E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Early Myelofibrosis patients with high molecular risk mutations |
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E.1.1.1 | Medical condition in easily understood language |
Early myelofibrosis with high molecular risk mutations. |
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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. |
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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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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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E.4 | Principal exclusion criteria |
Patients with prior treatment with ruxolitinib or other JAK inhibitors |
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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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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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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 | 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
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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. |
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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 | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |