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)
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Pfizer
- Enrollment
- 97
- Locations
- 28
- Primary Endpoint
- Percentage of Participants With Cephalosporin Class Effects and Additional Adverse Events (AEs)
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Single (Outcomes Assessor)
Eligibility Criteria
- Ages
- 3 Months to 17 Years (Child)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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).
- •Written informed consent from parent(s) or other legally acceptable representative(s), and informed assent from patient (if age appropriate according to local regulations)
- •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.
- •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
- •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
- •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).
- •Demonstrates either acute pyelonephritis or complicated lower UTI as defined by the following criteria:
- •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
- •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
- •Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
- •Previous enrolment or randomisation in the present study
- •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)
- •History of hypersensitivity reactions to carbapenems, cephalosporins, penicillins or other β-lactam antibiotics
- •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
- •Receipt of more than 24 hours of any systemic antibiotics after culture and before study drug therapy
- •Receipt of systemic antibiotics within 24 hours before obtaining the study qualifying pre-treatment baseline urine sample and before study drug therapy
- •The child is suspected or documented to have an infection caused by organisms resistant to the prophylactic antibiotics
- •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
- •Patient has suspected or known complete obstruction of any portion of the urinary tract, perinephric abscess, or ileal loops
- •Patient has had trauma to the pelvis or urinary tract
- •Patient has undergone renal transplantation
- •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)
- •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
- •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
- •Presence of any of the following clinically significant laboratory abnormalities:
- •Haematocrit <25% or haemoglobin <8 g/dL (<80 g/L, <4.9 mmol/L)
- •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.
- •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)
- •History of seizures, excluding well-documented febrile seizure of childhood
- •If female, currently pregnant or breast feeding
Arms & Interventions
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)
Intervention: Ceftazidime -avibactam (Drug)
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
Intervention: Cefepime (Drug)
Outcomes
Primary Outcomes
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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).
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.
Secondary Outcomes
- Plasma Concentrations of Ceftazidime and Avibactam(15, 30-90, 300-360 minutes post-dose on Day 3)
- Percentage of Participants With Favourable Clinical Response (CR) at End of 72 Hours Treatment: Clinically Evaluable (CE) Analysis Set at 72 Hours(End of 72 hours study drug treatment on Day 1)
- Percentage of Participants With Favourable Clinical Response (CR): Microbiological ITT (Micro-ITT) Analysis Population(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))
- Percentage of Participants With Favourable Clinical Response (CR): Intent-to-treat (ITT) Analysis Population(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))
- Percentage of Participants With Favourable Clinical Response (CR) at TOC: Clinically Evaluable (CE) Analysis Set at TOC(TOC visit (up to a maximum study duration of 50 days))
- Percentage of Participants With Favourable Clinical Response (CR): Microbiologically Evaluable (ME) Analysis Population(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))
- Percentage of Participants With Favourable Microbiological Response: Microbiologically Evaluable (ME) Analysis Population(EOIV visit (Day 4 to 15), EOT visit (up to Day 16))
- Percentage of Participants With Clinical Relapse at Late Follow-up (LFU) Visit: Microbiologically Evaluable (ME) Analysis Set at LFU(LFU visit (anytime up to a maximum study duration of 50 days))
- Percentage of Participants With Favourable Clinical Response (CR) at End of Intravenous Treatment (EOIV) Visit: Clinically Evaluable (CE) Analysis Set at EOIV(EOIV visit (anytime from Day 4 to 15))
- Percentage of Participants With Favourable Clinical Response (CR) at End of Treatment (EOT) Visit: Clinically Evaluable (CE) Analysis Set at EOT(EOT visit (up to Day 16))
- Percentage of Participants With Favourable Microbiological Response: Microbiological Intent-to-treat (Micro-ITT) Population(EOIV visit (Day 4 to 15), EOT visit(up to Day 16))
- Percentage of Participants With Clinical Relapse at Late Follow-up (LFU) Visit: Clinically Evaluable (CE) Analysis Set at LFU(LFU visit (anytime up to a maximum study duration of 50 days))
- Percentage of Participants With Emergent Infections: Microbiological Intent-to-treat (Micro-ITT) Population(Baseline up to 50 days)
- Percentage of Participants With Emergent Infections: Microbiologically Evaluable (ME) Analysis Population(Baseline up to 50 days)
- Percentage of Participants With Combined Response: Microbiologically Evaluable (ME) Analysis Population(EOIV visit (Day 4 to 15), TOC visit (up to a maximum study duration of 50 days))
- Percentage of Participants With Favourable Combined Response: Microbiological Intent-to-treat (Micro-ITT) Population(EOIV visit (Day 4 to 15), TOC visit (up to a maximum study duration of 50 days))