| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated urinary tract infections |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10046577 |
| E.1.2 | Term | Urinary tract infections |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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 |
|
| E.2.2 | Secondary objectives of the trial |
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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 one 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 ß-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 11 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
|
|
| E.4 | Principal 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:
(a)Haematocrit <25% or haemoglobin <8 g/dL (<80 g/L, <4.9 mmol/L)
(b)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)
XML File Identifier: JrzEcHJSHvqsZkn9e5XJ45UX6fQ=
Page 21/31
18.History of seizures, excluding well-documented febrile seizure of
childhood
19.If female, currently pregnant or breast feeding |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
To assess the safety and tolerability by :
a) adverse events (AEs) and serious adverse events(SAEs)
b) vital signs (pulse , blood pressure , respiratory rate, temperature)
c) ECG (electrocardiogram)
d) laboratory tests(complete blood count with differential and comprehensive metabolic panel )
e) creatinine clearance (CrCl) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
a) from ICF to LFU visit (27 to 50 days after start of study treatment)
b)from ICF to LFU visit (27 to 50 days after start of study treatment)
c) baseline, Day 1, TOC
d)baseline , Days 4 to 15, EoIV (end of intravenous treatment) and TOC (test of cure)
e)baseline |
|
| E.5.2 | Secondary end point(s) |
1.To assess the efficacy by:
a) clinical outcomes
b)microbiological response
c)clinical relapse
d) emergent infections
2. To evaluate the PK of CAZ-AVI in pediatric patients aged aged ≥3 months to <18 years with cIAI |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. a)end of 72 hours' treatment, end of intravenous treatment (EOIV), end of treatment (EOT) and test of cure (TOC)
b) EOIV, EOT, TOC and LFU
c)LFU
d)study duration
2.Days 2 and 3 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Czech Republic |
| Greece |
| Hungary |
| Korea, Republic of |
| Poland |
| Romania |
| Russian Federation |
| Taiwan |
| Turkey |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
