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MITHRIDATE: Ruxolitinib Versus Hydroxycarbamide or Interferon as First Line Therapy in High Risk Polcythemia Vera (MITHRIDATE)

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ClinicalTrials.gov Identifier: NCT04116502
Recruitment Status : Recruiting
First Posted : October 4, 2019
Last Update Posted : March 30, 2020
Sponsor:
Collaborators:
Novartis
MPN Voice
National Cancer Institute, France
Information provided by (Responsible Party):
University of Birmingham

Brief Summary:
The trial will be a phase III, randomised-controlled, multi-centre, international, open-label trial consisting of ruxolitinib versus best available therapy, where best available therapy is a choice of interferon alpha, any formulation permitted (IFN) or hydroxycarbamide (HC), and which will be elected by the Investigator prior to randomisation.

Condition or disease Intervention/treatment Phase
Polycythemia Vera Drug: Ruxolitinib Drug: Hydroxycarbamide Drug: Interferon-Alpha Phase 3

Detailed Description:

The trial will be a phase III, randomised-controlled, multi-centre, international, open-label trial consisting of ruxolitinib versus best available therapy, where best available therapy is a choice of interferon alpha, any formulation permitted (IFN) or hydroxycarbamide (HC), and which will be elected by the Investigator prior to randomisation.

There will be no cross-over either between arm A and B or between therapies on Arm B

HC and IFN will be provided as best available therapy, IFN can include standard of pegylated-interferon at Investigators discretion.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 586 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase III, Randomised, Open-label, Multicenter International Trial Comparing Ruxolitinib With Either HydRoxycarbamIDe or Interferon Alpha as First Line ThErapy for High Risk Polycythemia Vera
Actual Study Start Date : October 25, 2019
Estimated Primary Completion Date : August 1, 2026
Estimated Study Completion Date : February 1, 2028


Arm Intervention/treatment
Experimental: A- Ruxolitinib
Treatment with Ruxolitinib
Drug: Ruxolitinib
10mg of ruxolitinib twice daily (bd)
Other Name: Jakavi®

Active Comparator: B- Hydroxycarbamide OR Interferon A
Best Available Therapy (BAT), Treatment with hydroxycarbamide OR Interferon A
Drug: Hydroxycarbamide
Via standard hospital mechanisms
Other Name: Hydroxyurea

Drug: Interferon-Alpha
Any formulation, via standard hospital mechanisms
Other Name: Interferon, alpha interferon, Intron® A, Roferon® A




Primary Outcome Measures :
  1. Event Free Survival (EFS) [ Time Frame: the time from randomisation to the date of the first major thrombosis/haemorrhage, death,transformation to Myelodisplastic Syndromes, Acute Myeloid Leukaemia or Post-polycythemia Vera Myelofibrosis, if within the ~3 year trial period ]
    Event Free Survival


Secondary Outcome Measures :
  1. Major thrombosis [ Time Frame: Occuring while on treatment (over 3 years) ]
    As defined in the protocol, combined and split to venous and arterial

  2. Major haemorrhage [ Time Frame: Occuring while on treatment (over 3 years) ]
    As defined in the protocol

  3. Transformation to PPV-MF [ Time Frame: Occuring while on treatment (over 3 years) ]
    Transformation to PPV-MF

  4. Transformation to MDS and/or AML [ Time Frame: Occuring while on treatment (over 3 years) ]
    Transformation to MDS and/or AML

  5. Complete Haematological remission (CHR) [ Time Frame: 1 year post-treatment ]
    As defined by ELN response criteria at 1 year

  6. Symptom burden/Quality of life (MPN-SAF) [ Time Frame: Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36 ]
    As measured via MPN-SAF

  7. Symptom burden/Quality of life (MDASI) [ Time Frame: Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36 ]
    As measured via MDASI

  8. Symptom burden/Quality of life (EQ-5D) [ Time Frame: Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36 ]
    As measured via EQ-5D

  9. Health economics [ Time Frame: At the end of the trial (trial duration of approximately 8 years) ]
    Including cost utility and cost effectiveness analyses as defined by the protocol (e.g. QALYs)

  10. Peripheral blood JAK2 V617F allele burden [ Time Frame: At baseline and annually throughout the trial (from baseline until approximately 3 years post-randomisation) ]
    According to ELN response criteria

  11. Rates of discontinuation [ Time Frame: From treatment prior to protocol defined 3 years ]
    Trial discontinuation

  12. Rate and severity of adverse events [ Time Frame: Continuous throughout the trial (from randomisation until approximately 3 years post-randomisation)) ]
    collected according to CTCAE version 4.0 and the MITHRIDATE protocol

