E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Early Myelofibrosis patients with high molecular risk mutations |
Pazienti con mielofibrosi in fase precoce con rischio molecolare elevato di mutazioni |
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E.1.1.1 | Medical condition in easily understood language |
Early myelofibrosis with high molecular risk mutations |
Mielofibrosi in fase precoce con alto rischio di mutazioni |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
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 | 10028537 |
E.1.2 | Term | Myelofibrosis |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 evaluate the effect of ruxolitinib in delaying progression of MF from early disease to more advanced disease stages. |
Valutare l’effetto di ruxolitinib nel ritardare la progressione della mielofibrosi da malattia in fase precoce a malattia in stadi più avanzati. |
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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.
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Valutare il tempo di progressione di malattia della mielofibrosi con o senza ruxolitinib. Valutare le modifiche del volume splenico con o senza ruxolitinib. Valutare le modifiche dei sintomi utilizzando MF-7, EuroQol-5D-5L (EQ-5D) Valutare la sicurezza d’impiego e la tollerabilità di ruxolitinib. Valutare l’effetto di ruxolitinib sulla sopravvivenza globale. Valutare la farmacocinetica di ruxolitinib. Valutare l’efficacia di ruxolitinib post-progressione |
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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 |
Diagnosi confermata di mielofibrosi con fibrosi midollare almeno di Grado 1, indipendentemente dallo status mutazionale di JAK2. Pazienti con almeno una mutazione in uno dei cinque geni HMR (ASXL1, EZH2, SRSF2 e IDH1/2). I pazienti devono presentare una milza non palpabile o una milza palpabile sporgente < 5 cm dal margine costale sinistro al punto di maggior protrusione della milza. Pazienti con punteggio MF-7 < 15, con punteggio individuale di ciascun sintomo < 3. |
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E.4 | Principal exclusion criteria |
Patients with prior treatment with ruxolitinib or other JAK inhibitors |
Pazienti precedentemente trattati con ruxolitinib o qualsiasi altro inibitore di 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/ μL - MF-7 score ≥ 30 - Death from any cause |
La sopravvivenza libera da progressione (PFS-1) dalla data di randomizzazione fino al verificarsi di uno dei criteri per la progressione della malattia (vedere Sezione 10.4.1 per i dettagli sui criteri e conferma richiesta): - Progressive splenomegalia - Circolazione periferica conta cellule blastiche> 10% - trasformazione leucemica - Hb <10g / dl con assoluta diminuzione di almeno 3 g / dl rispetto al basale - Conta Globuli bianchi (WBC) > 25 x 103 / μl - MF-7 punteggio ≥ 30 - Morte per qualsiasi causa |
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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. |
L’analisi primaria dei dati dello studio sarà condotta una volta che saranno stati documentati 90 eventi PFS-1. |
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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 |
Il tempo alla progressione primaria Tempistiche per la prima splenomegalia progressiva come determinato dal volume della milza (da MRI / CT) Variazione del volume della milza (da MRI / CT) dal basale. Tempo alla prima progressione sintomatica come determinato da MF-7 Qualità migliorata degli anni di vita utilizzando EQ -5D. I cambiamenti nei sintomi utilizzando MF-7 e EQ-5D dal basale. Monitoraggio della frequenza, durata e gravità degli eventi avversi, tra cui anomalie dei segni vitali, parametri di laboratorio e dati ECG in generale le concentrazioni plasmatiche ruxolitinib di sopravvivenza. Caratterizzare PK utilizzando una popolazione approccio PK progressione sopravvivenza libera (PFS-2) valutati con incremento del 25% rispetto al nuovo livello di riferimento di PFS-1 in uno dei seguenti (Vedi Sezione 10.5.1 del protocollo per i dettagli): - splenomegalia progressiva - aumento del 25% del punteggio di MF-7 con punteggio assoluto ≥ 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. |
End point secondario valutato dopo aver documentato 90 eventi PFS-1 |
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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 | 13 |
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 | Information not present in EudraCT |
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. |
La fine dello studio avverrà dopo circa 1 anno dal 90 °evento PFS-1 sullo studio in cieco il trattamento è stato confermato e l'analisi primaria segnalata(5,5-6 aa).In seguito all'analisi primaria, se l'ob. Prim. è rispettato e viene valutata la necessità di un termine più lungo F/U dei pazienti, può continuare per un periodo fino ad un max di 5 anni dalla LPFV. I pazienti interromperanno il trattamento al termine dello studio, comprese F/U per le valutazioni post-trattamento e la sopravvivenza |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |