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)

NCT02497781 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: D4280C00016C35910052014-003244-13
• Study Type: interventional
• Target: 97
• Locations: 9 countries
• Sites: 28

Brief Summary

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.

Conditions

Complicated Urinary Tract Infections

Keywords

Complicated urinary tract infections (cUTIs)

Outcome Measures

Primary Outcomes (13)

• Percentage of Participants With Treatment-Emergent 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. 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 were absent before treatment or that worsened relative to pretreatment state. AEs included both SAE and non-SAE.

  Baseline until the LFU visit (up to a maximum study duration of 50 days)

• Percentage of Participants With Cephalosporin Class Effects and Additional Adverse Events (AEs)

  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.

  Baseline until the LFU visit (up to a maximum study duration of 50 days)

• Change From Baseline in Pulse Rate at End of Intravenous Treatment (EOIV) Visit

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

  Baseline, EOIV visit (anytime from Day 4 to 15)

• Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End of Intravenous Treatment (EOIV) Visit

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

  Baseline, EOIV visit (anytime from Day 4 to 15)

• Change From Baseline in Respiratory Rate at End of Intravenous Treatment (EOIV) Visit

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

  Baseline, EOIV visit (anytime from Day 4 to 15)

• Change From Baseline in Body Temperature at End of Intravenous Treatment (EOIV) Visit

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

  Baseline, EOIV visit (anytime from Day 4 to 15)

• Percentage of Participants With Abnormal Physical Examination Findings at End of Intravenous Treatment (EOIV) Visit

  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.

  EOIV visit (anytime from Day 4 to 15)

• Change From Baseline in Body Weight at End of Intravenous Treatment (EOIV) Visit

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

  Baseline, EOIV visit (anytime from Day 4 to 15)

• Percentage of Participants With Potentially Clinically Significant Abnormalities in Laboratory Parameters

  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).

  Baseline until the LFU visit (up to a maximum study duration of 50 days)

• Percentage of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters

  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 of \>=30 msec; \>=60 msec and \>90 msec. EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

  Baseline until the EOIV visit (anytime from Day 4 to 15)

• Percentage of Participants With Creatinine Clearance (CrCl) at 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.

  Day 7

• Percentage of Participants With Creatinine Clearance (CrCl) at End of Intravenous Treatment (EOIV) Visit

  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.

  EOIV visit (anytime from Day 4 to 15)

• Percentage of Participants With Creatinine Clearance (CrCl) at Test of Cure (TOC) Visit

  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. TOC visit occurred within 8 to 15 days after last dose of any study drug (IV or oral).

  TOC visit (up to a maximum study duration of 50 days)

Secondary Outcomes (16)

• Plasma Concentrations of Ceftazidime and Avibactam

  15, 30-90, 300-360 minutes post-dose on Day 3

• Percentage of Participants With Favourable Clinical Response (CR): Intent-to-treat (ITT) Analysis Population

  End of 72 hours study drug treatment, EOIV visit (anytime from Day 4 to 15), EOT visit (up to Day 16), TOC visit (up to a maximum study duration of 50 days)

• Percentage of Participants With Favourable Clinical Response (CR): Microbiological ITT (Micro-ITT) Analysis Population

  End of 72 hours study drug treatment, EOIV visit (anytime from Day 4 to 15), EOT visit (up to Day 16), TOC visit (up to a maximum study duration of 50 days)

• Percentage of Participants With Favourable Clinical Response (CR) at End of 72 Hours Treatment: Clinically Evaluable (CE) Analysis Set at 72 Hours

  End of 72 hours study drug treatment on Day 1

• Percentage of Participants With Favourable Clinical Response (CR) at End of Intravenous Treatment (EOIV) Visit: Clinically Evaluable (CE) Analysis Set at EOIV

  EOIV visit (anytime from Day 4 to 15)

Study Arms (2)

ceftazidime-avibactam (CAZ-AVI)

EXPERIMENTAL

CAZ-AVI to be administered every 8 hours as a 2-hour infusion (CAZ-AVI dose and frequency of IV administration will depend upon body weight and renal function)

Drug: Ceftazidime -avibactam

Cefepime

ACTIVE COMPARATOR

Patients randomised to receive cefepime should receive the dose, schedule and infusion duration as recommended in the local prescribing information or as prescribed by the investigator. The maximum dose of cefepime in any single infusion should not exceed 2000 mg

Drug: Cefepime

Interventions

Ceftazidime -avibactam DRUG

Patients randomised (3:1) to the CAZ-AVI or cefepime treatment

ceftazidime-avibactam (CAZ-AVI)

Cefepime DRUG

Patients randomised (3:1) to the CAZ-AVI or cefepime treatment

Cefepime

Eligibility Criteria

• Age: 3 Months - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Must be ≥3 calendar months to \<18 years of age. Patients aged ≥3 calendar months to \<1 year must have been born at term (defined as gestational age ≥37 weeks).
• Written informed consent from parent(s) or other legally acceptable representative(s), and informed assent from patient (if age appropriate according to local regulations)
• If female and has reached menarche, or has reached Tanner stage 3 development (even if not having reached menarche) (refer to Appendix E for further details on Tanner staging), the patient is authorised to participate in this clinical study if the following criteria are met:
• At screening:
• (i) (a) Patient reports sexual abstinence for the prior 3 months or reports use of at least 1 of the acceptable methods of contraception, including an intrauterine device (with copper banded coil), levonorgestrel intrauterine system (eg, Mirena®), or regular medroxyprogesterone injections (Depo-Provera®); or (b) Patient agrees to initiate sexual abstinence from the time of screening until 7 days after end of treatment with study drug; and (ii) Patient is advised to avoid conception from the time of screening until 7 days after receipt of study drug and agrees not to attempt pregnancy from the time of screening until 7 days after end of treatment with study drug; and (iii) Patient is provided guidelines regarding continuation of abstinence, initiation of abstinence, or about allowed contraception; and (iv) Patient has a negative serum β-human chorionic gonadotropin (β-hCG) test just prior to study entry. Since serum tests may miss an early pregnancy, relevant menstrual history and sexual history, including methods of contraception, should be considered. Note: if the result of the serum β-hCG test cannot be obtained prior to dosing of investigational product, a patient may be enrolled on the basis of a negative urine pregnancy test, though a serum β-hCG test result must still be obtained.
• Patient has a clinically suspected and/or bacteriologically documented cUTI or acute pyelonephritis judged by the Investigator to be serious and requires the patient to be hospitalised for treatment with intravenous (IV) therapy
• Patient has pyuria:
• Cohorts 1 to 3 as determined by a midstream clean catch or clean urethral catheterisation urine specimen with ≥10 white blood cells (WBCs) per high power field on standard examination of urine sediment or ≥10 WBCs/mm3 in unspun urine Cohort 4a and 4b as determined by a midstream clean catch or clean urethral catheterisation urine specimen or urine specimen obtained using urine collection pads(or supra-pubic collection if standard procedure in the assigned sites) ≥5 WBCs per high-power field on standard examination of urine sediment or ≥5 WBCs/mm3 in unspun urine
• Patient has a positive urine culture: 1 midstream clean catch or clean urethral catheterisation urine specimen taken within 48 hours of randomisation containing ≥105 colony-forming units (CFU)/mL of a recognised uropathogen known to be susceptible to the IV study therapy (CAZ-AVI and cefepime) Note: If patients meet all of entry criteria except for positive urine culture as outlined above, the patients may be enrolled before urine culture results are available if the results are likely (based on urinalysis and clinical findings) to be positive and study drugs are considered appropriate empiric therapy. If a patient urine culture is negative after 24 or 48 hours of treatment but the patient is improving, the Investigator can keep the patient on treatment. If the urine culture is negative and the patient is not improving, study treatment will be stopped, and the patient will be followed for the rest of the study including undergoing all safety assessments until late follow up (LFU).
• Demonstrates either acute pyelonephritis or complicated lower UTI as defined by the following criteria:
• Qualifying criteria: patients must have at least 1 of the following signs/symptoms (signs/symptoms must have onset or have worsened within 7 days of enrolment) in addition to pyuria:
• Dysuria (including perceived dysuria as referred by parent/caregiver) Urgency Frequency Abdominal pain Fever defined as oral temperature \>38.5°C (or equivalent by other methods) with or without patient symptoms of rigor, chills, warmth Nausea Vomiting Irritability Loss of appetite Flank pain
• Or patients considered to have complicated UTI as indicated by 2 of the previous qualifying signs/symptoms in (a) plus at least 1 complicating factor from the following:
• Recurrent UTI (2 or more within 12 months period) Obstructive uropathy that is scheduled to be surgically relieved during IV study therapy and before the EOT Functional or anatomical abnormality of the urogenital tract, including anatomic malformations or neurogenic bladder Vesicoureteral reflux Use of intermittent bladder catheterisation or presence of an indwelling bladder catheter for \>48 hours prior to the diagnosis of cUTI Urogenital procedure (eg, cystoscopy or urogenital surgery) within the 7 days prior to study entry

