Clinical trial 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)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Complicated Urinary Tract Infections
Keywords: Complicated urinary tract infections (cUTIs)
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
Collaborators: name: PRA Health Sciences
First posted: 2015-07-15
Enrollment: 97
Sex: ALL
Minimum age (years): 3
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline until the LFU visit (up to a maximum study duration of 50 days)
measure: Percentage of Participants With Cephalosporin Class Effects and Additional Adverse Events (AEs)
timeFrame: Baseline until the LFU visit (up to a maximum study duration of 50 days)
measure: Change From Baseline in Pulse Rate at End of Intravenous Treatment (EOIV) Visit
timeFrame: Baseline, EOIV visit (anytime from Day 4 to 15)
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End of Intravenous Treatment (EOIV) Visit
timeFrame: Baseline, EOIV visit (anytime from Day 4 to 15)
measure: Change From Baseline in Respiratory Rate at End of Intravenous Treatment (EOIV) Visit
timeFrame: Baseline, EOIV visit (anytime from Day 4 to 15)
measure: Change From Baseline in Body Temperature at End of Intravenous Treatment (EOIV) Visit
timeFrame: Baseline, EOIV visit (anytime from Day 4 to 15)
measure: Percentage of Participants With Abnormal Physical Examination Findings at End of Intravenous Treatment (EOIV) Visit
timeFrame: EOIV visit (anytime from Day 4 to 15)
measure: Change From Baseline in Body Weight at End of Intravenous Treatment (EOIV) Visit
timeFrame: Baseline, EOIV visit (anytime from Day 4 to 15)
measure: Percentage of Participants With Potentially Clinically Significant Abnormalities in Laboratory Parameters
timeFrame: Baseline until the LFU visit (up to a maximum study duration of 50 days)
measure: Percentage of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters
timeFrame: Baseline until the EOIV visit (anytime from Day 4 to 15)
measure: Percentage of Participants With Creatinine Clearance (CrCl) at Day 7
timeFrame: Day 7
measure: Percentage of Participants With Creatinine Clearance (CrCl) at End of Intravenous Treatment (EOIV) Visit
timeFrame: EOIV visit (anytime from Day 4 to 15)
measure: Percentage of Participants With Creatinine Clearance (CrCl) at Test of Cure (TOC) Visit
timeFrame: TOC visit (up to a maximum study duration of 50 days)
Secondary outcomes:
measure: Plasma Concentrations of Ceftazidime and Avibactam
timeFrame: 15, 30-90, 300-360 minutes post-dose on Day 3
measure: Percentage of Participants With Favourable Clinical Response (CR): Intent-to-treat (ITT) Analysis Population
timeFrame: 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)
measure: Percentage of Participants With Favourable Clinical Response (CR): Microbiological ITT (Micro-ITT) Analysis Population
timeFrame: 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)
measure: Percentage of Participants With Favourable Clinical Response (CR) at End of 72 Hours Treatment: Clinically Evaluable (CE) Analysis Set at 72 Hours
timeFrame: End of 72 hours study drug treatment on Day 1
measure: Percentage of Participants With Favourable Clinical Response (CR) at End of Intravenous Treatment (EOIV) Visit: Clinically Evaluable (CE) Analysis Set at EOIV
timeFrame: EOIV visit (anytime from Day 4 to 15)
measure: Percentage of Participants With Favourable Clinical Response (CR) at End of Treatment (EOT) Visit: Clinically Evaluable (CE) Analysis Set at EOT
timeFrame: EOT visit (up to Day 16)
measure: Percentage of Participants With Favourable Clinical Response (CR) at TOC: Clinically Evaluable (CE) Analysis Set at TOC
timeFrame: TOC visit (up to a maximum study duration of 50 days)
measure: Percentage of Participants With Favourable Clinical Response (CR): Microbiologically Evaluable (ME) Analysis Population
timeFrame: 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)
measure: Percentage of Participants With Favourable Microbiological Response: Microbiological Intent-to-treat (Micro-ITT) Population
timeFrame: EOIV visit (Day 4 to 15), EOT visit(up to Day 16)
measure: Percentage of Participants With Favourable Microbiological Response: Microbiologically Evaluable (ME) Analysis Population
timeFrame: EOIV visit (Day 4 to 15), EOT visit (up to Day 16)
measure: Percentage of Participants With Clinical Relapse at Late Follow-up (LFU) Visit: Clinically Evaluable (CE) Analysis Set at LFU
timeFrame: LFU visit (anytime up to a maximum study duration of 50 days)
measure: Percentage of Participants With Clinical Relapse at Late Follow-up (LFU) Visit: Microbiologically Evaluable (ME) Analysis Set at LFU
timeFrame: LFU visit (anytime up to a maximum study duration of 50 days)
measure: Percentage of Participants With Emergent Infections: Microbiological Intent-to-treat (Micro-ITT) Population
timeFrame: Baseline up to 50 days
measure: Percentage of Participants With Emergent Infections: Microbiologically Evaluable (ME) Analysis Population
timeFrame: Baseline up to 50 days
measure: Percentage of Participants With Favourable Combined Response: Microbiological Intent-to-treat (Micro-ITT) Population
timeFrame: EOIV visit (Day 4 to 15), TOC visit (up to a maximum study duration of 50 days)
measure: Percentage of Participants With Combined Response: Microbiologically Evaluable (ME) Analysis Population
timeFrame: EOIV visit (Day 4 to 15), TOC visit (up to a maximum study duration of 50 days)
Other outcomes:
Locations:
city: San Diego
country: United States
facility: Rady Children's Hospital San Diego
state: California
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Toledo
country: United States
facility: ProMedica Toledo Children's Hospital
state: Ohio
city: Kolin III
country: Czechia
facility: Lekarna Oblastni nemocnice Kolin, a.s.
city: Kolin III
country: Czechia
facility: Oblastni nemocnice Kolin, a.s., nemocnice Stredoceskeho kraje - Detske oddeleni
city: Most
country: Czechia
facility: Krajska Zdravotni, A.S. - Nemocnice Most, O.Z., Detske A Dorostove Oddeleni
city: Most
country: Czechia
facility: Lekarna Nemocnice Most., O.Z.
city: Ostrava - Poruba
country: Czechia
facility: Fakultni Nemocnice Ostrava - Klinika Detskeho Lekarstvi
city: Ostrava - Poruba
country: Czechia
facility: Lekarna Fakultni Nemocnice Ostrava
city: Goudi
country: Greece
facility: General Children's Hospital "Agia Sofia"
state: Attica
city: Goudi
country: Greece
facility: General Children's Hospital of Athens "P. & A. Kyriakou"
state: Attica
city: Thessaloniki
country: Greece
facility: "Hippokratio" General Hospital of Thessaloniki
state: Makedonia
city: Larissa
country: Greece
facility: University General Hospital of Larissa
state: Thessaly
city: Budapest
country: Hungary
facility: Egyesitett Szent Istvan es Szent Laszlo Korhaz - Rendelointezet, Gyermekinfektologiai Osztaly
city: Cegled
country: Hungary
facility: Toldy Ferenc Korhaz es Rendelointezet, Csecsemo- es Gyermekgyogyaszati Osztaly
city: Nagykanizsa
country: Hungary
facility: Kanizsai Dorottya Korhaz, Csecsemo es Gyermekgyogyaszati Osztaly
city: Szekszard
country: Hungary
facility: Tolna Megyei Balassa Janos Korhaz, Gyermekosztaly
city: Lodz
country: Poland
facility: Wojewodzki Specjalistyczny Szpital im. dr W1. Bieganskiego
state: Lodzkie
city: Bialystok
country: Poland
facility: Uniwersytecki Dzieciecy Szpital Kliniczny im. L. Zamenhofa w Bialymstoku
state: Podlaskie
city: Bucuresti
country: Romania
facility: Spitalul Clinic de Boli Infectioase si Tropicale "Dr. Victor Babes", Sectia B2 Boli Infectioase
city: Kemerovo
country: Russian Federation
facility: State Autonomous Healthcare Institution of Kemerovo Region "Kemerovo Regional Clinical Hospital"
city: Moscow
country: Russian Federation
facility: Federal State Budgetary Institution
city: Hualien
country: Taiwan
facility: Hualien Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Mackay Memorial Hospital
city: Izmir
country: Turkey
facility: Ege Universitesi Tip Fakultesi
city: Manisa
country: Turkey
facility: Celal Bayar Universitesi Hafsa Sultan Hastanesi
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.