| 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 |
|
| 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 | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10046577 |
| E.1.2 | Term | Urinary tract infections |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 |
| To assess the efficacy of cefepime/VNRX 5133 compared with meropenem with respect to both per patient microbiologic eradication and symptomatic resolution of all urinary tract infection (UTI)-core symptoms (or return to pre morbid baseline) at the Test of Cure (TOC) visit |
|
| E.2.2 | Secondary objectives of the trial |
• To determine the efficacy of cefepime/VNRX-5133 compared with meropenem with respect to the per patient microbiological response, per-pathogen microbiologic response, and symptomatic resolution of all UTI-core symptoms at various timepoints in various populations
• To determine the efficacy of cefepime/VNRX-5133 compared with meropenem with respect to the per patient microbiological response, per-pathogen microbiologic response, and symptomatic resolution of all UTI-core symptoms in patients with cUTI due to cefepime-resistant pathogens at various timepoints in various populations
• To evaluate the safety and tolerability profile of cefepime/VNRX-5133 compared with meropenem in the treatment of patients with a cUTI in the safety population
•To evaluate the steady-state pharmacokinetics (PK) of cefepime and VNRX-5133 in patients using a population PK model
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet the following general inclusion criteria to be eligible for inclusion in the study:
1. Provide signed informed consent
2. Adult male and female, ≥18 years of age
3. If female, meets at least 1 of the following criteria:
• Surgically sterile
• Age ≥50 years and postmenopausal for ≥12 months
• Age <50 years and postmenopausal for ≥2 years
• Patient has a negative serum pregnancy test and agrees not to attempt pregnancy and, if participating in sexual activity, agrees to use an effective dual method of contraception
4. Patient has pyuria as demonstrated by at least 1 of the following:
• Urine dipstick positive for leukocyte esterase
• White blood cells (WBC) >10 cells/μL in unspun urine
• WBC >10 cells/per high power field (HPF) in urine sediment
5. Demonstrates either AP or complicated lower UTI as defined by the following criteria:
a. AP is indicated by the presence of both of the following criteria:
• At least 1 of the following is present:
o Nausea or vomiting
o Chills or rigors or warmth associated with fever, defined as body temperature >38°C
• Has flank pain or costovertebral angle tenderness
b. Complicated lower UTI is indicated by the presence of all 3 of the following criteria:
• At least 1 of the following is present:
o Nausea or vomiting
o Chills or rigors or warmth associated with fever, defined as body temperature >38°C
• At least 1 of the following signs/symptoms is present:
o Dysuria
o Urinary urgency
o Urinary frequency
o Pelvic pain or suprapubic tenderness/pelvic tenderness
• At least 1 of the following complicating factors is present:
o Chronic urinary retention
o Obstructive uropathy (if complete obstruction, should intend to relieve obstruction within 48 hours after randomization)
o Neurogenic bladder with presence or history of urine residual volume of >100 mL
o Indwelling catheter (with expectation for permanent discontinuation of the catheter by Study Day 5)
6. Requires IV antibacterial therapy as initial treatment for cUTI
|
|
| E.4 | Principal exclusion criteria |
Patients who meet any of the following general exclusion criteria will not be eligible for inclusion in the study:
1. Receipt of effective antibacterial drug therapy for cUTI for a continuous duration of more than 24 hours during the previous 72 hours prior to randomization
2. Where a urine culture result is available:
• At least 1 uropathogen at ≥10^5 CFU/mL is resistant to a meropenem, or
• A gram-negative bacterial pathogen is not identified
• More than 2 microorganisms are isolated regardless of the colony count, or
• The patient has a confirmed fungal UTI with colony count ≥10^3 CFU/mL
3. Requirement for use of nonstudy systemic antibacterial drug therapy that would have a potential effect on outcome evaluations in patients with cUTI
4. Patients with suspected or confirmed prostatitis or urinary tract symptoms attributable to sexually transmitted disease
5. Patients with perinephric or renal abscess
6. Patients with renal transplantation or receiving hemodialysis or peritoneal dialysis
7. Patients with urinary diversions (e.g., ileal loops, cutaneous urostomy)
8. Patients who may need ongoing antibacterial drug prophylaxis after treatment of cUTI (such as vesico-ureteral reflux)
9. Any recent history of trauma to the pelvis or urinary tract
10. Patient has any urinary catheter or device or foreign body that will not be discontinued by Study Day 5, including, but not limited to, indwelling bladder catheter, urinary catheter, nephrostomy tubes, or stent
11. Patient is unlikely to respond to 7 days of antibacterial therapy for the treatment of cUTI without bacteremia or up to 14 days of therapy for treatment of cUTI with bacteremia
12. Patient has acute hepatitis, cirrhosis (Child-Pugh Class B or C), acute hepatic failure, or acute decompensation of chronic hepatic failure
13. Patient has had a heart, lung, heart-lung, or pancreatic transplant at any time; or bone marrow transplant in the preceding year
14. Patient has any of the following laboratory values:
• Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m^2 calculated by Modification of Diet in Renal Disease (MDRD) formula^2
• Hematocrit <25% or hemoglobin <8 g/dL
• Platelet count <50,000/mm^3
• Total bilirubin >3.0× the upper limit of normal (ULN), unless isolated hyperbilirubinemia is directly related to the acute infection or due to known Gilbert’s disease
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3.0× ULN at screening. Patients with values >3.0× ULN and <5.0× ULN are eligible if these values are acute and documented as being directly related to the infectious process being treated
• Alkaline phosphatase >3.0× ULN. Patients with values >3.0× ULN and <5.0× ULN are eligible if this value is acute and documented as being directly related to the infectious process being treated.
