Phase III Randomized Study of Olorofim Versus Liposomal Amphotericin B in Patients with Invasive Aspergillosis
- Trial ID
- 2024-513030-38-00
- Protocol
- F901318/0041
- Sponsor
- F2G Limited
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **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) due to **Aspergillus** species. This comparison is clinically relevant as it aims to determine the efficacy of olorofim, a novel antifungal agent, in reducing mortality in patients with serious fungal infections, potentially offering an alternative to existing treatments.
Secondary objectives include:
- Comparing the effects of treatment with olorofim versus AmBisome® followed by SOC on the 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 (EOT).
- Evaluating the investigator-assessed overall response, integrating clinical, radiological, and mycological responses at various time points, as well as serum galactomannan levels, all-cause mortality rate at Day 84, survival time, and DRC attribution of mortality to IA.
- Assessing the safety and tolerability of olorofim relative to AmBisome® followed by SOC up to Day 84 and follow-up visits.
- Collecting systemic exposure data for olorofim population pharmacokinetic (PK) modeling and H26C metabolite exposure data in certain regions.
- Gathering health variables to support comprehensive analysis.
Participants
The clinical trial involves a total of **161 participants** diagnosed with **invasive fungal infections** due to **Aspergillus spp.** The study population includes both male and female patients aged 18 years and older, with a minimum weight of 30 kg. Participants are required to have a proven or probable lower respiratory tract disease caused by Aspergillus species, as per the EORTC/MSG 2019 criteria. The trial population was selected based on specific inclusion criteria, including the need for antifungal therapy other than a mould-active azole and having had no more than 96 hours of potentially effective prior therapy. Participants must be able to comply with the protocol, and female participants must be non-lactating and at no risk of pregnancy. Male participants with female partners of childbearing potential must use highly effective contraception or abstain from sexual intercourse. The trial includes a vulnerable population, and participants' general health status is not specified by the sponsor. Lifestyle considerations such as diet and physical activity are not detailed in the provided data.
Plans and Procedures
The clinical trial is a **Phase III**, adjudicator-blinded, randomized study designed to evaluate the efficacy and safety of treatment with **olorofim** compared to treatment with **AmBisome** followed by standard of care in patients with invasive fungal disease caused by **Aspergillus** species. The trial employs a randomized, controlled design to ensure unbiased results, with participants being randomly assigned to either the test or comparator group. The study is expected to last until November 28, 2025, with recruitment having commenced on September 6, 2022. The primary endpoint is the all-cause mortality rate at Day 42 in the intent-to-treat population, while secondary endpoints include investigator-assessed overall response and quality of life measurements at various time points.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, weight, and specific medical conditions. Follow-up visits will occur at Day 14, Day 28, Day 42, Day 84, and at the end of treatment (EOT), with additional follow-up (FU) visits as necessary. These visits are designed to monitor the clinical, radiological, and mycological response to treatment, as well as to assess safety and any adverse events. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any remaining health concerns are addressed.
Participant involvement is expected to last up to 91 days, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include non-compliance with the protocol, withdrawal of consent, or any adverse events that pose a significant risk to the participant's health. The trial is conducted under strict ethical guidelines, ensuring the safety and well-being of all participants throughout the study duration.
Treatment
The clinical trial involves the administration of **AmBisome Liposomal Amphotericin B**, a **powder for concentrate for dispersion for infusion**. This experimental medication is formulated as a dispersion for infusion and is administered via the **intravenous route**. The active substance in this formulation is **amphotericine B, liposome**, which is classified under the ATC code **J02AA01**. The product is manufactured by Gilead Sciences Ireland Unlimited Company. The maximum treatment period for this medication is 91 days. The dosage is determined based on the patient's body weight, measured in milligrams per kilogram (mg/kg). The specific dosing schedule and monitoring of participant compliance are determined by the study protocol.
**Olorofim** is the comparator treatment in this study, provided in **tablet** form for **oral use**. The active substance is **olorofim**, and the product is developed by F2G Ltd. The maximum daily dose of Olorofim is 300 milligrams, with a total maximum dose of 150 milligrams over the treatment period. The treatment duration is also set at 91 days. Olorofim is designated as an orphan drug, with the designation number EU/3/16/1738. The dosing schedule and participant compliance are monitored according to the clinical trial protocol.
The study aims to evaluate the efficacy and safety of Olorofim compared to AmBisome followed by standard-of-care therapy in patients with invasive fungal disease caused by **Aspergillus species**. The trial is adjudicator-blinded and randomized, ensuring unbiased assessment of the treatment outcomes. Participants' adherence to the dosing regimen is closely monitored to ensure the integrity of the trial results.
