A Phase II/III, Randomized, Double-blind, Multicenter, Comparative Study to Determine the Efficacy and Safety of Cefepime- Tazobactam (WCK 4282) vs. Meropenem in the Treatment of Complicated Urinary Tract Infection or Acute Pyelonephritis in Adults
试验速览
- 阶段
- 2/3 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 304
- 试验地点
- 22
- 主要终点
- To assess the overall safety and tolerability of FEP-TAZ in the Safety
研究概览
简要总结
Wockhardt is developing FEP-TAZ (also known as WCK 4282), which is a combination of cefepime hydrochloride (FEP, an available 4th-generation cephalosporin) and tazobactam (TAZ, a clinically wellestablished inhibitor of certain Class A and Class C β-lactamases). FEP was first approved for clinical use in 1996, and since then has been approved for multiple indications (e.g., cUTI, complicated intra-abdominal infection, neutropenic fever, pneumonia). TAZ has been combined with piperacillin and more recently with a newer cephalosporin, ceftolozane. FEP-TAZ is a sterile powder blend of FEP hydrochloride (2 g) and TAZ sodium (2 g) for administration as an IV infusion. Combination Product Name: FEP-TAZ [cefepime hydrochloride + tazobactam sodium] for Injection Chemical name of FEP component: 1-[[(6R,7R)-7-[2-(2-amino-4-thiazolyl)-glyoxylamido]-2-carboxy-8- oxo-5-thia-1-azabicyclo[4.2.0] oct-2-en-3-yl]methyl]-1-methylpyrrolidinium chloride,72-(Z)-(Omethyloxime), monohydrochloride, monohydrate. Chemical name of TAZ component: Sodium (2S, 3S, 5R)-3-methyl-7-oxo-3-(1H-1, 2, 3-triazol-1-ylmethyl)- 4-thia- 1-azabicyclo [3.2.0] heptane-2-carboxylate-4,4-dioxide. In vitro and in vivo microbiologic studies indicate that FEP-TAZ has potent activity against ESBL- and Class C β-lactamase-producing Gram-negative pathogens. Against a large number of Gram-negative isolates collected worldwide in 2014, the minimum inhibitory concentration of FEP-TAZ to inhibit 90% (MIC90) of MDR pathogens ― including strains producing both Class A + C β-lactamases ― were significantly lower than ceftolozane-tazobactam MIC90 values and comparable to meropenem and ceftazidime-avibactam MIC90s (Sader, 2017)15. The spectrum of activity of FEP-TAZ is similar to that of carbapenems and encompasses most clinically-important MDR Gram-negative pathogens (e.g., Enterobacterales and P. aeruginosa that produce ESBLs, AmpC, and selected Class A and Class D carbapenemases, such as KPC and OXA-181), with the exception of metallo-β-lactamase-producing pathogens and MDR Acinetobacter spp. TAZ also restores the activity of FEP against anaerobic pathogens, such as Bacteroides spp. and Fusobacterium spp. Owing to the potent activity of FEP against susceptible Gram-positive pathogens (e.g., methicillin-sensitive S. aureus, Streptococcus pneumoniae, S. pyogenes and E. faecalis, FEP-TAZ ― unlike ceftazidime-avibactam or ceftolozane-tazobactam ― is likely to provide a monotherapy option for serious polymicrobial infections involving susceptible Gram-negative, Gram-positive aerobic pathogens, and anaerobic pathogens.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 盲法
- Double
入排标准
- 年龄范围
- 18.00 Year(s) 至 60.00 Year(s)（—）
- 性别
- All
入选标准
- •Male or female ≥ 18 years old
- •Provide a signed written informed consent prior to any study-specific procedures
- •Meet the following clinical criteria for either cUTI or AP: A.
- •Have at least TWO of the following new-onset or worsening symptoms or signs: Fever (oral, tympanic, or rectal temperature more than 38°C [more than 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 urethral catheterization or presence of an indwelling urethral catheter (Note: indwelling urethral catheters that have been in place for more than 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 post-void residual urine volume of more than and equal to 100 mL -Complete or partial obstructive uropathy (e.g., nephrolithiasis, tumor, fibrosis, urethral stricture) that is expected to be medically or surgically treated during study drug therapy (prior to EOT) -Azotemia, defined as BUN more than 20 mg/dL (or blood urea more than 42.8 mg/dL) or serum creatinine more than 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 (CVA) tenderness on physical examination, plus at least ONE of the following new-onset or worsening symptoms or signs: -Fever (oral, tympanic, or rectal temperature more than 38°C [more than 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, cUTI will be considered the study entry diagnosis for randomization and analysis purposes.
- •Evidence of pyuria within 48 hours prior to randomization, as determined by an adequate clean catch urine specimen for culture or other appropriate method to collect a urine culture that minimizes 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) -WBC count more than and equal to 10 cells/mm3 in unspun urine -WBC count more than and equal to 10 cells/ HPF in urine sediment (spun urine) Note: The screening/baseline urine sample (within 48 hours prior to randomization) will be submitted for culture; however, subjects may be randomized and administered study drug therapy prior to knowledge of screening/baseline urine culture results.
- •If known, the screening/baseline urine culture taken within 48 hours prior to randomization contains more than and equal to 105 CFU/mL of a Gram-negative uropathogen likely to be susceptible to meropenem
- •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 more than 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
- •Requires hospitalization with administration of parenteral antibiotic therapy to manage the cUTI or AP in accordance with standard of care
- •All females must have a negative urine or serum pregnancy test (beta human chorionic gonadotropin [beta 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) -Post-menopausal (defined by amenorrhea for at least 24 months following cessation of all exogenous hormonal treatments) -Combined (estrogen 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 subject 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.
排除标准
- •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 -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 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 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.
- •For subjects 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 25 percent of enrollment.
- •Receipt of more than 48 hours of prior antibiotic therapy and in the Investigators opinion, failed that prior antibiotic therapy -Documented to have cUTI or AP caused by a pathogen that is not susceptible to the prior antibiotic therapy
- •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
- •Pregnant or breastfeeding women
- •Likely to require more than 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
- •History of epilepsy or known seizure disorder requiring current treatment with anti-seizure medication
- •Creatinine clearance less than 30 mL/min or requirement for hemodialysis or CVVH
- •Current or anticipated neutropenia defined as less than 500 neutrophils/mm3 , or platelet count less than 50,000 per microliter
- •Screening serum total bilirubin more than and equal to 2 times the ULN (unless elevated indirect bilirubin due to known Gilberts syndrome), or AST or ALT more than and equal to 5 times ULN, or alkaline phosphatase more than and equal to 2 times ULN
- •History of Clostridioides difficile associated disease within 6 months prior to enrolment
- •History of serious or significant hypersensitivity or allergic reaction (e.g., anaphylaxis, urticaria, other significant reaction) to any β lactam antibiotic or the excipient L arginine
- •Prior receipt of FEP TAZ, prior randomization in this study, or use of any experimental drug or device within 30 days prior to enrolment
- •Unlikely to comply with the protocol (e.g., inability to return for all study visits), or any condition 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).
结局指标
主要结局
To assess the overall safety and tolerability of FEP-TAZ in the Safety
时间窗: Test of Cure visit - Day 28
population
时间窗: Test of Cure visit - Day 28
次要结局
- ï‚· To assess the clinical outcome at EOT (MITT and mMITT populations) and(at TOC (mMITT and CE populations))
研究者
Dr Sachin Bhagwat
Wockhardt