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NCT02497781

Evaluation of Safety, Pharmacokinetics and Efficacy of Ceftazidime and Avibactam (CAZ-AVI ) Compared With Cefepime in Children From 3 Months to Less Than 18 Years of Age With Complicated Urinary Tract Infections (cUTIs)

Completed Phase 2 Results posted Last updated 11 July 2018
What this trial tests

Phase 2 trial testing Ceftazidime -avibactam in Complicated Urinary Tract Infections in 97 participants. Completed in 15 September 2017.

Timeline
24 September 2015
Primary endpoint
15 September 2017
15 September 2017

Quick facts

Lead sponsorPfizer
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingsingle
Primary purposetreatment
Enrollment97
Start date24 September 2015
Primary completion15 September 2017
Estimated completion15 September 2017
Sites28 locations across Russia, Greece, Taiwan, Poland, Hungary, Romania, United States, Turkey (Türkiye)

Drugs / interventions tested

Conditions studied

Sponsor

Pfizer — full company profile →

Who can join

Adults 3 Months to 17, any sex, with Complicated Urinary Tract Infections. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Primary · Baseline until the LFU visit (up to a maximum study duration of 50 days)

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. Treatment-emergent AEs were events between first dose of study drug and up to late follow-up (LFU) visit (20 to 36 days after last dose of study treatment \[IV or oral\]) that wer

AEs
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)53.7
Cefepime53.6
SAEs
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)11.9
Cefepime7.1
Percentage of Participants With Cephalosporin Class Effects and Additional Adverse Events (AEs) Primary · Baseline until the LFU visit (up to a maximum study duration of 50 days)

Percentage of participants with Cephalosporin class effects (defined as adverse event of special interest (AEoSI) within the safety topics (ST) of hypersensitivity/anaphylaxis) and additional AEs (which included AEs of diarrhea, renal disorder, hematological disorder and liver disorder relevant to the cephalosporin class within the safety topics (ST) based on MedDRA 20.0) were reported in this outcome measure.

AE in the ST of Diarrhea
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)7.5
Cefepime10.7
AE in the ST of Hematological Disorders
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)0
Cefepime0
AEoSI in the ST of Hypersensitivity/Anaphylaxis
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)7.5
Cefepime7.1
AE in the ST of Liver Disorder
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)1.5
Cefepime0
AE in the ST of Renal Disorder
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)0
Cefepime0
Change From Baseline in Pulse Rate at End of Intravenous Treatment (EOIV) Visit Primary · Baseline, EOIV visit (anytime from Day 4 to 15)

EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

Baseline
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)111.5± 23.97
Cefepime119.1± 27.08
Change at EOIV
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)-11.9± 18.65
Cefepime-17.1± 24.58
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End of Intravenous Treatment (EOIV) Visit Primary · Baseline, EOIV visit (anytime from Day 4 to 15)

EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

SBP: Baseline
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)105.6± 14.88
Cefepime111.9± 14.61
SBP: Change at EOIV
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)-1.0± 15.11
Cefepime-5.4± 14.53
DBP: Baseline
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)62.6± 12.68
Cefepime69.1± 9.28
DBP: Change at EOIV
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)0.9± 15.41
Cefepime-5.0± 7.50
Change From Baseline in Respiratory Rate at End of Intravenous Treatment (EOIV) Visit Primary · Baseline, EOIV visit (anytime from Day 4 to 15)

EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

Baseline
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)25.8± 5.96
Cefepime27.0± 8.46
Change at EOIV
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)-2.5± 4.64
Cefepime-2.6± 7.96
Change From Baseline in Body Temperature at End of Intravenous Treatment (EOIV) Visit Primary · Baseline, EOIV visit (anytime from Day 4 to 15)

EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

Baseline
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)37.67± 1.043
Cefepime37.49± 1.031
Change at EOIV
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)-1.15± 1.096
Cefepime-0.90± 1.036
Percentage of Participants With Abnormal Physical Examination Findings at End of Intravenous Treatment (EOIV) Visit Primary · EOIV visit (anytime from Day 4 to 15)

Physical examination included an assessment of the following: general appearance, skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, respiratory system, cardiovascular system, abdomen, musculoskeletal system (including spine and extremities), and neurological system. Participants with new or aggravated abnormal physical examination findings with regard to baseline findings were reported. Abnormality in physical examinations were based on blinded observer's discretion. EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

