HU-F-AIM - A prospective, interventional study to evaluate HU-resistance in polycythemia vera patients who meet predictive parameters identified in the machine learning project PV-AIM

The primary objective of this study is the evaluation of **hydroxyurea** (HU) resistance or intolerance in patients with **polycythemia vera** (PV) who meet the predictive risk factors identified in the machine learning project PV-AIM, referred to as PV-AIM HU-resistance predictors, at the start of their regular HU treatment. This is clinically relevant as it aims to identify patients who may not respond adequately to HU therapy, allowing for more personalized treatment strategies and potentially improving patient outcomes.

Secondary objectives include:

• Evaluation of patients eligible for de novo HU therapy who simultaneously meet the PV-AIM HU-resistance predictors before starting HU treatment.
• Assessment of the development of HU resistance or intolerance at any time within the study period, including correlation with the PV-AIM HU-resistance predictors.
• Description of therapies administered after confirmation of HU resistance or intolerance, including the rationale for continuing treatment with HU or switching to alternative therapies.

The clinical trial focuses on patients diagnosed with **Polycythemia vera**, a condition characterized by an increased number of red blood cells. The study population includes both male and female participants aged 18 years and older. Participants are required to have a confirmed diagnosis of Polycythemia vera according to WHO criteria from 2008, 2016, or 2022. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. Participants must not have received any previous pharmacologic cytoreductive therapy or undergone phlebotomy in the last 14 days. The trial targets both high-risk individuals, defined as those aged 60 years or older or with a prior history of thrombosis, and low-risk individuals who exhibit signs of disease progression or an increasing risk of thromboembolism and bleeding. Female participants of childbearing potential are required to have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study treatment. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate **hydroxyurea** resistance in patients with **polycythemia vera** who meet specific predictive parameters identified through a machine learning project. This is a prospective, interventional study with a randomized, double-blind, controlled design. The trial is categorized as a phase 4 study and is expected to last until October 31, 2025, with recruitment having commenced on May 1, 2023. Participants will be involved in the study for a maximum treatment period of 15 months, during which they will receive oral administration of hydroxycarbamide, with a maximum daily dose of 20 mg/kg and a total dose not exceeding 9120 mg/kg.

The study involves a sequence of visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and previous treatment history. Participants must be 18 years or older, have a confirmed diagnosis of polycythemia vera, and meet other specific inclusion criteria. The primary endpoint is the proportion of patients exhibiting hydroxyurea resistance or intolerance within 6-9 months after starting treatment. Secondary endpoints include the proportion of patients meeting resistance predictors before treatment and those developing resistance at any time during the study.

Follow-up visits will be conducted to monitor the participants' response to treatment and assess any development of resistance or intolerance. The end-of-study visit will evaluate the overall outcomes and gather final data. Participants may be terminated early from the study if they develop significant adverse reactions, fail to comply with the study protocol, or withdraw consent. The study aims to provide valuable insights into the management of polycythemia vera and the effectiveness of hydroxycarbamide in patients identified as high-risk for resistance.

The clinical trial involves the administration of **HYDROXYCARBAMIDE**, also known as hydroxyurea, as the experimental medication. This pharmaceutical agent is provided in the form of a hard capsule. The active substance, **HYDROXYCARBAMIDE**, is of chemical origin. The medication is administered orally, with a dosage regimen of up to 20 mg/kg per day. The maximum total dose permitted during the trial is 9120 mg/kg, and the treatment period is limited to a maximum of 15 days. The trial aims to evaluate the resistance or intolerance to hydroxycarbamide in patients with polycythemia vera, who meet specific predictive parameters identified through a machine learning project.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of hydroxycarbamide to assess its efficacy and tolerance in the specified patient population. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

The efficacy of the clinical trial will be assessed by evaluating the **HU-resistance** and intolerance in patients with **Polycythemia Vera** (PV) who meet specific predictive parameters identified in the machine learning project PV-AIM. The primary endpoint is the proportion of PV patients exhibiting HU-resistance or intolerance within 6-9 months after initiating de novo treatment with Hydroxycarbamide, in the presence of the PV-AIM HU-resistance predictors at the start of treatment.

Secondary endpoints include the proportion of PV patients who meet the PV-AIM HU-resistance predictors before starting Hydroxycarbamide treatment, and the proportion of patients developing HU resistance or intolerance at any time within the maximum treatment period of 15 months. Additionally, the study will assess the proportion of patients developing resistance or intolerance in the presence or absence of the PV-AIM HU-resistance predictors at the start of treatment. For patients who develop resistance or intolerance according to the European LeukemiaNet (ELN) criteria during the 15-month period, the study will evaluate the proportion of "non-switchers" (patients remaining on Hydroxycarbamide despite meeting resistance or intolerance criteria) compared to "switchers," the timepoint of therapy switch, reasons for therapy switch or non-switch, and therapies applied during the follow-up period.