Clinical trial NCT01645124: Large-scale Trial Testing the Intensity of CYTOreductive Therapy in Polycythemia Vera (PV)
Official title: A Large-scale Trial Testing the Intensity of CYTOreductive Therapy to Prevent Cardiovascular Events In Patients With Polycythemia Vera (PV)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Polycythemia Vera
Keywords: Polycythemia
Hematocrit
Thrombosis
Lead sponsor: Consorzio Mario Negri Sud
Sponsor class: OTHER
Collaborators: name: Agenzia Italiana del Farmaco
name: A.O. Ospedale Papa Giovanni XXIII
First posted: 2012-07-20
Enrollment: 365
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: CYTO-PV is a phase III Prospective, Randomized, Open-label, with Blinded Endpoint evaluation (PROBE), multi-center, clinical trial in patients with diagnosis of Polycythemia vera (PV) treated at the best of recommended therapies (e.g.adequate control of standard cardiovascular risk factors). Irrespective of randomized interventions, all patients will be administered low-dose aspirin (when not contraindicated), i.e.the standard antithrombotic treatment in PV patients.

The purpose of this study to demonstrate that a more intensive cytoreductive therapy, plus low-dose aspirin when not contraindicated, with phlebotomy and/or hydroxyurea (HU), aimed at maintaining hematocrit (HCT) \< 45% is more effective than a less intensive cytoreduction (either with phlebotomy or HU plus low-dose aspirin when not contraindicated) maintaining HCT in the range of 45-50% in the reduction of CV deaths plus thrombotic events (stroke, acute coronary syndrome \[ACS\], transient ischemic attack \[TIA\], pulmonary embolism \[PE\], splanchnic thrombosis, deep vein thrombosis \[DVT\], and any other clinically relevant thrombotic event), in patients with Polycythemia Vera treated at the best of recommended therapies (e.g. adequate control of standard cardiovascular risk factors).

Detailed description: Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by clonal proliferation of hematopoietic progenitors resulting in expansion of the erythrocyte mass, and its clinical course is affected by cardiovascular events, the main cause of morbidity and mortality. Arterial thrombotic events are predominant, particularly large vessel arterial events including cerebrovascular accidents, myocardial infarction, and peripheral arterial occlusion. Based on the complex relationship between thrombosis, hematocrit, and parameters of tissue perfusion and blood viscosity, the latter has been proved to be an exponential function of the hematocrit. Red cell aggregation increases at high hematocrit (HCT) levels, creating the potential for vascular stasis. As a result, enhanced interplay between platelet, leukocytes and vessel wall increases the risk of thrombosis.

Considering the lack of effective therapeutic strategy targeted at the mutated allele JAK2V617F, there is no known treatment that eradicates the abnormal clone, apart from anecdotal cases of bone marrow transplantation. Cytoreductive treatment by phlebotomy or chemotherapy, however, has dramatically reduced the number of thrombotic complications and substantially improved survival and today there is agreement that the goal of cytoreductive treatment should be to keep the HCT value below 0.45 in all PV patients.

This was suggested on the basis of a small, retrospective study of PV that more than 30 years ago showed a progressive increase in the incidence of vascular occlusive episodes at HCT levels higher than 44% and in patients treated according to the drugs and the therapeutic tenets of the time. However no clinical trial has confirmed such findings. The results of the two largest prospective studies currently available (namely PVSG-1 and ECLAP) suggest no difference in the risk of thrombosis among patients kept at HCT below 50%.

An association between relevant outcome events (namely. thrombotic events, mortality, and haematological progression) and HCT in the evaluable range of 40-55% was found in the ECLAP population neither in the multivariate analysis at baseline nor in the time-dependent multivariate analysis. The ECLAP trial demonstrated the antithrombotic efficacy of low-dose aspirin in this setting and the use of this therapy in clinical practice is likely to decrease meaningfully, though not eliminate, the high risk of thrombosis of PV patients.

In conclusion, the high incidence of thrombotic events irrespective of low-dose aspirin administration as well as of haematological transformation in the long term which have been shown in PV patients study suggest the need to investigate in depth the benefit/risk profile of current therapeutic options for cytoreductive therapy. CYTO-PV is aimed at assessing the benefit risk profile of cytoreductive therapy with phlebotomy and/or HU aimed at maintaining HCT \< 45% Vs. maintaining HCT in the range 45-50%. It is an independent, investigator-generated pragmatic trial with broad selection criteria to mimic clinical practice in order to strengthen the transferability of its results to the population of PV patients; it has been designed to be conducted, without need of special facilities, in the framework of the Italian Group of hematologic Adult diseases ("GIMEMA"). The optimization of therapeutic management of PV patients will allow to improve the prognosis of PV patients, the allocation of the resources the Italian National Health Service (IHS), and the knowledge about the benefit/risk profile of pharmacological cytoreduction in PV

Eligibility criteria: Inclusion Criteria:

Males and females aged 18 years or more are eligible for the study if they meet all the following inclusion criteria:

* New diagnosis of PV according to WHO 2007 diagnostic criteria including Jak 2 V617F mutation status;
* Old diagnosis of PV confirmed with JAK-2 positivity and clinical course of the disease;
* Ability and willingness to comply with all study requirements;
* Written informed consent (obtained before any study specific procedure).

