This is a Phase 2 Study to Evaluate the Efficacy, Safety, and Tolerability of Intravenous Ertapenem-zidebactam Versus Ceftazidime-Avibactam in the Treatment of Hospitalized Adult Patients With Complicated Urinary Tract Infection or Acute Pyelonephritis

Wockhardt

Status and phase: Not yet enrolling; Phase 2

Conditions: Acute Pyelonephritis; Complicated Urinary Tract Infections(cUTI)

Treatments: Drug: Ertapenem-zidebactam; Drug: Ceftazidime-Avibactam; Drug: Ertapenam-Zidebactam

Study type: Interventional

Funder types: Industry

Identifiers

NCT07840105

W-6777-202

Details and patient eligibility

About

This is a Phase 2 randomized open label multicentre three arm comparative study evaluating the efficacy safety tolerability and pharmacokinetics of intravenous ertapenem zidebactam ERT ZID compared with ceftazidime avibactam CAZ AVI in adults with complicated urinary tract infection cUTI or acute pyelonephritis AP. Approximately 279 hospitalized participants aged 18 years and above will be enrolled from approximately 30 study sites in India and Europe and randomized in a 1 to 1 to 1 ratio to receive ERT ZID for 5 to 7 days ERT ZID for 7 to 10 days or CAZ AVI for 7 to 10 days. The primary endpoint is overall success at Test of Cure defined by clinical cure and microbiological eradication. Secondary assessments include clinical response microbiological response by pathogen outcomes pharmacokinetic parameters and plasma protein binding with safety monitored through adverse events laboratory tests vital signs and electrocardiograms.

Enrollment: 279 estimated patients

Sex: All

Ages: 18 to 90 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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:

1. 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

2. Have at least ONE of the following complicating factors:

   • Use of intermittent urethral catheterization or presence of an indwelling urethral catheter (Note: indwelling urethral catheters that have been in place for >24 hours 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 postvoid residual urine volume of ≥100 mL
   • Complete or partial obstructive uropathy (e.g., nephrolithiasis, tumour, fibrosis, urethral stricture) that is expected to be medically or surgically treated during study drug therapy (prior to EOT)
   • Azotemia, defined as blood urea nitrogen >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) 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, AP will be considered the study entry diagnosis for randomization and analysis purposes. 4. Evidence of pyuria within 48 hours prior to randomization, as determined by an adequate midstream clean-catch urine specimen or other appropriate method that minimizes the risk of bacterial contamination with ONE of the following findings:

   • Positive leukocyte esterase on urinalysis, (where positive result is at least "++" or moderate as indicated on a urine dipstick)

   • White blood cell (WBC) count ≥10 cells/mm3 in unspun urine -WBC count ≥10 cells/high-power field in urine sediment (spun urine) Note: The screening/baseline urine sample (within 48 hours prior to randomization) will be submitted for culture; however, trial participants may be randomized and administered study drug therapy prior to knowledge of screening/baseline urine culture results. 5. If known, the screening/baseline urine culture taken within 48 hours prior to randomization contains ≥105 colony forming units (CFU)/mL of a gram negative uropathogen likely to be susceptible to CAZ-AVI.

     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 randomization or within 24 hours after randomization, unless removal or replacement is considered unsafe or contraindicated; note that temporary urethral catheters that have been in place for >24 hours prior to Screening must be removed or replaced prior to collection of the Screening urine sample for urinalysis and culture, unless removal or replacement is considered unsafe or contraindicated.

   Note: Urinary stone(s) (nephrolithiasis) present at Screening are also considered a removable source of infection.

   7. Requires hospitalization with administration of parenteral antibiotic therapy to manage the cUTI or AP in accordance with standard of care.

   8. All females (except those who have a documented surgical sterilization or are postmenopausal as defined below) must have a negative urine or serum pregnancy test (beta-human chorionic gonadotropin [β-HCG]) at Screening

   AND agree to the use of one of the following highly effective methods of contraception from Screening through TOC:

   • Surgical sterilization (defined as bilateral oophorectomy or bilateral salpingectomy, but excluding bilateral tubal occlusion)
   • Postmenopausal (defined by amenorrhea for at least 24 months following cessation of all exogenous hormonal treatments)
   • Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal)
   • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable)
   • Intrauterine device
   • Intrauterine hormone-releasing system
   • Sexual intercourse with only vasectomized partners, or
   • Abstinence, defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the trial participant Note: A serum or urine pregnancy test will be performed at Screening for all female participants except those who are documented postmenopausal or surgically sterile.

   A negative result is required to confirm eligibility. All males must agree to use an acceptable barrier method of birth control (i.e., condom) with female partner(s) and must not donate sperm from Screening through TOC.

   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 disease
      • 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 trial participant requiring haemodialysis
      • Where a urine culture result is available: - At least 1 uropathogen at ≥105 colony forming units per millilitre (CFU/mL) is resistant to CAZ-AVI, or - A gram-negative bacterial pathogen is not identified, or - The trial participant has a confirmed fungal cUTI with colony count ≥103 CFU/mL

   2. cUTI or AP that is known at Screening to be caused by a pathogen that is resistant to CAZ-AVI, including infection caused by fungi (e.g., candiduria) or mycobacteria (e.g., urogenital tuberculosis).

   3. Receipt of potentially effective systemic antibacterial therapy within 72 hours prior to randomization, with the exception of any of the following:

      • Receipt of a single dose of an allowed short-acting antibacterial agent within 72 hours prior to randomization (see Section25.1). For trial participants without documentation of failure on this prior therapy and/or documented uropathogen resistant to this prior therapy, this exception will be capped at a maximum of 10% of enrolment.
      • Receipt of >48 hours of prior antibiotic therapy and in the investigator's opinion, failed that prior antibiotic therapy (i.e., worsening signs and symptoms).
      • Documented to have cUTI or AP caused by a pathogen that is not susceptible to the prior antibiotic therapy.

   4. Trial participants who may need ongoing antibacterial drug prophylaxis after treatment of cUTI (such as vesico-ureteral reflux etc).

   5. Confirmed or clinical suspicion of CAZ-AVI resistance.

   6. History of previous exposure to CAZ-AVI treatment (full course of treatment) in the last 90 days prior to randomization

   7. 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 trial participant is unlikely to survive the study period.

   8. Pregnant or breastfeeding women.

   9. Likely to require >10 days of antibiotic treatment to cure the current acute cUTI or AP, 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.

   10. 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).

   11. History of epilepsy or known seizure disorder requiring current treatment with anti-seizure medication, or confirmed or suspected encephalopathy (e.g., myoclonus, altered mental status, depressed level of consciousness).

   12. Trial participant requires concomitant treatment with valproic acid, divalproex, or probenecid.

   13. CrCl <30 mL/min or requirement for haemodialysis or CVVH

   14. Current or anticipated neutropenia defined as <500 neutrophils/mm3, or platelet count <50,000 per microliter.

   15. Screening serum total bilirubin ≥2 times the upper limit of normal (ULN) (unless elevated indirect bilirubin due to known Gilbert's syndrome), alanine aminotransferase ≥5 × ULN (or aspartate aminotransferase ≥5 × ULN if alanine aminotransferase activity not available), or alkaline phosphatase ≥2 × ULN.

   16. History of Clostridioides difficile-associated disease within 6 months prior to enrolment.

   17. History of serious or significant hypersensitivity or allergic reaction (e.g., anaphylaxis, urticaria, other significant reaction) to any β-lactam antibiotic.

   18. Prior receipt of ERT-ZID, prior randomization in this study, or use of any experimental drug or device within 30 days prior to enrolment.

   19. Unlikely to comply with the protocol (e.g., inability to return for all study visits), or any condition (including social circumstances) or clinically significant abnormality that, in the opinion of the investigator, is likely to interfere with optimal study participation (e.g., evaluation of study drug efficacy, determination of safety, or completion of the expected course of treatment).

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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279 participants in 3 patient groups

Ertapenem-zidebactam

Experimental group

Treatment:

Drug: Ertapenem-zidebactam

Ceftazidime-Avibactam

Active Comparator group

Treatment:

Drug: Ceftazidime-Avibactam

Ertapenem Zidebactam

Experimental group

Treatment:

Drug: Ertapenam-Zidebactam