The purpose of this study is to compare treatment with olorofim versus treatment with AmBisome® followed by standard of care (SOC) in patients with IFD caused by proven IA or probable lower respiratory tract disease Aspergillus species (invasive aspergillosis, IA).
The mortality rate in immunosuppressed patients with IA is high even with effective modern antifungal drug treatment. Intrinsic and acquired resistance to azoles and amphotericin B, the two most effective classes of treatment, have been identified in Aspergillus species and are linked to this increased mortality. Currently marketed antifungal drugs have limitations including limited dosage forms, DDIs, and significant adverse reactions. For patients with IA who do not respond to or cannot tolerate a triazole therapy, treatment options are even more limited. Olorofim is an antifungal candidate with a novel mechanism of action offering activity against resistant organisms, differences in safety profile, along with oral dosing, predictable and reliable pharmacokinetic (PK) profile and limited potential for DDIs. The present study is designed to compare the efficacy, safety, and tolerability of olorofim with that of AmBisome® followed by guideline-based hierarchy standard of care (SOC) in patients with IA whose infection is either refractory to or unsuitable for azole therapy.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
225
Loading Dose: 5 tablets (150 mg) to be taken twice daily at a 12-hour (± 1 hour) interval on Day 1 Maintenance Dose: 3 tablets (90 mg) to be taken twice daily at 12-hour (± 1 hour) intervals from Day 2 until Day 84 (± 7 days)
Initial course of at least 10 days of AmBisome® administered daily at a dose of 3 mg/kg by IV infusion over a 30- to 60-minute period or according to local guidelines Administration of SOC will follow international, national, or local guidelines and product labelling.
All-cause mortality
To compare all-cause mortality (ACM) at Day 42 following treatment with olorofim versus treatment with AmBisome® followed by standard of care (SOC) in the intent-to-treat (ITT) population of patients with Invasive Fungal Disease (IFD) caused by proven Invasive Aspergillosis (IA) at any site or probable lower respiratory tract disease (LRTD) Aspergillus species (invasive aspergillosis, IA).
Time frame: Treatment Day 42
Adjudicated Assessment of Overall outcome
To compare the effects of treatment with olorofim versus treatment with AmBisome® followed by SOC on Data Review Committee (DRC)-adjudicated assessment of overall outcome in patients with proven IA or probable LRTD IA at Day 42, Day 84, and End of Treatment.
Time frame: Day 42, Day 84, and End of Treatment (anytime during the study between first administration and Day 84)
Investigator-assessed overall response
Investigator-assessed overall response (integrating clinical, radiological, and mycological response).
Time frame: Day 14, Day 28, Day 42, Day 84, EOT (End of Treatment - Maximum Treatment 84 days [± 7 Days]), and 4-week Follow-up (FU).
To compare the effects of treatment with olorofim versus treatment with AmBisome® followed by SOC on Galactomannan index.
The Sponsor's expert advisors suggested that an appropriate rule would be a failure of the GM to decline from baseline. The experts also state that they have seen very significant variation on retesting of both BAL and serum GM samples and believe it is more appropriate to state a fixed reduction of ≥ 1.0 units than any percentage reduction. These rules are used for changes in GM that document failure of therapy: 1. Serum: After 8 or more days of treatment, serum GM has neither (1) fallen by ≥ 1 unit nor (2) to \< 0.5 based on measurements taken at least 8 days apart. 2. BAL: After 8 or more days of treatment, positive GM from BAL in a patient with a previous BAL test that did not meet the definition of positive (too low or entirely negative) without regard for the interval of time between samples.
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University of Alabama at Birmingham
Birmingham, Alabama, United States
City of Hope National Medical Center
Duarte, California, United States
University of California Davis Health System
Sacramento, California, United States
UCSF Helen Diller Medical Center at Parnassus Heights
San Francisco, California, United States
University of Florida
Gainesville, Florida, United States
Augusta University
Augusta, Georgia, United States
University of Chicago Medical Center
Chicago, Illinois, United States
University of Kansas Medical Center
Kansas City, Kansas, United States
The Johns Hopkins Hospital
Baltimore, Maryland, United States
NIH Clinical Center ,NIAID,NIH
Bethesda, Maryland, United States
...and 130 more locations
Time frame: Day 14, Day 28, Day 42, Day 84, EOT (End of Treatment - Maximum Treatment 84 days [± 7 Days]) and 4-week Follow-up (FU)
To collect additional olorofim and the disproportionate metabolite H26C pharmacokinetic (PK) data for inclusion in a Population PK model
To collect plasma concentration of olorofim and H26C metabolic for for PK analysis (pre-dose and intensive PK). No non-compartmental PK analysis will be performed on the data relating to pre-dose samples and intensive PK samples, apart from data collected from selected regions, which will be reported separately. All relevant olorofim data will be provided to support population PK modelling, which will be reported separately.
Time frame: Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 70, Day 84, and at EOT (End of Treatment - Maximum Treatment 84 days [± 7 Days])
Data Review Committee's Assessment of Patient Mortality
Study data will be independently assessed by a blinded DRC consisting of independent experts in the diagnosis and management of IA, providing an independent adjudication of each patient's mortality based on the survival status collect at time frame.
Time frame: Day 42 and 84 and EOT (End of Treatment - Maximum Treatment 84 days [± 7 Days])
Diagnosis of a secondary fungal infection
To compare incidence of a secondary fungal infection when patients treated with olorofim versus treatment with AmBisome followed by SOC.
Time frame: at any time through End Of Treatment
Quality of life as measured by the 5 Level 5 Dimension (EQ-5D-5L) at Baseline
To assess patient's quality of life measured by the 5-Level 5-Dimension EuroQol Group Health-related Quality of Life Questionnaire (EQ-5D-5L) in both treatment groups
Time frame: Days 14 and EOT (End of Treatment - Maximum Treatment 84 days [± 7 Days])
Survival status
All-cause mortality will be assessed using survival status at time frame.
Time frame: Day 42, Day 84, and End Of Treatment and at the 4 weeks ± 7 days FU
Safety Assessment
To monitor incidence of Adverse Events and Serious Adverse Events in both treatment arms (Olorofim or AmBisome followed by Standard of Care).
Time frame: up to the Day 84 and 4-week Follow-up (FU)