Randomized, open-label, multicenter phase 3 study to assess the efficacy and safety of GIVinostat versus hydroxyurea IN JAK2V617F-positive high-risk Polycythemia Vera patients: the GIV-IN PV TRIAL

The primary objective of this phase 3 study is to demonstrate the **superiority** of Givinostat compared to hydroxyurea in terms of efficacy at Week 48 in patients with JAK2V617F-positive high-risk **Polycythemia Vera**. This is clinically relevant as it aims to establish a more effective treatment option for managing this condition, potentially improving patient outcomes. Additionally, the study seeks to evaluate the long-term safety and tolerability of Givinostat during the Extended Treatment Phase, which is crucial for understanding the risk-benefit profile of the drug over an extended period.

Secondary objectives include assessing the safety, tolerability, and efficacy parameters of the treatments. These objectives are important for providing a comprehensive evaluation of the therapeutic potential and safety of Givinostat, ensuring that any benefits are not outweighed by adverse effects.

The clinical trial involves a total of **74 participants** diagnosed with **JAK2V617F-positive high-risk Polycythemia Vera**. The study population includes both male and female subjects, aged 18 years and older, who are not considered part of a vulnerable population. Participants were selected based on their ability to provide informed consent and their diagnosis confirmed according to the 2016 WHO criteria. Key lifestyle considerations include the requirement for female participants of childbearing potential to use highly effective contraception, and male participants to use condoms and ensure their partners use effective contraception during the study. Participants must also have a normalized hematocrit level and an ECOG performance status of 2 or less at screening. The trial does not specify any particular dietary or physical activity requirements for participants.

The clinical trial is designed as a **randomized**, open-label, multicenter phase 3 study to evaluate the efficacy and safety of **Givinostat** compared to **hydroxyurea** in patients with JAK2V617F-positive high-risk **Polycythemia Vera**. The trial is structured into two phases: the Core Treatment Phase and the Extended Treatment Phase. The primary objective of the Core Treatment Phase is to demonstrate the superiority of Givinostat over hydroxyurea in terms of efficacy at Week 48, while the Extended Treatment Phase aims to assess the long-term safety and tolerability of Givinostat. The trial is expected to conclude by September 2031, with recruitment starting in April 2024.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, diagnosis, and risk factors. The Core Treatment Phase will include regular follow-up visits to monitor efficacy and safety, with a primary endpoint assessment at Week 48. The Extended Treatment Phase will continue to monitor safety and efficacy in participants who complete the Core Treatment Phase. The end-of-study visit will occur after the completion of the Extended Treatment Phase or upon early termination.

Participant involvement is expected to last up to 48 weeks for the Core Treatment Phase, with the possibility of extension into the Extended Treatment Phase. Conditions that may lead to early termination from the study include the occurrence of major adverse events, non-compliance with study protocols, or withdrawal of consent. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Givinostat** is the primary experimental medication under investigation. It is available in hard capsule form with dosages of 50 mg, 75 mg, and 100 mg. The maximum daily dose for Givinostat is 200 mg, with a total maximum dose of 67,200 mg over a treatment period of 48 weeks. The route of administration is oral, and it is classified under antineoplastic agents and anti-inflammatory and antirheumatic products. Givinostat is designated as an orphan drug for this study.

**Hydroxycarbamide** serves as a comparator treatment in the trial. It is also administered orally in the form of hard capsules. The maximum daily dose is 3 g, with a total maximum dose of 1,008 g over a 48-week treatment period. Hydroxycarbamide is categorized as a chemical substance.

Additional non-experimental treatments include **Enoxaparin Sodium**, a low molecular weight heparin, provided as a solution for injection in pre-filled syringes. The maximum daily dose is 2,000 IU, with a total maximum dose of 4,000 IU over a 1-week period. The administration route is subcutaneous injection.

**Vitamin K antagonists** are included as auxiliary treatments, administered orally. The maximum daily dose is 10 mg, with a total maximum dose of 30 mg over a 1-week period. These are used to manage anticoagulation in participants.

**Dabigatran Etexilate**, a direct oral anticoagulant, is administered orally with a maximum daily dose of 150 mg and a total maximum dose of 220 mg over a 5-week period. This medication is used to prevent thromboembolic events.

**Carbasalate Calcium**, synonymous with acetylsalicylic acid, is administered orally with a maximum daily dose of 160 mg and a total maximum dose of 325 mg over a 1-week period. It is used for its antiplatelet properties.

**Rivaroxaban**, another direct oral anticoagulant, is administered orally with a maximum daily dose of 2.5 mg and a total maximum dose of 100 mg over a 42-day period. It is used to prevent and treat thromboembolic disorders.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy and safety of Givinostat compared to Hydroxycarbamide in patients with high-risk Polycythemia Vera, with a focus on long-term safety and tolerability.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint for the core treatment phase is the proportion of patients achieving a response at Week 48. This response is defined by several criteria: achieving a complete hematological response (CHR) characterized by a hematocrit (HCT) level of less than 45% without the need for phlebotomy in the previous three months, a white blood cell (WBC) count of ≤ 10 × 10⁹/L, and a platelet (PLT) count of ≤ 400 × 10⁹/L. Additionally, normal spleen size, as measured by imaging techniques such as MRI or CT scan, is required, with specific size criteria for males and females. The absence of progressive disease, major hemorrhagic events, and major thrombotic events from Week 25 to Week 48 is also necessary for a response.

Secondary endpoints include the proportion of patients achieving a complete hematological response at Week 48, the time from randomization to the first observed CHR, and the proportion of patients with a normal spleen size at Week 48. Long-term efficacy will be evaluated by the proportion of patients with a response at yearly assessment visits and the duration of the first CHR. Additional efficacy measures include the time from randomization to the first HCT response without phlebotomy, the time to the first WBC response, and the time to the first PLT response up to Week 48. Changes from baseline in physical examination findings, Eastern Cooperative Oncology Group (ECOG) performance status, vital signs, electrocardiograms (ECGs), serum chemistry, hematology, serology, and urinalysis results will also be assessed.

The extended treatment phase will focus on the type, incidence, and severity of treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs), TEAEs leading to discontinuation, or deaths in eligible patients who continue in the study. The efficacy assessments will be conducted using validated imaging techniques and laboratory tests at specified time points, ensuring a comprehensive evaluation of the treatment's impact on patients with high-risk **Polycythemia Vera**.