Evaluation of Safety, Tolerability, and Pharmacokinetics of Meropenem-Vaborbactam in Pediatric Patients with Complicated Urinary Tract Infection, Including Acute Pyelonephritis

Trial ID: 2024-516360-29-00
Protocol: ML-VAB-201-3248-2
Sponsor: Rempex Pharmaceuticals Inc.

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Diseases & Conditions

Urinary tract infection Pyelonephritis acute

Objectives

The primary objective of this study is to assess the **safety** and **tolerability** of Vabomere, a combination of meropenem and vaborbactam, when administered by intravenous infusion in children aged 3 months to less than 12 years with **complicated urinary tract infection (cUTI)**, including **acute pyelonephritis (AP)**. This is clinically relevant as it aims to ensure that the treatment is safe and well-tolerated in a pediatric population, which is crucial for effective management of these infections in children.

Secondary objectives include:

Characterizing the **pharmacokinetics** of meropenem and vaborbactam in the specified pediatric age group with cUTI, including AP. Understanding the pharmacokinetics is essential for optimizing dosing regimens and ensuring therapeutic efficacy.
Assessing the **efficacy** of Vabomere administered by IV infusion in the same pediatric population. Evaluating efficacy is important to confirm the therapeutic benefit of the treatment in resolving infections.

Participants

The clinical trial involves a total of **30 participants** who are children aged **≥ 3 months to < 12 years**. The study population includes both **male and female** subjects, with a focus on assessing the safety and tolerability of Vabomere administered by intravenous infusion in children with **Complicated Urinary Tract Infection (cUTI)**, including **Acute Pyelonephritis (AP)**. Participants were selected based on specific inclusion criteria, such as having a clinically suspected or bacteriologically documented cUTI or AP that necessitates hospitalization for at least three days of intravenous antibiotic treatment. The trial population is characterized by a requirement for hospitalization and antibacterial therapy, with lifestyle considerations including the need for effective contraception for females of childbearing potential and males who have reached Tanner stage 3. The study includes a vulnerable population, as it involves children who may have complicating factors such as indwelling urinary catheters or known urogenital abnormalities. The selection process ensures that participants have a baseline urine specimen obtained for culture by an acceptable method within 48 hours before the start of the study drug therapy.

Plans and Procedures

The clinical trial is a **Phase 2** study designed to evaluate the safety, tolerability, and pharmacokinetics of **Meropenem-Vaborbactam** in pediatric patients with **complicated urinary tract infection (cUTI)**, including **acute pyelonephritis (AP)**. The trial is structured as an open-label, single-arm study, where all participants receive the investigational product, administered as a **solution for infusion** via **intravenous infusion**. The trial is expected to commence recruitment in April 2025 and conclude by September 2027, with the maximum treatment period for each participant being 14 days.

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 evidence of pyuria. Following the screening, eligible participants will be admitted for hospitalization, where they will receive at least three days of intravenous antibiotic therapy. The study includes regular follow-up visits to monitor safety and efficacy, with assessments of adverse events, clinical laboratory changes, and vital signs. The end-of-study visit will occur after the completion of the treatment period, where final evaluations will be conducted to assess the primary and secondary endpoints, including safety, tolerability, and pharmacokinetic parameters.

The expected length of participant involvement is between 7 to 14 days, depending on the clinical response and the investigator's judgment. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, withdrawal of consent, or any situation where continued participation is deemed not in the best interest of the participant. The primary endpoint focuses on safety and tolerability, while secondary endpoints include pharmacokinetic parameters and efficacy measures, such as clinical cure and microbiological response.

Treatment

The clinical trial involves the administration of **Meropenem-Vaborbactam**, a combination of two active substances, **meropenem** and **vaborbactam**. This experimental medication is provided in the form of a **solution for infusion** and is administered via **intravenous infusion**. The maximum daily dose is 12 grams, with a total maximum dose of 168 grams over a treatment period not exceeding 14 days. The medication is not formulated specifically for pediatric use, although the trial targets children aged 3 months to less than 12 years with complicated urinary tract infections, including acute pyelonephritis. The pharmaceutical product is manufactured by Melinta Therapeutics Inc.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the safety, tolerability, and pharmacokinetics of the experimental drug, Vabomere, in the specified pediatric population. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol and to accurately assess the drug's effects.

Efficacy

The efficacy of the clinical trial involving **Meropenem-Vaborbactam** will be assessed through several secondary endpoints. These include evaluating the overall response, which combines per-subject clinical cure and favorable microbiological response. Clinical cure is defined as the complete resolution or significant improvement of signs and symptoms of complicated urinary tract infection (cUTI) or acute pyelonephritis (AP) present at baseline, with no new symptoms, and the subject being alive. A favorable microbiological response, or microbiological eradication, is characterized by a reduction of baseline pathogen(s) to less than 10^3 CFU/mL and at least a 1-log reduction from baseline, or a negative urine culture. Additionally, a negative repeated blood culture is required if the blood culture was positive for pathogen(s) growth at baseline, with the subject remaining alive.

