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)

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.

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