A Phase 3, Multicenter, Randomized, Double-blind Study of the Efficacy and Safety of Rezafungin for Injection vs. Intravenous Caspofungin Followed by Oral Fluconazole Step Down in the Treatment of Subjects With Candidemia and/or Invasive Candidiasis
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 199
- 试验地点
- 132
- 主要终点
- All-Cause Mortality (US FDA Only)
研究概览
简要总结
The purpose of this pivotal study is to determine if intravenous Rezafungin is efficacious and safe in the treatment of candidemia and/or invasive candidiasis when compared to caspofungin (followed by optional oral fluconazole).
详细描述
A Phase 3, multicenter, prospective, randomized, double-blind, efficacy and safety study of Rezafungin for Injection versus an active comparator regimen of caspofungin followed by optional oral fluconazole step-down therapy in subjects with candidemia and/or invasive candidiasis.
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
- Quadruple (Participant, Care Provider, 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
- •Willing and able to provide written informed consent. If the subject is unable to consent for himself/herself, a legally acceptable representative must provide informed consent on his/her behalf.
- •Males or females ≥18 years of age.
- •Established mycological diagnosis of candidemia and/or invasive candidiasis from a sample taken ≤4 days (96 hours) before randomization defined as
- •≥1 blood culture positive for yeast or Candida OR
- •Positive test for Candida from a Sponsor-approved rapid in vitro diagnostic (IVD) OR
- •Positive gram stain (or other method of direct microscopy) for yeast or positive culture for Candida spp. from a specimen obtained from a normally sterile site.
- •Presence of one or more systemic signs attributable to candidemia or invasive candidiasis appearing from ≤12 hours prior to the qualifying positive culture through time of randomization.
- •Willing to initiate or continue medical treatment to cure infections, including receipt of antibiotics and surgical procedures, if required.
- •Female subjects of childbearing potential (all female subjects between 18 years <2 years post-menopausal unless surgically sterile) must agree to and comply with using one barrier method (e.g., female condom with spermicide) plus one other highly effective method of birth control, or sexual abstinence while participating in this study. Male subjects must be vasectomized, abstain from sexual intercourse, or agree to use barrier contraception, and also agree not to donate sperm while participating in the study and for 90 days thereafter (and at least 120 days from the last dose of study drug).
- •For Candidemia only subjects, drawing of a set of blood cultures within 12 hours prior to randomization in the study. The result of these blood cultures is not required for inclusion in the study.
排除标准
- •Any of the following forms of invasive candidiasis at baseline:
- •Septic arthritis in a prosthetic joint (septic arthritis in a native joint is allowed)
- •Osteomyelitis
- •Endocarditis or myocarditis
- •Meningitis, endophthalmitis, chorioretinitis, or any central nervous system infection
- •Chronic disseminated candidiasis
- •Urinary tract candidiasis due to ascending Candida infection secondary to obstruction or surgical instrumentation of the urinary tract
- •Received systemic treatment with an antifungal agent at approved doses for treatment of candidemia for >48 hours (e.g., >2 doses of a once daily antifungal agent or >4 doses of a twice daily antifungal agent) ≤4 days (96 hours) before randomization
- •a. Exception: Receipt of antifungal therapy to which any Candida spp. isolated in culture is not susceptible
- •Alanine aminotransferase or aspartate aminotransferase levels >10-fold the upper limit of normal
- •Severe hepatic impairment in subjects with a history of chronic cirrhosis (Child-Pugh score >9)
- •Presence of an indwelling vascular catheter or device that cannot be removed or an abscess that cannot be drained and is likely to be the source of candidemia or invasive candidiasis
- •Known hypersensitivity to Rezafungin for Injection, caspofungin, any echinocandin, or to any of their excipients
- •Meets National Cancer Institute Common Terminology Criteria for Adverse Events, version 5, criteria for ataxia, tremor, motor neuropathy, or sensory neuropathy of Grade 2 or higher
- •History of severe ataxia, tremor, or neuropathy or a diagnosis of multiple sclerosis or a movement disorder (including Parkinson's Disease or Huntington's Disease)
- •Planned or ongoing therapy at Screening with a known neurotoxic medication
- •Previous participation in this or any previous rezafungin study
- •Current participation in another interventional treatment trial with an investigational agent
- •Recent use of an investigational medicinal product within 28 days of the first dose of study drug or presence of an investigational device at the time of screening.
- •Pregnant or lactating females
- •The Principal Investigator (PI) is of the opinion the subject should not participate in the study
研究组 & 干预措施
Group 1: Rezafungin for Injection
Subjects in Rezafungin treatment group will receive a 400 mg loading dose in Week 1, followed by 200 mg once weekly, for a total of 2 to 4 doses.
Daily intravenous placebo infusions, when not administered Rezafungin and a daily placebo for oral step-down therapy (first eligibility on Day 4 or later as advised by a site's national/regional/local guidelines) administered every day.
