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 Administered Imipenem-cilastatin in Patients With Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,690
- 试验地点
- 81
- 主要终点
- Number of Participants With Overall Response at the Test-of-Cure (TOC) Visit in the Microbiological Intent-to-Treat (Micro-ITT) Population
研究概览
简要总结
The primary purpose of this study is to assess the efficacy of oral TBP-PI-HBr as compared with intravenous (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 participants (greater than or equal to (≥)18 years of age) with cUTI or AP.
详细描述
The study included a pre-planned interim analysis with stopping criteria for efficacy and futility that was performed by an independent data monitoring committee (IDMC). For full details please refer to the protocol and statistical analysis plan.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Have a diagnosis of cUTI or AP.
- •Have an adequate urine specimen for evaluation and culture obtained within 24 hours prior to randomization with evidence of pyuria that includes at least one of the following:
- •at least 10 white blood cells (WBCs) per high power field (HPF) in urine sediment
- •at least 10 WBCs per millimeters cubed (mm^3) in unspun urine
- •positive leukocyte esterase (LE) on urinalysis Note: Participants 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 participant will survive with effective antimicrobial therapy and appropriate supportive care for the anticipated duration of the study.
排除标准
- •Presence of any known or suspected disease or condition that may confound the assessment of efficacy.
- •Gross hematuria requiring intervention other than administration of study drug or removal/placement of urinary tract instrumentation.
- •Urinary tract surgery within 7 days prior to randomization or urinary tract surgery planned during the study period.
- •Creatinine clearance (CrCl) of ≤30 milliliters per minute (mL/min), as estimated by the Cockcroft-Gault formula.
- •Anticipated concomitant use of non-study antimicrobial drug therapy between randomization and the LFU visit that would potentially effect outcome evaluations of cUTI/AP.
- •Receipt of a potentially effective antimicrobial within 72 hours prior to study randomization.
- •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.
- •History of epilepsy or known seizure disorder (excluding a history of childhood febrile seizures).
- •History of proven or suspected Clostridioides difficile associated diarrhoea.
- •History of human immunodeficiency virus (HIV) infection.
- •QT interval corrected using Fridericia's formula (QTcF) >480 milliseconds (msec) based on screening ECG.
- •History of known genetic metabolism anomaly associated with carnitine deficiency.
- •Requirement for concomitant use of valproic acid, divalproex sodium, or probenecid between randomization and EOT.
- •Note: Other inclusion and exclusion criteria as per protocol may apply.
研究组 & 干预措施
TBP-PI-HBr
Participants received TBP-PI-HBr 600 milligrams (mg), two x 300mg film-coated tablets, orally (PO) and a dummy infusion intravenously (IV), every 6 hours (q6h) from Day 1 through Day 10. Participants with estimated baseline creatinine clearance (CrCl) greater than (>) 30 millilitres per minute (mL/min) and less than or equal to (≤) 50 mL/min received TBP-PI-HBr 300 mg q6h.
干预措施: TBP-PI-HBr (Drug)
TBP-PI-HBr
Participants received TBP-PI-HBr 600 milligrams (mg), two x 300mg film-coated tablets, orally (PO) and a dummy infusion intravenously (IV), every 6 hours (q6h) from Day 1 through Day 10. Participants with estimated baseline creatinine clearance (CrCl) greater than (>) 30 millilitres per minute (mL/min) and less than or equal to (≤) 50 mL/min received TBP-PI-HBr 300 mg q6h.
干预措施: Dummy Infusion (Drug)
Imipenem-cilastatin
Participants received imipenem-cilastatin 500 mg, IV and matched dummy tablets, PO, q6h from Day 1 through Day 10. Dose adjustments for imipenem-cilastatin were made for participants with estimated baseline CrCl less than (<) 90mL/min per approved imipenem-cilastatin package insert. Participants with baseline CrCl levels greater than or equal to (≥) 60 to < 90 mL/min were administered imipenem-cilastatin, 400 mg IV q6h and participants with baseline CrCl levels >30 to <60 mL/min, were administered 300mg IV, q6h.
干预措施: Imipenem-cilastatin (Drug)
Imipenem-cilastatin
Participants received imipenem-cilastatin 500 mg, IV and matched dummy tablets, PO, q6h from Day 1 through Day 10. Dose adjustments for imipenem-cilastatin were made for participants with estimated baseline CrCl less than (<) 90mL/min per approved imipenem-cilastatin package insert. Participants with baseline CrCl levels greater than or equal to (≥) 60 to < 90 mL/min were administered imipenem-cilastatin, 400 mg IV q6h and participants with baseline CrCl levels >30 to <60 mL/min, were administered 300mg IV, q6h.
干预措施: Dummy Tablets (Drug)
结局指标
主要结局
Number of Participants With Overall Response at the Test-of-Cure (TOC) Visit in the Microbiological Intent-to-Treat (Micro-ITT) Population
时间窗: At Day 17 (TOC)
Overall response includes combined clinical cure plus microbiological eradication. Clinical cure is defined as a complete resolution or significant improvement of signs and symptoms of cUTI or AP present at baseline and no new symptoms, such that no further antibacterial therapy is warranted, and participant is alive. Microbiological eradication (favorable microbiological response) is defined as a reduction of baseline uropathogens to \<10\^3 CFU/mL and negative repeated blood culture if blood culture was positive for uropathogen growth at baseline and participant is alive.
次要结局
- Number of Participants With Overall Response (Combined Per-Participant Clinical Cure and Favorable Microbiological Response) at the TOC Visit in the Microbiologically Evaluable (ME) Population(At Day 17 (TOC))
- Number of Participants With Overall Response at the End-of-Treatment (EOT) and Late Follow-Up (LFU) Visits in the Micro-ITT Population(At Day 10 (EOT) and Day 28 (LFU))
- Number of Participants With Overall Response at EOT and LFU Visits in the ME Population(At Day 10 (EOT) and Day 28 (LFU))
- Number of Participants With Clinical Response at EOT, TOC and LFU Visits in the Micro-ITT Population(At Day 10 (EOT), Day 17 (TOC), and Day 28 (LFU))
- Number of Participants With Clinical Response at EOT, TOC and LFU Visits in the CE Population(At Day 10 (EOT), Day 17 (TOC), and Day 28 (LFU))
- Number of Participants With Clinical Response at EOT, TOC and LFU Visits in the ME Population(At Day 10 (EOT), Day 17 (TOC), and Day 28 (LFU))
- Number of Participants With Microbiological Response at EOT, TOC and LFU Visits in the Micro-ITT Population(At Day 10 (EOT), Day 17 (TOC), and Day 28 (LFU))
- Number of Participants With Microbiological Response at EOT, TOC and LFU Visits in the ME Population(At Day 10 (EOT), Day 17 (TOC) and Day 28 (LFU))
- Number of Participants With Overall Response at EOT, TOC, and LFU Visits in Participants With Drug-Resistant Enterobacterales in Micro-ITT Population(Day 10 (EOT), Day 17 (TOC) and Day 28 (LFU))
- Number of Participants With Overall Response at EOT, TOC, and LFU Visits in Participants With Drug-Resistant Enterobacterales in the ME Population(Day 10 (EOT), Day 17 (TOC) and Day 28 (LFU))
- Number of Participants With Clinical Response at the EOT and TOC Visits in Participants With Drug-resistant Enterobacterales in the Micro-ITT Population(Day 10 (EOT) and Day 17 (TOC))
- Number of Participants With Clinical Response at the LFU Visit in Participants With Drug-resistant Enterobacterales in the Micro-ITT Population(At Day 28 (LFU))
- Number of Participants With Clinical Response at the EOT, TOC and LFU Visits in Participants With Drug-resistant Enterobacterales in the ME Population(Day 10 (EOT), Day 17 (TOC) and Day 28(LFU))
- Number of Participants With Microbiological Response at the EOT and TOC Visits in Participants With Drug-resistant Enterobacterales in the Micro-ITT Population(Day 10 (EOT) and Day 17 (TOC))
- Number of Participants With Microbiological Response at the LFU Visit in Participants With Drug-resistant Enterobacterales in the Micro-ITT Population(At Day 28 (LFU))
- Number of Participants With Microbiological Response at the EOT and TOC Visits in Participants With Drug-resistant Enterobacterales in the ME Population(Day 10 (EOT) and Day 17 (TOC))
- Number of Participants With Microbiological Response at the LFU Visit in Participants With Drug-resistant Enterobacterales in the ME Population(At Day 28 (LFU))
- Number of Participants With at Least One Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events(From first dose of study drug (Day 1) up to last follow-up visit (Day 28))
- Plasma Concentrations of TBP-PI-HBr(0.25 hour (h), 0.5h, 1h, 1.5h, 2h, 4h and 6h postdose at Day 2)