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A Study to Investigate PK, Safety, Tolerability of Cefepime-enmetazobactam in Pediatric Participants With cUTI

Primary Purpose

Complicated Urinary Tract Infection

Status
Not yet recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
cefepime and enmetazobactam combination
Sponsored by
Allecra
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Complicated Urinary Tract Infection

Eligibility Criteria

undefined - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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: 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 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 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 or suspected to be susceptible to cefepime-enmetazobactam. Participant has pyuria, defined as dipstick analysis positive for leukocyte esterase OR: 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. 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 β-lactam 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 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. (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: 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. 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. 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.

Sites / Locations

  • Fakultní nemocnice Hradec Králové -Ústav klinické biochemie a diagnostiky
  • Hopital des Enfants
  • Debreceni Egyetem Klinikai Központ Gyermekgyógyászati Klinika
  • SZPZOZ im. Dzieci Warszawy w Dziekanowie Leśnym
  • Národný ústav detských chorôb (NÚDCH)
  • Hospital Universitario La Paz

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

cefepime and enmetazobactam unique study arm

Arm Description

Each study participant will receive a two-hour intravenous administration of cefepime and enmetazobactam every 8 hours, as single drug in fixed dose combination (FDC) formulation at a ratio of 4 to 1.

Outcomes

Primary Outcome Measures

Pharmacokinetics Cmax
Maximum Plasma Concentration [Cmax] ; unit= mg/L
Pharmacokinetics Tmax
Time to reach Cmax (Tmax) ; unit= h
Pharmacokinetics AUC0-tau
Area under the plasma concentration time curve from time zero to the end of the dosing interval (AUC0-tau) ; unit= mg.h/L
Pharmacokinetics AUC0-inf
Area under the concentration time curve from time zero extrapolated to infinity (AUC0-inf) ; unit= mg.h/L
Pharmacokinetics t1/2
Elimination half-life (t1/2), apparent terminal elimination rate constant (λz) ; unit= h
Pharmacokinetics CL & Vd
Clearance (CL, volume of plasma cleared of the drug per unit time) ; unit= L, Volume of distribution (Vd) ; unit= L
Pharmacokinetics Cmin
Trough observed plasma concentration (Cmin) ; unit= mg/L
Safety and Tolerability
Patients with treatment emergent adverse events (AE); unit=percentage
Safety and Tolerability
Patients with drug related related treatment emergent (AE); unit=percentage
Safety and Tolerability
Patients with study intervention discontinuation due to AE; unit=percentage
Safety and Tolerability
Patients with serious adverse event (SAE); unit=percentage
Safety and Tolerability
Patients with drug related serious adverse event; unit=percentage

Secondary Outcome Measures

Efficacy assessment
Efficacy Overall success rate (Combined clinical and microbiological success rate) Clinical response Microbiological response The main efficacy endpoint is the overall success rate (Combined clinical and microbiological success) in the m-MITT population at TOC. The other efficacy endpoints are listed below: Clinical response of cure at TOC in m-MITT population Microbiological response of eradication at TOC in m-MITT population Overall success rate at Day 3, end-of-therapy (EOT), LFU in m-MITT population Clinical response rate at the Day 3, EOT, LFU visits in m-MITT population Microbiological response rate at the Day 3, EOT, LFU visits in m-MITT population Overall success rate at Day 3, EOT, TOC, LFU in Clinically Evaluable (CE) and in microbiologically evaluable (ME) populations Clinical response rate at Day 3, EOT, TOC, LFU in CE and ME populations Microbiological response at the Day 3, EOT, LFU visits in CE and ME populations

Full Information

First Posted
January 30, 2023
Last Updated
April 21, 2023
Sponsor
Allecra
Collaborators
Linical Co., Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT05826990
Brief Title
A Study to Investigate PK, Safety, Tolerability of Cefepime-enmetazobactam in Pediatric Participants With cUTI
Official Title
Single Group Phase 2 Study to Investigate Pharmacokinetics, Safety and Tolerability of Cefepime-Enmetazobactam Administered by IV Over 2 Hr in Male or Female Participants From Birth to Less Than 18 Years of Age Hospitalised With cUTI
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
April 15, 2023 (Anticipated)
Primary Completion Date
September 30, 2025 (Anticipated)
Study Completion Date
March 30, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Allecra
Collaborators
Linical Co., Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase 2 study is part of regulatory commitments in the United States (PSP) and Europe (PIP) to evaluate cefepime-enmetazobactam in paediatric participants with cUTI to support extension of the indication for cefepime-enmetazobactam to children with cUTI.
Detailed Description
The purpose of this study is to evaluate the blood concentrations and safety of the fixed dose combination of 2 drugs, cefepime with enmetazobactam administered intravenously in participants aged from birth to less than 18-years of age, hospitalised with a complicated urinary tract infection. The treatment duration will be between 3 and 7 days, depending on the time needed for disappearance of signs and symptoms of the infection. The participant will need to be hospitalised 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Complicated Urinary Tract Infection