Exclusion Criteria:

* Pregnant or lactating women or women of childbearing potential who are not protected from pregnancy by an accepted method of contraception;
* Known hypersensitivity or contraindication to study treatments;
* Significant liver (AST or ALT \> 2.5 times ULN) or renal disease (creatinine \> 2 mg/ml);
* Presence of any life-threatening condition or of any disease (e.g. cancer) that is likely to significantly shorten life expectancy;
* History of active substance or alcohol abuse within the last year;
* Any condition that in the opinion of the investigator would jeopardize the evaluation of efficacy or safety or be associated with poor adherence to the protocol - Baseline and FUP visits schedule and assessments
* Logistic problem related to the patient.

Primary outcomes:
measure: Reduction of PEP (Primary End Point)defined as CV deaths plus thrombotic events
timeFrame: Expected average of 5 years
Secondary outcomes:
measure: PEP plus minor thrombosis, hospitalization and malignancy
timeFrame: Expected average of 5 years
Other outcomes:
measure: Aadverse Events
timeFrame: Expected average of 5 years
Locations:
city: San Giovanni Rotondo
country: Italy
facility: IRCCS Ospedale Casa Sollievo della Sofferenza di San Giovanni Rotondo
state: Foggia
city: Rionero in Vulture
country: Italy
facility: IRCCS Centro di Riferimento Oncologico di Basilicata (CROB)
state: Potenza
city: Orbassano
country: Italy
facility: Azienda Ospedaliero-Universitaria San Luigi Gonzaga di Orbassano
state: Torino
city: Ancona
country: Italy
facility: Azienda Ospedaliera Universitaria Ospedali Riuniti di Ancona
city: Bari
country: Italy
facility: Azienda Ospedaliera Universitaria Ospedale Consorziale Policlinico di Bari
city: Bergamo
country: Italy
facility: Azienda Ospedali Riuniti di Bergamo
city: Brindisi
country: Italy
facility: Azienda Unità Sanitaria Locale di Brindisi BR/1- Ospedale "Di Summa - Perrino"
city: Cagliari
country: Italy
facility: Ospedale Armando Businco
city: Catania
country: Italy
facility: Azienda Ospedaliera Universitaria-'Policlinico- Vittorio Emanuele'-Ospedale Ferrarotto Alessi di Catania
city: Cuneo
country: Italy
facility: Azienda Ospedaliera S. Croce e Carle di Cuneo
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi di Firenze
city: Messina
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Martino di Messina
city: Milano
country: Italy
facility: Fondazione IRCSS Cà Granda- Ospedale Maggiore Policlinico
city: Milano
country: Italy
facility: Ospedale S.Raffaele
city: Monza
country: Italy
facility: Ospedale S.Gerardo di Monza
city: Novara
country: Italy
facility: Azienda Ospedaliera Universitaria'Maggiore della Carità' di Novara
city: Padova
country: Italy
facility: Università di Padova
city: Palermo
country: Italy
facility: Azienda Ospedaliero-Universitaria Policlinico Giaccone di Palermo
city: Pavia
country: Italy
facility: IRCCS Policlinico S. Matteo di Pavia
city: Pesaro
country: Italy
facility: Azienda Ospedaliera S. Salvatore, Presidio San Salvatore Muraglia
city: Prato
country: Italy
facility: AUSL 4 Prato, Ospedale "Misericordia e Dolce" di Prato
city: Reggio Emilia
country: Italy
facility: Ospedale di S.Maria Nuova
city: Roma
country: Italy
facility: IRCCS Istituto Regina Elena (IFO)
city: Roma
country: Italy
facility: Università degli Studi di Roma "La Sapienza"
city: Roma
country: Italy
facility: Policlinico Universitario Gemelli di Roma
city: Vicenza
country: Italy
facility: Ospedale San Bortolo di Vicenza
Study officials:
affiliation: A.O. Ospedale Papa Giovanni XXIII
name: Tiziano Barbui, MD
role: STUDY_CHAIR
References:
citation: Marchioli R, Finazzi G, Specchia G, Cacciola R, Cavazzina R, Cilloni D, De Stefano V, Elli E, Iurlo A, Latagliata R, Lunghi F, Lunghi M, Marfisi RM, Musto P, Masciulli A, Musolino C, Cascavilla N, Quarta G, Randi ML, Rapezzi D, Ruggeri M, Rumi E, Scortechini AR, Santini S, Scarano M, Siragusa S, Spadea A, Tieghi A, Angelucci E, Visani G, Vannucchi AM, Barbui T; CYTO-PV Collaborative Group. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013 Jan 3;368(1):22-33. doi: 10.1056/NEJMoa1208500. Epub 2012 Dec 8.