干预措施: Rezafungin for Injection (Drug)
Group 1: Rezafungin for Injection
Subjects in Rezafungin treatment group will receive a 400 mg loading dose in Week 1, followed by 200 mg once weekly, for a total of 2 to 4 doses.
Daily intravenous placebo infusions, when not administered Rezafungin and a daily placebo for oral step-down therapy (first eligibility on Day 4 or later as advised by a site's national/regional/local guidelines) administered every day.
干预措施: oral placebo (Drug)
Group 2: Caspofungin
Subjects in caspofungin arm will receive a total treatment of ≥14 days beginning with a single caspofungin 70 mg IV loading dose on Day 1 followed by 50 mg IV once daily up to 28 days. After ≥3 days of caspofungin treatment(or the minimum duration of IV therapy advised by the site's national/regional/local guidelines, whichever is greater), subjects may be switched to oral fluconazole if specific parameters are met.
If the subject qualifies, then oral step-down therapy of fluconazole (6 mg/kg to the nearest 200 mg) is administered. After switch to oral step down before Day 8, subjects in the caspofungin group will receive IV placebo on Day 8 to preserve the study blind.
干预措施: Caspofungin (Drug)
Group 2: Caspofungin
Subjects in caspofungin arm will receive a total treatment of ≥14 days beginning with a single caspofungin 70 mg IV loading dose on Day 1 followed by 50 mg IV once daily up to 28 days. After ≥3 days of caspofungin treatment(or the minimum duration of IV therapy advised by the site's national/regional/local guidelines, whichever is greater), subjects may be switched to oral fluconazole if specific parameters are met.
If the subject qualifies, then oral step-down therapy of fluconazole (6 mg/kg to the nearest 200 mg) is administered. After switch to oral step down before Day 8, subjects in the caspofungin group will receive IV placebo on Day 8 to preserve the study blind.
干预措施: Fluconazole (Drug)
Group 2: Caspofungin
Subjects in caspofungin arm will receive a total treatment of ≥14 days beginning with a single caspofungin 70 mg IV loading dose on Day 1 followed by 50 mg IV once daily up to 28 days. After ≥3 days of caspofungin treatment(or the minimum duration of IV therapy advised by the site's national/regional/local guidelines, whichever is greater), subjects may be switched to oral fluconazole if specific parameters are met.
If the subject qualifies, then oral step-down therapy of fluconazole (6 mg/kg to the nearest 200 mg) is administered. After switch to oral step down before Day 8, subjects in the caspofungin group will receive IV placebo on Day 8 to preserve the study blind.
干预措施: intravenous placebo (Drug)
结局指标
主要结局
All-Cause Mortality (US FDA Only)
时间窗: Day 30 (-2 days)
The number and percentage of subjects in each treatment group who are alive and deceased (or with missing data) in the mITT population.
Global Response as Assessed by Data Review Committee (EU European Medicines Agency [EMA] Only)
时间窗: Day 14 (±1 day)
The number and percentage of subjects in each treatment group who have a global response of cure (clinical cure as assessed by the Investigator, radiological cure \[for qualifying invasive candidiasis subjects at baseline\], and mycological eradication, as confirmed by the Data Review Committee \[DRC\]), failure and indeterminate in the mITT population. A global response of cure is indicative of an efficacious outcome and the desired result, whereas a response of failure is indicative of a non-efficacious outcome and the undesired response. Indeterminate responses indicate there was not enough data obtained to determine if the response was cure or failure. Definitions for the global responses of cure, failure, and indeterminate are complex. Detailed definitions for the possible responses to this outcome measure type are provided in Table 7 (Global Response) of the clinical protocol.
次要结局
- All-Cause Mortality (EU EMA Only)(Day 30 (-2 days))
- Global Response as Assessed by Data Review Committee (US FDA Only)(Day 14 (±1 day))
- Comparison of Mycological Eradication by Visit(Day 5, Day 14 (±1 day), Day 30 (-2 days), End of Treatment (EOT) (≤2 days of last dose), and Follow-up (Days 52-59))
- Evaluate Pharmacokinetics (Cmax)(Day 1, 10 minutes before the end of infusion)
- Comparison of Investigators' Assessment of Clinical Response by Visit(Day 5, Day 14 (±1 day), Day 30 (-2 days), End of Treatment (EOT) (≤2 days of last dose), and Follow-up (Days 52-59))
- Number of Subjects With Treatment-Emergent Adverse Events [Safety and Tolerability](Day 1 through Follow-up Visit (Days 52-59))
- Comparison of Global Response (as Assessed by the DRC) by Visit(Day 5, Day 30 (-2 days), End of Treatment (EOT) (≤2 days of last dose) and Follow-up (Days 52-59))
- Comparison of Radiological Response by Investigator by Visit(Day 5, Day 14 (±1 day), Day 30 (-2 days), End of Treatment (EOT) (≤2 days of last dose), and Follow-up (Days 52-59))
- Evaluate Pharmacokinetics (Cmin)(Day 22, pre-dose, within 30 minutes prior to the start of infusion)