Phase 2 Study on Pharmacokinetics, Safety, and Tolerability of Cefepime-Enmetazobactam in Pediatric Patients with Complicated Urinary Tract Infections
- Trial ID
- 2024-518003-22-00
- Protocol
- AT-202
- Sponsor
- Orchid Pharma Europe GmbH
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the **pharmacokinetics**, safety, and tolerability of the combination of cefepime-enmetazobactam in pediatric patients from birth to less than 18 years of age who are hospitalized with complicated urinary tract infections (cUTI), including acute pyelonephritis. This is clinically relevant as it aims to establish the appropriate dosing and safety profile of this antibiotic combination in a vulnerable population, ensuring effective treatment while minimizing potential adverse effects.
The secondary objectives are to assess the efficacy of the cefepime-enmetazobactam combination in all pediatric population subsets within the same age range with cUTI. Evaluating efficacy is crucial for confirming the therapeutic benefit of the treatment in resolving infections and improving patient outcomes.
Participants
The clinical trial involves a study population comprising **pediatric patients** from birth to less than 18 years of age, diagnosed with **complicated urinary tract infections** (cUTI), including acute pyelonephritis. The trial includes both male and female participants, with a focus on those who are considered a vulnerable population due to their age and health condition. The sponsor has not provided the total number of participants. Participants were selected based on their clinical presentation of cUTI or acute pyelonephritis, requiring hospitalization for intravenous therapy. The study population includes individuals with sufficient intravascular access and those who have provided informed consent through their legal representatives. Lifestyle considerations such as diet and physical activity are not specified, but participants must demonstrate clinical signs and symptoms of the infection. The trial does not specify any particular lifestyle habits or restrictions beyond the medical criteria for participation.
Plans and Procedures
The clinical trial is designed to evaluate the **pharmacokinetics**, safety, and tolerability of cefepime-enmetazobactam in pediatric patients with complicated urinary tract infections (cUTI), including acute pyelonephritis. This is a Phase 2, single-group treatment study involving participants from birth to less than 18 years of age. The trial employs a non-randomized, open-label design, where all participants receive the investigational product, EXBLIFEP, administered via intravenous infusion over a two-hour period. The study is expected to conclude by December 31, 2025, with recruitment having commenced on November 1, 2022.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, clinical diagnosis, and sufficient intravascular access. The screening visit will also involve obtaining informed consent from parents or legal representatives and assent from the participant, if applicable. Following the screening, participants will receive the study intervention for a maximum treatment period of seven days. During this period, follow-up visits will be conducted to monitor treatment emergent adverse events, laboratory parameters, and vital signs. The primary endpoints include pharmacokinetic parameters such as Cmax and AUC, as well as safety assessments like monitoring for adverse events of special interest, including hypersensitivity reactions and encephalopathy.
The end-of-study visit will occur after the completion of the treatment period, where final assessments of clinical and microbiological response will be conducted. The overall duration of participant involvement is expected to be approximately two weeks, including the treatment and follow-up periods. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The study aims to provide valuable data to support the extension of the indication for cefepime-enmetazobactam in pediatric populations with cUTI.
Treatment
The clinical trial involves the administration of **EXBLIFEP**, a combination of **cefepime** and **enmetazobactam**, formulated as a **powder for concentrate for solution for infusion**. This investigational product is intended for intravenous infusion. The pharmaceutical form is a solution for infusion, and the medication is administered intravenously over a period of two hours. The maximum daily dose is 180 milliliters per kilogram, with a total maximum dose of 1260 milliliters per kilogram over a treatment period not exceeding seven days. The active substances, cefepime and enmetazobactam, are of chemical origin and are provided by ADVANZ PHARMA LIMITED. The product is not a pediatric formulation, and it is not classified as an orphan drug.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the pharmacokinetics, safety, and tolerability of the cefepime-enmetazobactam combination in pediatric patients with complicated urinary tract infections, including acute pyelonephritis. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The trial does not include any additional medications or interventions beyond the investigational product.
Efficacy
Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include pharmacokinetic parameters such as **Cmax**, Tmax, AUClast, AUC0-tau (repeat dose), AUC0-inf, AUCextr, half-life, λz, CL, Vd, Cmin, CLss (repeat dose), Vss (repeat dose), and accumulation ratio (repeat dose). Additionally, treatment-emergent adverse events will be monitored, including any increase in ALT or AST greater than three times the age-specific upper limit of normal, total bilirubin greater than two times the upper limit of normal, Clostridium difficile-associated diarrhea, hypersensitivity reactions, and encephalopathy or seizures. Laboratory parameters, ECGs, vital signs, and physical examinations will also be part of the primary efficacy assessment.
The secondary endpoints focus on the overall success rate, which combines clinical and microbiological success rates, as well as individual assessments of clinical and microbiological responses. These endpoints will be measured and collected at specified timepoints throughout the trial, ensuring a comprehensive evaluation of the treatment's efficacy in participants with complicated urinary tract infections, including acute pyelonephritis. The data collected will be analyzed to determine the efficacy of cefepime-enmetazobactam in the pediatric population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- Written informed consent from parent(s) or other legally acceptable representative(s), and informed assent from participant (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) the participant is authorized to participate in this clinical study if the following criteria are met: i. 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 ii. 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 iii. 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.
- 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.
- The causative pathogen is confirmed to be either susceptible to cefepime (if results are available) or suspected to be susceptible to cefepime-enmetazobactam, and the patient is suitable for treatment with cefepime according to the investigator judgement.
- 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.
- 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)
- 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.
- Likely to survive the current illness or hospitalization.
- Sufficient intravascular access (peripheral or central) to receive study intervention.
Exclusion Criteria
- 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 βlactam agents
- Previous enrolment in this study, or in another interventional study ≤30 days before i.v. administration of study intervention.
- Concurrent infection requiring systemic antibiotics in addition to the i.v. study intervention therapy at the time of first study intervention administration.
- Receipt of systemic antibiotics within 24 hours before obtaining the study qualifying pretreatment baseline urine sample and before study intervention therapy. Exception are: • Receipt up to 24 hours of short-acting antibacterial agent with a daily dose not completed. (Refer protocol ► Section 10.5, Appendix 5 for the list of allowed and disallowed antibiotics). • 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.
- 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.
- Participant has suspected or known complete obstruction of any portion of the urinary tract, perinephric abscess, or ileal loops.
- Participant has trauma to the pelvis or urinary tract.
- Participant has undergone renal transplantation.
- 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).
- 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.
- At the time of first study intervention administration, known presence of a cUTI caused by pathogens resistant to Cefepime - enmetazobactam.
- 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” equation (Schwartz et al. 2009))
- Participant has baseline QTcB (corrected Bazett’s formula) of greater than 450 msec.
- History of seizures, excluding well-documented febrile seizures of childhood.
- If female, currently pregnant or breast feeding.
- If male with a partner of childbearing potential who is pregnant, planning to become pregnant or is breastfeeding.
- Participant has acidosis and a history of L-arginine hypersensitivity
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 01 Nov 2022 | 5 |
 France | Not Yet Recruiting | 01 Nov 2022 | 5 |
 Hungary | Not Recruiting | 01 Nov 2022 | 5 |
 Poland | Not Recruiting | 01 Nov 2022 | 5 |
 Slovakia | Not Recruiting | 01 Nov 2022 | 5 |
 Spain | Not Recruiting | 01 Nov 2022 | 5 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
EXBLIFEP 2 g/0.5 g powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 180 | 7 | PRD11314228 |