Clinical trial NCT01782131: A Study of the Safety and Efficacy of Posaconazole Versus Voriconazole for the Treatment of Invasive Aspergillosis (MK-5592-069)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Fungal Infections
Invasive Pulmonary Aspergillosis
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2013-02-01
Enrollment: 585
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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.

Primary outcomes:
measure: Percentage of Participants Who Died Through Day 42 in the Intention to Treat Population
timeFrame: Up to ~42 days
Secondary outcomes:
measure: Percentage of Participants Who Died Through Day 42 in the Full Analysis Set Population
timeFrame: Up to ~42 days
measure: Percentage of Participants Who Died Through Day 84 in the ITT Population
timeFrame: Up to ~84 days
measure: Percentage of Participants Who Died Through Day 84 in the FAS Population
timeFrame: Up to ~ 84 days
measure: Percentage of Participants Achieving Global Clinical Response at Week 12 in the FAS Population
timeFrame: Up to 12 weeks (± 4 weeks)
measure: Percentage of Participants Achieving Global Clinical Response at Week 6 in the FAS Population
timeFrame: Up to 6 weeks (± 2 weeks)
measure: Number of Participants Experiencing Mortality at Day 42, Day 84, and Day 114 in the FAS Population (Kaplan-Meier Time To Death Estimate)
timeFrame: Up to ~16 weeks (± 2 weeks)
measure: Number of Participants Who Died Due to Invasive Aspergillosis Through Day 42 in the FAS Population
timeFrame: Up to 42 days
measure: Number of Participants Who Died Due to Invasive Aspergillosis Through Day 84 in the FAS Population
timeFrame: Up to 84 days
measure: Percentage of Participants With Tier 1 Treatment Emergent Adverse Events
timeFrame: Up to ~16 weeks (± 2 weeks)
measure: Percentage of Participants With at Least One Adverse Event
timeFrame: Up to ~16 weeks (± 2 weeks)
measure: Percentage of Participants With at Least One Drug Related Adverse Event
timeFrame: Up to ~16 weeks (± 2 weeks)
measure: Percentage of Participants With at Least One Serious Adverse Event
timeFrame: Up to ~16 weeks (± 2 weeks)
measure: Percentage of Participants With at Least One Serious Drug Related Adverse Event
timeFrame: Up to ~16 weeks (± 2 weeks)
measure: Percentage of Participants Who Discontinued Study Treatment Due to an Adverse Event
timeFrame: Up to ~12 weeks
measure: Steady State Average Concentration (Cavg) of Posaconazole With Food Intake
timeFrame: Baseline, and at pre-dose on Day 7, Week 2, Week 4, Week 6, and Week 12
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Maertens JA, Rahav G, Lee DG, Haider S, Ramirez-Sanchez IC, Klimko N, Ponce-de-Leon A, Han S, Wrishko R, Winchell GA, Grandhi A, Waskin H; study investigators. Pharmacokinetic and Exposure Response Analysis of the Double-Blind Randomized Study of Posaconazole and Voriconazole for Treatment of Invasive Aspergillosis. Clin Drug Investig. 2023 Sep;43(9):681-690. doi: 10.1007/s40261-023-01282-7. Epub 2023 Sep 7.
citation: Maertens JA, Rahav G, Lee DG, Ponce-de-Leon A, Ramirez Sanchez IC, Klimko N, Sonet A, Haider S, Diego Velez J, Raad I, Koh LP, Karthaus M, Zhou J, Ben-Ami R, Motyl MR, Han S, Grandhi A, Waskin H; study investigators. Posaconazole versus voriconazole for primary treatment of invasive aspergillosis: a phase 3, randomised, controlled, non-inferiority trial. Lancet. 2021 Feb 6;397(10273):499-509. doi: 10.1016/S0140-6736(21)00219-1.