Clinical Trial Results:
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 Hospitalised and Receiving Systemic Antibiotic Therapy for Suspected or Confirmed Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia
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Summary
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EudraCT number |
2018-002841-12 |
Trial protocol |
SK GB EE GR NL IT |
Global end of trial date |
07 May 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
05 Apr 2022
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First version publication date |
05 Apr 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
C3591025
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04040621 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Pfizer Inc.
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Sponsor organisation address |
235 E 42nd Street, New York, United States, NY 10017
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Public contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
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Scientific contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001313-PIP01-12 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
26 Sep 2021
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
07 May 2021
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
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.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
15 Jun 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
China: 2
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Country: Number of subjects enrolled |
Taiwan: 2
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Worldwide total number of subjects |
4
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
2
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Children (2-11 years) |
2
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Hospitalised pediatric subjects who were receiving systemic antibiotic therapy for suspected or confirmed nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP) were enrolled. | ||||||
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Pre-assignment
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Screening details |
Only 4 subjects were enrolled before trial was stopped prematurely. Data cannot be reported per cohort as planned because doing so would risk re-identification of subjects. Thus, to avoid this potential risk, only disposition and baseline characteristics data are reported for all subjects as 1 reporting group and no data for endpoints are reported. | ||||||
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Period 1
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Period 1 title |
Overall study (overall period)
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
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Arms
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Arm title
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All Enrolled Subjects: Ceftazidime-Avibactam (CAZ-AVI) | ||||||
Arm description |
Subjects received 50 milligram (mg)/kilogram (kg) of CAZ and 12.5 mg/kg of AVI intravenously. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
CAZ-AVI
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received 50 mg/kg of CAZ and 12.5 mg/kg of AVI intravenously.
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Baseline characteristics reporting groups
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Reporting group title |
All Enrolled Subjects: Ceftazidime-Avibactam (CAZ-AVI)
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Reporting group description |
Subjects received 50 milligram (mg)/kilogram (kg) of CAZ and 12.5 mg/kg of AVI intravenously. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
All Enrolled Subjects: Ceftazidime-Avibactam (CAZ-AVI)
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Reporting group description |
Subjects received 50 milligram (mg)/kilogram (kg) of CAZ and 12.5 mg/kg of AVI intravenously. | ||
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End point title |
Plasma Concentration Time Summary for Ceftazidime and Avibactam [1] | ||||||||
End point description |
Pharmacokinetics (PK) analysis set included all subjects who received a complete IV study dose of CAZ-AVI and had at least 1 ceftazidime and/or avibactam plasma measurement available. Data cannot be reported because doing so would risk re-identification of subjects.
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End point type |
Primary
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End point timeframe |
Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be reported for this endpoint. |
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| Notes [2] - Data cannot be reported because doing so would risk re-identification of subjects. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Curve From Time Zero to Extrapolated Infinite Time of CAZ-AVI (AUCinf) [3] | ||||||||
End point description |
PK analysis set included all subjects who received a complete IV study dose of CAZ-AVI and had at least 1 ceftazidime and/or avibactam plasma measurement available. 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. Data cannot be reported because doing so would risk re-identification of subjects.
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End point type |
Primary
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End point timeframe |
Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be reported for this endpoint. |
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| Notes [4] - Data cannot be reported because doing so would risk re-identification of subjects. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Plasma Concentration-Time Profile From Time 0 to 8 Hours (AUC0-8 hours) [5] | ||||||||
End point description |
PK analysis set included all subjects who received a complete IV study dose of CAZ-AVI and had at least 1 ceftazidime and/or avibactam plasma measurement available. Data cannot be reported because doing so would risk re-identification of subjects.
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End point type |
Primary
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End point timeframe |
Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8 hours post dose
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be reported for this endpoint. |
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| Notes [6] - Data cannot be reported because doing so would risk re-identification of subjects. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Concentration-Time Profile From Time 0 to Time to Last Quantifiable Concentration (AUClast) of CAZ-AVI [7] | ||||||||
End point description |
PK analysis set included all subjects who received a complete IV study dose of CAZ-AVI and had at least 1 ceftazidime and/or avibactam plasma measurement available. Data cannot be reported because doing so would risk re-identification of subjects.
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End point type |
Primary
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End point timeframe |
Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be reported for this endpoint. |
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| Notes [8] - Data cannot be reported because doing so would risk re-identification of subjects. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Last Quantifiable Plasma Concentration (Tlast) of CAZ-AVI [9] | ||||||||
End point description |
PK analysis set included all subjects who received a complete IV study dose of CAZ-AVI and had at least 1 ceftazidime and/or avibactam plasma measurement available. Data cannot be reported because doing so would risk re-identification of subjects.
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End point type |
Primary
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End point timeframe |
Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose
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| Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be reported for this endpoint. |
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| Notes [10] - Data cannot be reported because doing so would risk re-identification of subjects. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Maximum Observed Plasma Concentration (Cmax) of CAZ-AVI [11] | ||||||||
End point description |
PK analysis set included all subjects who received a complete IV study dose of CAZ-AVI and had at least 1 ceftazidime and/or avibactam plasma measurement available. Data cannot be reported because doing so would risk re-identification of subjects.
