Complicated urinary tract infections (cUTIs)

Primary Safety Objective: Evaluate the safety and tolerability of CAZ-AVI given at the selected dose regimen versus cefepime in paediatric patients aged ≥3 months to <18 years with cUTI Secondary Objective: 1. Evaluate the descriptive efficacy of CAZ-AVI versus cefepime in paediatric patients aged ≥3 months to <18 years with cUTI 2. Evaluate the PK of CAZ-AVI in paediatric patients aged ≥3 months to <18 years with cUTI

Ceftazidime Avibactam powder for concentrate for solution for infusion 2000 mg / 500 mg

Avibactam
Ceftazidime

powder for concentrate for solution for infusion

2000 mg / 500 mg

 Adverse events (AEs) and serious adverse events
(SAEs) from the signing of the Informed
Consent/Assent Form to the LFU (27 to 50 days
after start of study treatment)
 Cephalosporin class effects and additional AEs
(including, but not limited to, seizures,
Clostridium difficile-associated diarrhoea, allergic
reactions, hepatic abnormalities, haemolytic
anaemia, and changes in renal function)
 Clinical: vital signs (pulse, blood pressure,
respiratory rate, temperature), electrocardiogram
(ECG), and physical examinations
 Laboratory: complete blood count with
differential and comprehensive metabolic panel
 Creatinine clearance (CrCl)

1. Must be ≥3 calendar months to <18 years of age.
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 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 4 as determined by a midstream clean catch or clean urethral
catheterisation urine specimen (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 LFU.
7. Demonstrates either acute pyelonephritis or complicated lower UTI as defined by
the following criteria:
(a) 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
(b) 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 medically or 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 grade
 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

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 (eg, cystic fibrosis, severe burns, malignancy, hepatitis B
virus, hepatitis C virus, or human immunodeficiency virus) 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:
(a) Haematocrit <25% or haemoglobin <8 g/dL (<80 g/L, <4.9 mmol/L)
(b) Absolute neutrophil count <500/mm3
(c) Platelet count <50,000/mm3
(d) 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 d): unless if these values are acute and directly related to the infectious process being
treated.
17. Creatinine clearance ≤50 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