| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated urinary tract infections including acute pyelonephritis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Complicated urinary tract infections including infections reaching patients kidneys |
|
| 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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10037597 |
| E.1.2 | Term | Pyelonephritis acute |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 | 10021881 - Infections and infestations |
|
| 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 |
| The primary objectives are to determine the pharmacokinetics, safety, and tolerability of cefepime-enmetazobactam in all paediatric population subsets from birth to less than 18 years of age with cUTI . |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of this study are to assess efficacy of the combination of cefepime-enmetazobactam in all paediatric population subsets from birth to less than 18 years of age with cUTI. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant must be from birth to <18 years of age. Participants up to 2 months must have been born at term or preterm with a gestational age ≥32 weeks.
2. Written informed consent from parent(s) or other legally acceptable representative(s), and informed assent from participant (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) the participant is authorized to participate in this clinical study if the following criteria are met:
a) Participant has a negative urine and/or serum human chorionic gonadotropin test at screening visit. As serum tests may miss an early pregnancy, relevant menstrual history, and sexual history, including methods of contraception, should be considered
b) Participant agrees to avoid conception from the time of screening until 7 days after receipt of study intervention and agrees not to attempt pregnancy from the time of screening until 7 days after EOT with study intervention, and participant agrees to follow guidelines received regarding continuation of abstinence, initiation of abstinence or about allowed contraception, and
c) Participant reports sexual abstinence for the prior 3 months or reported the use of at least 1 of the acceptable methods of contraception, including an intrauterine device (with copper banded coil), levonorgestrel intrauterine system or regular medroxyprogesterone injections, or participant agrees to initiate sexual abstinence from the time of screening until 7 days after end of treatment (EOT) with study intervention.
4. Participant has a clinically suspected and/or bacteriologically documented complicated urinary tract infection (cUTI) or acute pyelonephritis judged by the investigator to require the participant to be hospitalized for treatment with intravenous (i.v.) therapy.
5. The causative pathogen is confirmed or suspected to be susceptible to cefepime-enmetazobactam.
6. Participant has pyuria, defined as dipstick analysis positive for leukocyte esterase OR:
a) If ≥1 year of age: White blood cell (WBC) count >10 cells/µL in unspun urine or ≥10 cells/high power field in spun urine.
b) If <1 year of age: WBC count >5 cells/µL in unspun urine or ≥5 cells/high power field in spun urine.
7. Participant demonstrates clinical signs and/or symptoms of either acute pyelonephritis or cUTI at the Screening Visit, as defined by the following criteria:
a. For pyelonephritis, participants must have at least 2 of the following new or worsening signs and/or symptoms:
i. If 0 to <2 years of age:
• Fever (as defined by the investigator)
• Failure to thrive
• Recent weight loss
• Irritability
• Poor feeding
• Lack of normal level of activity
• Abdominal tenderness on physical examination
• Vomiting
ii. If 2 to <18 years of age:
• Fever (as defined by the investigator)
• Dysuria
• Urinary urgency
• Urinary frequency
• New-onset urinary incontinence
• Suprapubic pain, flank pain, or abdominal pain
• Suprapubic tenderness or CVA tenderness on physical examination
• Nausea or vomiting
OR
b. For cUTI, participants must have at least 2 of the new or worsening signs and/or symptoms listed above AND must have at least 1 of the following complicating factors:
• Obstructive uropathy
• Congenital, functional, or anatomic abnormality of the urogenital tract
• Temporary indwelling urinary catheter
• Bladder instrumentation within <24 hours
• Recurrent UTI (≥2 events within a 12-month period)
8. Have a baseline urine culture specimen obtained within 48 hrs prior to the first dose of the study intervention. (Participants may be enrolled in this study and start i.v. study intervention therapy before the Investigator knows the results of the baseline urine culture in the event the causative pathogen is suspected to be susceptible to cefepime-enmetazobactam).
Specimen is to be obtained by suprapubic aspiration, clean intermittent urethral catheterization, indwelling urethral catheter, or mid- stream clean catch.
9. Likely to survive the current illness or hospitalization.
10. Sufficient intravascular access (peripheral or central) to receive study intervention. |
|
| E.4 | Principal exclusion criteria |
1. History of serious allergy, hypersensitivity (e.g., anaphylaxis), or any serious reaction to cefepime, any cephalosporin, penicillins, β-lactamase inhibitors (e.g., tazobactam, sulbactam, or clavulanic acid), or other β-lactam agents.
2. Previous enrolment in this study, or in another interventional study ≤30 days before i.v. administration of study intervention.
3. Concurrent infection requiring systemic antibiotics in addition to the i.v. study intervention therapy at the time of first study intervention administration.
4. Receipt of systemic antibiotics within 24 hours before obtaining the study qualifying pre-treatment baseline urine sample and before study intervention therapy. Exceptions are:
• Receipt up to 24 hours of short-acting antibacterial agent with a daily dose not completed.
• Patients who received prior antimicrobial therapy for the current cUTI/AP, and 1) in the Investigator’s opinion, failed that prior antibiotic therapy (i.e., presented with worsening signs and symptoms), AND 2) were documented that the pathogen is non-susceptible to the prior antibiotic therapy.
• Patients who have received antimicrobial prophylaxis for recurrent cUTI and then presented signs and symptoms consistent with an active new cUTI or AP.
5. A permanent indwelling bladder catheter or instrumentation including nephrostomy or current urinary catheter or anticipation of urinary catheter placement that would not be removed during the course of i.v. study intervention therapy administration.
6. Participant has suspected or known complete obstruction of any portion of the urinary tract, perinephric abscess, or ileal loops.
7. Participant has trauma to the pelvis or urinary tract.
8. Participant has undergone renal transplantation.
9. Participant has a condition or history of any illness that, in the opinion of the investigator, would have made the participant unsuitable for the study (e.g., may have confounded the results of the study or posed additional risk in administering the study therapy to the participant).
10. Participant is considered unlikely to survive the 6-week study period or had a rapidly progressive illness, including septic shock, that was associated with a high risk of mortality.
11. At the time of first study intervention administration, known presence of a cUTI caused by pathogens resistant to Cefepime - enmetazobactam.
12. 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) for children ≥ 1 month, or <13 g/dL (<130 g/L, <8.0 mmol/L) for children < 1 month.
b. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST)>3 times the age-specific upper limit of normal (ULN), or total bilirubin >2 times ULN (except known Gilbert’s disease) and Absolute Neutrophil count<1000/ mm3.
c. eGFR <30 mL/min/1.73m2. (updated creatinine-based “Bedside Schwartz”)
13. Participant has baseline QTcB (corrected Bazett’s formula) of greater than 450 msec.
14. History of seizures, excluding well-documented febrile seizures of childhood.
15. If female, currently pregnant or breast feeding. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Cmax, Tmax, AUC0-tau (repeat dose), AUC0-inf, t1/2, λz, CL, Vd, Cmin.
• Treatment emergent adverse events including monitoring of adverse events of special interests:
o Any increase in ALT or AST >3 times the age-specific upper limit of normal or total bilirubin >2
times ULN.
o Clostridium difficile-associated diarrhoea (CDAD)/Pseudomembranous colitis
o Hypersensitivity reactions, anaphylactic reactions, angioedema
o Encephalopathy/ seizures / convulsions/delirium
• Laboratory parameters, ECGs, vital signs, and physical examination
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The treatment duration will be 3 - 7 days, depending on the time needed for disappearance of symptoms of the infection.
The participant will be hospitalized at least during the treatment administration period. After the last administration of cefepime and enmetazobactam, there will be the end of treatment visit (EOT), then 2 follow-up visits at 7 days (Test of Cure (TOC)), then 14 days (Late Follow-up (LFU)) after the end of treatment visit. The End of study Visit (EOS) will be conducted via telephone call (or a visit deemed necessary as per the investigator) 28 days after the EOT visit. The participants may be discharged from hospital at the discretion of the investigator after the end of treatment visit but will be required to return to the hospital for the 2 follow-up visits.
|
|
| E.5.2 | Secondary end point(s) |
• Overall Response (composite of clinical and microbiological outcome)
• Clinical response
• Microbiological response
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Day 3 or 7, EOT, TOC, LFU are the timepoints for the secondary endpoints. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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