The trial will be a phase III, randomised-controlled, multi-centre, international, open-label trial consisting of ruxolitinib versus best available therapy, where best available therapy is a choice of interferon alpha, any formulation permitted (IFN) or hydroxycarbamide (HC), and which will be elected by the Investigator prior to randomisation.
Name: Ruxolitinib
Name: Hydroxycarbamide
Name: Interferon-Alpha
Description: Event Free Survival
Measure: Event Free Survival (EFS) Time: the time from randomisation to the date of the first major thrombosis/haemorrhage, death,transformation to Myelodisplastic Syndromes, Acute Myeloid Leukaemia or Post-polycythemia Vera Myelofibrosis, if within the ~3 year trial periodDescription: As defined in the protocol, combined and split to venous and arterial
Measure: Major thrombosis Time: Occuring while on treatment (over 3 years)Description: As defined in the protocol
Measure: Major haemorrhage Time: Occuring while on treatment (over 3 years)Description: Transformation to PPV-MF
Measure: Transformation to PPV-MF Time: Occuring while on treatment (over 3 years)Description: Transformation to MDS and/or AML
Measure: Transformation to MDS and/or AML Time: Occuring while on treatment (over 3 years)Description: As defined by ELN response criteria at 1 year
Measure: Complete Haematological remission (CHR) Time: 1 year post-treatmentDescription: As measured via MPN-SAF
Measure: Symptom burden/Quality of life (MPN-SAF) Time: Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36Description: As measured via MDASI
Measure: Symptom burden/Quality of life (MDASI) Time: Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36Description: As measured via EQ-5D
Measure: Symptom burden/Quality of life (EQ-5D) Time: Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36Description: Including cost utility and cost effectiveness analyses as defined by the protocol (e.g. QALYs)
Measure: Health economics Time: At the end of the trial (trial duration of approximately 8 years)Description: According to ELN response criteria
Measure: Peripheral blood JAK2 V617F allele burden Time: At baseline and annually throughout the trial (from baseline until approximately 3 years post-randomisation)Description: Trial discontinuation
Measure: Rates of discontinuation Time: From treatment prior to protocol defined 3 yearsDescription: collected according to CTCAE version 4.0 and the MITHRIDATE protocol
Measure: Rate and severity of adverse events Time: Continuous throughout the trial (from randomisation until approximately 3 years post-randomisation))Description: in patients with splenomegaly
Measure: Spleen response Time: Response at 1 year post randomisationDescription: Time free from venesection
Measure: Time free from venesection Time: Defined as the mean time between venesections while on trial treatment (treatment duration of 3 years)Description: Malignancy independent to the original diagnosis
Measure: Secondary malignancy Time: Occuring throughout the trial (from randomisation until approximately 3 years post-randomisation)Description: Change in QRisk score
Measure: Change in QRisk score Time: Collected at baseline and years 1, 2 and 3Description: Progression of marrow fibrosis (bone marrow collected and analysed at the Weatherall Institute of Molecular Medicine (WIMM) in Oxford
Measure: Progression of marrow fibrosis Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)Description: Impact of treatment on molecular signatures of disease (as analysed by the WIMM in Oxford)
Measure: Impact of treatment on molecular signatures of disease Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)Description: within the stem/progenitor cell compartment (as analysed by the WIMM in Oxford)
Measure: Clonal involvement Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)Description: (acquisition of additional mutations, as analysed by the WIMM in Oxford)
Measure: Clonal evolution Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)Description: of other disease-association mutations (as analysed by the WIMM in Oxford)
Measure: Reduction of peripheral blood allele burden Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)Description: and any change over time (as analysed by the WIMM in Oxford)
Measure: Assessment of the prevalence of clonality markers for haematological disease Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)Description: (angina, acute coronary syndrome, acute MI; arrhythmia)
Measure: Cardiac event Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)Description: Pulmonary hypertension as assessed clinically
Measure: Pulmonary hypertension Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)Description: e.g. angiogram, angioplasty, CABG
Measure: Coronary intervention Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)Description: e.g. LVEF% on ECHO/MUGA and/or NYHA classification
Measure: Deterioration in cardiac function Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)Description: TIA, haemorrhagic CVA, non-haemorrhagic CVA
Measure: Cerebrovascular event Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)Description: peripheral vascular disease: claudication, carotid stenosis
Measure: Arterial vascular event Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)Description: including DVT, PE, Cerebral, splanchnic, other
Measure: Venous thrombosis Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)Description: Pregnancy loss
Measure: Pregnancy loss Time: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)Allocation: Randomized
Parallel Assignment
There is one SNP
Peripheral blood JAK2 V617F allele burden. --- V617F ---
Symptom burden/(QALY)quality of life years gained 7. Health economics including cost utility and cost effectiveness analyses 8. Peripheral blood JAK2 V617F allele burden according to ELN response criteria 9. Rates of discontinuation 10. --- V617F ---