Abdomen
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)0
Cefepime3.6
Cardiovascular System
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)1.5
Cefepime0
General Appearance
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)0
Cefepime0
Head and Neck
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)1.5
Cefepime3.6
Lymph Nodes
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)0
Cefepime3.6
Musculoskeletal System
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)0
Cefepime0
Neurological System
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)0
Cefepime0
Respiratory System
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)3.0
Cefepime0
Change From Baseline in Body Weight at End of Intravenous Treatment (EOIV) Visit Primary · Baseline, EOIV visit (anytime from Day 4 to 15)

EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

Baseline
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)24.55± 19.361
Cefepime25.24± 21.527
Change at EOIV
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)-0.08± 0.613
Cefepime0.14± 0.510
Percentage of Participants With Potentially Clinically Significant Abnormalities in Laboratory Parameters Primary · Baseline until the LFU visit (up to a maximum study duration of 50 days)

Criteria for potentially clinically significant laboratory abnormalities: hematology (platelets: \<0.4\*lower limit of normal \[LLN\], \>2\*upper limit of normal \[ULN\], \>40% decrease from baseline \[DFB\],\>100% Increase from baseline \[IFB\]; Chemistry (Bicarbonate: \<0.7\*LLN, \>1.3\*ULN, \>50% DFB, \>30% IFB).

Chemistry: Bicarbonate
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)2.0
Cefepime0
Hematology: Platelets
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)1.6
Cefepime0
Percentage of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters Primary · Baseline until the EOIV visit (anytime from Day 4 to 15)

PCS criteria for abnormal value of ECG parameters: QT interval \>=450 milliseconds (msec); 480 msec; \>=500 msec; Increase from baseline (IFB) of \>=30 msec; \>=60 msec and \>90 msec; Decrease from baseline (DFB) of \>=30 msec; \>=60 msec and \>90 msec. QT interval using Bazett's correction (QTcB): \>=450 milliseconds (msec); 480 msec; \>=500 msec; Increase from baseline (IFB) of \>=30 msec; \>=60 msec and \>90 msec; DFB of \>=30 msec; \>=60 msec and \>90 msec. QT interval using Fridericia's correction (QTcF): \>=450 msec; 480 msec; \>=500 msec; IFB of \>=30 msec; \>=60 msec and \>90 msec; DFB

QT Interval : >450 msec
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)0
Cefepime0
QT Interval : >480 msec
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)0
Cefepime0
QT Interval : >500 msec
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)0
Cefepime0
Maximum IFB QT Interval : > 30 msec
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)19.4
Cefepime14.3
Maximum IFB QT Interval : > 60 msec
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)7.5
Cefepime3.6
Maximum IFB QT Interval : >90 msec
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)3.0
Cefepime0
Maximum DFB QT Interval : > 30 msec
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)9.0
Cefepime17.9
Maximum DFB QT Interval : > 60 msec
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)4.5
Cefepime0
Percentage of Participants With Creatinine Clearance (CrCl) at Day 7 Primary · Day 7

CrCl is a measure of glomerular filtration rate (GMFR), an index of kidney function. It is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Percentage of participants with CrCl in the following categories were reported: \<30 mL/min/1.73 m\^2, \>=30 to \<50 mL/min/1.73 m\^2, \>=50 mL/min/1.73 m\^2 to \<80 mL/min/1.73 m\^2, and \>=80 mL/min/1.73 m\^2.

CrCl: <30mL/min/1.73 m^2
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)0
Cefepime0
CrCl: >=30 to <50mL/min/1.73 m^2
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)0
Cefepime0
CrCl: >=50 to <80mL/min/1.73 m^2
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)11.1
Cefepime0
CrCl: >=80mL/min/1.73 m^2
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)88.9
Cefepime100
Percentage of Participants With Creatinine Clearance (CrCl) at End of Intravenous Treatment (EOIV) Visit Primary · EOIV visit (anytime from Day 4 to 15)

CrCl is a measure of glomerular filtration rate (GMFR), an index of kidney function. It is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Percentage of participants with CrCl in the following categories were reported: \<30 mL/min/1.73 m\^2, \>=30 to \<50 mL/min/1.73 m\^2, \>=50 mL/min/1.73 m\^2 to \<80 mL/min/1.73 m\^2, and \>=80 mL/min/1.73 m\^2. EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

