Evaluation of Safety, Tolerability, and Pharmacokinetics of Meropenem-Vaborbactam in Pediatric Patients with Complicated Urinary Tract Infections
- Trial ID
- 2024-514656-32-00
- Protocol
- VABOR-KIDS-01
- Sponsor
- Menarini Ricerche S.p.A.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **pharmacokinetics** (PK) of meropenem and vaborbactam following multiple intravenous infusion doses of Vaborem® in pediatric participants aged 3 months to less than 18 years with complicated urinary tract infections (cUTI), including acute pyelonephritis (AP). Understanding the PK profile is clinically relevant as it informs dosing regimens to optimize therapeutic efficacy and minimize potential toxicity in this vulnerable population.
Secondary objectives include:
- Assessing the safety and tolerability of multiple intravenous infusion doses of Vaborem® in the same pediatric cohort. This is crucial for determining the risk-benefit profile of the treatment in children, ensuring that the therapeutic benefits outweigh any adverse effects.
Participants
The clinical trial involves **paediatric participants** aged 3 months to less than 18 years, both male and female, who are hospitalized due to **complicated urinary tract infection (cUTI)**, including acute pyelonephritis (AP). The sponsor has not provided the total number of participants. The study population was selected based on the requirement for hospitalization and a minimum of three days of intravenous antibiotic treatment for cUTI/AP, as determined by the investigator's judgment. Participants must exhibit evidence of pyuria and current or suspected cUTI or AP, indicated by specific clinical signs and symptoms, along with complicating factors such as a history of recurrent UTIs or anatomical abnormalities of the urogenital tract. The trial includes a vulnerable population, and informed consent is required from a parent or legal representative, with assent from the participant where appropriate. Lifestyle considerations such as diet and physical activity are not specified in the provided data.
Plans and Procedures
The clinical trial is designed to evaluate the **pharmacokinetics** (PK), safety, and tolerability of Vaborem (Meropenem-Vaborbactam) in a pediatric population with complicated urinary tract infections (cUTI), including acute pyelonephritis (AP). This is an open-label, multicenter, single-arm study involving participants aged 3 months to less than 18 years. The trial is categorized as a Phase 4 study and is part of a pediatric program agreed upon with the European regulatory agency to extend the use of Vaborem in children. The study will assess the PK parameters such as area under the concentration-time curve (AUC), maximum plasma concentration (Cmax), and other related metrics following multiple intravenous infusion doses.
The trial will commence with a screening visit to confirm eligibility based on inclusion criteria, such as age, hospitalization requirement for cUTI/AP, and evidence of pyuria. Participants will then receive the study drug, Vaborem, administered via intravenous infusion. The maximum treatment period is 14 days, with a maximum daily dose of 12 grams and a total dose not exceeding 168 grams. The study will include follow-up visits to monitor adverse events, serious adverse events, and changes in clinical laboratory values and vital signs. The primary endpoint focuses on deriving individual PK parameters, while secondary endpoints include the assessment of adverse events and changes in clinical parameters.
The expected duration of participant involvement is up to 14 days, with conditions for early termination including withdrawal of consent, adverse events, or any other medical reasons deemed necessary by the investigator. The trial is estimated to start recruitment on January 15, 2025, and conclude by July 15, 2026. Participants will be closely monitored throughout the study to ensure safety and efficacy, with an end-of-study visit to assess the overall outcomes and gather final data.
Treatment
The clinical trial involves the administration of **Vaborem**, a combination of **meropenem** and **vaborbactam**, formulated as a **powder for concentrate for solution for infusion**. This pharmaceutical form is intended for intravenous infusion. The medication is provided in a dosage of 1 g/1 g, with a maximum daily dose of 12 grams and a total maximum dose of 168 grams over a treatment period of up to 14 days. The administration route is exclusively via intravenous infusion, ensuring direct delivery into the bloodstream for optimal therapeutic effect. The trial aims to evaluate the pharmacokinetics of this combination in a pediatric population with complicated urinary tract infections, including acute pyelonephritis.
**Meropenem** is a broad-spectrum beta-lactam antibiotic belonging to the carbapenem class, known for its efficacy against a wide range of Gram-positive and Gram-negative bacteria. It acts by inhibiting bacterial cell wall synthesis, leading to cell lysis and death. In this trial, meropenem is combined with **vaborbactam**, a novel beta-lactamase inhibitor that protects meropenem from degradation by certain beta-lactamase enzymes produced by resistant bacteria. This combination enhances the antibacterial activity of meropenem, particularly against resistant strains.
There are no non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, included in this study. The focus is solely on the administration of Vaborem to assess its safety, tolerability, and pharmacokinetics in the specified patient population. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol and to accurately assess the pharmacokinetic parameters of the drug combination.
Efficacy
Efficacy in this clinical trial will be assessed through the evaluation of pharmacokinetic (PK) parameters of **meropenem** and **vaborbactam** following multiple intravenous infusion doses of Vaborem in pediatric participants with complicated urinary tract infections (cUTI), including acute pyelonephritis. The primary endpoints include individual PK parameters derived with updated population PK models, such as the area under the concentration-time curve (AUC), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), drug clearance (CL), half-life (t1/2), minimum plasma concentration (Cmin), and steady-state volume of distribution (Vss).
Secondary endpoints will focus on safety and tolerability, including the monitoring of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESI). Additionally, changes in clinical laboratory values and vital signs following Vaborem administration will be compared to baseline values. The trial is designed to provide comprehensive data on the pharmacokinetics, safety, and tolerability of Vaborem in the specified pediatric population, contributing to the extension of its use in this demographic as part of a pediatric program agreed with the European regulatory agency.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written informed consent before initiation of any study-related procedures. Parent or legal representative has given informed consent, as appropriate, and the participant has given assent where appropriate.
- Male or female, from birth to < 18 years of age. Participants aged < 3 months are eligible if gestational age at birth is > 32 weeks.
- Require hospitalization and a minimum of 3 days of IV antibiotic treatment for suspected or confirmed Gram negative infection as per Investigator’s judgement.
- Confirmed or suspected Gram negative infection, according to the diagnostic criteria reported in APPENDIX 1 for participants aged 3 months < 18 years and in APPENDIX 2 for participants < 3 months of age.
Exclusion Criteria
- History of any moderate or significant hypersensitivity or allergic reaction to betalactam antibiotics (e.g., cephalosporins, penicillins, carbapenems, or monobactams).
- Unable or unwilling, in the judgement of the Investigator, to comply with the protocol or complete the clinical study.
- Is or has an immediate family member of the Investigator or Site staff directly involved in the proposed study.
- Receipt of an antibacterial drug for the investigated Gram negative infection for a continuous duration of more than 24 hours during the previous 72 hours. Exceptions apply to: a. participants who have received >48 hours of prior systemic antibiotic therapy for the investigated infection with unequivocal clinical or microbiological evidence of treatment failure (i.e., worsening of signs and symptoms); b. participants who have received antimicrobial prophylaxis or who have received antibiotics for another indication and have developed signs and symptoms of investigated infection.
- Participants with a concurrent infection requiring additional systemic antimicrobial treatment.
- Any surgical or medical condition which, in the opinion of the Investigator, would put the participant at increased risk (e.g. unlikely to survive to the study period, or with rapidly progressive illness including septic shock) or is likely to interfere with study procedures or PK of the study drug.
- Females who are of childbearing potential (i.e. fertile, following menarche unless permanently sterile due to hysterectomy, bilateral salpingectomy and bilateral oophorectomy) and unwilling to practice abstinence or use at least two methods of contraception (see APPENDIX 3 - BIRTH CONTROL METHODS APPLICABLE IN VABOR-KIDS-01 STUDY) during the entire study period and up to 28 days after VaboremⓇ discontinuation.
- Pregnant or breastfeeding female adolescent participants or a positive serum β human chorionic gonadotropin (hCG) pregnancy test at Screening.
- Male adolescents who are unwilling to practice abstinence or use an acceptable method of birth control during the entire study period (i.e. condom with spermicide).
- Renal function at screening as estimated by creatinine clearance <50 mL/min/1.73m2 (<30 mL/min/1.73 m2 in participants aged < 3 months) using the Schwartz eGFR formula.
- Presence of any condition reported as exclusion criteria in Appendix 1 and Appendix 2.
- Anticipated need for antibacterial therapy longer than 14 days.
- Endocarditis, osteomyelitis, abscess, meningitis, C. difficile infection diagnosed within 7 days prior to start of treatment.
- On treatment or expected to receive immunosuppressive agents, valproic acid or probenecid.
- Evidence of significant hepatic disease or dysfunction, including known acute viral hepatitis or hepatic encephalopathy
- Presence of immunodeficiency or an immunocompromised condition including hematologic malignancy, bone marrow transplant, or receiving immunosuppressive therapy such as cancer chemotherapy, medications for the rejection of transplantation, and long-term use of systemic corticosteroids (equivalent to >2mg/kg/day for more than 1 week or > 1mg/kg/day in participants under 20kg for more than 14 days of prednisone or systemic equivalent.).
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 × ULN, or total bilirubin >1.5 × ULN (except for known Gilbert’s disease).
- Receipt of any investigational medication or investigational device during the last 30 days prior to start of treatment and until the End of Study visit.
- Requirement at time of enrollment, for any reason, for additional systemic antibiotic therapy (other than study drug) or antifungal therapy.
- Known history of human immunodeficiency virus (HIV) infection with a CD4 count <200/mm3 or, in children aged <5 years, CD4% <15%.
- Presence of neutropenia (<500 polymorphonuclear leukocytes- PMNs/mm3) unless justified by the investigated infection as per Investigator’s judgement.
- Presence of thrombocytopenia (<60,000 platelets/mm3).
- Presence of severe anemia (Hb < 8 g/dL)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 15 Jan 2025 | 4 |
 France | Recruiting | 15 Jan 2025 | 8 |
 Italy | Recruiting | 15 Jan 2025 | 13 |
 Poland | Recruiting | 15 Jan 2025 | 6 |
 Spain | Recruiting | 15 Jan 2025 | 13 |
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 |
|---|---|---|---|---|---|---|
Vaborem 1 g/1 g powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 12 | 14 | PRD7110245 |