MITHRIDATE: Ruxolitinib Versus Hydroxycarbamide or Interferon as First Line Therapy in High Risk Polycythemia Vera

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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. There will be no cross-over either between arm A and B or between therapies on Arm B HC and IFN will be provided as best available therapy, IFN can include standard of pegylated-interferon at Investigators discretion.

Official Title
-----------------
A Phase III, Randomised, Open-label, Multicenter International Trial Comparing Ruxolitinib With Either HydRoxycarbamIDe or Interferon Alpha as First Line ThErapy for High Risk Polycythemia Vera

Conditions
-----------------
Polycythemia Vera

Intervention / Treatment
-----------------
* Drug: Ruxolitinib
* Drug: Hydroxycarbamide
* Drug: Interferon-Alpha


Participation Criteria
=================
Eligibility Criteria
-----------------
Population: High risk PV defined as WBC >11 x 10^9/l* AND at least ONE of the following Age >60 years Prior thrombosis or haemorrhage Platelet count >1000 x 10^9/l* (*At any time since diagnosis) Inclusion Criteria: Patient ≥18 years of age Diagnosis of PV meeting the WHO criteria within the past 10 years Meets criteria of high risk* PV (see above for specific population) Patients may have received antiplatelet agents and venesection Patients may have received ONE cytoreductive therapy for PV less than 5 years (BUT they should not be resistant or intolerant to that therapy) Able to provide written informed consent Exclusion Criteria: Diagnosis of PV > 10 years previously Absence of any JAK-2 mutation Patients with any contraindications to any of the investigational medical products Treatment with >1 cytoreductive therapy OR a cytoreductive treatment duration exceeding 5 years OR resistance/intolerance to that therapy Active infection including hepatitis B, hepatitis C, Tuberculosis Pregnant or lactating patients (Women of childbearing potential must have a negative urine or blood Human Chorionic Gonadotropin pregnancy test prior to trial entry) Patients and partners of childbearing potential not prepared to adopt highly effective contraception measures (if sexually active) whilst on treatment and for at least 6 months after completion of study medication ECOG Performance Status Score ≥ 3 Uncontrolled rapid or paroxysmal atrial fibrillation, uncontrolled or unstable angina, recent (6 months) myocardial infarction or acute coronary syndrome or any clinically significant cardiac disease > NYHA (New York Heart Association) Class II Patients who have transformed to myelofibrosis Previous treatment with ruxolitinib Previous (within the last 12 months) or current platelet count <100 x 109/L or neutrophil count < 1 x 109/L not due to therapy Inadequate liver function as defined by ALT/AST > 2.0 x ULN Inadequate renal function as defined by eGFR < 30 ml/min Unable to give informed consent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A- Ruxolitinib<br>Treatment with Ruxolitinib | Drug: Ruxolitinib<br>* 10mg of ruxolitinib twice daily (bd)<br>* Other names: Jakavi®;|
| Active Comparator: B- Hydroxycarbamide OR Interferon A<br>Best Available Therapy (BAT), Treatment with hydroxycarbamide OR Interferon A | Drug: Hydroxycarbamide<br>* Via standard hospital mechanisms<br>* Other names: Hydroxyurea;Drug: Interferon-Alpha<br>* Any formulation, via standard hospital mechanisms<br>* Other names: Interferon, alpha interferon, Intron® A, Roferon® A;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival (EFS) | Event Free Survival | the time from randomisation to the date of the first major thrombosis/haemorrhage, death,transformation to Myelodysplastic Syndromes, Acute Myeloid Leukaemia or Post-polycythemia Vera Myelofibrosis, if within the  3 year trial period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major thrombosis | As defined in the protocol, combined and split to venous and arterial | Occurring while on treatment (over 3 years) | 
| Major haemorrhage | As defined in the protocol | Occurring while on treatment (over 3 years) | 
| Transformation to PPV-MF | Transformation to PPV-MF | Occurring while on treatment (over 3 years) | 
| Transformation to MDS and/or AML | Transformation to MDS and/or AML | Occurring while on treatment (over 3 years) | 
| Complete Haematological remission (CHR) | As defined by ELN response criteria at 1 year | 1 year post-treatment | 
| Symptom burden/Quality of life (MPN-SAF) | As measured via MPN-SAF | Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36 | 
| Symptom burden/Quality of life (MDASI) | As measured via MDASI | Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36 | 
| Symptom burden/Quality of life (EQ-5D) | As measured via EQ-5D | Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36 | 
| Health economics | Including cost utility and cost effectiveness analyses as defined by the protocol (e.g. QALYs) | At the end of the trial (trial duration of approximately 8 years) | 
| Peripheral blood JAK2 V617F allele burden | According to ELN response criteria | At baseline and annually throughout the trial (from baseline until approximately 3 years post-randomisation) | 
| Rates of discontinuation | Trial discontinuation | From treatment prior to protocol defined 3 years | 
| Rate and severity of adverse events | collected according to CTCAE version 4.0 and the MITHRIDATE protocol | Continuous throughout the trial (from randomisation until approximately 3 years post-randomisation)) | 
| Spleen response | in patients with splenomegaly | Response at 1 year post randomisation | 
| Time free from venesection | Time free from venesection | Defined as the mean time between venesections while on trial treatment (treatment duration of 3 years) | 
| Secondary malignancy | Malignancy independent to the original diagnosis | Occurring throughout the trial (from randomisation until approximately 3 years post-randomisation) | 
| Change in QRisk score | Change in QRisk score | Collected at baseline and years 1, 2 and 3 |