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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02497781
Recruitment Status : Completed
First Posted : July 15, 2015
Results First Posted : April 10, 2018
Last Update Posted : July 11, 2018
Sponsor:
Collaborator:
PRA Health Sciences
Information provided by (Responsible Party):
Pfizer

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.

Condition or disease Intervention/treatment Phase
Complicated Urinary Tract Infections Drug: Ceftazidime -avibactam Drug: Cefepime Phase 2

Detailed Description:

This study will be a single-blind, randomised, multi-centre, active controlled trial. Patients aged from 3 months to less than 18 years with complicated urinary tract infections (cUTIs) will be randomised to 1 of 2 treatment groups (3:1 ratio): Ceftazidime and avibactam (CAZ AVI )or cefepime. Randomisation will be stratified by age cohort.

Patients will receive intravenous (IV) treatment for a minimum of 72 hours (3 full days, ie, 9 doses if given 3 times daily, or 6 doses if given twice daily) before having the option to switch to an oral therapy . The decision to switch to oral therapy is entirely at the Investigator's discretion, if the patient has good or sufficient clinical response, and the patient is tolerating oral fluids or food.

Patients will be assessed for safety and efficacy throughout the study, and blood samples will be taken for pharmacokinetic assessment. The duration of each patient's participation in the study will be a minimum of 27 days to a maximum of 50 days after start of study treatment including (intravenous treatment or oral switch therapy) 7 to 14 days of active treatment. The late follow-up visit (LFU) is to be performed 20 to 36 days after the last dose of any treatment.

The assessments at the test of cure (TOC) visit should be performed in person 8 to 15 days after last dose of any study drug Maximum duration of study drug or oral switch therapy is up to Day 14.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 97 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Single Blind, Randomised, Multi-centre, Active Controlled, Trial To Evaluate Safety, Tolerability, Pharmacokinetics And Efficacy Of Ceftazidime And Avibactam Compared With Cefepime In Children From 3 Months To Less Than 18 Years Of Age With Complicated Urinary Tract Infections (Cutis)
Actual Study Start Date : September 24, 2015
Actual Primary Completion Date : September 15, 2017
Actual Study Completion Date : September 15, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: ceftazidime-avibactam (CAZ-AVI)
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
Patients randomised (3:1) to the CAZ-AVI or cefepime treatment

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




Primary Outcome Measures :
  1. Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 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 were absent before treatment or that worsened relative to pretreatment state. AEs included both SAE and non-SAE.

  2. Percentage of Participants With Cephalosporin Class Effects and Additional Adverse Events (AEs) [ Time Frame: 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.

  3. Change From Baseline in Pulse Rate at End of Intravenous Treatment (EOIV) Visit [ Time Frame: Baseline, EOIV visit (anytime from Day 4 to 15) ]
    EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

  4. Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End of Intravenous Treatment (EOIV) Visit [ Time Frame: Baseline, EOIV visit (anytime from Day 4 to 15) ]
    EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

  5. Change From Baseline in Respiratory Rate at End of Intravenous Treatment (EOIV) Visit [ Time Frame: Baseline, EOIV visit (anytime from Day 4 to 15) ]
    EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

  6. Change From Baseline in Body Temperature at End of Intravenous Treatment (EOIV) Visit [ Time Frame: Baseline, EOIV visit (anytime from Day 4 to 15) ]
    EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

  7. Percentage of Participants With Abnormal Physical Examination Findings at End of Intravenous Treatment (EOIV) Visit [ Time Frame: 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.

  8. Change From Baseline in Body Weight at End of Intravenous Treatment (EOIV) Visit [ Time Frame: Baseline, EOIV visit (anytime from Day 4 to 15) ]
    EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

  9. Percentage of Participants With Potentially Clinically Significant Abnormalities in Laboratory Parameters [ Time Frame: 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).

  10. Percentage of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters [ Time Frame: 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 of >=30 msec; >=60 msec and >90 msec. EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

  11. Percentage of Participants With Creatinine Clearance (CrCl) at Day 7 [ Time Frame: 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.

  12. Percentage of Participants With Creatinine Clearance (CrCl) at End of Intravenous Treatment (EOIV) Visit [ Time Frame: 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.

  13. Percentage of Participants With Creatinine Clearance (CrCl) at Test of Cure (TOC) Visit [ Time Frame: TOC visit (up to a maximum study duration of 50 days) ]
    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).


Secondary Outcome Measures :
  1. Plasma Concentrations of Ceftazidime and Avibactam [ Time Frame: 15, 30-90, 300-360 minutes post-dose on Day 3 ]
  2. Percentage of Participants With Favourable Clinical Response (CR): Intent-to-treat (ITT) Analysis Population [ Time Frame: 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) ]
    Favorable CR was defined as a CR of improvement and cure(at end of 72 hours(hr) and EOIV) and a CR of cure(at EOT and TOC).Cure is resolution of all acute signs/symptoms of cUTI/improvement to such an extent that no further antimicrobial therapy required.Improvement is:1)at end of 72hr study drug treatment: improvement but not enough to switch to oral therapy and still on IV study drug at end of 72hr and meet following criterion: Absence of new signs/symptoms, and improvement in at least 1 symptom/sign(ie, fever,pain,tenderness,elevated WBCs,elevated CRP) from Baseline,and with no worsening of any symptom/sign. 2) at EOIV: participants who switched to oral therapy and had afebrile(temperature<=38.0°C) for >=24hr;absence of new and improvement in at least 1 symptom/sign from Baseline and worsening of none.EOT visit occurred within 48hr after completion of the last dose of oral switch therapy or at time of premature discontinuation/early withdrawal from study(if on oral switch therapy).

  3. Percentage of Participants With Favourable Clinical Response (CR): Microbiological ITT (Micro-ITT) Analysis Population [ Time Frame: 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) ]
    Favorable CR was defined as a CR of improvement and cure(at end of 72 hours(hr) and EOIV) and a CR of cure(at EOT and TOC).Cure is resolution of all acute signs/symptoms of cUTI/improvement to such an extent that no further antimicrobial therapy required.Improvement is:1)at end of 72hr study drug treatment: improvement but not enough to switch to oral therapy and still on IV study drug at end of 72hr and meet following criterion: Absence of new signs/symptoms, and improvement in at least 1 symptom/sign(ie, fever,pain,tenderness,elevated WBCs,elevated CRP) from Baseline,and with no worsening of any symptom/sign. 2) at EOIV: participants who switched to oral therapy and had afebrile(temperature<=38.0°C) for >=24hr;absence of new and improvement in at least 1 symptom/sign from Baseline and worsening of none.EOT visit occurred within 48hr after completion of the last dose of oral switch therapy or at time of premature discontinuation/early withdrawal from study(if on oral switch therapy).

  4. Percentage of Participants With Favourable Clinical Response (CR) at End of 72 Hours Treatment: Clinically Evaluable (CE) Analysis Set at 72 Hours [ Time Frame: End of 72 hours study drug treatment on Day 1 ]
    Favourable clinical response was defined as a CR of improvement and cure. Cure was defined as resolution of all acute signs and symptoms of complicated urinary tract infections (cUTIs) or improvement to such an extent that no further antimicrobial therapy was required. Clinical Improvement included all the participants who had improvement but not enough to switch to oral therapy and were still on IV study drug at End of 72 hours and had meet the following criterion: absence of new signs and symptoms, and improvement in at least 1 symptom or sign (fever, pain, tenderness, elevated WBCs, elevated CRP) from baseline, and with no worsening of any symptom or sign.

  5. Percentage of Participants With Favourable Clinical Response (CR) at End of Intravenous Treatment (EOIV) Visit: Clinically Evaluable (CE) Analysis Set at EOIV [ Time Frame: EOIV visit (anytime from Day 4 to 15) ]
    Favourable clinical response was defined as a CR of improvement and cure. Cure was defined as resolution of all acute signs and symptoms of complicated urinary tract infections (cUTIs) or improvement to such an extent that no further antimicrobial therapy was required. Clinical Improvement included all the participants who had switched to oral therapy and had meet the following criterion: afebrile (temperature <=38.0°C) for at least 24 hours, absence of new and improvement in at least 1 symptom or sign (fever, pain, tenderness, elevated WBCs, elevated c-reactive-protein) from baseline and worsening of none. EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

  6. Percentage of Participants With Favourable Clinical Response (CR) at End of Treatment (EOT) Visit: Clinically Evaluable (CE) Analysis Set at EOT [ Time Frame: EOT visit (up to Day 16) ]
    Favourable clinical response was defined as a CR cure. Cure was defined as resolution of all acute signs and symptoms of complicated urinary tract infections (cUTIs) or improvement to such an extent that no further antimicrobial therapy was required. EOT visit occurred within 48hr after completion of the last dose of oral switch therapy or at time of premature discontinuation/early withdrawal from study(if on oral switch therapy).

  7. Percentage of Participants With Favourable Clinical Response (CR) at TOC: Clinically Evaluable (CE) Analysis Set at TOC [ Time Frame: TOC visit (up to a maximum study duration of 50 days) ]
    Favourable clinical response was defined as resolution of all acute signs/symptoms of cUTIs or improvement to such an extent that no further antimicrobial therapy was needed. Participants who met the following criterion: Incomplete resolution or worsening of cUTI signs or symptoms or development of new signs or symptoms requiring alternative non-study antimicrobial therapy or death in which cUTI was contributory. TOC visit occurred within 8 to 15 days after last dose of any study drug (IV or oral).

  8. Percentage of Participants With Favourable Clinical Response (CR): Microbiologically Evaluable (ME) Analysis Population [ Time Frame: 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) ]
    Favorable CR was defined as a CR of improvement and cure(at end of 72 hours(hr) and EOIV) and a CR of cure(at EOT and TOC).Cure is resolution of all acute signs/symptoms of cUTI/improvement to such an extent that no further antimicrobial therapy required.Improvement is:1)at end of 72hr study drug treatment: improvement but not enough to switch to oral therapy and still on IV study drug at end of 72hr and meet following criterion: Absence of new signs/symptoms, and improvement in at least 1 symptom/sign(ie, fever,pain,tenderness,elevated WBCs,elevated CRP) from Baseline,and with no worsening of any symptom/sign. 2) at EOIV: participants who switched to oral therapy and had afebrile(temperature<=38.0°C) for >=24hr;absence of new and improvement in at least 1 symptom/sign from Baseline and worsening of none.EOT visit occurred within 48hr after completion of the last dose of oral switch therapy or at time of premature discontinuation/early withdrawal from study(if on oral switch therapy).

  9. Percentage of Participants With Favourable Microbiological Response: Microbiological Intent-to-treat (Micro-ITT) Population [ Time Frame: EOIV visit (Day 4 to 15), EOT visit(up to Day 16) ]
    Favourable microbiological response was achieved when all baseline pathogens were eradicated. EOIV visit occurred within 24 hours after completion of last infusion of the study drug. EOT visit occurred within 48 hours after completion of the last dose of oral switch therapy or at time of premature discontinuation/early withdrawal from study if on oral switch therapy (which occurred within the maximum study treatment duration of 14 days).

  10. Percentage of Participants With Favourable Microbiological Response: Microbiologically Evaluable (ME) Analysis Population [ Time Frame: EOIV visit (Day 4 to 15), EOT visit (up to Day 16) ]
    Favourable microbiological response was achieved when all baseline pathogens were eradicated. EOIV visit occurred within 24 hours after completion of last infusion of the study drug. EOT visit occurred within 48 hours after completion of the last dose of oral switch therapy or at time of premature discontinuation/early withdrawal from study if on oral switch therapy (which occurred within the maximum study treatment duration of 14 days).

  11. Percentage of Participants With Clinical Relapse at Late Follow-up (LFU) Visit: Clinically Evaluable (CE) Analysis Set at LFU [ Time Frame: LFU visit (anytime up to a maximum study duration of 50 days) ]
    A participant was said to have clinical relapse if met either 1 of the following criteria: reappearance or worsening of signs and symptoms of cUTI that required further antimicrobial therapy and/or surgery or death after TOC in which cUTI was contributory. LFU visit occurred within 20 to 36 days after last dose of study treatment (IV or oral).

  12. Percentage of Participants With Clinical Relapse at Late Follow-up (LFU) Visit: Microbiologically Evaluable (ME) Analysis Set at LFU [ Time Frame: LFU visit (anytime up to a maximum study duration of 50 days) ]
    A participant was said to have clinical relapse if met either 1 of the following criteria: reappearance or worsening of signs and symptoms of cUTI that required further antimicrobial therapy and/or surgery, or death after TOC in which cUTI was contributory. LFU visit occurred within 20 to 36 days after last dose of study treatment (IV or oral).

  13. Percentage of Participants With Emergent Infections: Microbiological Intent-to-treat (Micro-ITT) Population [ Time Frame: Baseline up to 50 days ]
    Emergent infections were categorized as super-infection and new infections. Superinfection: A urine culture identified pathogen other than a baseline pathogen during the course of active treatment with study therapy along with worsening signs and symptoms of infection requiring alternative antimicrobial therapy. New infection: A urine culture identified pathogen other than a baseline pathogen at any time after study treatment had finished along with worsening signs and symptoms of infection requiring alternative antimicrobial therapy. Percentage of participants with any (super infections or new infections) of the infections were reported.

  14. Percentage of Participants With Emergent Infections: Microbiologically Evaluable (ME) Analysis Population [ Time Frame: Baseline up to 50 days ]
    Emergent infections were categorized as super-infection and new infections. Superinfection: A urine culture identified pathogen other than a baseline pathogen during the course of active treatment with study therapy along with worsening signs and symptoms of infection requiring alternative antimicrobial therapy. New infection: A urine culture identified pathogen other than a baseline pathogen at any time after study treatment had finished along with worsening signs and symptoms of infection requiring alternative antimicrobial therapy. Percentage of participants with any (super infections or new infections) of the infections were reported.