15. Patient has a history of serious hypersensitivity (e.g., anaphylaxis), serious allergy, or any serious reaction to cephalosporin, penicillin, carbapenem, or other β lactam antibacterials
16. Patient is considered unlikely to survive the 4- to 5-week study period or have a rapidly progressive or terminal illness, including septic shock, that is associated with a high risk of mortality
17. Patient requires concomitant medication with valproic acid or divalproex
18. Patient is in a situation or has a condition that, in the investigator’s opinion, may interfere with optimal participation in the study, or is unlikely to comply with protocol (e.g., inability to fully comprehend and clearly respond to questions on the PPSQ and DPSQ in a reliable manner, uncooperative attitude, inability to return for follow-up visit, or unlikely to complete the study)
19. Patient is participating in any other clinical study that involves the administration of an investigational product at the time of presentation or during the course of the study or has received treatment with an investigational product in the 30 days prior to study enrollment
20. Female patients who are pregnant, lactating, or planning to become pregnant during this study
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the demonstration of microbiological success (any bacterial pathogens found at study entry are eradicated to <10^3 CFU/mL on urine culture) and the demonstration of symptomatic clinical success (symptomatic resolution or return to pre-morbid baseline of all UTI-core symptoms including frequency, urgency, dysuria, suprapubic/pelvic pain, and flank pain, patient is alive, and patient has not received additional antibacterial therapy for cUTI) at TOC in the microbiological intent-to-treat (microITT) population. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please refer to Table 1 - Schedule of Assessments in the protocol |
|
| E.5.2 | Secondary end point(s) |
Clinical and Microbiological Efficacy:
-The proportion of patients with both microbiological success and symptomatic clinical success at TOC in the extended microITT population, clinically evaluable (CE)-TOC and microbiologically evaluable (ME)- TOC populations
-The proportion of patients with both microbiological success and symptomatic clinical success at EOT in the micro-ITT, ME-EOT and CEEOT populations, and at LFU in the micro-ITT, ME-LFU and CE-LFU populations
-The proportion of patients with per-patient microbiological success at EOT, TOC and LFU in the micro-ITT, ME- EOT, ME-TOC and ME-LFU populations
-The proportion of patients with symptomatic clinical success at EOT, TOC and LFU in the micro-ITT population and CE-EOT, CE-TOC and CELFU populations
-The proportion of patients with clinical success based on investigator opinion at TOC in the micro-ITT population
-The proportion of patients with per-pathogen microbiological success at EOT in the micro-ITT and ME-EOT populations, TOC in the micro-ITT and ME-TOC populations, and at LFU in the micro-ITT and ME-LFU populations
-The proportion of patients with both microbiological success and symptomatic clinical success among those with cefepime-resistant pathogens at EOT in the micro-ITT, ME-EOT and CE-EOT populations, TOC in the micro-ITT, ME-TOC, and CE-TOC populations, and at LFU in the micro-ITT, ME-LFU and CE-LFU populations
-The proportion of patients with per-patient microbiological success among those with cefepime-resistant pathogens at EOT in the micro-ITT and ME-EOT populations, TOC in the micro-ITT and ME-TOC populations, and at LFU in the micro-ITT and ME-LFU populations
-The proportion of patients with per-pathogen microbiological success among those with cefepime-resistant pathogens at EOT in the micro-ITT and ME-EOT populations, TOC in the micro-ITT and ME-TOC populations,
and at LFU in the micro-ITT and ME-LFU populations
-The proportion of patients with symptomatic clinical success among those with cefepime-resistant pathogens at EOT in the micro-ITT and CEEOT populations, TOC in the micro-ITT and CE-TOC populations, and at LFU in the micro-ITT and CE-LFU populations
Safety and Tolerability:
• Safety and tolerability will be assessed based on the incidence and severity of adverse events (AEs) and serious adverse events (SAEs), exposure, mortality, reasons for discontinuation of study drug and study withdrawal, vital sign measurements, and clinically significant changes in clinical chemistry, hematology, urinalysis, and coagulation laboratory values.
Pharmacokinetics:
• The population PK analysis using data from the study will be described in a population PK analysis plan and summarized in a separate report.
Resolution of Fever:
• The time to first defervescence (≤37.8°C) in the microITT population for patients who have fever (>38°C) at baseline will be assessed as an exploratory endpoint.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to Table 1 - Schedule of Assessments in the protocol |
|
| 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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Brazil |
| China |
| Mexico |
| Peru |
| Russian Federation |
| Serbia |
| Turkey |
| Ukraine |
| United States |
| Bulgaria |
| Croatia |
| Hungary |
| Latvia |
| Romania |
| Czechia |
| Argentina |
|
| 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
|
| The end of the study is defined as the date of receipt of the last data point for statistical analysis of the last patient participating in the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 6 |
Print
