Study to Identify and Describe Predictive Factors for Thromboembolic Events in Patients With High-risk Polycythemia Vera

Study Overview
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Brief Summary
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This is a prospective observational study that will enroll patients with high-risk Polycythemia Vera (PV) with at least one Thromboembolic Event (TE) after diagnosis or up to 2 years prior to diagnosis. This is a non-randomized study, and to ensure a sufficient number of patients in both cohorts, enrollment in each cohort will be terminated once the target of 150 patients has been reached.

Detailed Description
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All patients are already on treatment with hydroxyurea or ruxolitinib at enrollment as per clinical practice and independently of their participation in this study. In addition, the follow-up visits and the evaluation procedures required in the study protocol correspond to current clinical practice. According to local regulations related to observational studies, assessments such as blood tests are justified by the purpose and rationale of the study (i.e., the identification of possible predictive factors of TEs) and are considered current clinical practice. Data related to other procedures will be collected only if such procedures are performed as per clinical practice but are not required otherwise. Patients in both cohorts will be followed for 3 years after enrollment and will have visits at Months 6, 12, 18, 24, 30 and 36. A time window of ± 1 month is permitted for all visits.

Official Title
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Prospective Observational Study to Identify and Describe Predictive Factors for Thromboembolic Events in Patients With High-risk Polycythemia Vera

Conditions
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Polycythemia Vera

Intervention / Treatment
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* Other: Hydroxyurea
* Other: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study. Age ≥18 years. Diagnosis of PV according to WHO 2008 or WHO 2016 and high-risk stratification according to European LeukemiaNet (ELN) classification. At least one TE after diagnosis or up to 2 years prior to diagnosis. Patients on treatment with hydroxyurea at enrollment and for at least 18 months prior to enrollment or those on treatment with ruxolitinib who started treatment up to 18 months before enrollment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Hydroxyurea<br>Patients being treated with hydroxyurea at enrollment and for at least 18 months prior to enrollment. Patients may switch to ruxolitinib treatment during the study in case of inadequate response or intolerance. | Other: Hydroxyurea<br>* Prospective observational study. There is no treatment allocation. Patients prescribed with Hydroxyurea are eligible to enroll into this study.<br>|
| Ruxolitinib<br>Patients on treatment with ruxolitinib who started treatment up to 18 months prior to enrollment. | Other: Ruxolitinib<br>* Prospective observational study. There is no treatment allocation. Patients prescribed with Ruxolitinib are eligible to enroll into this study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of abnormalities presented in patients with Thromboembolic Events (TEs) during the follow up | Demographics, blood pressure, laboratory blood tests, and use of antiplatelets and/or anticoagulants are predictors of TE occurrence, a univariate Cox regression model for repeated events will be applied for each predictor considering all the TEs occurring within 12 months and the time from baseline to each occurrence. Predictors found statistically significant at the 5% level will then be considered in a multivariate Cox regression model for repeated events. | Up to 36 months | 
| Blood pressure | Blood pressure is going to be collected | Up to month 36 | 
| Number of patients with abnormal Body Mass Index (BMI) | Number of patients with abnormal Body Mass Index (BMI) will be collected | Up to month 36 | 
| Number of patients with abnormal weight | Number of patients with abnormal weight will be collected | Up to month 36 | 
| Number of patients with abnormal Neutrophil (NEP) count | Number of patients with abnormal Neutrophil (NEP) count will be collected | Up to 36 months | 
| Number of patients with abnormal White blood Count (WBC) | Number of patients with abnormal White blood Count (WBC) will be collected | Up to 36 months | 
| Number of patients with abnormal Lymphocytes (LYP) count | Number of patients with abnormal Lymphocytes (LYP) count will be collected | Up to 36 months | 
| Number of participants using antiplatelets and/or anticoagulants on the incidence of TEs | Number of participants using antiplatelets and/or anticoagulants on the incidence of Thromboembolic Events (TEs) will be collected | Up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Synergistic combinations of predictive factors | Synergistic combinations of predictive factors (Red cell Distribution Width, neutrophils, lymphocytes, neutrophil/ lymphocyte ratio and platelets). Synergy score is defined as the product of the individual significances of variable 1 and 2 (expected) divided by the significance of the two-variable model (observed) To investigate cases of extreme synergy, instances in which two variables split the given cohort into high-risk and low-risk patients are far better than either variable alone. A simple synergy scoring metric to rank variable in terms of synergy (S):S12=(P1*P2)/P12 where P1 and P2 are the maximum possible (Cox regression derived) p-values for variable 1 and variable 2 and P12 was the max. p-value possible from the combination of variables 1 and 1. This synergy is intended to capture a variable that may provide exclusive non-redundant information when attempting to split a cohort based on risk and may provide an added insight into the functional/clinical rationale of a model | Up to 36 months | 
| Yearly incidence of TEs | Yearly incidence of Thromboembolic Events (TEs) will be collected | 36 months | 
| Incidence of arterial and venous TEs in the hydroxyurea and ruxolitinib cohorts | Incidence of arterial and venous TEs in the hydroxyurea and ruxolitinib cohorts will be collected | 36 months | 
| Incidence and severity of adverse events | Incidence and severity of adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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polycythemia vera, high-risk polycythemia vera, PV, Ruxolitinib, NIS, Italy, TE, predictive factors, hydroxyurea