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End point type |
Primary
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End point timeframe |
Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose
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| Notes [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be reported for this endpoint. |
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| Notes [12] - Data cannot be reported because doing so would risk re-identification of subjects. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Reach Maximum Observed Plasma Concentration (Tmax) of CAZ-AVI [13] | ||||||||
End point description |
PK analysis set included all subjects who received a complete IV study dose of CAZ-AVI and had at least 1 ceftazidime and/or avibactam plasma measurement available. Data cannot be reported because doing so would risk re-identification of subjects.
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End point type |
Primary
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End point timeframe |
Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose
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| Notes [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be reported for this endpoint. |
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| Notes [14] - Data cannot be reported because doing so would risk re-identification of subjects. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Termination Elimination Half-Life (t1/2) of CAZ-AVI [15] | ||||||||
End point description |
PK analysis set included all subjects who received a complete IV study dose of CAZ-AVI and had at least 1 ceftazidime and/or avibactam plasma measurement available. t1/2 = Loge(2)/kel. Data cannot be reported because doing so would risk re-identification of subjects.
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End point type |
Primary
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End point timeframe |
Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose
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| Notes [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be reported for this endpoint. |
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| Notes [16] - Data cannot be reported because doing so would risk re-identification of subjects. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Clearance (CL) of CAZ-AVI [17] | ||||||||
End point description |
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 metabolised 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. PK analysis set included all subjects who received a complete IV study dose of CAZ-AVI and had at least 1 ceftazidime and/or avibactam plasma measurement available. Data cannot be reported because doing so would risk re-identification of subjects.
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End point type |
Primary
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End point timeframe |
Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose
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| Notes [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be reported for this endpoint. |
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| Notes [18] - Data cannot be reported because doing so would risk re-identification of subjects. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Volume of Distribution of CAZ-AVI [19] | ||||||||
End point description |
PK analysis set included all subjects who received a complete IV study dose of CAZ-AVI and had at least 1 ceftazidime and/or avibactam plasma measurement available. Vss = CL × MRT, MRT = 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. Data cannot be reported because doing so would risk re-identification of subjects.
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End point type |
Primary
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End point timeframe |
Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose
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| Notes [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be reported for this endpoint. |
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| Notes [20] - Data cannot be reported because doing so would risk re-identification of subjects. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Volume of Distribution During Terminal Phase (Vz) of CAZ-AVI [21] | ||||||||
End point description |
PK analysis set included all subjects who received a complete IV study dose of CAZ-AVI and had at least 1 ceftazidime and/or avibactam plasma measurement available. Vz = Dose/(AUCinf × kel). Data cannot be reported because doing so would risk re-identification of subjects.
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End point type |
Primary
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End point timeframe |
Day 1: 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 13, 24 hours post dose
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| Notes [21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be reported for this endpoint. |
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| Notes [22] - Data cannot be reported because doing so would risk re-identification of subjects. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | ||||||
End point description |
An Adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalisation; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Safety set included all subjects who had received any amount of IV study dose of CAZ AVI. Data cannot be reported because doing so would risk re-identification of subjects.
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End point type |
Secondary
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End point timeframe |
Baseline up to 28 days after last dose of study treatment
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| Notes [23] - Data cannot be reported because doing so would risk re-identification of subjects. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Subjects With Death and Discontinuations due to Adverse Events (AEs) | ||||||
End point description |
An Adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Safety set included all subjects who had received any amount of IV study dose of CAZ AVI. Data cannot be reported because doing so would risk re-identification of subjects.
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End point type |
Secondary
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End point timeframe |
Baseline up to 28 after last dose of study treatment
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| Notes [24] - Data cannot be reported because doing so would risk re-identification of subjects. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Subjects With Clinically Significant Physical Examination Abnormalities | ||||||
End point description |
Parameters assessed for physical examination included: body weight and height. Abnormality was judged by investigator. Safety set included all subjects who had received any amount of IV study dose of CAZ-AVI. Data cannot be reported because doing so would risk re-identification of subjects.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 3 (48 hours post dose on Day 1)
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| Notes [25] - Data cannot be reported because doing so would risk re-identification of subjects. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Subjects With Clinically Significant Abnormal Laboratory Values | ||||||
End point description |
Following parameters were analysed 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, RBC, 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). Safety set. Data cannot be reported because doing so would risk re-identification of subjects.
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End point type |
Secondary
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End point timeframe |
Baseline up to Day 3 (48 hours post dose on Day 1)
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| Notes [26] - Data cannot be reported because doing so would risk re-identification of subjects. |
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| No statistical analyses for this end point | |||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
Up to 48 hours after the end of infusion
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Adverse event reporting additional description |
Data cannot be reported because doing so would risk re-identification of subjects.
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Assessment type |
Non-systematic | ||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||
Dictionary version |
24.1
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Reporting groups
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Reporting group title |
All Enrolled Subjects: Ceftazidime-Avibactam (CAZ-AVI)
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Reporting group description |
Subjects received 50 mg/kg of CAZ and 12.5 mg/kg of AVI intravenously. | ||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||
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| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Data cannot be reported per cohort as planned because doing so would risk re-identification of subjects. |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||||||
Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| Only 4 subjects were enrolled in this study, with each enrolled in a different cohort. Endpoints and AE data were not reported by cohort as planned in the protocol because doing so would risk re-dentification of the individual subjects. | |||||||