Efficacy
The efficacy of the treatment in this clinical trial will be assessed using several key endpoints. The primary efficacy endpoint is the **all-cause mortality (ACM)** rate at Day 42 in the intent-to-treat (ITT) population. Secondary endpoints include investigator-assessed overall response, which integrates clinical, radiological, and mycological responses at multiple timepoints: Day 14, Day 28, Day 42, Day 84, end-of-treatment (EOT), and follow-up (FU). Additionally, the Data Review Committee will adjudicate the overall response at Day 42, Day 84, and EOT. Serum galactomannan (GM) levels will be measured at Day 14, Day 28, Day 42, Day 84, EOT, and FU. Other secondary endpoints include the ACM rate at Day 84, survival time, and the Data Review Committee's attribution of mortality to invasive aspergillosis (IA) at Day 42 and Day 84. The diagnosis of a secondary fungal infection at any time through EOT will also be evaluated. Quality of life will be assessed using the EQ-5D-5L instrument at baseline, Day 14, and EOT.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 1.Male and female patients ages ≥ 18 years and weighing ≥ 30 kg, […] or Patients unable to write and/or read but who fully understand the oral information given by the Investigator
- Patients with proven IA at any site or probable LRTD IA per EORTC/MSG 2019 criteria as adapted for this study (see Appendix 2) 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. Patients must meet at least one of these criteria a) Proven or suspected azole resistance in patients who have had ≤ 96 hours of potentially effective prior therapy b) Breakthrough infection on mould-active triazole prophylaxis: patients who have had any duration of prophylaxis prior to the breakthrough but ≤ 96 hours of potentially effective prior therapy. c) Any other medical reason an azole is inappropriate for the patient at screening. In all cases, patients must have had ≤ 96 hours of potentially effective prior therapy. d)Invasive aspergillosis refractory to triazole therapy in patients who have had ≤ 28 days of prior therapy where refractory IA was defined per an international expert meeting report
- AmBisome® is an appropriate therapy for the patient. a) For avoidance of doubt, prior therapy with an amphotericin B (eg, AmBisome® or other) is not an exclusion provided that such prior therapy does not exceed the rules for maximum duration of potentially effective prior therapy discussed as part of Inclusion Criterion 3.
- Ability and willingness to comply with the protocol.
- Female patients must be non-lactating and at no risk of pregnancy
- Male patients with female partners of childbearing potential must either totally abstain from sexual intercourse or use a highly effective means of contraception
Exclusion Criteria
- Women who are pregnant or breastfeeding.
- Known history of allergy, hypersensitivity, or any serious reaction to any component of the study drug (olorofim or AmBisome®).
- Patients with only chronic aspergillosis, aspergilloma or allergic bronchopulmonary aspergillosis.
- Suspected mucormycosis (zygomycosis). Evidence for the presence of olorofim non-susceptible filamentous fungi such as Mucorales should be urgently followed up. Increased vigilance for the possibility of mucormycosis (zygomycosis) is required for suspected IA with negative baseline GM.
- 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 (for avoidance of doubt, prior use of an echinocandin is permitted; if ongoing prophylaxis for Candida is needed, then fluconazole must be an acceptable choice [see Section 5.8.4.1, discussion of concomitant antifungal agents]).
- Microbiological findings (eg, bacteriological, virological) or other potential conditions that are temporally related and suggest a different aetiology for the clinical features.
- Patients with human immunodeficiency virus (HIV) infection who are currently not receiving antiretroviral therapy. Patients with HIV infection receiving antiretroviral therapy can participate in the study. In cases where HIV infection is first diagnosed at the same time as the invasive fungal infection, if antiretroviral therapy is commenced at the time of enrolment, then such patients are eligible for enrolment.
- Any known or suspected condition of the patient that may jeopardize adherence to the protocol requirements or impede the accurate measurement of efficacy (eg, neutropenia not expected to resolve, patients with uncontrolled malignancy who are treatment refractory or receiving only palliative therapy).
- Patients with a concomitant medical condition that, in the opinion of the Investigator, may be an unacceptable additional risk to the patient should he/she participate in the study
- Patients previously enrolled in a study with olorofim/F901318.
- Treatment with any investigational drug in any clinical trial within the 30 days prior to the first administration of study drug except for unblinded protocols (eg, open-label oncological regimen variations or biologic studies). Prior to enrolling patients who are on other open-label studies it is the site’s responsibility to ensure that the study criteria for that study allow for enrolment into this study.
- Patients receiving treatment limited to supportive care due to predicted short survival time.
- Patients with a baseline prolongation of Fridericia’s Correction Formula (QTcF) ≥ 500 msec, or at high risk for QT/QTc prolongation
- Evidence of hepatic dysfunction with any of the following abnormal laboratory parameters at screening (for avoidance of doubt, liver transplant recipients may be enrolled if their laboratory parameters do not meet the exclusions): a) Total bilirubin ≥ 2 × upper limit of the normal range (ULN) b) Alanine transaminase or aspartate transaminase (AST) ≥ 3 × ULN c) Patients with known cirrhosis or chronic hepatic failure (regardless of ALT/AST/total bilirubin).
- Prohibited concomitant medications: concomitant administration of inhibitors of human DHODH (teriflunomide and leflunomide) are prohibited. There are currently no other absolutely prohibited concomitant medications or vaccines, but there are medications with potentially significant DDIs, and the management of potential interactions should be considered before study enrolment
- Additional exclusion criteria required by local regulatory authorities
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 06 Sept 2022 | 17 |
 France | Not Recruiting | 06 Sept 2022 | 10 |
 Germany | Not Recruiting | 06 Sept 2022 | 5 |
 Italy | Not Recruiting | 06 Sept 2022 | 18 |
 The Netherlands | Not Recruiting | 06 Sept 2022 | — |
 Spain | Not Recruiting | 06 Sept 2022 | 8 |
| Netherlands | — | — | 6 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
AmBisome Liposomal Amphotericin B 50mg Powder for Concentrate for Dispersion for Infusion | Comparator | POWDER FOR CONCENTRATE FOR DISPERSION FOR INFUSION | INTRAVENOUS USE | 0 | 91 | PRD01742MIG |
Olorofim | Test | TABLET | ORAL USE | 300 | 91 | PRD11293521 |