A Phase 3 Randomized Study of the Efficacy and Safety of Posaconazole Versus Voriconazole for the Treatment of Invasive Aspergillosis in Adults and Adolescents (Phase 3; Protocol No. MK-5592-069)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 585
- 主要终点
- Percentage of Participants Who Died Through Day 42 in the Intention to Treat Population
研究概览
简要总结
The purpose of this study is to evaluate the safety and efficacy of posaconazole (POS) versus voriconazole (VOR) in the treatment of adults and adolescents with invasive aspergillosis (IA). The primary hypothesis is that the all-cause mortality through Day 42 in the POS treatment group is non-inferior to that in the VOR treatment group.
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
- 13 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Weight >40 kg (88 lb) and ≤150 kg (330 lb); if between 13 and 14 years of age must weigh >= 50 kg (110 lb)
- •Must meet the criteria for proven, probable, or possible IA as per 2008 European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) disease definitions at the time of randomization. Proven IA will include those participants with the demonstration of fungal elements (by cytology, microscopy, or culture) in diseased tissue (sterile sampling). Probable IA includes participants with at least 1 host factor, clinical criteria, as well as mycological criteria including both direct and indirect methods. Possible IA includes participants with at least 1 host factor and clinical criteria but without mycological criteria. A modification to the 2008 EORTC/MSG criteria regarding risk factors has been made to allow for the inclusion of participants with any duration of neutropenia as an acceptable inclusion host factor.
- •If with possible IA at time of randomization must be willing or be in process of an ongoing diagnostic work up which is anticipated to result in a mycological diagnosis of proven or probable IA postrandomization.
- •Must have a central line (e.g., central venous catheter, peripherally-inserted central catheter, etc.) in place or planned to be in place prior to beginning IV study therapy. If without central catheter access, must be clinically stable and able to receive oral study therapy.
- •Acute IA defined as duration of clinical syndrome of <30 days.
- •Must be willing to adhere to dosing, study visit schedule, and mandatory procedures as outlined in the protocol. The participant must be willing to continue on study therapy for up to 12 weeks and remain in the study through the 1-month follow-up visit.
- •The participant must have the ability to transition to oral study therapy during the course of the study.
- •Female participants of child-bearing potential must be using a medically accepted method of birth control before beginning study-drug treatment and agree to continue its use for 30 days after stopping study medication
- •Is not taking prohibited antifungal prophylaxis or treatment
排除标准
- •Chronic (>1 month duration) IA, relapsed/recurrent IA, or refractory IA which has not responded to antifungal therapy.
- •Has pulmonary sarcoidosis, aspergilloma, or allergic bronchopulmonary aspergillosis (ABPA).
- •Known mixed invasive mold fungal infection including Zygomycetes, and/or a known invasive Aspergillus fungal infection in which either study drug may not be considered active.
- •Receipt of any systemic (oral, intravenous, or inhaled) antifungal therapy for this infection episode for 4 or more consecutive days (>= 96 hours) immediately before randomization.
- •Developed the current episode of IA infection during receipt of >13 days of antifungal prophylaxis with an agent considered to be a mold-active antifungal agent.
- •Receipt of posaconazole or voriconazole as empirical treatment for this infection for 4 days (96 hours) or more within the 15 days immediately before randomization.
- •Has condition that, in the opinion of the investigator, may interfere with optimal participation in the study.
- •Known hypersensitivity or other serious adverse reaction to any azole antifungal therapy or to any other ingredient of the study medication used.
- •Females who are pregnant, intend to become pregnant, or are nursing at the time of randomization.
- •Known history of Torsade de Pointes, unstable cardiac arrhythmia or proarrhythmic conditions, or a history of recent myocardial infarction within 90 days of study entry.
- •Has significant liver dysfunction
- •Hepatic cirrhosis or a Child-Pugh score of C (severe hepatic impairment) at the time of randomization.
- •Severe renal insufficiency (estimated creatinine clearance <20 mL/min) or on hemodialysis at the time of randomization or likely to require dialysis during the study.
