| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated urinary tract infection or acute pyelonephritis |
| Komplikovaná uroinfekce nebo akutní pylonefritida |
|
| E.1.1.1 | Medical condition in easily understood language |
| Complicated urinary tract infection or acute pyelonephritis |
|
| 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 | 10021881 - Infections and infestations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10037597 |
| E.1.2 | Term | Pyelonephritis acute |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 demonstrate that FEP-TAZ is non-inferior to meropenem in overall success (clinical response plus microbiological eradication) in the mMITT population at the Day 5 visit and overall success (clinical cure plus microbiological eradication) in the mMITT population at the Test-of-Cure (TOC) visit
• To assess the overall safety and tolerability of FEP-TAZ in the Safety population
|
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate overall outcome at Day 5 and TOC in the Microbiological Evaluable (ME) Population and at End-of-IV-Therapy (EOIV) and End-of-Therapy (EOT) in the mMITT population
• To evaluate clinical outcome at Day 5 (mMITT, ME, and Clinically Evaluable [CE]) populations), EOIV and EOT (mMITT population); and at TOC (mMITT, ME, and CE populations)
• To evaluate microbiological outcome at Day 5 (mMITT and ME populations), EOIV and EOT (mMITT population), and TOC (mMITT and ME populations)
• To evaluate by-pathogen overall as well as individual clinical and microbiological outcomes at Day 5 and TOC (mMITT and ME populations)
• To evaluate by-pathogen clinical outcomes at Day 5 and TOC in subjects with bacteremia where the causative pathogen was also a uropathogen (mMITT and ME populations)
• To evaluate the pharmacokinetics (PK) of FEP-TAZ in adult subjects with complicated urinary tract infection ( cUTI) or acute pyelonephritis (AP)
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female ≥18 years of age
2. Provide a signed written informed consent prior to any study-specific procedures
3. Meet the following clinical criteria for either cUTI or AP:
A. cUTI:
a. Have at least TWO of the following new-onset or worsening symptoms or signs:
• Fever (oral, tympanic, or rectal temperature >38°C [>100.4°F]), which must be observed and documented by a health care provider
• Nausea or vomiting
• Dysuria, increased urinary frequency, or urinary urgency
• Lower abdominal, suprapubic, or pelvic pain
b. Have at least ONE of the following complicating factors:
• Use of intermittent bladder catheterization or presence of an indwelling bladder catheter (Note: indwelling bladder catheters that have been in place for >24 h prior to Screening must be removed or replaced prior to collection of the screening urine for urinalysis and culture, unless removal or replacement is considered unsafe or contraindicated)
• Current known functional or anatomical abnormality of the urogenital tract, including anatomic malformations or neurogenic bladder, or with a post-void residual urine volume of ≥100 mL
• Complete or partial obstructive uropathy (e.g., nephrolithiasis, tumor, fibrosis, urethral stricture) that is expected to be medically or surgically treated during IV study drug therapy (prior to EOIV)
• Azotemia, defined as BUN >20 mg/dL (or blood urea >42.8 mg/dL) or serum creatinine >1.4 mg/dL, due to known prior intrinsic renal disease
• Documented history of urinary retention in men (e.g., previously diagnosed benign prostatic hypertrophy) with a post-void residual urine volume of ≥100 mL
B. AP, defined as acute flank pain (onset within 7 days prior to randomization) or costovertebral angle tenderness on physical examination, plus at least ONE of the following new-onset or worsening symptoms or signs:
• Fever (oral, tympanic, or rectal temperature >38°C [>100.4°F]), which must be observed and documented by a health care provider
• Nausea or vomiting
• Dysuria, increased urinary frequency, or urinary urgency
Note: If criteria for both cUTI and AP are met, the infection type will be considered a cUTI for randomization and analysis purposes.