CrCl: <30mL/min/1.73 m^2
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)0
Cefepime0
CrCl: >=30 to <50mL/min/1.73 m^2
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)0
Cefepime0
CrCl: >=50 to <80mL/min/1.73 m^2
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)20.0
Cefepime13.6
CrCl: >=80mL/min/1.73 m^2
GroupValue95% CI
Ceftazidime- Avibactam (CAZ-AVI)80.0
Cefepime86.4

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline until the LFU visit (up to a maximum study duration of 50 days). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Ceftazidime- Avibactam (CAZ-AVI)
Serious: 8/67 (12%)
Deaths: 0/67
Cefepime
Serious: 2/28 (7%)
Deaths: 0/28

Serious adverse events (8 terms)

ReactionSystemCeftazidime- Avibactam (CA…Cefepime
Urinary tract infectionInfections and infestations——
Pyelonephritis acuteInfections and infestations——
Abdominal painGastrointestinal disorders——
ConstipationGastrointestinal disorders——
CystitisInfections and infestations——
Viral infectionInfections and infestations——
Nervous system disorderNervous system disorders——
NephrolithiasisRenal and urinary disorders——
Other adverse events (5 terms — click to expand)

ReactionSystemCeftazidime- Avibactam (CA…Cefepime
DiarrhoeaGastrointestinal disorders——
RhinitisInfections and infestations——
RashSkin and subcutaneous tissue disorders——
VomitingGastrointestinal disorders——
IntertrigoSkin and subcutaneous tissue disorders——

Most-reported serious reactions: Urinary tract infection, Pyelonephritis acute, Abdominal pain, Constipation, Cystitis, Viral infection, Nervous system disorder, Nephrolithiasis.

Data from ClinicalTrials.gov NCT02497781 adverse events section.

Sponsor's own description

This study will assess the safety, tolerability and efficacy of ceftazidime and avibactam (CAZ-AVI )versus cefepime in children from 3 months to less than 18 years old with complicated urinary tract infections.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. New β-Lactamase Inhibitors in the Clinic.
    Papp-Wallace KM, Bonomo RA. · · 2016 · cited 121× · PMID 27208767 · DOI 10.1016/j.idc.2016.02.007
  2. Resistance to Novel β-Lactam-β-Lactamase Inhibitor Combinations: The "Price of Progress".
    Papp-Wallace KM, Mack AR, Taracila MA, Bonomo RA. · · 2020 · cited 94× · PMID 33011051 · DOI 10.1016/j.idc.2020.05.001
  3. Carbapenem-Resistant Enterobacteriaceae Infections in Children.
    Chiotos K, Han JH, Tamma PD. · · 2016 · cited 57× · PMID 26711126 · DOI 10.1007/s11908-015-0510-9
  4. Safety and Efficacy of Ceftazidime-Avibactam in the Treatment of Children ≥3 Months to <18 Years With Complicated Urinary Tract Infection: Results from a Phase 2 Randomized, Controlled Trial.
    Bradley JS, Roilides E, Broadhurst H, Cheng K, et al · · 2019 · cited 55× · PMID 31335570 · DOI 10.1097/inf.0000000000002395
  5. Phase I Study Assessing the Pharmacokinetic Profile, Safety, and Tolerability of a Single Dose of Ceftazidime-Avibactam in Hospitalized Pediatric Patients.
    Bradley JS, Armstrong J, Arrieta A, Bishai R, et al · · 2016 · cited 40× · PMID 27503642 · DOI 10.1128/aac.00862-16
  6. Population Pharmacokinetic Modeling and Probability of Pharmacodynamic Target Attainment for Ceftazidime-Avibactam in Pediatric Patients Aged 3 Months and Older.
    Franzese RC, McFadyen L, Watson KJ, Riccobene T, et al · · 2022 · cited 23× · PMID 34687548 · DOI 10.1002/cpt.2460
  7. Ceftazidime-avibactam induced renal disorders: past and present.
    Shi Y, Wu J, Mi W, Zhang X, et al · · 2024 · cited 7× · PMID 38318141 · DOI 10.3389/fphar.2024.1329307
  8. Population Pharmacokinetic Modeling for Ceftazidime-Avibactam Renal Dose Adjustments in Pediatric Patients 3 months and Older.
    Franzese R, Riccobene T, Carrothers T, Vourvahis M, et al · · 2023 · cited 4× · PMID 36239478 · DOI 10.1002/cpt.2764

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