E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Early Myelofibrosis patients with high molecular risk mutations |
Mielofibrosis temprana con mutaciones moleculares de alto riesgo. |
|
E.1.1.1 | Medical condition in easily understood language |
Early myelofibrosis with high molecular risk mutations. |
Mielofibrosis temprana con mutaciones moleculares de alto riesgo |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 evaluate the effect of ruxolitinib in delaying progression of MF from early disease to more advanced disease stages. |
Evaluar el efecto de ruxolitinib en retrasar la progresión de MF de enfermedad temprana a enfermedad avanzada. |
|
E.2.2 | Secondary objectives of the trial |
To evaluate time to disease progression of MF with or without ruxolitinib. To evaluate the changes in spleen volume with or without ruxolitinib. To assess the changes in symptoms using MF-7, EuroQol-5D-5L (EQ-5D). To assess the safety and tolerability of ruxolitinib. To evaluate the effect of ruxolitinib on overall survival. To assess the pharmacokinetics of ruxolitinib.
To evaluate the efficacy of ruxolitinib post progression |
Evaluar el tiempo hasta progresión de la enfermedad de MF con o sin ruxolitinib. Evaluar los cambios en el volumen del bazo con o sin ruxolitinib. Determinar los cambios en los síntomas utilizando MF-7, EuroQoL-5D-5L (EQ-5D). Determinar la seguridad y tolerabilidad de ruxolitinib. Evaluar el efecto de ruxolitinib en la supervivencia global. Determinar la farmacocinética de ruxolitinib. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Confirmed diagnosis of MF with bone marrow fibrosis of at least Grade 1; irrespective of JAK2 mutational status Patients with at least one mutation in one of the five HMR genes (ASXL1, EZH2, SRSF2 and IDH1/2) Patients with non-palpable spleen or spleen palpable ? 5 cm from the left costal margin to the point of greatest splenic protrusion Patients with MF-7 score of ? 15, with each individual symptom score of ? 3 |
Diagnóstico confirmado de MF con fibrosis de médula ósea de al menos Grado 1; independientemente del estado mutacional JAK2. Pacientes con al menos una mutación en uno de los cinco genes HMR (ASXL1, EZH2, SRSF2 e IDH1/2). Pacientes con bazo no palpable o bazo palpable </=5 cm desde el margen costal izquierdo al punto de mayor protrusión esplénica. Pacientes con puntuación MF-7 </= 15, con puntuación de cada síntoma individual </= 3. |
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E.4 | Principal exclusion criteria |
Patients with prior treatment with ruxolitinib or other JAK inhibitors |
Pacientes con tratamiento previo con ruxolitinib u otros inhibidores JAK. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression free survival (PFS-1) from date of randomization until the occurrence of any of the criteria for disease progression (See Section 10.4.1 for details on criteria and required confirmation): - Progressive splenomegaly - Circulating peripheral blast counts > 10% - Leukemic transformation - Hb < 10g/dl with absolute decrease of at least 3 g/dl from baseline - White blood cell (WBC) counts > 25 x 103/ ?L - MF-7 score ? 30 - Death from any cause |
Supervivencia libre de progresión (PFS-1) desde la fecha de aleatorización hasta la presencia de alguno de los criterios de progresión de la enfermedad (Ver la Sección 10.4.1 para detalles sobre criterios y confirmación necesaria): -Esplenomegalia progresiva -Recuentos de blastos en circulación periférica > 10% -Transformación leucémica -Hb < 10 g/dl con disminución absoluta de al menos 3 g/dl desde la basal -Recuentos de leucocitos (WBC) > 25 x 103/microlitro |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary endpoint evaluated after 90 PFS-1 events are documented. |
La variable principal de valoración se evaluará despúes de 90 eventos PFS-1 documentados |
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E.5.2 | Secondary end point(s) |
Time to primary progression Time to first progressive splenomegaly as determined by spleen volume (by MRI/CT) Change in spleen volume (by MRI/CT) from baseline Time to first symptomatic progression as determined by MF-7 Quality-adjusted life years using EQ-5D Changes in symptoms using MF-7 and EQ-5D from baseline Monitoring the frequency, duration, and severity of adverse events including abnormalities in vital signs, laboratory parameters and ECG data Overall survival Plasma ruxolitinib concentrations. Characterize PK by utilizing a Population PK approach Progression free survival (PFS-2) assessed by 25% increase over new baseline of PFS-1 in any of the following (See Section 10.5.1 of the protocol for details): - Progressive splenomegaly - 25 % increase in MF-7 score with absolute score ? 30 |
Tiempo hasta progresión principal Tiempo hasta esplenomegalia progresiva determinado por el volumen del bazo (mediante RM/TC) Cambio en el volumen del bazo (mediante RM/TC) desde la basal Tiempo hasta la primera progresión sintomática determinada mediante MF-7 Años de vida ajustado por calidad utilizando EQ-5D Cambios en síntomas utilizando MF-7 y EQ-5D desde la basal Monitorizando la frecuencia, duración, y severidad de los acontecimientos adversos incluyendo anomalías en constantes vitales, parámetros de laboratorio y datos de ECG Supervivencia global Concentraciones plasmáticas de ruxolitinib. Caracterizar PK utilizando un enfoque de Población PK Supervivencia libre de progresión (PFS-2) evaluado por aumento del 25% sobre nueva basal de PFS-1 en cualquiera de los siguientes (Ver Sección 10.5.1 para detalles): - Esplenomegalia progresiva -Aumento del 25% en la puntuación MF-7 con puntuación absoluta >/= 30 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoint evaluated after 90 PFS-1 events are documented. |
La variable secundaria de valoración se evaluará despúes de 90 eventos PFS-1 documentados. |
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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 | No |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
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 | 101 |
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 |
Austria |
Belgium |
Brazil |
Bulgaria |
China |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Greece |
Hong Kong |
Hungary |
Israel |
Italy |
Japan |
Korea, Republic of |
Norway |
Poland |
Portugal |
Russian Federation |
Singapore |
Spain |
Sweden |
Switzerland |
Taiwan |
Thailand |
Turkey |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
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
|
The End of Study will occur after approximately 1year after the 90th PFS-1 event on blinded study treatment has been confirmed & the primary analysis reported(estimated study duration 5.5 - 6 years).Following the primary analysis, if the primary objective is met & a need for longer term F/U of patients is assessed, the study may continue for an extended period of up to 5 years from LPFV.Patients will be discontinued at the end of study including any F/U for post treatment assessments & survival. |
Tras aproximadamente 1 año después que el 90º acontecimiento de PFS-1 con el tratamiento ciego se haya confirmado y el análisis principal notificado(duración estimada del estudio 5,5 - 6 años). Tras el análisis principal, si se cumple el objetivo principal y se evalúa una necesidad de seguimiento de los pacientes, el estudio puede continuar durante hasta 5 años desde LPFV. Los pacientes se retirarán al final del estudio incluyendo cualquier evaluación post-tratamiento y de supervivencia. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |