| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| invasive fungal infections due to Aspergillus spp. |
| infecciones fúngicas invasivas debidas a Aspergillus spp. |
|
| E.1.1.1 | Medical condition in easily understood language |
| invasive fungal infections |
| infecciones fúngicas invasivas |
|
| 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 |
|
| 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). |
| Comparar la mortalidad por cualquier causa (MCC) en el día 42 posterior al tratamiento con olorofim versus AmBisome® seguido de la práctica clínica habitual en pacientes por intención de tratar (IdT) con MI causada provocada por el género Aspergillus (aspergilosis invasiva, AI). |
|
| 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. |
•Comparar efectos del tto con olorofim versus AmBisome® seguido de la práctica clínica habitual en la evaluación del CRD de los resultados en pacientes con AI el día 42, 84 y FdT)
•Comparar efectos del tto con olorofim versus AmBisome® seguido de la
práctica clínica habitual:
-Respuesta evaluada por el investigador el día 14, 28, 42, 84, FdT y seguimiento
-Indice Galactomanano día 14, 28, 42, 84, FdT y seguimiento
-Mortalidad por cualquier causa día 84
-Tiempo de supervivencia
-Comité de Revisión de Datos atribución de mortalidad a AI día 42 y 84
-Diagnóstico de micosis secundaria en cualquier momento hasta el FdT
-Calidad de vida medida de 5 niveles y 5 dimensiones del (EQ-5D-5L) al inicio, dia14, 28, 42, 84 y FdT
•Evaluar la seguridad y tolerabilidad del tratamiento con olorofim versus
AmBisome® seguido de la práctica clínica habitual hasta día 84 y seguimiento
•Recopilar datos de exposición aolorofim para la modelización (FC) de la
población
•Recoger variables de salud |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| ECG Substudy Protocol Addendum |
| Addendum del Protocolo de Substudio de ECG |
|
| E.3 | Principal inclusion criteria |
1.Male and female patients ages ≥ 18 years and weigh more than 40kg, […] 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 […]
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). […]
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.
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.
8.Patients must be able to take oral medication.
For more details, please refer to the protocol. |
1.Pacientes de ambos sexos de ≥ 18 años que pesen más de 40 kg, [...] o Pacientes que no puedan o sepan leer o escribir pero que entiendan completamente la información proporcionada verbalmente por el investigador
2.Pacientes con AI probada en cualquier centro o probable EVRI por AI [...]
3.Pacientes que requieran tratamiento con un fármaco antifúngico diferente a los azoles activos antifúngicos en base a AI resistente al tratamiento con azoles activos antifúngicos, resistencia probada a los azoles activos antifúngicos, infección de brecha en la profilaxis antifúngica con triazoles o interacciones farmacológicas con los azoles (o potencial de interacciones farmacológicas). [...] Los pacientes deben cumplir al menos uno de estos criterios:
a) Resistencia confirmada o sospechada a los azoles en pacientes con ≤ 96 horas de tratamiento previo potencialmente eficaz [...]
b)Infección de brecha en la profilaxis con triazol: pacientes que hayan tenido alguna duración de la profilaxis antes de la brecha pero con ≤96 horas de tratamiento previo potencialmente eficaz.
c) Interacciones farmacológicas (o potencial de interacciones farmacológicas) en pacientes con ≤96 horas de tratamiento previo potencialmente eficaz.
d) Aspergilosis invasiva resistente al tratamiento con triazol en pacientes con ≤28 días de tratamiento previo
4.AmBisome® es un tratamiento adecuado para el paciente.
5.Capacidad y disposición para cumplir el protocolo.
6.Las pacientes no deben estar en periodo de lactancia y no pueden correr el riesgo de embarazo [...]
7.Los pacientes de sexo masculino con parejas femeninas que puedan quedarse embarazadas deben abstenerse totalmente de tener relaciones
sexuales o usar un método anticonceptivo.
8.Los pacientes deben ser capaces de tomar medicación por vía oral
Para obtener más detalles, consulte el protocolo. |
|
| 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 (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 use of an echinocandin as Candida prophylaxis (see 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.Human immunodeficiency virus (HIV) infection but not currently receiving antiretroviral therapy. 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:
a)Total bilirubin ≥ 2 × upper limit of the normal range (ULN)
b)Alanine transaminase or aspartate transaminase ≥ 3 × ULN
c)Patients with known cirrhosis or chronic hepatic failure.
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. |
1.Mujeres embarazadas o en periodo de lactancia.
2.Antecedentes conocidos de alergia, hipersensibilidad o cualquier
reacción grave a algún componente del fármaco del estudio (olorofim o
AmBisome®).
3.Únicamente pacientes con aspergilosis crónica, aspergiloma o aspergilosis broncopulmonar alérgica.
