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)
Condition: Complicated Urinary Tract Infections
MeSH terms: Infections; Communicable Diseases; Urinary Tract Infections
Intervention: Ceftazidime -avibactam; Cefepime
Intervention description: Patients randomised (3:1) to the CAZ-AVI or cefepime treatment; Patients randomised (3:1) to the CAZ-AVI or cefepime treatment
Intervention MeSH terms: Ceftazidime; Cefepime; Avibactam; Avibactam, ceftazidime drug combination
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Enrollment: 97.0
Sex: All
Minimum age: 3 Months
Maximum age: 17 Years
Healthy volunteers: No
Keywords: Complicated urinary tract infections (cUTIs)

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.
    

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