Plasma samples from each blood draw will be utilized to estimate population pharmacokinetic (PK) parameters, including Cmax, Cmin, Tmax, t1/2, AUC0-8, AUC0-inf, Vss, Vz, and CL for both meropenem and vaborbactam. These PK parameters will provide further insights into the drug's efficacy. The trial will involve a multi-center, open-label, single-arm, Phase 2 study design, focusing on children aged ≥ 3 months to < 12 years with cUTI, including AP. The study will assess the safety, tolerability, and pharmacokinetics of Vabomere administered by intravenous infusion.

Inclusion and Exclusion Criteria

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Inclusion Criteria

1.Male or female, aged ≥ 3 months to < 12 years of age. • Subjects aged ≥ 3 months to < 1 year must not have been born at gestational age < 28 weeks (i.e., preterm infants are considered eligible except for extreme preterm born < 28 weeks gestational age);
Written informed consent from parent(s) or legally acceptable representative(s), and informed assent from subject (if age appropriate according to the local regulations) before initiation of any study-related procedures;
Have a clinically suspected and/or bacteriologically documented cUTI or AP judged by the Investigator that requires subject to be hospitalized for treatment with at least 3 days of IV antibiotics;
Evidence of pyuria, confirmed by either of the following: a. A urine specimen that is positive for leukocyte esterase via urine dipstick or urinalysis, or b. A urine specimen with either > 10 WBCs per microliter from an unspun urine or > 5 WBCs per high power field from a centrifuged specimen;
Symptomatic or asymptomatic cUTI or AP as designated by the following clinical signs and symptoms. Symptomatic cUTI If 2 years of age or older, the subject must have at least TWO of the following signs and symptoms: • Fever (oral temp. > 38.0° C, tympanic temp. > 38.3° C, or rectal or core temperature > 38.8° C) • Dysuria • Increased urinary frequency • Urgency • Suprapubic, flank, or abdominal pain • Secondary urinary incontinence • Nausea or vomiting If less than 2 years of age, the subject must have at least TWO of the following: • Fever (oral temp. > 38.0° C, tympanic temp. > 38.3° C, or rectal or core temp. > 38.8° C) • Failure to thrive • Recent weight loss • Irritability • Jaundice • Abdominal tenderness • Vomiting • Poor feeding • Lethargy AND • Have at least ONE complicating factor as listed below (Complicating Factors); Asymptomatic cUTI • Must be unable to perceive symptoms of UTI due to congenital and acquired spinal cord injury or abnormality AND • Have at least ONE complicating factor as listed below (Complicating Factors); Complicating Factors • Indwelling urinary catheter or other indwelling urinary tract instrumentation that is anticipated to be removed during the course of IV study therapy; • Use of intermittent urinary catheterization; • Urogenital surgery within the 7 days before administration of the first dose of IV study drug; • Known functional or anatomic abnormality of the urogenital tract; • Obstructive uropathy where the obstruction is likely to resolve or be relieved during IV study drug therapy administration; • Previously documented vesicoureteral reflux; • Neurogenic disturbance of micturition with significant impact on bladder emptying, with bladder residual volume ≥ 50 mL for children weighing < 40 kg and ≥ 100 mL for children weighing ≥ 40 kg, as previously determined by voiding cystourethrogram (VCUG), ultrasound, or urinary catheterization immediately post void; • Recurrent UTI (defined as 2 or more previous UTIs within a 12-month period)); • Evidence that the current UTI may be caused by a resistant organism, including a suspected breakthrough infection in a child receiving chronic antimicrobial prophylaxis for the prevention of UTI; • Prior documentation of congenital structural or functional urologic abnormality, including but not limited to findings from prenatal or postnatal ultrasound or postnatal VCUG; Nephrolithiasis; Acute Pyelonephritis Subjects enrolled with a diagnosis of AP must have both: • Evidence of systemic inflammatory response as demonstrated by at least ONE of the following: • Fever (oral temp. > 38.0° C, tympanic temp. >38.3° C, or rectal or core temp. >38.8° C) or hypothermia (rectal or core temp. <35.0° C) • Leukocytosis, defined as WBC > 15,000 cells/μL OR > 15% immature neutrophils, regardless of the total peripheral WBC count • C-reactive protein ≥ 20 mg/L AND • At least ONE of the following signs or symptoms: • Nausea • Vomiting • Chills • Dysuria • Increased urinary frequency • Urgency • Lower back or flank pain or costovertebral angle tenderness;
Have a pretreatment “baseline” urine specimen obtained for culture by an acceptable method, including suprapubic aspiration (SPA), clean urethral catheterization, indwelling urethral catheter, or mid-stream clean catch (urine specimens obtained from externally placed urine bags will not be allowed) within 48 hours before the start of the administration of the first dose of IV study drug therapy. Note: subjects who are not able to perceive symptoms of UTI due to congenital or acquired spinal cord injury or abnormality and are enrolled with the diagnosis of ”asymptomatic cUTI” are required to provide 2 baseline urine cultures from urine specimens obtained at least 1 hour apart. If enrolled as asymptomatic cUTI, both baseline urine cultures must return positive results of an appropriate gram-negative organism;
Must, based on the judgment of the Investigator, require hospitalization initially and 7 to 14 days of antibacterial therapy for the treatment of the presumed cUTI. Note: the subject must be anticipated to require at least 3 days of IV antibiotic therapy initially;
Females of childbearing potential must agree to sexual abstinence from the time of screening until 7 days after the end of study treatment;
Males must be willing to practice abstinence from the time of screening until 7 days after the end of study treatment.

