E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
invasive fungal infections due to Aspergillus spp. |
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E.1.1.1 | Medical condition in easily understood language |
invasive fungal infections |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10017533 |
E.1.2 | Term | Fungal infection |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main 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) patients with Invasive Fungal Disease (IFD) caused by Aspergillus species (invasive aspergillosis [IA). |
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E.2.2 | Secondary objectives of the trial |
•To compare the treatment effects with olorofim versus AmBisome® followed by SOC on Data Review Committee-adjudicated assessment of overall outcome in patients with IA at Day 42, 84, and End Of Treatment. •To compare the treatment effects with olorofim versus treatment with AmBisome® followed by SOC on: -Investigator-assessed overall response at Day 14, 28, 42, 84, EOT, and Follow up (FU) -Galactomannan index at Day 14, 28, 42, 84, EOT, FU -All cause mortality at Day 84 -Survival time -Data Review Committee 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, Days 14, 28, 42, 84, and 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 pharmacokinetic modelling. •To collect health variables. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Male and female patients ages ≥18 years and weighing more than 40 kg 2) Patients with proven IA at any site or probable LRTD IA per EORTC/MSG 2019 criteria as adapted for this study 3) 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). 4) AmBisome® is an appropriate therapy for the patient. 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 abstain from sexual intercourse or use a highly effective means of contraception 8) Patients must be able to take oral medication. |
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E.4 | Principal 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 use of an 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
All cause mortality rate at Day 42 in the ITT population. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary 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, Day 28, Day 42, Day 84, and EOT
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Day 14, Day 28, Day 42, Day 84, End Of Treatment and Follow-Up
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
randomised, adjudicator-blinded, sponsor-blinded, multicentre, active comparator, parallel, two-arm |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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 |
Israel |
Thailand |
Turkey |
United Kingdom |
United States |
Viet Nam |
Belgium |
France |
Germany |
Netherlands |
Poland |
Spain |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 33 |
E.8.9.1 | In the Member State concerned days | 25 |
E.8.9.2 | In all countries concerned by the trial months | 39 |
E.8.9.2 | In all countries concerned by the trial days | 9 |