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
cefepime and enmetazobactam unique study arm
Arm Type
Experimental
Arm Description
Each study participant will receive a two-hour intravenous administration of cefepime and enmetazobactam every 8 hours, as single drug in fixed dose combination (FDC) formulation at a ratio of 4 to 1.
Intervention Type
Drug
Intervention Name(s)
cefepime and enmetazobactam combination
Other Intervention Name(s)
cefepime-enmetazobactam
Intervention Description
Cefepime and enmetazobactam fixed dose combination administered intravenously every 8 hours as single drug formulation
Primary Outcome Measure Information:
Title
Pharmacokinetics Cmax
Description
Maximum Plasma Concentration [Cmax] ; unit= mg/L
Time Frame
Day 1 - Day 2
Title
Pharmacokinetics Tmax
Description
Time to reach Cmax (Tmax) ; unit= h
Time Frame
Day 1 - Day 2
Title
Pharmacokinetics AUC0-tau
Description
Area under the plasma concentration time curve from time zero to the end of the dosing interval (AUC0-tau) ; unit= mg.h/L
Time Frame
Day 1 - Day 2
Title
Pharmacokinetics AUC0-inf
Description
Area under the concentration time curve from time zero extrapolated to infinity (AUC0-inf) ; unit= mg.h/L
Time Frame
Day 1 - Day 2
Title
Pharmacokinetics t1/2
Description
Elimination half-life (t1/2), apparent terminal elimination rate constant (λz) ; unit= h
Time Frame
Day 1 - Day 2
Title
Pharmacokinetics CL & Vd
Description
Clearance (CL, volume of plasma cleared of the drug per unit time) ; unit= L, Volume of distribution (Vd) ; unit= L
Time Frame
Day 1 - Day 2
Title
Pharmacokinetics Cmin
Description
Trough observed plasma concentration (Cmin) ; unit= mg/L
Time Frame
Day 1 - Day 2
Title
Safety and Tolerability
Description
Patients with treatment emergent adverse events (AE); unit=percentage
Time Frame
before 1st study intervention until EOT +28 Days (±5 Days)
Title
Safety and Tolerability
Description
Patients with drug related related treatment emergent (AE); unit=percentage
Time Frame
before 1st study intervention until EOT +28 Days (±5 Days)
Title
Safety and Tolerability
Description
Patients with study intervention discontinuation due to AE; unit=percentage
Time Frame
before 1st study intervention until EOT +28 Days (±5 Days)
Title
Safety and Tolerability
Description
Patients with serious adverse event (SAE); unit=percentage
Time Frame
before 1st study intervention until EOT +28 Days (±5 Days)
Title
Safety and Tolerability
Description
Patients with drug related serious adverse event; unit=percentage
Time Frame
before 1st study intervention until EOT +28 Days (±5 Days)
Secondary Outcome Measure Information:
Title
Efficacy assessment
Description
Efficacy Overall success rate (Combined clinical and microbiological success rate) Clinical response Microbiological response The main efficacy endpoint is the overall success rate (Combined clinical and microbiological success) in the m-MITT population at TOC. The other efficacy endpoints are listed below: Clinical response of cure at TOC in m-MITT population Microbiological response of eradication at TOC in m-MITT population Overall success rate at Day 3, end-of-therapy (EOT), LFU in m-MITT population Clinical response rate at the Day 3, EOT, LFU visits in m-MITT population Microbiological response rate at the Day 3, EOT, LFU visits in m-MITT population Overall success rate at Day 3, EOT, TOC, LFU in Clinically Evaluable (CE) and in microbiologically evaluable (ME) populations Clinical response rate at Day 3, EOT, TOC, LFU in CE and ME populations Microbiological response at the Day 3, EOT, LFU visits in CE and ME populations
Time Frame
7 Days (±2 Days) after the end-of-therapy (EOT)

10. Eligibility

Sex
All
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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: 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 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 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 or suspected to be susceptible to cefepime-enmetazobactam. Participant has pyuria, defined as dipstick analysis positive for leukocyte esterase OR: 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. 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 β-lactam 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 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. (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: 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. 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. 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.
Facility Information:
Facility Name
Fakultní nemocnice Hradec Králové -Ústav klinické biochemie a diagnostiky
City
Hradec Králové
ZIP/Postal Code
500 05
Country
Czechia
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sylva Skalova, MD
Phone
00 420 495 832 840
Email
sylva.skalova@fnhk.cz
Facility Name
Hopital des Enfants
City
Toulouse
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lucas Percheron, MD
Phone
00 335 67 77 10 95
Email
percheron.l@chu-toulouse.fr
Facility Name
Debreceni Egyetem Klinikai Központ Gyermekgyógyászati Klinika
City
Debrecen
Country
Hungary
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tamás Szabó, MD
Phone
00 3630 5769 835
Email
szabotamas@med.unideb.hu
Facility Name
SZPZOZ im. Dzieci Warszawy w Dziekanowie Leśnym
City
Łomianki
Country
Poland
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joanna Samotyjek
Phone
00 486 032 81617
Email
joanna.samotyjek@szpitaldziekanow.pl
Facility Name
Národný ústav detských chorôb (NÚDCH)
City
Bratislava
Country
Slovakia
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ludmila Podradska
Facility Name
Hospital Universitario La Paz
City
Madrid
Country
Spain
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alejandro Zarauza
Phone
00 34 69 99 48226
Email
alexzarauzasant@gmail.com

12. IPD Sharing Statement

Plan to Share IPD
No

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A Study to Investigate PK, Safety, Tolerability of Cefepime-enmetazobactam in Pediatric Participants With cUTI

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