Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12609000046202
Ethics application status
Approved
Date submitted
16/10/2008
Date registered
20/01/2009
Date last updated
4/07/2012
Type of registration
Retrospectively registered

Titles & IDs
Public title
A large-scale trial testing the intensity of CYTOreductive therapy to prevent cardiovascular events In patients with Polycythemia Vera (PV)
Scientific title
A Prospective, Randomized, Open-label, with Blinded Endpoint evaluation (PROBE), multi-center, controlled , clinical trial on the effectiveness of the cytoreductive therapies (i.e. Phlebotomy and Hydroxyurea (HU)) in reducing cardiovascular (CV) deaths and thrombotic events in patients with Polycythemia Vera (PV)
Universal Trial Number (UTN)
Trial acronym
CYTO-PV
Linked study record

Health condition
Health condition(s) or problem(s) studied:
polycythemia vera 3833 0
To assess the benefit/risk profile of cytoreductive therapy with phlebotomy and/or hydroxyurea (HU) aimed at maintaining hematocrit (HCT) < 45% Vs. maintaining HCT in the range of 45-50% in patients with PV treated at the best of recommended therapies (e.g., low dose of aspirin when indicated and adequated control of standard cardiovascular risk factors) 3834 0
Condition category
Condition code
Blood 4022 4022 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
To assess the benefit/risk profile of cytoreductive therapy, plus low-dose aspirin when not contraindicated, with phlebotomy and/or hydroxyurea (HU, oral administration) aimed at maintaining hematocrit (HCT) < 45% Vs. maintaining HCT in the range of 45-50% in patients with PV treated at the best of recommended therapies (e.g., low dose of aspirin when indicated and adequate control of standard cardiovascular risk factors).To demonstrate that maintaining HCT < 45% (either with phlebotomy or HidroxyUrea (HU) (standard cytoreduction) is more effective than maintaining HCT in the range of 45-50% (either with phlebotomy or HU) (experimental cytoreduction) 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).
All patients will be treated with phlebotomy and/or HU with the goal to reach and maintain the target HCT established by randomization.
Phlebotomy should be performed initially by removing 250-500 ml of every other day or twice a week until the target HCT is obtained.
HU should be administered initially at a dose of 0.5-1.0 g daily. The patient is followed with weekly blood counts adjusting dose to achieve a platelet count < 400,000/mmc. If neutropenia occurs, the dose of HU should be lowered so as not to reduce leukocyte < 3,500/mmc.
Blood counts at regular intervals (monthly) will establish the frequency of future phlebotomies with the goal to maintain the target HCT. Supplemental iron therapy should not be given.
LENGTH OF STUDY: 5 years
Intervention code [1] 3557 0
Prevention
Comparator / control treatment
two different level of hematocrit:
45-50% (experimental therapy) Vs. <45% (standard therapy).
To assess the benefit/risk profile of cytoreductive therapy, plus low-dose aspirin when not contraindicated, with phlebotomy and/or hydroxyurea (HU, oral administration) aimed at maintaining hematocrit (HCT) < 45% Vs. maintaining HCT in the range of 45-50% in patients with PV treated at the best of recommended therapies (e.g., low dose of aspirin when indicated and adequate control of standard cardiovascular risk factors).To demonstrate that maintaining HCT < 45% (either with phlebotomy or HidroxyUrea (HU) (standard cytoreduction) is more effective than maintaining HCT in the range of 45-50% (either with phlebotomy or HU) (experimental cytoreduction) 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).
All patients will be treated with phlebotomy and/or HU with the goal to reach and maintain the target HCT established by randomization.
Phlebotomy should be performed initially by removing 250-500 ml of every other day or twice a week until the target HCT is obtained.
HU should be administered initially at a dose of 0.5-1.0 g daily. The patient is followed with weekly blood counts adjusting dose to achieve a platelet count < 400,000/mmc. If neutropenia occurs, the dose of HU should be lowered so as not to reduce leukocyte < 3,500/mmc.
Blood counts at regular intervals (monthly) will establish the frequency of future phlebotomies with the goal to maintain the target HCT. Supplemental iron therapy should not be given.
LENGTH OF STUDY: 5 years
Control group
Active