4.Sospecha de mucormicosis (cigomicosis). Los indicios de presencia de hongos filamentosos no sensibles al olorofim requieren un seguimiento urgente. Es necesario aumentar la vigilancia de la posibilidad de mucormicosis (cigomicosis) en caso de sospecha de AI con un resultado negativo en GM inicial.
5.Pacientes con una segunda micosis conocida de cualquier tipo, distinta de la candidiasis que se puede tratar con fluconazol.
6.Uso de equinocandina como profilaxis de Candida (ver discusión sobre agentes antimicóticos concomitantes).
7.Hallazgos microbianos (p. ej., bacteriolológicos, virológicos) u otras afecciones potenciales que estén temporalmente relacionadas y sugieran una etiología diferente para las características clínicas.
8.Infección por el virus de la inmunodeficiencia humana (VIH) sin tratamiento antirretrovírico actual. En casos donde la infección por VIH se diagnostique por primera vez de forma simultánea a la micosis invasiva, si se inició el tratamiento antirretrovírico en el momento de la inscripción, los pacientes son aptos para la inscripción.
9.Cualquier enfermedad conocida o sospechada del paciente que pueda comprometer el cumplimiento de los requisitos del protocolo o impedir la medición precisa de la eficacia (p. ej., neutropenia que no se prevé que se resuelva, pacientes con neoplasia maligna no controlada que sean resistentes al tratamiento o que reciban solo tratamiento paliativo).
10.Pacientes con una enfermedad concomitante que, en opinión del investigador, pueda ser un riesgo adicional inaceptable para el paciente si participa en el estudio.
11.Pacientes inscritos previamente en un estudio con olorofim/F901318.
12.Tratamiento con cualquier fármaco en investigación en algún ensayo clínico durante los 30 días previos a la primera administración del fármaco del estudio excepto los protocolos sin ocultación (p. ej., variaciones en la pauta oncológica abierta o estudios biológicos). Antes de inscribir a los pacientes que se encuentran en otros estudios abiertos, es responsabilidad del centro asegurarse de que los criterios del estudio
para ese estudio permiten la inscripción en este estudio.
13.Pacientes que reciben tratamiento limitado a cuidados paliativos debido a un tiempo previsto de supervivencia corto.
14.Pacientes con una prolongación inicial del intervalo del QT con la fórmula de ajuste de Fridericia (QTcF) ≥500 ms o con alto riesgo de prolongación del QT/QTc.
15.Evidencia de disfunción hepática con cualquiera de los siguientes parámetros analíticos anómalos en la selección:
a.Bilirrubina total ≥2 veces el límite superior de la normalidad (LSN)
b.Alanina transaminasa o aspartato transaminasa ≥3 × LSN
c.Pacientes con cirrosis conocida o insuficiencia hepática crónica.
16.Medicación concomitante prohibida: Está prohibida la administración concomitante de inhibidores de dihidroorotato deshidrogenasa (DHODH) humana (teriflunomida y leflunomida). Actualmente no hay otras medicaciones concomitantes o vacunas prohibidas, pero hay medicamentos con interacciones farmacológicas (IF) potencialmente significativas y se debe considerar el tratamiento de las posibles interacciones antes de la inscripción en el estudio.
17.Los criterios de exclusión adicionales requeridos por las autoridades normativas locales. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| All cause mortality rate at Day 42 in the ITT population. |
| Tasa de mortalidad por cualquier causa el día 42 en la población de IdT. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| 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 |
•Evaluación de la tasa de respuesta global adjudicada por el comité de revisión de datos en el FdT (análisis secundario clave), en el día 42 y el día 84.
•Evaluación por parte del investigador de la respuesta clínica, radiológica y micológica el día 14, el día 28, el día 42, el día 84, al FdT y el seguimiento.
•GM en suero el día 14, el día 28, el día 42, el día 84, al FdT y el seguimiento.
•Tasa de mortalidad por cualquier causa el día 84.
•Tiempo de supervivencia.
•Atribución del comité de revisión de datos a AI el día 42 y el día 84.
•Diagnóstico de una micosis secundaria en cualquier momento del FdT.
•Calidad de vida, evaluado mediante el EQ-5D-5L al inicio, el día 14, el día 28, el día 42, el día 84 y al FdT. |
|
| 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 |
| - Día 14, 28, 42, 84, find de tratamiento y seguimiento. |
|
| 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 |
| aleatorizado, doble ciego, multicéntrico, comparador activo, paralelo de dos brazos |
| randomised, adjudicator-blinded, sponsor-blinded, multicentre, active comparator, parallel, two-arm |
|
| 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 |
|
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| 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 |
| Australia |
| Brazil |
| Canada |
| Egypt |
| Israel |
| Korea, Democratic People's Republic of |
| Malaysia |
| Singapore |
| Taiwan |
| Thailand |
| Turkey |
| United States |
| Vietnam |
| Belgium |
| France |
| Germany |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
|
| 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
|
|
| 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 | 36 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 36 |
Print