You may not qualify if:

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
• Previous enrolment or randomisation in the present study
• Participation in another clinical study with an investigational product (IP) during the last 30 days before the first dose of IV study drug or have previously participated in the current study or in another study of CAZ-AVI (in which an active agent was received)
• History of hypersensitivity reactions to carbapenems, cephalosporins, penicillins or other β-lactam antibiotics
• Concurrent infection, including, but not limited to, central nervous system infection requiring systemic antibiotics in addition to the IV study drug therapy at the time of randomisation
• Receipt of more than 24 hours of any systemic antibiotics after culture and before study drug therapy
• Receipt of systemic antibiotics within 24 hours before obtaining the study qualifying pre-treatment baseline urine sample and before study drug therapy
• The child is suspected or documented to have an infection caused by organisms resistant to the prophylactic antibiotics
• A permanent indwelling bladder catheter or instrumentation including nephrostomy or current urinary catheter that will not be removed or anticipation of urinary catheter placement that will not be removed during the course of IV study drug therapy administration
• Patient has suspected or known complete obstruction of any portion of the urinary tract, perinephric abscess, or ileal loops
• Patient has had trauma to the pelvis or urinary tract
• Patient has undergone renal transplantation
• Patient has a condition or history of any illness that, in the opinion of the Investigator, would make the patient unsuitable for the study (eg, may confound the results of the study or pose additional risk in administering the study therapy to the patient)
• Patient is considered unlikely to survive the 6 to 8 week study period or have a rapidly progressive illness, including septic shock that is associated with a high risk of mortality
• At the time of randomisation, patient is known to have a cUTI caused by pathogens resistant to the antimicrobials planned to be used in the study

Sponsors & Collaborators

• Pfizer: lead
• PRA Health Sciences: collaborator

Study Sites (28)

Rady Children's Hospital San Diego

San Diego, California, 92123, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

ProMedica Toledo Children's Hospital

Toledo, Ohio, 43606, United States

Location

Lekarna Oblastni nemocnice Kolin, a.s.

Kolin III, 280 02, Czechia

Location

Oblastni nemocnice Kolin, a.s., nemocnice Stredoceskeho kraje - Detske oddeleni

Kolin III, 280 02, Czechia

Location

Krajska Zdravotni, A.S. - Nemocnice Most, O.Z., Detske A Dorostove Oddeleni

Most, 434 64, Czechia

Location

Lekarna Nemocnice Most., O.Z.

Most, 434 64, Czechia

Location

Fakultni Nemocnice Ostrava - Klinika Detskeho Lekarstvi

Ostrava - Poruba, 708 52, Czechia

Location

Lekarna Fakultni Nemocnice Ostrava

Ostrava - Poruba, 708 52, Czechia

Location

General Children's Hospital "Agia Sofia"

Goudi, Attica, 11527, Greece

Location

General Children's Hospital of Athens "P. & A. Kyriakou"

Goudi, Attica, 11527, Greece

Location

"Hippokratio" General Hospital of Thessaloniki

Thessaloniki, Makedonia, 54642, Greece

Location

University General Hospital of Larissa

Larissa, Thessaly, 41110, Greece

Location

Egyesitett Szent Istvan es Szent Laszlo Korhaz - Rendelointezet, Gyermekinfektologiai Osztaly

Budapest, 1097, Hungary

Location

Toldy Ferenc Korhaz es Rendelointezet, Csecsemo- es Gyermekgyogyaszati Osztaly

Cegléd, 2700, Hungary

Location

Kanizsai Dorottya Korhaz, Csecsemo es Gyermekgyogyaszati Osztaly

Nagykanizsa, 8800, Hungary

Location

Tolna Megyei Balassa Janos Korhaz, Gyermekosztaly

Szekszárd, 7100, Hungary

Location

Uniwersytecki Dzieciecy Szpital Kliniczny im. L. Zamenhofa w Bialymstoku

Bialystok, Podlaskie Voivodeship, 15-274, Poland

Location

Wojewodzki Specjalistyczny Szpital im. dr W1. Bieganskiego

Lodz, Łódź Voivodeship, 91-347, Poland

Location

Spitalul Clinic de Boli Infectioase si Tropicale "Dr. Victor Babes", Sectia B2 Boli Infectioase

Bucharest, 030303, Romania

Location

State Autonomous Healthcare Institution of Kemerovo Region "Kemerovo Regional Clinical Hospital"

Kemerovo, 650066, Russia

Location

Federal State Budgetary Institution

Moscow, 119991, Russia

Location

Hualien Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation

Hualien City, 97002, Taiwan

Location

Taichung Veterans General Hospital

Taichung, 40705, Taiwan

Location

National Taiwan University Hospital

Taipei, 100, Taiwan

Location

Mackay Memorial Hospital

Taipei, 10449, Taiwan

Location

Ege Universitesi Tip Fakultesi

Izmir, 35100, Turkey (Türkiye)

Location

Celal Bayar Universitesi Hafsa Sultan Hastanesi

Manisa, 45030, Turkey (Türkiye)

Location

Related Publications (2)

• Franzese RC, McFadyen L, Watson KJ, Riccobene T, Carrothers TJ, Vourvahis M, Chan PLS, Raber S, Bradley JS, Lovern M. Population Pharmacokinetic Modeling and Probability of Pharmacodynamic Target Attainment for Ceftazidime-Avibactam in Pediatric Patients Aged 3 Months and Older. Clin Pharmacol Ther. 2022 Mar;111(3):635-645. doi: 10.1002/cpt.2460. Epub 2021 Nov 22.

  PMID: 34687548 DERIVED

• Bradley JS, Roilides E, Broadhurst H, Cheng K, Huang LM, MasCasullo V, Newell P, Stone GG, Tawadrous M, Wajsbrot D, Yates K, Gardner A. 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. Pediatr Infect Dis J. 2019 Sep;38(9):920-928. doi: 10.1097/INF.0000000000002395.

  PMID: 31335570 DERIVED

MeSH Terms

Interventions

avibactam, ceftazidime drug combination; Cefepime

Intervention Hierarchy (Ancestors)

Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 16, 2015
• First Posted: July 15, 2015
• Study Start: September 24, 2015
• Primary Completion: September 15, 2017
• Study Completion: September 15, 2017
• Last Updated: July 11, 2018
• Results First Posted: April 10, 2018

Record last verified: 2018-06

Locations

TU (2); RO (1); RU (2); HU (4); GR (4); PL (2); CZ (6); US (3); TW (4)