- •Known hereditary problem of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
- •Acute symptomatic pancreatitis within 6 months of study entry or a diagnosis of chronic pancreatitis at the time of randomization.
- •Active skin lesion consistent with squamous cell carcinoma at the time of randomization, or a current or prior history of malignant melanoma within 5 years of study entry.
- •On artificial ventilation or receiving acute Continuous Positive Airway Pressure (CPAP)/Bilevel Positive Airway Pressure (BPAP) at the time of randomization.
- •Known or suspected Gilbert's disease at the time of randomization.
- •Requires treatment with other medications that cannot be stopped and for which there is a known contraindication to co-administration of one or more of the study drugs.
研究组 & 干预措施
Voriconazole
Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
干预措施: Voriconazole (Drug)
Posaconazole (POS)
Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
干预措施: Posaconazole (Drug)
Posaconazole (POS)
Participants received 300 mg posaconazole (POS) intravenous (IV) twice per day (BID) on Day 1, and then received 300 mg POS IV plus placebo IV once per day (QD) starting on Day 2 until clinically stable when participants transitioned to oral POS tablets plus oral placebo tablets QD for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
干预措施: Placebo (Drug)
Voriconazole
Participants received 6 mg/kg voriconazole (VOR) IV twice per day (BID) on Day 1, and then received 4 mg/kg VOR IV BID on Day 2 until clinically stable when participants transitioned to oral therapy with VOR capsules or VOR placebo capsules BID for up to 12 weeks of treatment. Most participants were expected to initiate treatment with IV therapy and transition to oral therapy as clinically indicated, with some participants initiating treatment with oral therapy, per clinical judgment.
干预措施: Placebo (Drug)
结局指标
主要结局
Percentage of Participants Who Died Through Day 42 in the Intention to Treat Population
时间窗: Up to ~42 days
The percentage of participants who died with posaconazole (POS) compared to voriconazole (VOR) in the first line treatment of invasive aspergillosis (IA) in the Intention to Treat (ITT) population through Day 42 was assessed.
次要结局
- Percentage of Participants Who Died Through Day 42 in the Full Analysis Set Population(Up to ~42 days)
- Percentage of Participants Achieving Global Clinical Response at Week 6 in the FAS Population(Up to 6 weeks (± 2 weeks))
- Percentage of Participants With at Least One Serious Adverse Event(Up to ~16 weeks (± 2 weeks))
- Percentage of Participants Who Died Through Day 84 in the ITT Population(Up to ~84 days)
- Percentage of Participants Who Died Through Day 84 in the FAS Population(Up to ~ 84 days)
- Percentage of Participants With at Least One Drug Related Adverse Event(Up to ~16 weeks (± 2 weeks))
- Percentage of Participants Who Discontinued Study Treatment Due to an Adverse Event(Up to ~12 weeks)
- Steady State Average Concentration (Cavg) of Posaconazole With Food Intake(Baseline, and at pre-dose on Day 7, Week 2, Week 4, Week 6, and Week 12)
- Percentage of Participants Achieving Global Clinical Response at Week 12 in the FAS Population(Up to 12 weeks (± 4 weeks))
- Number of Participants Who Died Due to Invasive Aspergillosis Through Day 42 in the FAS Population(Up to 42 days)
- Percentage of Participants With at Least One Adverse Event(Up to ~16 weeks (± 2 weeks))
- Percentage of Participants With at Least One Serious Drug Related Adverse Event(Up to ~16 weeks (± 2 weeks))
- Number of Participants Experiencing Mortality at Day 42, Day 84, and Day 114 in the FAS Population (Kaplan-Meier Time To Death Estimate)(Up to ~16 weeks (± 2 weeks))
- Number of Participants Who Died Due to Invasive Aspergillosis Through Day 84 in the FAS Population(Up to 84 days)
- Percentage of Participants With Tier 1 Treatment Emergent Adverse Events(Up to ~16 weeks (± 2 weeks))