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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 : Not yet recruiting
First Posted : October 4, 2019
Last Update Posted : October 4, 2019
Sponsor:
Collaborators:
Novartis
MPN Voice
National Cancer Institute, France
Information provided by (Responsible Party):
University of Birmingham

Tracking Information
First Submitted Date  ICMJE September 9, 2019
First Posted Date  ICMJE October 4, 2019
Last Update Posted Date October 4, 2019
Estimated Study Start Date  ICMJE October 2019
Estimated Primary Completion Date August 1, 2026   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 3, 2019)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: October 3, 2019)
  • Major thrombosis [ Time Frame: Occuring while on treatment (over 3 years) ]
    As defined in the protocol, combined and split to venous and arterial
  • Major haemorrhage [ Time Frame: Occuring while on treatment (over 3 years) ]
    As defined in the protocol
  • Transformation to PPV-MF [ Time Frame: Occuring while on treatment (over 3 years) ]
    Transformation to PPV-MF
  • Transformation to MDS and/or AML [ Time Frame: Occuring while on treatment (over 3 years) ]
    Transformation to MDS and/or AML
  • Complete Haematological remission (CHR) [ Time Frame: 1 year post-treatment ]
    As defined by ELN response criteria at 1 year
  • 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
  • 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
  • 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
  • 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)
  • 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
  • Rates of discontinuation [ Time Frame: From treatment prior to protocol defined 3 years ]
    Trial discontinuation
  • 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
  • Spleen response [ Time Frame: Response at 1 year post randomisation ]
    in patients with splenomegaly
  • 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
  • Secondary malignancy [ Time Frame: Occuring throughout the trial (from randomisation until approximately 3 years post-randomisation) ]
    Malignancy independent to the original diagnosis
  • Change in QRisk score [ Time Frame: Collected at baseline and years 1, 2 and 3 ]
    Change in QRisk score
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: October 3, 2019)
  • 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
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • Cardiac event [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    (angina, acute coronary syndrome, acute MI; arrhythmia)
  • Pulmonary hypertension [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    Pulmonary hypertension as assessed clinically
  • Coronary intervention [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    e.g. angiogram, angioplasty, CABG
  • 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
  • Cerebrovascular event [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    TIA, haemorrhagic CVA, non-haemorrhagic CVA
  • Arterial vascular event [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    peripheral vascular disease: claudication, carotid stenosis
  • Venous thrombosis [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    including DVT, PE, Cerebral, splanchnic, other
  • Pregnancy loss [ Time Frame: Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation) ]
    Pregnancy loss
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE MITHRIDATE: Ruxolitinib Versus Hydroxycarbamide or Interferon as First Line Therapy in High Risk Polcythemia Vera
Official Title  ICMJE 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
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Polycythemia Vera
Intervention  ICMJE
  • Drug: Ruxolitinib
    10mg of ruxolitinib twice daily (bd)
    Other Name: Jakavi®
  • 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
Study Arms  ICMJE
  • Experimental: A- Ruxolitinib
    Treatment with Ruxolitinib
    Intervention: Drug: Ruxolitinib
  • Active Comparator: B- Hydroxycarbamide OR Interferon A
    Best Available Therapy (BAT), Treatment with hydroxycarbamide OR Interferon A
    Interventions:
    • Drug: Hydroxycarbamide
    • Drug: Interferon-Alpha
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: October 3, 2019)
586
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 1, 2028
Estimated Primary Completion Date August 1, 2026   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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*
  • Diagnosed <10 years
  • Received treatment for < 5 years *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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Kate Davies +44(0)121 414 3792 mithridate@trials.bham.ac.uk
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04116502
Other Study ID Numbers  ICMJE RG_16-148
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of Birmingham
Study Sponsor  ICMJE University of Birmingham
Collaborators  ICMJE
  • Novartis
  • MPN Voice
  • National Cancer Institute, France
Investigators  ICMJE
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
PRS Account University of Birmingham
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP