2023-503785-22-00已完成3 期
A Phase 3, randomized, double-blind, double-dummy, multicenter, multinational study to assess the efficacy and safety of orally administered tebipenem pivoxil hydrobromide (TBP-PI-HBr) compared to intravenously (IV) administered imipenem-cilastatin in patients with complicated urinary tract infection (cUTI) or acute pyelonephritis (AP)
干预措施
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,454
- 试验地点
- 67
- 主要终点
- Overall response (combined per-patient clinical cure and favorable microbiological response) at the TOC visit in the micro-ITT Population
研究概览
简要总结
To assess the efficacy of oral TBP-PI-HBr as compared with IV imipenem-cilastatin with respect to the overall response (combined clinical cure plus microbiological eradication) at the Test-of-Cure (TOC) visit in hospitalized adult patients (≥18 years of age) with cUTI/AP
研究设计
- 分配方式
- Randomized
- 主要目的
- Follow-up
- 盲法
- Double (Monitor, Subject, Investigator)
入排标准
- 年龄范围
- 18 years 至 65+ years（18-64 Years, 65+ Years）
- 接受健康志愿者
- 否
入选标准
- •male and female patients at least 18 years of age, patients enrolled in India must be ≤90 years of age
- •able to provide informed consent
- •able to ingest oral tablets for the anticipated treatment duration. If present at Baseline, nausea and/or vomiting should be mild or well controlled with antiemetic therapy
- •have a diagnosis of cUTI or AP as defined below: a. cUTI definition: at least TWO of the following signs and symptoms: • chills, rigors, or fever (oral, tympanic, rectal or core temperature >38.0°C [>100.4°F]); fever must be observed and documented by a health care provider • dysuria, urgency to void, or increased urinary frequency • nausea or vomiting, as reported by the patient • lower abdominal pain, suprapubic pain, pelvic pain or flank pain/costovertebral angle tenderness. AND at least ONE of the following risk factors for cUTI: • implanted urinary tract instrumentation (e.g., nephrostomy tube, ureteric stents, or other urinary tract prosthetic material), ongoing intermittent bladder catheterization, or presence of an indwelling bladder catheter (Note: 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 abnormalities of the urinary tract, neurogenic bladder, or post-void residual urine volume of ≥100 milliliters (mL) within the past 6 months • 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 visit) • known intrinsic renal disease with blood urea nitrogen (BUN) >20 mg/deciliter (dL), or blood urea >42.8 mg/dL, or serum creatinine (Cr) >1.4 mg/dL • urinary retention, including urinary retention in men due to previously diagnosed benign prostatic hyperplasia (BPH). b. AP definition: acute flank pain (onset within 7 days prior to randomization) or costovertebral angle tenderness on physical examination AND at least ONE of the following signs and symptoms: • chills, rigors, or fever (oral, tympanic, rectal or core temperature >38.0°C [>100.4°F]); fever must be observed and documented by a health care provider • peripheral white blood cell count (WBC) >10,000/cubic millimeter (mm3) or bandemia (>15% immature polymorphonuclear neutrophils [PMNs], regardless of WBC count) • nausea or vomiting, as reported by the patient • dysuria, urgency to void, or increased urinary frequency.
- •have an adequate urine specimen for evaluation and culture obtained within 24 h prior to randomization with evidence of pyuria that includes at least one of the following: • at least 10 WBCs per high power field (HPF) in urine sediment • at least 10 WBCs per mm3 in unspun urine • positive leukocyte esterase (LE) on urinalysis. Note: Patients may be randomized and administered study drug prior to knowledge of urine culture results, but pyuria must be documented
- •expectation, in the judgment of the Investigator, that the patient will survive with effective antimicrobial therapy and appropriate supportive care for the anticipated duration of the study
- •willing to comply with all the study activities and procedures throughout the duration of the study
- •willing to agree to use a highly effective method of birth control; male patients must agree to not engage in sexual activity with a female partner that could lead to pregnancy (i.e., heterosexual vaginal intercourse) or must agree to use an effective barrier method of contraception from Screening through the LFU visit and for 90 days following the last dose; females of childbearing potential (FOCP) must have a negative pregnancy test at Screening and agree to abstain from sexual activity that could lead to pregnancy (i.e., heterosexual vaginal intercourse or in vitro fertilization) from the time of Screening through the EOT visit, or agree to use a highly effective method of contraception from the time of Screening throughout the study (through the LFU visit). Highly effective methods of birth control include one or more of the following: • an approved hormonal contraceptive associated with inhibition of ovulation including oral, implantable, transdermal, injectable, intravaginal contraceptive used consistently for at least 1 month prior to study drug dosing • an intrauterine device or intrauterine hormone-releasing system • male sexual partner who has been vasectomized for at least 3 months prior to Screening and who has obtained a follow-up negative sperm count
- •female of nonchildbearing potential based on at least 1 of the following criteria: • post-menopausal status defined as amenorrhea for at least 12 months prior to randomization • Follicle Stimulating Hormone (FSH) levels in the laboratory defined post-menopausal range; in the absence of amenorrhea for at least 12 months prior to randomization, at least two FSH measurements demonstrating levels in the post-menopausal range are required • patient report of surgical sterilization (i.e., bilateral tubal ligation, hysterectomy, bilateral oophorectomy/salpingectomy) at least 6 weeks prior to randomization
排除标准
- •presence of any known or suspected disease or condition that may confound the assessment of efficacy, including but not limited to the following: • perinephric or renal corticomedullary abscess • uncomplicated urinary tract infection (uUTI [acute cystitis that does not meet the cUTI disease definition; refer to Inclusion Criterion 4.a]) • polycystic kidney disease • recent history of trauma to the pelvis or urinary tract • confirmed or suspected acute or chronic bacterial prostatitis, orchitis, or epididymitis • chronic vesicoureteral reflux • previous or planned renal transplantation • previous or planned cystectomy or ileal loop surgery • known or suspected non-renal source of infection (e.g., infective endocarditis, osteomyelitis, meningitis, pneumonia) • confirmed or suspected infection that is caused by a pathogen that is resistant to either study drug (e.g., carbapenem-resistant pathogen), including infection caused by fungi (e.g., candiduria) or mycobacteria (e.g., urogenital tuberculosis) or an intrinsically resistant bacterial species not expected to respond to oral IP or comparator IV (e.g., Pseudomonas species)
- •severe hepatic impairment at Screening, as evidenced by alanine aminotransferase (ALT) or aspartate aminotransferase (AST)>5×upper limit of normal (ULN) or total bilirubin >3×ULN, or clinical signs of cirrhosis or end-stage hepatic disease (e.g., ascites, hepatic encephalopathy)
- •pregnant or lactating women
- •receipt of any investigational device or investigational medication during the last 30 days or 5 half-lives, whichever is longer, prior to randomization
- •known history of human immunodeficiency virus (HIV) infection with known CD4 count <200/mm3 or acquired immunodeficiency syndrome (AIDS)-defining illness within the past year
- •presence of immunodeficiency or an immunocompromised condition including neutropenia (<1,000 neutrophils/mm3 obtained from the local laboratory at Screening), hematologic malignancy, bone marrow transplant, or receiving immunosuppressive therapy such as cancer chemotherapy, medications for the rejection of transplantation, and long-term use of systemic corticosteroids (e.g., ≥20 mg/day of prednisone or systemic equivalent for at least 2 weeks)
- •QT interval corrected using Fridericia’s formula (QTcF) >480 msec based on screening electrocardiogram (ECG)
- •history of significant hypersensitivity or allergic reaction to β-lactam antimicrobials (e.g., cephalosporins, penicillins, carbapenems), product excipients (mannitol, microcrystalline cellulose, crospovidone, magnesium stearate, colloidal silicon dioxide, and Opadry®) or any contraindication to the use of imipenem-cilastatin
- •history of known genetic metabolism anomaly associated with carnitine deficiency (e.g., carnitine transporter defect, methylmalonic aciduria, propionic acidemia)
- •requirement for concomitant use of valproic acid, divalproex sodium, or probenecid between randomization and EOT
- •unable or unwilling to comply with the protocol
- •history of epilepsy or known seizure disorder (excluding a history of childhood febrile seizures)
- •an employee of the Investigator or study center with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, as well as a family member of the employee or the Investigator
- •history of proven or suspected Clostridioides difficile associated diarrhea
- •gross hematuria requiring intervention other than administration of study drug or removal/placement of urinary tract instrumentation
- •urine Gram stain (if performed by site) fails to demonstrate a Gram negative bacillus (i.e., negative Gram stain or Gram stain demonstrating only a Gram-positive organism) Note: Urine Gram stain should be performed, if possible, to inform eligibility but is not mandatory for Screening
- •urinary tract surgery within 7 days prior to randomization or urinary tract surgery planned during the study period (except surgery required for relieving an obstruction or placing urinary tract instrumentation)
- •creatinine clearance (CrCl) of ≤30 mL/min
- •anticipated concomitant use of non-study antimicrobial drug therapy between randomization and the LFU visit that would potentially effect outcome evaluations of cUTI/AP, including but not limited to antimicrobials with potential activity against Gram-negative pathogens, antimicrobial drug prophylaxis, and antimicrobial bladder irrigation
- •receipt of a potentially effective antimicrobial within 72 h prior to study randomization
研究组 & 干预措施
Placebo to match Tebipenem pivoxil, tablet
Placebo
干预措施: Placebo to match Tebipenem pivoxil, tablet (Drug)
IMIPENEM AND CILASTATIN
Comparator
干预措施: IMIPENEM AND CILASTATIN (Drug)
SODIUM CHLORIDE
Placebo
干预措施: SODIUM CHLORIDE (Drug)
Tebipenem pivoxil
Test
干预措施: Tebipenem pivoxil (Drug)
结局指标
主要结局
Overall response (combined per-patient clinical cure and favorable microbiological response) at the TOC visit in the micro-ITT Population
Overall response (combined per-patient clinical cure and favorable microbiological response) at the TOC visit in the micro-ITT Population
次要结局
- Overall response at the TOC visit in the ME Population
- Overall response at the EOT and LFU visits in the micro-ITT and ME Populations
- Clinical response at the EOT, TOC and LFU visits in the micro-ITT, Clinically Evaluable (CE) and ME Populations
- Microbiological response at the EOT, TOC and LFU visits in the micro-ITT and ME Populations
- Overall, Clinical and Microbiological response at the TOC, EOT and LFU visits in the micro-ITT and ME Populations in patients with drug resistant Enterobacterales
- Treatment-emergent AEs (TEAEs) and SAEs and change from Baseline results for clinical laboratory tests, ECGs, and vital sign measurements in the Safety Population
- TBP plasma concentration in the TBP PK Population
- Exploratory: Clinical response and Microbiological response at Day 5 in the micro-ITT Population
- Exploratory: Time (days) to defervescence in patients with a documented fever at Screening or Day 1 in the micro-ITT Population
- Exploratory: Occurrence of superinfection and new infection in the micro-ITT Population
- Exploratory: TBP or imipenem concentration in urine in the Urine PK Population subgroup
- Exploratory: Composite ordinal endpoint (DOOR) at TOC and LFU in the micro-ITT Population
研究者
David Hong
Scientific
Spero Therapeutics Inc.
研究点 (67)
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