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

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.

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*
• Hypertension or diabetes requiring pharmacological therapy (*At any time since diagnosis)

Inclusion criteria

• Patient ≥18 years of age
• Diagnosis of PV meeting the WHO criteria within the past 15 years
• Meets criteria of high risk* PV (see above for specific population)
• Patients must have a screening haemoglobin of >8g/dl
• Patients may have received antiplatelet agents and venesection
• Patients may have received ONE cytoreductive therapy for PV less than 10 years (BUT they should not be resistant or intolerant to that therapy)
• Able to provide written informed consent

Exclusion criteria

• Diagnosis of PV > 15 years previously
• Absence of 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 10 years OR resistance/intolerance to that therapy
• Active infection including Human Immunodeficiency Virus (HIV), hepatitis B, hepatitis C, autoimmune hepatitis, 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 with lactose allergies, hypersensitivities, or rare hereditary problems, of galactose intolerance, total lactase deficiency or glucose- galactose malabsorption
• Patients with uncontrolled neuropsychiatric disorders
• Patients with uncontrolled cutaneous cancers
• Patients and partners 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 (within the last 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 mls/min
• Unable to give informed consent

Additional Exclusion Criteria for France Only

• All women of childbearing potential (as per Appendix 8 definition)
• No affiliation with the French healthcare system
• Persons under psychiatric care that would impede understanding of informed consent and optimal treatment and follow-up
• Adults subject to a legal protection measure (guardianship, curatorship and safeguard of justice)
• Patients deprived of their liberty by a judicial or administrative decision