Phase III Randomized Open-Label Multicenter Trial of Ruxolitinib vs. Hydroxycarbamide or Peginterferon Alfa-2a in High-Risk Polycythemia Vera Patients

The primary objective of this study is to compare the **time to combined incidence** of major thrombosis, major haemorrhage, death, transformation to Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), or post-Polycythemia Vera (PPV) Myelofibrosis in high-risk Polycythemia Vera (PV) patients randomized to receive ruxolitinib versus the best available therapy. This is clinically relevant as it aims to determine the efficacy of ruxolitinib in reducing severe complications and disease progression in high-risk PV patients, potentially improving patient outcomes and survival rates.

Secondary objectives include: - Comparing the incidence of major thrombosis, major haemorrhage, and transformation to PPV Myelofibrosis in high-risk PV patients receiving ruxolitinib or best available therapy. - Comparing the incidence of transformation to MDS and/or AML and complete haematological response between best available therapy and ruxolitinib. - Determining the symptom burden, quality of life, and health economics, including cost utility and cost-effectiveness analyses, and establishing the change in peripheral blood JAK2 V617F allele burden. - Determining the rates of discontinuation from treatment and the rate and severity of adverse events in both treatment groups. - Comparing spleen response and time free from venesection in both treatment groups. - Comparing the incidence of secondary malignancy and the change in QRisk in both treatment groups. - Exploring the impact of treatment on the progression of marrow fibrosis and the molecular signature of the disease. - Establishing the clonal evolution and involvement within the stem/progenitor cell compartment in each treatment arm. - Establishing the change in peripheral blood allele burden and assessing the prevalence of clonality markers for disease, including their change over time by treatment arm. - Determining the correlation of thrombosis markers with clinical thrombosis events in each treatment arm. - Establishing the incidence rate in each treatment arm of cardiac events, pulmonary hypertension, coronary intervention, deterioration in cardiac function, cerebrovascular events, arterial vascular events, venous thrombosis, and pregnancy loss.

The clinical trial involves a total of **293 participants** diagnosed with **Polycythaemia Vera (PV)**, a condition characterized by an increased number of red blood cells. The study population includes both male and female subjects aged 18 years and older, with a specific focus on individuals classified as high-risk PV patients. Participants were selected based on their diagnosis of PV according to WHO criteria within the past 15 years and must meet high-risk criteria, such as elevated white blood cell count and additional risk factors like age over 60, prior thrombosis, or major hemorrhage. The trial includes individuals who have a screening hemoglobin level greater than 8g/dl and may have previously received antiplatelet agents or venesection. Participants are required to have undergone one or fewer cytoreductive therapies for less than 10 years, provided they are not resistant or intolerant to the therapy. The study does not exclude based on gender, and it includes a vulnerable population, ensuring a comprehensive assessment of the trial's objectives.

The clinical trial is a **randomized**, open-label, multicenter international study designed to compare the efficacy of **ruxolitinib** with either **hydroxycarbamide** or **peginterferon alfa-2a** as first-line therapy for high-risk **polycythemia vera**. The trial aims to evaluate the time to the combined incidence of major thrombosis, major hemorrhage, death, transformation to myelodysplastic syndrome, acute myeloid leukemia, or post-PV myelofibrosis in high-risk patients. The study is expected to commence recruitment on October 19, 2024, and conclude by April 30, 2030, with a maximum treatment period of 96 weeks for participants.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of polycythemia vera, and risk factors. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, assess hematological response, and document any adverse events. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination, which may result from adverse events, lack of efficacy, or withdrawal of consent.

The expected length of participant involvement is up to 96 weeks, with conditions for early termination including significant adverse reactions, disease progression, or voluntary withdrawal. The primary endpoint is event-free survival, defined as the time from randomization to the first occurrence of a major event. Secondary endpoints include rates of major thrombosis, major hemorrhage, transformation to myelofibrosis or leukemia, and complete hematological response, among others. Exploratory endpoints will assess the progression of marrow fibrosis, clonal evolution, and metabolic events. The trial will adhere to rigorous scientific standards to ensure the validity and reliability of the findings.

The clinical trial involves the administration of three distinct treatments. The first treatment is **Hydroxycarbamide medac 500 mg capsule, hard**, which is an anti-cancer drug. The active substance is **hydroxycarbamide**, also known as hydroxyurea, and it is presented in a hard capsule form. The medication is administered orally with a maximum daily dose of 1000 mg and a total maximum dose of 2920000 mg over a treatment period of up to 96 weeks. The pharmaceutical product is manufactured by MEDAC GESELLSCHAFT FÜR KLINISCHE SPEZIALPRÄPARATE MBH (WEDEL) and is classified under the ATC code L01XX05.

The second treatment is **Pegasys 90 micrograms solution for injection in pre-filled syringe**, containing the active substance **peginterferon alfa-2a**. This medication is a protein-based anti-cancer drug and is administered subcutaneously. The maximum daily dose is 180 micrograms, with a total maximum dose of 525600 micrograms over a 96-week treatment period. The product is manufactured by PHARMAAND GMBH and is categorized under the ATC code L03AB11.

The third treatment is **Jakavi 5 mg tablets**, which contains the active substance **ruxolitinib**. This medication is a Janus Kinase (JAK) inhibitor and is administered orally. The maximum daily dose is 50 mg, with a total maximum dose of 146000 mg over a 96-week treatment period. The product is manufactured by NOVARTIS EUROPHARM LIMITED and is used as a test treatment in the trial. It is classified under the ATC code L01EJ01.

All treatments are administered according to the specified dosing schedules, and participant compliance is monitored throughout the trial. The trial aims to compare the efficacy of ruxolitinib against the best available therapy, which includes either hydroxycarbamide or peginterferon alfa-2a, in patients with high-risk polycythemia vera.

The efficacy of the clinical trial will be assessed through a comprehensive evaluation of both primary and secondary endpoints. The primary endpoint is **Event Free Survival (EFS)**, which is defined as the time from randomization to the occurrence of the first event, including major thrombosis, major hemorrhage, death, or transformation to Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), or post-Polycythemia Vera Myelofibrosis (PPV-MF). Patients who do not experience an event during the trial will be censored at their last known date of follow-up.

Secondary endpoints include a range of clinical and patient-reported outcomes: major thrombosis (both combined and split into venous and arterial), major hemorrhage, transformation to PPV-MF, transformation to AML and/or MDS, complete hematological response (CHR) as defined by European LeukemiaNet (ELN) response criteria at one year, symptom burden and quality-adjusted life years (QALY) gained, health economics including cost utility and cost-effectiveness analyses, peripheral blood JAK2 V617F allele burden according to ELN response criteria, rates of discontinuation, adverse events, spleen response in patients with splenomegaly at baseline, time free from venesection, rate of second malignancies, and change in Qrisk score.

Exploratory endpoints will further investigate the progression of marrow fibrosis, the impact of treatment on molecular signatures of disease, clonal involvement within the stem/progenitor cell compartment, clonal evolution, reduction of peripheral blood allele burden of other disease-associated mutations, prevalence of clonality markers for hematological disease, and correlation of thrombosis biomarkers with clinical thrombosis events. Additionally, exploratory metabolic endpoints will assess cardiac events, pulmonary hypertension, coronary interventions, deterioration in cardiac function, cerebrovascular events, arterial vascular events, venous thrombosis, and pregnancy loss.