 12 hours of CAZ-AVI administration.

Exclusion Criteria for Part A Subjects Only:

1. Subject received a blood or a blood component transfusion within 24 hours of the start of CAZ AVI infusion.
2. Subject is expected to be discharged less than 24 hours after the start of CAZ AVI infusion.

Exclusion Criteria for Part B Subjects Only:

1. At study entry, subject has confirmed or strongly suspected infection with a pathogen known to be resistant to CAZ-AVI or only a Gram-positive pathogen or viral, fungal, or parasitic pathogens as the sole cause of infection.
2. Confirmed or suspected central nervous system (CNS) infection (eg, meningitis, brain abscess, subdural abscess).
3. Anticipated need for antibacterial therapy longer than 14 days (eg, osteomyelitis, endocarditis). This applies to both study treatment with CAZ-AVI as well as adjunctive IV antibacterial treatment for suspected co infection with Gram-positive organisms or multi drug resistant Gram-negative organisms.
4. Receipt of more than 24 hours of nonstudy systemic antibacterial treatment for Gram-negative organisms after culture and before administration of study doses of CAZ-AVI. Empiric coverage with an aminoglycoside for suspected multidrug resistant organisms is permitted, provided CAZ-AVI is initiated within 24 hours after culture.
5. Intravenous treatment with chloramphenicol within 24 hours of administration of study doses of CAZ-AVI.
6. Subject is expected to be discharged less than 48 hours after the start of CAZ-AVI infusion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A, Cohorts 1-3; Single dose pharmacokinetics. This arm will include three age cohorts.	Drug: Part A: Single Dose Ceftazidime-Avibactam, Cohorts 1-3; Single intravenous infusion of ceftazidime-avibactam over 2 hours
Experimental: Part B, Cohorts 1-3; Multi-dose pharmacokinetics. This arm will include three age cohorts.	Drug: Part B: Multiple-dose Ceftazidime-Avibactam, Cohorts 1-3; Multiple intravenous infusions of ceftazidime-avibactam over 2 hours, repeated every 8 hours up to 14 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Concentrations of Ceftazidime and Avibactam 2 Hours Post-dose: Part A		2 hours post dose on Day 1
Plasma Concentrations of Ceftazidime and Avibactam 2 Hours and 30 Minutes Post-dose: Part A		2 hours and 30 minutes post dose on Day 1
Plasma Concentrations of Ceftazidime and Avibactam of 7 Hours Post-dose: Part A		7 hours post dose on Day 1
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs): Part B	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in participant hospitalization; life-threatening experience (immediate risk of dying) ; persistent or significant disability/incapacity; congenital anomaly.	Day 1 up to maximum of Day 49
Number of Participants Who Died: Part B		Day 1 up to maximum of Day 49
Number of Participants Who Discontinued Treatment and Study Due to AEs: Part B		Day 1 up to maximum of Day 49
Number of Participants With Clinically Significant Laboratory Parameters Occurred in More Than 2 Participants: Part B	Number of participants in Part B with clinically significant abnormal laboratory parameters that occurred in more than 2 participants from Day 1 up to 35 days after the last dose of CAZ-AVI were reported in this outcome measure. Clinically significant labs were abnormal laboratory results which the investigator reported as being clinically significant. Only parameters with non-zero values are reported.	Day 1 up to maximum of Day 49

