A Multicenter, Randomized, Double-blind, Placebo-controlled, Adaptive, Non-inferiority Trial to Investigate Shortening Treatment Duration in Uncomplicated Candidemia: the CanTEN Trial
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 420
- 试验地点
- 15
- 主要终点
- Rate of recurrent candidemia and/or other proven invasive candidiasis at 30 days after end of study treatment (Day 37)
研究概览
简要总结
CanTEN is a multicenter, randomized, double-blind, placebo-controlled, adaptive, non-inferiority phase 4 trial investigating a shortened treatment duration in patients with uncomplicated candidemia. Current guidelines recommend a 14-day treatment after documented clearance of candidemia. The traditional 14-day treatment duration for uncomplicated candidemia is not sufficiently evidence-based. In a variety of bacterial infections, shorter treatment has been proven safe and efficacious, thus reducing resistance development, toxicity, and costs.
This study aims to demonstrate the non-inferiority of 10 days (Group B) of treatment compared to 14 days (Group A) in patients with a controlled source of candidemia. Once the primary endpoint have been assessed in 50% of the participants, an unblinded interim analysis will be conducted. If non-inferiority can be demonstrated, Group C will be initiated with a 7-day treatment duration.
The primary endpoint is the rate of recurrent candidemia and/or other proven invasive candidiasis at 30 days after end of study treatment (Day 37). Secondary endpoints include the time from randomization to recurrent candidemia and/or other proven invasive candidiasis, clinical cure, radiological cure and mycological eradication at the end of study treatment (Day 7) and at 30 days after end of study treatment (Day 37). In addition, all-cause mortality and mortality attributable to candidemia and/or other proven invasive candidiasis will be measured at 30 days after end of study treatment (Day 37) . Additional secondary endpoints include candidemia-attributable healthcare resources use at 30 days after end of study treatment (Day 37), Caspofungin-related adverse events (AEs) occurring until 30 days after last administration of caspofungin and patient reported outcome measures (PROMs; EQ-5D-5L and WHODAS 2.0) on Day 1 and Day 37. As an exploratory endpoint, the study will examine the impact of age, sex, relevant comorbidities, SOFA and qSOFA score, use of vasopressors and Candida species on recurrence of candidemia.
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
- •1. Participants ≥18 years on the day of informed consent.
- •2. Written informed consent by participant, according to applicable guidelines and laws.
- •3. For female participants of child-bearing potential only: willingness to practice highly effective contraception or abstinence for the duration of the trial, i.e. until 30 days after end of study treatment. Highly effective contraception methods include sterilization, combined estrogen and progestogen-containing hormonal contraception (oral, intravaginal, transdermal), progestogen-only hormonal contraception (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner. In case of nausea, diarrhoea or vomiting, oral contraception cannot be used; a non-oral highly effective method of contraception must be used instead.
- •4. Treatment with caspofungin for candidemia, initially proven by Candida-positive blood culture.
- •5. Uncomplicated candidemia defined as follows:
- •a. 7 consecutive days of caspofungin treatment after documented clearance of candidemia, i.e. caspofungin treatment on Day -7 to Day -1 prior to study treatment. Documented clearance of candidemia is defined as first (since diagnosis of candidemia) Candida-negative blood-culture on Day -7 AND no Candida-positive blood cultures from Day -6 to Day -
- •b. Treatment is planned for another 7 days, i.e. for the entire duration of study treatment from Day 1 to Day
- •Please note there is no Day 0 in this study. Day -1 is directly followed by Day
- •c. Less than 120 hours between the initial Candida-positive blood culture and the first Candida-negative blood-culture.
- •d. Source control for candidemia as follows:
- •Any central venous access device (e.g., central venous catheter, peripherally inserted central catheters, Shaldon catheters, Hickman and Broviac lines, or implanted port systems) must have been removed/replaced within 48 hours after the start of caspofungin treatment when candidemia was first diagnosed.
- •Any implantable cardiac electronic device, ventricular assist device, extracorporeal membrane oxygenation support system, or indwelling intravascular foreign body must have been removed/replaced within 48 hours after the start of caspofungin treatment when candidemia was first diagnosed.
- •Any intraabdominal candidiasis (e.g., intraabdominal abscess, peritonitis) must have been treated successfully within 5 days after start of treatment (caspofungin with or without surgery) when candidemia was first diagnosed.
排除标准
- •1. Any Candida-positive blood culture within 7 days prior to the start of study treatment, i.e. on Day -7 to Day -
- •2. Complicated candidemia defined by any of the following:
- •a. History of candidemia within 3 months prior to the current candidemia episode.
- •b. History or current presence of extra-abdominal deep-seated candidiasis, i.e. central nervous system infection, chorioretinitis, endophthalmitis, intravascular infection, endocarditis, renal abscess, osteomyelitis, or joint infection.
- •c. History of intra-abdominal candidiasis within 3 months prior to the current candidemia episode. Only exception: a very first episode of intra-abdominal candidiasis has been treated successfully within 5 days after the initial diagnosis of the current candidemia episode.
- •d. Candidemia caused by echinocandin-resistant Candida isolate.
- •3. Hematological malignancy without remission.
- •4. Allogeneic hematopoietic stem-cell transplantation within 1 year prior to screening.
- •5. Acute graft-versus-host disease grade III or IV.
- •6. Hypersensitivity to caspofungin or any of the excipients.
- •7. Ongoing glucocorticosteroids ≥0.3 mg/kg of prednisone equivalent per day at the initial diagnosis of the current candidemia episode with a planned cumulative administration of more than 3 weeks or ongoing administration of more than three weeks.
- •8. Concomitant rifampin/rifampicin, phenytoin, carbamazepine, efavirenz or nevirapine during study participation.
- •9. Absolute neutrophil count <0.5 G/L at screening.
- •10. Absolute neutrophil count <0.5 G/L of any duration expected during study treatment.
- •11. Child-Pugh score >9 at screening.
- •12. Pregnant women and breastfeeding mothers. Prior to enrolment, pregnancy must be ruled out by a negative blood pregnancy test for all women of child-bearing potential.
- •13. Active intravenous illicit drug use.
- •14. Administration of an investigational drug (i.e. not yet authorized)
- •a. Within 30 days before the first dose of study treatment in this trial OR
- •b. Within five half-lives before the first dose of study treatment in this trial whichever is longer. An investigational drug is defined as a drug not authorized for any indication in the country where this trial is conducted.
- •15. Previous participation in this trial.
- •16. Person who is in a relationship of dependence/employment with the Sponsor or the investigator.
研究组 & 干预措施
Group A (7 days of caspofungin on-study)
Group A ist standard in terms of duration of caspofungin treatment. Study treatment is 7 days of caspofungin. The number of days on caspofungin prior to study treatment and during study treatment thus totals 14 after documented clearance of candidemia, as per SmPC label. The single caspofungin dose is as per SmPC label throughout, according to participant's body weight and administered IV. once daily.
干预措施: Caspofungin only within the study (Drug)
Group B (3 days of caspofungin followed by 4 days placebo on-study)
Group B is investigational, i.e. off-label in terms of duration of caspofungin treatment. Study treatment is 3 days of caspofungin followed by 4 days of placebo. The number of days on caspofungin prior to study treatment and during study treatment thus totals 10 after documented clearance of candidemia. The single caspofungin dose is as per SmPC label throughout, according to participant's body weight and administered IV once daily.
干预措施: Caspofungin for 3 days within the study (Drug)
Group B (3 days of caspofungin followed by 4 days placebo on-study)
Group B is investigational, i.e. off-label in terms of duration of caspofungin treatment. Study treatment is 3 days of caspofungin followed by 4 days of placebo. The number of days on caspofungin prior to study treatment and during study treatment thus totals 10 after documented clearance of candidemia. The single caspofungin dose is as per SmPC label throughout, according to participant's body weight and administered IV once daily.
干预措施: Placebo for 4 days within the study (Drug)
Group C (7 days of placebo on-study)
Group C is investigational, i.e. off-label in terms of duration of caspofungin treatment, as there is no caspofungin administered on study. Study treatment is 7 days of placebo. The number of days on caspofungin prior to study treatment thus totals 7 after documented clearance of candidemia, with no caspofungin administered during study treatment. Group C may only be started depending on the results of the interim analysis.
干预措施: Placebo only within the study (Drug)
结局指标
主要结局
Rate of recurrent candidemia and/or other proven invasive candidiasis at 30 days after end of study treatment (Day 37)
时间窗: Day 37 of study (end of the study for the individual participant)
次要结局
- Time from randomization to recurrent candidemia and/or other proven invasive candidiasis(From enrolment to Day 37 of study)
- Clinical cure, radiological cure and mycological eradication at end of study treatment (Day 7)(Day 7 of study)
- Clinical cure, radiological cure and mycological eradication at 30 days after end of study treatment (Day 37)(Day 37 of study)
- All-cause mortality at 30 days after end of study treatment (Day 37)(Day 37 of study)
- Mortality attributable to candidemia and/or other invasive candidiasis at 30 days after end of study treatment, as determined by the DSMB(Day 37 of study)
- Candidemia-attributable healthcare resources at 30 days after end of study treatment, including length of stay in ICU or IMC or general ward, duration of mechanical ventilation, cost of antifungal therapy since onset of candidemia(Day 37 of study)
- Caspofungin-related adverse events (AEs) occurring until 30 days after last administration of caspofungin.(From enrolment to Day 37 of study)
- Patient reported outcome measures (PROMs) on Day 1 and Day 37: Health-related quality of life per EQ-5D-5L + Physical fuctioning as per WHODAS 2.0(Day 1 and Day 37 of study)
研究者
Oliver Cornely, MD
Univ.-Prof. Dr. med.
University of Cologne