E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Early Myelofibrosis patients with high molecular risk mutations |
Patients atteints de myélofibrose précoce avec mutations à haut risque moléculaire |
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E.1.1.1 | Medical condition in easily understood language |
Early myelofibrosis with high molecular risk mutations. |
Myélofibrose précoce avec mutations à haut risque moléculaire |
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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 | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10074692 |
E.1.2 | Term | Post essential thrombocythaemia myelofibrosis |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10074691 |
E.1.2 | Term | Post polycythaemia vera myelofibrosis |
E.1.2 | System Organ Class | 100000004864 |
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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. |
Evaluer l’effet du ruxolitinib à retarder la progression de la MF d’un stade précoce vers un stade avancé. |
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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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Evaluer le temps jusqu’à progression avec et sans ruxolitinib
Evaluer les changements de volume de la rate avec et sans ruxolitinib
Evaluer les changements des symptômes en utilisant les scores MF-7 et EuroQol-5D-5L (EQ-5D)
Evaluer la sécurité d’emploi et la tolérance du ruxolitinib
Evaluer l’effet du ruxolitinib sur la survie globale
Caractériser le profil pharmacocinétique (PK) du ruxolitinib
Evaluer l’efficacité du ruxolitinib après PFS-1
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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
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Diagnostic confirmé de MF avec fibrose de la moelle osseuse de Grade 1 au minimum ; indépendament du statut mutationnel JAK2.
Patients avec au moins une mutation de l’un des 5 genes ASXL1, EZH2, SRSF2 et IDH1/2. (HMR)
Patients avec rate non palpable ou à 5 cm de débord costal.
Patients ayant un score MF-7 ≤ 15 avec score ≤ 3 pour chaque symptôme.
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E.4 | Principal exclusion criteria |
Patients with prior treatment with ruxolitinib or other JAK inhibitors |
Traitement antérieur par le ruxolitinib ou un autre inhibiteur de 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
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Survie sans progression (PFS-1) depuis la randomisation jusqu’à l’apparition d’un des critères de progression
suivant:
● Splénomégalie progressive
● Nombre de blastes dans le sang périphérique > 10%
● Transformation leucémique
● Hémoglobine (Hb) < 10g/dL avec diminution d’au moins 3g/dL par rapport à la basseline
● Nombre de globules blancs > 25 x103/ μL
● Score MF-7 ≥ 30
● Décès quelle qu’en soit la cause |
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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. |
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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
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Temps jusqu’à la première progression
Temps jusqu’à la première progression de la splénomégalie (évalué par IRM/TDM).
Changement du volume de la rate par rapport à la baseline. (évalué par IRM/TDM)
Temps jusqu’à la première progression symptomatique déterminée par le score MF-7
Qualité de vie ajustée déterminée par le score EQ-5D
Changements des symptômes par rapport à la baseline déterminée par les scores MF-7 et EQ-5D
Suivi de la fréquence, durée et sévérité des effets indésirables incluant les anomalies des signes vitaux, des paramètres
biologiques et des électrocardiogrammes (ECG)
Survie globale
Concentrations plasmatiques en ruxolitinib ; caractérisation de la PK par une approche population PK
PFS-2 évaluaée par une augmentation de 25% par rapport à la nouvelle baseline (PFS-1) dans chacun des cas
suivants :
● Splénomégalie progressive
● Augmentation de 25% du score MF-7 avec un score ≥ 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. |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 | 10 |
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 | 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
|
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 fin d'étude arrivera environ 1 an après le 90ème événement confirmé de PFS-1 pendant la période de traitement en aveugle de l'étude & la première analyse effectuée (soit 5,5 - 6 ans). Si l’objectif principal est atteint & s’il est nécessaire de prolonger la période de suivi des patients à long terme, l’étude pourrait continuer jusqu’à 5 ans après la première visite du dernier patient. La fin d’étude inclura tout suivi concernant les évaluations post-traitement et la survie.
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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 | 5 |
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 |