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    Summary
    EudraCT Number:2021-000386-32
    Sponsor's Protocol Code Number:F901318/0041
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-08-23
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2021-000386-32
    A.3Full title of the trial
    A Phase III, adjudicator-blinded, randomised study to evaluate the efficacy and safety of treatment with olorofim versus treatment with AmBisome® followed by standard of care (SOC) in patients with invasive fungal disease (IFD) caused by Aspergillus species.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate the efficacy and safety of olorofim versus AmBisome® for treatment of invasive aspergillosis.
    A.4.1Sponsor's protocol code numberF901318/0041
    A.5.4Other Identifiers
    Name:Product INN: Number:Olorofim
    Name:IND No.:Number:124027
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorF2G Ltd.
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF2G Ltd.
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF2G Biotech GmbH
    B.5.2Functional name of contact pointClinical Trial Operations
    B.5.3 Address:
    B.5.3.1Street AddressSeilerstätte 17/13
    B.5.3.2Town/ cityVienna
    B.5.3.3Post code1010
    B.5.3.4CountryAustria
    B.5.4Telephone number4319974267
    B.5.6E-mailoffice-at@f2g.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/16/1738
    D.3 Description of the IMP
    D.3.1Product nameolorofim
    D.3.2Product code F901318
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPEnteral use (Noncurrent)
    Oral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOlorofim
    D.3.9.1CAS number 1928707-56-5
    D.3.9.2Current sponsor codeF901318
    D.3.9.4EV Substance CodeSUB166663
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name AmBisome
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAmBisome
    D.3.4Pharmaceutical form Powder for concentrate for dispersion for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAmphotericin B
    D.3.9.3Other descriptive nameAmphotericin B
    D.3.9.4EV Substance CodeSUB05486MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    invasive fungal infections due to Aspergillus spp.
    E.1.1.1Medical condition in easily understood language
    invasive fungal infections
    E.1.1.2Therapeutic area Diseases [C] - Bacterial Infections and Mycoses [C01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10017533
    E.1.2Term Fungal infection
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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 IFD caused by proven IA at any site or probable lower respiratory tract disease (LRTD) Aspergillus species.
    E.2.2Secondary objectives of the trial
    •To compare the treatment effects with olorofim vs. AmBisome® followed by SOC on Data Review Committee (DRC)-adjudicated assessment of overall outcome in patients with IA at Day 42, 84, EOT
    •To compare the treatment effects with olorofim vs. treatment with AmBisome® followed by SOC on:
    -Investigator-assessed overall response at Day 14, 28, 42, 84, EOT, FU
    -Galactomannan index at Day 14, 28, 42, 84, EOT, FU
    -All cause mortality at Day 84
    -Survival time
    -DRC attribution of mortality to IA at Day 42 and 84
    -Diagnosis of a secondary fungal infection at any time through EOT
    -Quality of life as measured by the 5 Level 5 Dimension (EQ-5D-5L) at Baseline, Day 14, EOT
    •To assess the safety and tolerability of treatment with olorofim relative to AmBisome® followed by SOC up to Day 84 and FU visits
    •To collect olorofim systemic exposure data for population PK modelling and to collect H26C metabolite systemic exposure data in certain geographical regions
    •To collect health variables
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Male and female patients ages ≥ 18 years and weigh ≥ 30kg, […] or Patients unable to write and/or read but who fully understand the oral information given by the Investigator
    2.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.
    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.
    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 triazole prophylaxis: patients who have had any duration of prophylaxis prior to the breakthrough but ≤ 96 hours of potentially effective prior therapy.
    c)Azole DDIs (or potential for DDIs) in patients who 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
    4.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.
    5.Ability and willingness to comply with the protocol.
    6.Female patients must be non-lactating and at no risk of pregnancy […]
    7.Male patients with female partners of childbearing potential must either totally abstain from sexual intercourse or use a highly effective means of contraception.
    For more details, please refer to the protocol.
    E.4Principal 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 (olorofim or AmBisome®).
    3.Patients with only chronic aspergillosis, aspergilloma or allergic bronchopulmonary aspergillosis.
    4.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.
    5.Patients with a known active second fungal infection of any type, other than candidiasis being treated with fluconazole.
    6.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]).
    7.Microbiological findings (eg, bacteriological, virological) or other potential conditions that are temporally related and suggest a different aetiology for the clinical features.
    8.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.
    9.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 and receiving only palliative therapy).
    10.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.
    11.Patients previously enrolled in a study with olorofim/F901318.
    12.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.
    13.Patients receiving treatment limited to supportive care due to predicted short survival time.
    14.Patients with a baseline prolongation of Fridericia's Correction Formula (QTcF) ≥ 500 msec, or at high risk for QT/QTc prolongation.
    15.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).
    16.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.
    17.Additional exclusion criteria required by local regulatory authorities.
    E.5 End points
    E.5.1Primary end point(s)
    All cause mortality rate at Day 42 in the ITT population.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 42
    E.5.2Secondary end point(s)
    •Data Review Committee-adjudicated assessment of overall response rate at EOT (key secondary analysis) and at Day 42 and Day 84.
    •Investigator assessment of clinical, radiological, and mycological response at Day 14, Day 28, Day 42, Day 84, End Of Treatment , and Follow up.
    •Galactomannan index on Day 14, Day 28, Day 42, Day 84, End Of Treatment, and Follow-Up.
    •All cause mortality rate at Day 84.
    •Survival time.
    •Data Review Committee attribution of mortality to IA at Day 42 and Day 84.
    •Diagnosis of a secondary fungal infection at any time through EOT.
    •Quality of life as judged by EQ-5D-5L at baseline, Day 14, EOT
    E.5.2.1Timepoint(s) of evaluation of this end point
    -Day 14, Day 28, Day 42, Day 84, End Of Treatment and Follow-Up
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    randomised, adjudicator-blinded, sponsor-blinded, multicentre, active comparator, parallel, two-arm
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    AmBisome
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA38
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Egypt
    Malaysia
    Singapore
    Korea, Democratic People's Republic of
    Taiwan
    Australia
    Brazil
    Canada
    China
    Israel
    Japan
    Thailand
    United Kingdom
    United States
    Viet Nam
    Belgium
    France
    Germany
    Netherlands
    Poland
    Spain
    Türkiye
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months36
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months36
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 169
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 56
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patients unable to write/read but who fully understand the oral information who have given oral informed consent witnessed in writing by an independent person and in compliance with local regulations.
    Unconscious patients may not enter the study.
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    immunocompromised patients patients who weigh at least 40 kg
    F.4 Planned number of subjects to be included
    F.4.1In the member state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 68
    F.4.2.2In the whole clinical trial 225
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients still requiring antifungal treatment at the Day 84 (± 7 days) study visit may be eligible to enter a Managed Access Programme for post-study therapy with olorofim; this option will be available to patients from either study arm via a separate protocol. Access to olorofim via the Managed Access Programme is not guaranteed and availability may depend on the local regulatory authority.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-09-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-12-22
    P. End of Trial
    P.End of Trial StatusOngoing
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