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Exclusion Criteria

History of hypersensitivity or allergic reaction to beta-lactam antibiotics (e.g., cephalosporins, penicillins, carbapenems, monobactams);
Subjects undergoing dialysis or with estimated glomerular filtration rate eGFR < 30 ml/min/1.73m˄2, as calculated using the updated bedside Schwartz formula: eGFR = k × (height in cm) ÷ serum creatinine, where k = 0.45 in term infants to 1 year of age, k = 0.55 in children > 1 year of age;
Treatment within 30 days prior to enrollment with valproic acid or probenecid;
Evidence of significant hepatic disease or dysfunction, including known acute viral or inactive chronic hepatitis or hepatic encephalopathy, or aspartate aminotransferase or alanine aminotransferase > 3 × upper limit normal (ULN), or total bilirubin > 1.5 × ULN;
Immunodeficiency or an immunocompromised condition, including hematologic malignancy, bone marrow transplant, or receiving immunosuppressive therapy such as cancer chemotherapy, medication for the rejection of transplantation, and long-term use of systemic corticosteroids (equivalent to ≥ 20 mg a day of prednisone or systemic equivalent for ≥ 2 weeks);
Receipt of any investigational medication or investigational device during the last 30 days or during 5 half-lives of an investigational medication, whichever is longer, prior to enrollment;
Requirement at time of enrollment for any reason for additional systemic antibiotic therapy (other than study drug) or systemic antifungal therapy;
Known history of human immunodeficiency virus infection, with a (helper T cell) CD4 count < 200/mm˄3;
Presence of neutropenia (< 500 polymorphonuclear leukocytes [PMNs]/mm3);
Presence of thrombocytopenia (< 60,000 platelets/mm3);
Presence of any of the following conditions: • Perinephric abscess, • Kidney replacement therapy (i.e., dialysis, peritoneal dialysis, hemofiltration) • Renal corticomedullary abscess, • Uncomplicated cystitis, • Polycystic kidney disease, • Previous or planned renal transplantation, • Subjects receiving hemodialysis, • Previous or planned cystectomy or ileal loop surgery or pelvic trauma with urinary tract damage, or • Known candiduria at the time of the cUTI/AP diagnosis;
Known Vabomere-resistant gram-negative organism from studyqualifying urine or blood culture, confirmed cUTI or AP only due to gram-positive organism from study-qualifying urine or blood culture, or known or suspected infection with organisms that are not adequately covered by Vabomere (e.g., viral, mycobacterial, fungal) Note: if determined after enrollment, the subject may remain on study drug at the Investigator’s discretion;
Gross hematuria requiring intervention other than administration of study drug;
Known non-renal source of infection such as endocarditis, osteomyelitis, abscess, meningitis, C. difficile infection, or pneumonia diagnosed within 7 days prior to enrollment
Unable or unwilling, in the judgment of the Investigator, to comply with the protocol or complete the clinical study (e.g., unlikely to survive 28 days from initiation of Study Drug);
An employee of the Investigator or study center with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, or a family member of the employee or the Investigator;
Receipt of a potentially effective antibacterial drug therapy for cUTI for a continuous duration of more than 24 hours during the previous 72 hours prior to enrollment. Exceptions: subjects with unequivocal clinical evidence of treatment failure (i.e., worsening signs and symptoms), urine culture confirms resistance to the initial antibiotic, or the subject developed signs and symptoms of cUTI or AP while on antibiotics for another indication;
Any surgical or medical condition which, in the opinion of the Investigator, would put the subject at increased risk or is likely to interfere with study procedures or PK of the study drug;
Known or suspected nervous system disorder that suggests a predisposition to seizures, including febrile seizures in the previous 12 months;
Pregnant or breastfeeding female adolescent subjects with a positive serum or high-sensitivity urine β human chorionic gonadotropin (hCG) pregnancy test at Screening; If pregnancy test results are not yet available prior to the first dose of study treatment, a highsensitivity urine test may be performed; subjects with a positive hCG result must be withdrawn from the study;

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	01 Apr 2025	4
Bulgaria	Not Recruiting	01 Apr 2025	27
Croatia	Not Recruiting	01 Apr 2025	2
Greece	Not Recruiting	01 Apr 2025	11
Poland	Not Recruiting	01 Apr 2025	3
Spain	Not Recruiting	01 Apr 2025	4