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs): Part A	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.	Day 1 up to maximum of Day 35
Number of Participants Who Died: Part A		Day 1 up to maximum of Day 35
Number of Participants Who Discontinued Treatment and Study Due to AEs: Part A		Day 1 up to maximum of Day 35
Plasma Concentrations of Ceftazidime and Avibactam 2 Hours, 2 Hours and 30 Minutes, 7 Hours Post Doses on Day 1: Part B		2 hours, 2 hours 30 mins, and 7 hours post dose on Day 1
Number of Participants According to Clinical Outcome At End of IV Treatment(EOIV), End of Treatment(EOT), Test of Cure(TOC) and Late Follow-Up(LFU): Intent to Treat (ITT) Analysis Population: Part B	Clinical outcome assessed based on clinical cure, improvement, failure, indeterminate. Clinical cure=resolution of acute signs, symptoms.Clinical improvement=participants switched to oral therapy;met following criteria at EOIV:afebrile for 24 hours(H);improvement in at least 1 symptom,sign.Clinical failure=received >48H of therapy, met any of these:therapy discontinuation due to insufficient effect, AE, death. Indeterminate=data not available for evaluation(death;lost to follow up;diagnosis of CNS infection, osteomyelitis, endocarditis or necrotizing enterocolitis after enrollment). EOIV (Up to 14 days), EOT (Up to 27 days), TOC (Up to 34 days), LFU (Up to 49 days).	EOIV, EOT, TOC, LFU
Number of Participants According to Clinical Outcome At End of IV Treatment(EOIV), End of Treatment(EOT), Test of Cure(TOC) and Late Follow-Up(LFU) in Micro-ITT Analysis Population: Part B	Clinical outcome assessed based on clinical cure, improvement, failure, indeterminate. Clinical cure=resolution of acute signs, symptoms.Clinical improvement=participants switched to oral therapy;met following criteria at EOIV:afebrile for 24 hours(H);improvement in at least 1 symptom,sign.Clinical failure=received >48H of therapy, met any of these:therapy discontinuation due to insufficient effect, AE, death. Indeterminate=data not available for evaluation(death;lost to follow up;diagnosis of CNS infection, osteomyelitis, endocarditis or necrotizing enterocolitis after enrollment). EOIV (Up to 14 days), EOT (Up to 27 days), TOC (Up to 34 days), LFU (Up to 49 days).	EOIV, EOT, TOC, LFU
Number of Participants According to Clinical Outcome At End of IV Treatment(EOIV), End of Treatment(EOT), Test of Cure(TOC) and Late Follow-Up(LFU) in Modified-ITT Analysis Population: Part B	Clinical outcome assessed based on clinical cure, improvement, failure, indeterminate. Clinical cure=resolution of acute signs, symptoms.Clinical improvement=participants switched to oral therapy;met following criteria at EOIV:afebrile for 24 hours(H);improvement in at least 1 symptom,sign.Clinical failure=received >48H of therapy, met any of these:therapy discontinuation due to insufficient effect, AE, death. Indeterminate=data not available for evaluation(death;lost to follow up;diagnosis of CNS infection, osteomyelitis, endocarditis or necrotizing enterocolitis after enrollment). EOIV (Up to 14 days), EOT (Up to 27 days), TOC (Up to 34 days), LFU (Up to 49 days).	EOIV, EOT, TOC, LFU
Number of Participants According to Microbiological Response at TOC Visit in Micro-ITT Population: Part B	Microbiological response was assessed based on eradication, presumed eradication, persistence, presumed persistence, indeterminate. Eradication: source specimen demonstrated absence of the original baseline pathogen. Presumed eradication: source specimen was not available to culture and the participant was assessed as a clinical cure. Persistence: source specimen demonstrated continued presence of the original baseline pathogen. Presumed persistence: source specimen was not available to culture and the participant was assessed as a clinical failure. Indeterminate: source specimen was not available to culture and the participant's clinical outcome was assessed as indeterminate.	Up to 34 days
Number of Participants With Emergent Infections in Micro-ITT Analysis Population: Part B	Emergent infections included superinfection and new infection. Superinfection: a culture identified pathogen other than a baseline pathogen during the course of active treatment with study therapy requiring alternative antimicrobial therapy. New infection: a culture identified pathogen other than a baseline pathogen at any time after study treatment has finished requiring alternative antimicrobial therapy.	Day 1 up to maximum of Day 49
Number of Participants With Clinically Significant Laboratory Parameters Occurred in More Than 2 Participants: Part A	Number of participants in Part A with clinically significant abnormal laboratory parameters that occurred in more than 2 participants from Day 1 up to 35 days after the last dose of CAZ-AVI were reported in this outcome measure. Clinically significant labs were abnormal laboratory results which the investigator reported as being clinically significant.	Day 1 up to maximum of Day 35

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Allergan
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2020
• Primary Completion (Actual): December 30, 2022
• Study Completion (Actual): December 30, 2022

Study Registration Dates

• First Submitted: September 27, 2019
• First Submitted That Met QC Criteria: October 10, 2019
• First Posted (Actual): October 14, 2019

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: February 27, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Gram-negative, ceftazidime-avibactam, neonate, infant
• Additional Relevant MeSH Terms: Bacterial Infections and Mycoses; Infections; Bacterial Infections; Gram-Negative Bacterial Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Third Generation Cephalosporins; Beta Lactam Antibiotics; Avibactam; Ceftazidime; Avibactam, ceftazidime drug combination
• Other Study ID Numbers: C3591024; 2018-002800-16 (EudraCT Number); NOOR (Other Identifier: Alias Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No