4. Evidence of pyuria within 48 h prior to randomization, as determined by a midstream clean catch or catheterized urine specimen with ONE of the following findings:
• Positive leukocyte esterase on urinalysis, (where positive result is at least "++" or moderate as indicated on the urine dipstick provided in the laboratory kit),
• WBC count ≥10 cells/mm3 in unspun urine
• WBC count ≥10 cells/ hpf in urine sediment
Note: The screening urine sample (within 48 h prior to randomization) will be submitted for culture; however, subjects may be randomized and administered study drug therapy prior to knowledge of baseline urine culture results
5. If known, urine culture taken within 48 hours prior to randomization contains ≥105 CFU/mL of a Gram-negative uropathogen likely to be susceptible to meropenem
6. Expectation, in the judgment of the Investigator, that any implanted urinary instrumentation (e.g., nephrostomy tubes, ureteric stents) will be surgically removed or replaced before or within 24 h after randomization, unless removal or replacement is considered unsafe or contraindicated; note that temporary bladder catheters that have been in place for >24 h prior to Screening must be removed or replaced prior to collection of the screening urine for urinalysis and culture, unless removal or replacement is considered unsafe or contraindicated
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|
| E.4 | Principal exclusion criteria |
1. Known or suspected disease or condition that, in the opinion of the investigator, may confound the assessment of efficacy, including but not limited to the following:
• Perinephric or renal abscess
• Uncomplicated lower UTI (e.g., cystitis)
• Recent trauma to the pelvis or urinary tract
• Polycystic kidney diseases
• Chronic vesicoureteral reflux
• Previous or planned cystectomy or permanent urinary diversion (e.g., ileal loop, cutaneous ureterostomy)
• Acute or chronic bacterial prostatitis, orchitis, or epididymitis
• Concurrent non-renal source of infection (e.g., endocarditis, osteomyelitis, abscess, meningitis, pneumonia)
• Previous or planned renal transplant or subject requiring hemodialysis
• cUTI or AP that is known at Screening to be caused by a pathogen that is resistant to meropenem, including infection caused by fungi (e.g., candiduria) or mycobacteria (e.g., urogenital tuberculosis)
2. Receipt of potentially-effective systemic antibacterial therapy within 72 h prior to randomization, with the exception of:
a. Receipt of a single dose of a short-acting antibacterial agent within 72 h of randomization (Appendix I) (no more than 15% of subjects will be enrolled with this exception), OR
b. Receipt of >48 h of prior antibiotic therapy and (1) in the Investigator's opinion, failed that prior antibiotic therapy (i.e., worsening signs and symptoms), AND (2) documented to have cUTI or AP caused by a pathogen that is nonsusceptible to the prior antibiotic therapy, AND (3) the causative pathogen is known to be either susceptible, intermediate, or of unknown susceptibility to meropenem
3. Rapidly progressive or terminal illness with a high risk of mortality due to any cause, including but not limited to acute hepatic failure, respiratory failure, or septic shock, such that the subject is unlikely to survive the study period
4. Pregnant or breastfeeding women
5. Likely to require > 10 days of antibiotic treatment to cure the current acute cUTI, or likely to receive any additional systemic antimicrobial therapy during the study period (including antibacterial, antimycobacterial, or antifungal therapy or prophylaxis) other than study drug, with the exception of (1) a single oral dose of any antifungal treatment for vaginal candidiasis, or (2) a glycopeptide (e.g., vancomycin), oxazolidinone (e.g., linezolid), or daptomycin given for a Gram-positive infection
6. Urinary tract surgery within 7 days prior to randomization or urinary tract surgery planned during the study period (except surgery required to relieve an obstruction or place a stent or nephrostomy) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• proportion of subjects with an overall sucess (clinical response and microbiological eradication)
• overall success (clinical cure and microbiologic eradication) at TOC in the mMITT population |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 5
Day 17 (Test of Cure) |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Last day of IV Therapy (End of IV Therapy)
• Day 7-10 (End of Therapy)
• Day 26 (Late Follow-up) |
|
| 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 | Yes |
| 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 | No |
| 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 | Yes |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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 |
| Belarus |
| Bulgaria |
| Czech Republic |
| India |
| Latvia |
| Lithuania |
| Mexico |
| Peru |
| Poland |
| Romania |
| Ukraine |
| United States |
|
| 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
|
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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