  15. Percentage of Participants With Favourable Combined Response: Microbiological Intent-to-treat (Micro-ITT) Population [ Time Frame: EOIV visit (Day 4 to 15), TOC visit (up to a maximum study duration of 50 days) ]
    Combined response was the combined assessment of clinical response and microbiological response. Favorable clinical response was defined as a clinical response of improvement and cure (at EOIV) and a clinical response of cure (at TOC). Cure defined as: resolution of all acute signs/symptoms of cUTI/improvement to such an extent that no further antimicrobial therapy required. Improvement defined as: participants who switched to oral therapy and had afebrile (temperature<=38.0°C) for >=24 hr; absence of new and improvement in at least 1 symptom or sign (ie, fever, pain, tenderness, elevated WBCs, elevated CRP) from Baseline and worsening of none. Favourable microbiological response was absence of the original baseline pathogen in source specimen. EOIV visit occurred within 24 hours after completion of last infusion of the study drug. TOC visit occurred within 8 to 15 days after last dose of any study drug (IV or oral).

  16. Percentage of Participants With Combined Response: Microbiologically Evaluable (ME) Analysis Population [ Time Frame: EOIV visit (Day 4 to 15), TOC visit (up to a maximum study duration of 50 days) ]
    Combined response was the combined assessment of clinical response and microbiological response. Favorable clinical response was defined as a clinical response of improvement and cure (at EOIV) and a clinical response of cure (at TOC). Cure defined as: resolution of all acute signs/symptoms of cUTI/improvement to such an extent that no further antimicrobial therapy required. Improvement defined as: participants who switched to oral therapy and had afebrile (temperature<=38.0°C) for >=24 hr; absence of new and improvement in at least 1 symptom or sign (ie, fever, pain, tenderness, elevated WBCs, elevated CRP) from Baseline and worsening of none. Favourable microbiological response was absence of the original baseline pathogen in source specimen. EOIV visit occurred within 24 hours after completion of last infusion of the study drug. TOC visit occurred within 8 to 15 days after last dose of any study drug (IV or oral).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   3 Months to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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).
  2. Written informed consent from parent(s) or other legally acceptable representative(s), and informed assent from patient (if age appropriate according to local regulations)
  3. 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.

  4. 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
  5. 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

  6. 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).
  7. Demonstrates either acute pyelonephritis or complicated lower UTI as defined by the following criteria:

    1. 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

    2. 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

Exclusion Criteria:

  1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
  2. Previous enrolment or randomisation in the present study
  3. 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)
  4. History of hypersensitivity reactions to carbapenems, cephalosporins, penicillins or other β-lactam antibiotics
  5. 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
  6. Receipt of more than 24 hours of any systemic antibiotics after culture and before study drug therapy
  7. Receipt of systemic antibiotics within 24 hours before obtaining the study qualifying pre-treatment baseline urine sample and before study drug therapy
  8. The child is suspected or documented to have an infection caused by organisms resistant to the prophylactic antibiotics
  9. 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
  10. Patient has suspected or known complete obstruction of any portion of the urinary tract, perinephric abscess, or ileal loops
  11. Patient has had trauma to the pelvis or urinary tract
  12. Patient has undergone renal transplantation
  13. 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)
  14. 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
  15. 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
  16. Presence of any of the following clinically significant laboratory abnormalities:

    1. Haematocrit <25% or haemoglobin <8 g/dL (<80 g/L, <4.9 mmol/L)
    2. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3×the age-specific upper limit of normal (ULN), or total bilirubin >2×ULN (except known Gilbert's disease) For a) to b): unless if these values are acute and directly related to the infectious process being treated.
  17. Creatinine clearance <30 mL/min/1.73 m2 calculated using the child's measured height (length) and serum creatinine within the updated "bedside" Schwartz formula (Schwartz et al 2009):

    CrCl (mL/min/1.73m2)=0.413×height (length) (cm)/serum creatinine (mg/dL)

  18. History of seizures, excluding well-documented febrile seizure of childhood
  19. If female, currently pregnant or breast feeding

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02497781


Locations
Show Show 28 study locations
Sponsors and Collaborators
Pfizer
PRA Health Sciences
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
  Study Documents (Full-Text)

Documents provided by Pfizer:
Study Protocol  [PDF] July 17, 2017
Statistical Analysis Plan  [PDF] December 13, 2017

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02497781    
Other Study ID Numbers: D4280C00016
C3591005 ( Other Identifier: Alias Study Number )
2014-003244-13 ( EudraCT Number )
First Posted: July 15, 2015    Key Record Dates
Results First Posted: April 10, 2018
Last Update Posted: July 11, 2018
Last Verified: June 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Pfizer:
Complicated urinary tract infections (cUTIs)
Additional relevant MeSH terms:
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Infection
Communicable Diseases
Urinary Tract Infections
Urologic Diseases
Ceftazidime
Cefepime
Avibactam
Avibactam, ceftazidime drug combination
Anti-Bacterial Agents
Anti-Infective Agents
beta-Lactamase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action