Invasive Aspergillosis
Conditions
Keywords
Invasive fungal disease (IFD), Aspergillus species, Olorofim, Non-azole antifungal, Azole resistance
Brief summary
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).
Detailed description
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.
Interventions
DRUGOlorofim
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)
DRUGAmBisome®
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.
Sponsors
Iqvia Pty Ltd
Shionogi
F2G Biotech GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Masking description
Adjudicator and sponsor-blinded.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male and female patients ages over 18 years and weighing more than 30 kg 2. Patients with proven IA at any site or probable LRTD IA per EORTC/MSG 2019 criteria as adapted for this study and where the duration of specific therapy for this episode of IA has been ≤ 28 days. For purposes of this inclusion, the duration of specific therapy includes any mould-active therapy given for this episode of IA whether subsequently judged potentially effective or not. 3. Patients requiring therapy with an antifungal agent other than a mould-active azole, and who have had ≤ 96 hours of potentially effective prior therapy. Potentially effective prior therapy includes any agent to which the infecting strain of Aspergillus is likely to be susceptible. There are no exclusions or limitations on such agents (eg, AmBisome® is permitted) other than their duration. 4. AmBisome® is an appropriate therapy for the patient.
Exclusion criteria
1. Women who are pregnant or breastfeeding. 2. Known history of allergy, hypersensitivity, or any serious reaction to any component of the study drug 3. Patients with only chronic aspergillosis, aspergilloma, or allergic bronchopulmonary aspergillosis. 4. Suspected mucormycosis (zygomycosis). 5. Patients with a known active second fungal infection of any type, other than candidiasis that can be treated with fluconazole. 6. The requirement for ongoing use of echinocandin as Candida prophylaxis. 7. Microbiological findings (eg, bacteriological, virological) or other potential conditions that are temporally related and suggest a different aetiology for the clinical features. 8. Human immunodeficiency virus (HIV) infection but not currently receiving antiretroviral therapy. 9. Patients with a baseline prolongation of QT using Fridericia's Correction Formula (QTcF) ≥ 500 msec, or at high risk for QT/QTc prolongation. 10. Evidence of hepatic dysfunction.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause mortality | Treatment Day 42 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-assessed overall response | Day 14, Day 28, Day 42, Day 84, EOT (End of Treatment - Maximum Treatment 84 days [± 7 Days]), and 4-week Follow-up (FU). | Investigator-assessed overall response (integrating clinical, radiological, and mycological response). |
| To compare the effects of treatment with olorofim versus treatment with AmBisome® followed by SOC on Galactomannan index. | Day 14, Day 28, Day 42, Day 84, EOT (End of Treatment - Maximum Treatment 84 days [± 7 Days]) and 4-week Follow-up (FU) | 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. |
| To collect additional olorofim and the disproportionate metabolite H26C pharmacokinetic (PK) data for inclusion in a Population PK model | 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]) | 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. |
| Data Review Committee's Assessment of Patient Mortality | Day 42 and 84 and EOT (End of Treatment - Maximum Treatment 84 days [± 7 Days]) | 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. |
| Adjudicated Assessment of Overall outcome | Day 42, Day 84, and End of Treatment (anytime during the study between first administration and Day 84) | 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. |
| Quality of life as measured by the 5 Level 5 Dimension (EQ-5D-5L) at Baseline | Days 14 and EOT (End of Treatment - Maximum Treatment 84 days [± 7 Days]) | 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 |
| Survival status | Day 42, Day 84, and End Of Treatment and at the 4 weeks ± 7 days FU | All-cause mortality will be assessed using survival status at time frame. |
| Safety Assessment | up to the Day 84 and 4-week Follow-up (FU) | To monitor incidence of Adverse Events and Serious Adverse Events in both treatment arms (Olorofim or AmBisome followed by Standard of Care). |
| Diagnosis of a secondary fungal infection | at any time through End Of Treatment | To compare incidence of a secondary fungal infection when patients treated with olorofim versus treatment with AmBisome followed by SOC. |
Countries
Australia, Belgium, Brazil, Canada, China, France, Germany, Israel, Italy, Japan, Netherlands, New Zealand, Singapore, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Outcome results
None listed