Olorofim Aspergillus Infection Study

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase III, Adjudicator-blinded, Randomised Study to Evaluate Efficacy and Safety of Treatment With Olorofim Versus Treatment With AmBisome® Followed by Standard of Care in Patients With Invasive Fungal Disease Caused by Aspergillus Species

Conditions
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Invasive Aspergillosis

Intervention / Treatment
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* Drug: Olorofim
* Drug: AmBisome®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients ages over 18 years and weighing more than 40 kg Patients with proven IA at any site or probable LRTD IA per EORTC/MSG 2019 criteria as adapted for this study Patients requiring therapy with an antifungal agent other than a mould-active azole on the basis of IA refractory to mould-active azole therapy, proven resistance to the mould active azoles, breakthrough infection on mould-active triazole prophylaxis, or azole drug-drug interactions (or potential for drug-drug interactions). AmBisome® is an appropriate therapy for the patient. Exclusion Criteria: Women who are pregnant or breastfeeding. Known history of allergy, hypersensitivity, or any serious reaction to any component of the study drug Patients with only chronic aspergillosis, aspergilloma, or allergic bronchopulmonary aspergillosis. Suspected mucormycosis (zygomycosis). Patients with a known active second fungal infection of any type, other than candidiasis that can be treated with fluconazole. The use of an echinocandin as Candida prophylaxis. Microbiological findings (eg, bacteriological, virological) or other potential conditions that are temporally related and suggest a different aetiology for the clinical features. Human immunodeficiency virus (HIV) infection but not currently receiving antiretroviral therapy. Patients with a baseline prolongation of QT using Fridericia's Correction Formula (QTcF) ≥ 500 msec, or at high risk for QT/QTc prolongation. Evidence of hepatic dysfunction.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Olorofim<br>Olorofim versus AmBisome followed by Standard of Care (SOC) | Drug: Olorofim<br>* 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)<br>* Other names: Olorofim (F901318);|
| Active Comparator: AmBisome<br>Olorofim versus AmBisome followed by Standard of Care (SOC) | Drug: AmBisome®<br>* 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.<br>* Other names: AmBisome® (liposomal amphotericin B);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) or probable lower respiratory tract disease Aspergillus species (invasive aspergillosis, IA). | Treatment Day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 (anytime during the study between first administration and Day 84). | Day 42, Day 84, and End of Treatment (anytime during the study between first administration and Day 84) | 
| Investigator-assessed overall response | To compare the effects of treatment with olorofim versus treatment with AmBisome® followed by SOC on Investigator integrated assessessment of clinical signs and symptoms, radiological response and mycological response related to the IFD caused by Aspergillus species. | Day 14, Day 28, Day 42, Day 84, End of Treatment (anytime during the study between first administration and Day 84) and 4-week Follow-up (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). | up to the Day 84 and 4-week Follow-up (FU) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aspergillus species, Invasive fungal disease (IFD), Olorofim, Non-azole antifungal, Azole resistance