  13. Spleen response [ Time Frame: Response at 1 year post randomisation ]
    in patients with splenomegaly

  14. Time free from venesection [ Time Frame: Defined as the mean time between venesections while on trial treatment (treatment duration of 3 years) ]
    Time free from venesection

  15. Secondary malignancy [ Time Frame: Occuring throughout the trial (from randomisation until approximately 3 years post-randomisation) ]
    Malignancy independent to the original diagnosis

  16. Change in QRisk score [ Time Frame: Collected at baseline and years 1, 2 and 3 ]
    Change in QRisk score


Other Outcome Measures:
  1. Progression of marrow fibrosis [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    Progression of marrow fibrosis (bone marrow collected and analysed at the Weatherall Institute of Molecular Medicine (WIMM) in Oxford

  2. Impact of treatment on molecular signatures of disease [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    Impact of treatment on molecular signatures of disease (as analysed by the WIMM in Oxford)

  3. Clonal involvement [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    within the stem/progenitor cell compartment (as analysed by the WIMM in Oxford)

  4. Clonal evolution [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    (acquisition of additional mutations, as analysed by the WIMM in Oxford)

  5. Reduction of peripheral blood allele burden [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    of other disease-association mutations (as analysed by the WIMM in Oxford)

  6. Assessment of the prevalence of clonality markers for haematological disease [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    and any change over time (as analysed by the WIMM in Oxford)

  7. Cardiac event [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    (angina, acute coronary syndrome, acute MI; arrhythmia)

  8. Pulmonary hypertension [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    Pulmonary hypertension as assessed clinically

  9. Coronary intervention [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    e.g. angiogram, angioplasty, CABG

  10. Deterioration in cardiac function [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    e.g. LVEF% on ECHO/MUGA and/or NYHA classification

  11. Cerebrovascular event [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    TIA, haemorrhagic CVA, non-haemorrhagic CVA

  12. Arterial vascular event [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    peripheral vascular disease: claudication, carotid stenosis

  13. Venous thrombosis [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    including DVT, PE, Cerebral, splanchnic, other

  14. Pregnancy loss [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    Pregnancy loss



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Population:

High risk PV defined as WBC >11 x 109/l* AND at least ONE of the following

  • Age >60 years
  • Prior thrombosis or haemorrhage
  • Platelet count >1000 x 109/l*

    • At any time since diagnosis

Inclusion Criteria:

  1. Patient ≥18 years of age
  2. Diagnosis of PV meeting the WHO criteria within the past 10 years
  3. Meets criteria of high risk* PV (see above for specific population)
  4. Patients may have received antiplatelet agents and venesection
  5. Patients may have received ONE cytoreductive therapy for PV less than 5 years (BUT they should not be resistant or intolerant to that therapy)
  6. Able to provide written informed consent

Exclusion Criteria:

  1. Major thrombosis (both combined and split into venous and arterial)
  2. Major haemorrhage
  3. Transformation to PPV-MF
  4. Transformation to AML and/or MDS
  5. Complete haematological response (CHR) as defined by ELN response criteria at 1 year
  6. Symptom burden/(QALY)quality of life years gained
  7. Health economics including cost utility and cost effectiveness analyses
  8. Peripheral blood JAK2 V617F allele burden according to ELN response criteria
  9. Rates of discontinuation
  10. Adverse events
  11. Spleen response in patients with splenomegaly at Baseline.
  12. Time free from venesection
  13. Rate of second malignancies
  14. Change in QRisk score
  15. Unable to give informed consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04116502


Contacts
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Contact: Kate Davies +44(0)121 414 3792 mithridate@trials.bham.ac.uk

Locations
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United Kingdom
Guys' Hospital Recruiting
London, United Kingdom, SE1 9RT
Contact: Claire Harrison, FRCP,FRCPath         
Churchill Hospital Recruiting
Oxford, United Kingdom, OX3 7LE
Contact: Adam Mead, FRCPath         
Sponsors and Collaborators
University of Birmingham
Novartis
MPN Voice
National Cancer Institute, France
Investigators
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Principal Investigator: Claire Harrison Acting on behalf of the Sponsor (UK), Guy's Hospital, London, UK, SE1 9RT
Principal Investigator: Jean-Jacques Kiladjian (France) Clinical Investigations Center, Saint-Louis Hospital, Paris, France

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Responsible Party: University of Birmingham
ClinicalTrials.gov Identifier: NCT04116502    
Other Study ID Numbers: RG_16-148
First Posted: October 4, 2019    Key Record Dates
Last Update Posted: March 30, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Polycythemia Vera
Polycythemia
Hematologic Diseases
Bone Marrow Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Neoplasms
Bone Marrow Diseases
Myeloproliferative Disorders
Interferons
Interferon-alpha
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Physiological Effects of Drugs