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Olorofim Aspergillus Infection Study

PHASE3RECRUITING

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).

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Male and female patients ages over 18 years and weighing more than 30 kg

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.

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.

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 requirement for ongoing use of 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.

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2022-03-31

Primary completion: 2025-09-14

Study completion finish: 2026-11-01

Study type

TREATMENT

Phase

PHASE3

Trial ID

NCT05101187

Intervention or treatment

DRUG: Olorofim

DRUG: AmBisome®

Conditions

• Invasive Aspergillosis

Condition: Invasive Aspergillosis
DRUG: Olorofim and other drugs
Parkville, Victoria, Australia and more
Sponsor: F2G Biotech GmbH

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Find a site

Closest Location:

Royal Melbourne Hospital

Research sites nearby

Select from list below to view details:

Royal Melbourne Hospital
Parkville, Victoria, Australia
Fiona Stanley Hospital
Murdoch, Western Australia, Australia
Royal NorthShore Hospital
Saint Leonards, New South Wales, Australia
Royal Brisbane & Women's Hospital
Herston, Queensland, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
ACTIVE_COMPARATOR: Olorofim Olorofim versus AmBisome followed by Standard of Care (SOC)	DRUG: Olorofim 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)
ACTIVE_COMPARATOR: AmBisome Olorofim versus AmBisome followed by Standard of Care (SOC)	DRUG: AmBisome® 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.

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome 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) at any site or probable lower respiratory tract disease (LRTD) Aspergillus species (invasive aspergillosis, IA).	Treatment Day 42

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome 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.	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).	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.	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.	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.	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.	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	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.	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).	up to the Day 84 and 4-week Follow-up (FU)

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References

Clinical Trials Gov: Olorofim Aspergillus Infection Study