Outcomes
Primary outcome [1] 4924 0
Reduction of Cardio Vascular deaths plus thrombotic events.
Fatal events, Total mortality includes: CV death: Death occurring within 28 days after the onset of the documented diagnosis of myocardial infarction or stroke, in the absence of any other evident cause; sudden deaths; deaths from heart failure; all other deaths classified as CV (e.g., International Classification of Disease, ninth edition, Clinical Modification [ICD9] codes 390-459, 798., 557.0, 362.3; 593.8). If the patient affected by a serious non CV disease died for CV event, the latter will be considered the cause of death. Death from malignancy (e.g., ICD9 codes 140.-239.; 238.4; 238.7; 289.8). Death from hematological malignancy (e.g., ICD9 codes 200.-208., 238.4, 289.8, 238.7). Death from PV-related malignancy: Death due to myelofibrosis, myelodysplastic syndrome, leukemia. (e.g., ICD9 codes 289.8, 238.7, 204-208 [with the exception of 238.4, 204.1, 205.1, 206.1, 207.1, 208.1]). Death from other hematological malignancy. Death due to non-PV-related malignancy (e.g., myeloma, lymphoma). Death from other malignancy: Death due to any other malignancy not included above. Other cause of death: Known cause of death not included above. Unknown cause of death

Non-fatal cardiovascular events, Myocardial infarction: Presence of at least two of the following: a) typical ischemic chest pain, pulmonary edema, syncope or shock; b) development of pathological Q-waves and/or appearance or disappearance of localized ST-elevation followed by T-wave inversion in two or more of twelve standard electrocardiograph leads; and c) increase in the concentration of serum enzymes consistent with MI (e.g. CreatineKinasi (CK) > 2 times the upper limit of normality or elevation of levels of troponin). The diagnosis can be based also on necropsy findings of Miocardial Infarction (MI) of an age corresponding to the time of onset of symptoms.
Stroke (e.g., ICD9 codes 430.-434): A diagnosis of nonfatal stroke requires unequivocal signs or symptoms of a neurologic deficit with sudden onset and a duration of more than 24 hours. The diagnosis has to be confirmed with the use of computed tomography (CT), magnetic resonance imaging, or other objective means or on autopsy. These criteria are also used for the diagnosis of fatal stroke. Alternatively, we use the diagnosis reported in the hospital records or on the death certificate.
Transient ischemic attack (e.g., ICD9 code 435): A transient ischemic attack is defined as the abrupt onset of unilateral motor or sensory disturbance, speech defect, homonymous hemianopia, constructional apraxia, or transient monocular blindness (defined as the abrupt onset of a unilateral decrease in visual acuity involving a portion or the entirety of the visual field) that resolved completely in less than 24 hours.
Pulmonary embolism. (e.g., ICD9 code 415.1): Pulmonary embolism is defined by a positive pulmonary angiogram, a ventilation?perfusion scan or CT scan indicating a high probability of pulmonary embolism, or evidence of pulmonary embolism on autopsy. Deep venous thrombosis is defined by a typical clinical picture with positive results on investigation involving such techniques as phlebography, ultrasonography, impedance plethysmography, or CT.
Deep vein thrombosis (e.g., ICD9 codes 451.1; 452,453).
Other arterial or venous thrombosis considered as relevant in patient?s history.
Timepoint [1] 4924 0
5 years
Secondary outcome [1] 8307 0
Assessment of the full benefit/risk profile of experimental treatments in terms of efficacy and safety endpoints.
Non-fatal cardiovascular events, Myocardial infarction: Presence of at least two of the following: a) typical ischemic chest pain, pulmonary edema, syncope or shock; b) development of pathological Q-waves and/or appearance or disappearance of localized ST-elevation followed by T-wave inversion in two or more of twelve standard electrocardiograph leads; and c) increase in the concentration of serum enzymes consistent with MI (e.g. CreatineKinasi (CK) > 2 times the upper limit of normality or elevation of levels of troponin). The diagnosis can be based also on necropsy findings of Miocardial Infarction (MI) of an age corresponding to the time of onset of symptoms.
Stroke (e.g., ICD9 codes 430.-434): A diagnosis of nonfatal stroke requires unequivocal signs or symptoms of a neurologic deficit with sudden onset and a duration of more than 24 hours. The diagnosis has to be confirmed with the use of computed tomography (CT), magnetic resonance imaging, or other objective means or on autopsy. These criteria are also used for the diagnosis of fatal stroke. Alternatively, we use the diagnosis reported in the hospital records or on the death certificate.
Transient ischemic attack (e.g., ICD9 code 435): A transient ischemic attack is defined as the abrupt onset of unilateral motor or sensory disturbance, speech defect, homonymous hemianopia, constructional apraxia, or transient monocular blindness (defined as the abrupt onset of a unilateral decrease in visual acuity involving a portion or the entirety of the visual field) that resolved completely in less than 24 hours.
Pulmonary embolism. (e.g., ICD9 code 415.1): Pulmonary embolism is defined by a positive pulmonary angiogram, a ventilation?perfusion scan or CT scan indicating a high probability of pulmonary embolism, or evidence of pulmonary embolism on autopsy. Deep venous thrombosis is defined by a typical clinical picture with positive results on investigation involving such techniques as phlebography, ultrasonography, impedance plethysmography, or CT.
Deep vein thrombosis (e.g., ICD9 codes 451.1; 452,453).
Other arterial or venous thrombosis considered as relevant in patient?s history.
Timepoint [1] 8307 0
5 years

Eligibility
Key inclusion criteria
Age > 18 years
Diagnosis of PV according to World Health Organisation (WHO) criteria
Ability and willingness to comply with all study requirements
Written and signed informed consent
Minimum age
18 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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 (aspartate amino transferasi (AST) or alanine aminotransferasi (ALT) > 2.5 times upper limit normal (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 follow-up (F-UP) visits schedule and assessments

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
central randomisation by phone /fax /computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratified allocation. Factors such as centre, age gender or previous treatment are used for the stratification.
The “biased coin” strategy will be used to establish the probability of allocating patients to the study arms, thus assuring the balance of patients’ characteristics within the randomization strata.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
21/05/2008
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
1000
Accrual to date
Final
Recruitment outside Australia
Country [1] 1280 0
Italy
State/province [1] 1280 0

Funding & Sponsors
Funding source category [1] 4014 0
Government body
Name [1] 4014 0
Agenzia Italiana del Farmaco
Country [1] 4014 0
Italy
Primary sponsor type
Other
Name
Consorzio Mario Negri Sud
Address
Via Nazionale 8/a
66030 Santa Maria imbaro (Chieti)
Country
Italy
Secondary sponsor category [1] 3606 0
Charities/Societies/Foundations
Name [1] 3606 0
Gruppo Italiano Malattie EMatologiche nell'Adulto - Italian Group for Adult Hematologic Diseases (GIMEMA)
Address [1] 3606 0
Via Rovigo, 1 00161 Roma
Country [1] 3606 0
Italy

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 6095 0
Comitato di Bioetica - Ospedali Riuniti di Bergamo
Ethics committee address [1] 6095 0
Ethics committee country [1] 6095 0
Date submitted for ethics approval [1] 6095 0
Approval date [1] 6095 0
08/02/2008
Ethics approval number [1] 6095 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 29041 0
Address 29041 0
Country 29041 0
Phone 29041 0
Fax 29041 0
Email 29041 0
Contact person for public queries
Name 12198 0
Roberto Marchioli
Address 12198 0
Via Nazionale 8/A
66030 Santa Maria Imbaro (Chieti)
Country 12198 0
Italy
Phone 12198 0
+39 0872 570250
Fax 12198 0
+39 0872 570206
Email 12198 0
[email protected]
Contact person for scientific queries
Name 3126 0
Domenico Addeo
Address 3126 0
Via Nazionale 8/A
66030 Santa Maria Imbaro (Chieti)
Country 3126 0
Italy
Phone 3126 0
+39 0872 570286
Fax 3126 0
+39 0872 570206
Email 3126 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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