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    Summary
    EudraCT Number:2016-001406-42
    Sponsor's Protocol Code Number:30032016
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2016-04-07
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2016-001406-42
    A.3Full title of the trial
    Statin- and bisphosphonate treatment in patients with the Philadelphia-negative chronic myeloproliferative neoplasms - essential thrombocytosis, polycythemia vera and hypercellular myelofibrosis.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Statin- and bisphosphonate treatment in patients with the Philadelphia-negative chronic myeloproliferative neoplasms - essential thrombocytosis, polycythemia vera and hypercellular myelofibrosis.
    A.4.1Sponsor's protocol code number30032016
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorHæmatologisk Afdeling, Sjælland Sygehus, Roskilde
    B.1.3.4CountryDenmark
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportHæmatologisk Afdeling, Sjælland Sygehus, Roskilde
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHæmatologisk Afdeling, Sjælland Sygehus, Roskilde
    B.5.2Functional name of contact pointKFE
    B.5.3 Address:
    B.5.3.1Street AddressKøgevej 7-13
    B.5.3.2Town/ cityRoskilde
    B.5.3.3Post code4000
    B.5.3.4CountryDenmark
    B.5.4Telephone number004547324800
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAtorvastatin
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNATORVASTATIN
    D.3.9.1CAS number 134523-00-5
    D.3.9.4EV Substance CodeSUB05600MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number20 to 80
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameZoledronic acid
    D.3.4Pharmaceutical form Concentrate for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNZOLEDRONIC ACID
    D.3.9.1CAS number 118072-93-8
    D.3.9.4EV Substance CodeSUB00176MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    The Philadelphia-negative chronic myeloproliferative neoplasms: Essential thrombocytosis, polycythemia vera and hypercellular myelofibrosis.
    E.1.1.1Medical condition in easily understood language
    Chronic bloodcancer
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10028577
    E.1.2Term Myeloproliferative disorder NOS
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10074689
    E.1.2Term Post polycythemia vera myelofibrosis
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10028576
    E.1.2Term Myeloproliferative disorder
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10074692
    E.1.2Term Post essential thrombocythaemia myelofibrosis
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10074690
    E.1.2Term Post essential thrombocythemia myelofibrosis
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10074691
    E.1.2Term Post polycythaemia vera myelofibrosis
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10028538
    E.1.2Term Myelofibrosis with myelometaplasia
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10015495
    E.1.2Term Essential thrombocytosis
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10015494
    E.1.2Term Essential thrombocythemia
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10013238
    E.1.2Term Disorder myeloproliferative
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. In patients wit newly diagnosed low-risk MPNs to compare treatment with atorvastatin, zoledronic acid, atorvastatin + zoledronic acid and no treatment.

    2. In patients wit newly diagnosed high-risk MPNs to compare treatment with interferon + atorvastatin, interferon + zoledronic acid, interferon + atorvastatin + zoledronic acid and interferon treatment alone.
    E.2.2Secondary objectives of the trial
    1. To describe biochemical markers of inflammation and disease burden in a population of MPN patients observed prospectively.
    2. To describe the thrombophilic profile in MPN patients during treatment.
    3. To describe Peripheral insulin resistence in patients with MPN at diagnosis at during treatment.
    4. To describe circulating immune cell function at time of diagnosis and during treatment.
    5. To describe MPN patients co-morbidity status at time of diagnosis.
    6. To evaluate the effect of atorvastatin treatment in patients with reactive thrombocytosis and leucocytosis (non-MPN).
    7. To describe biochemical markers of inflammation and disease burden in a population of non-MPN patients.
    8. To describe if patients with non-MPN have peripheral insulin resistance, and to evaluate the effect of treatment.
    9. To describe patients with non-MPN co-morbidity status at time of diagnosis.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Low-risk MPN patients
    1. WHO 2016 classified ET, PV or hyperproliferativ primary myelofibrosis og prePMF (thrombocytosis and/or leukocytosis without anemia).
    2. Age > 18 years.
    3. Expected survival > 1 year.
    4. Fulfills criteria for low-risk MPN disease:
    a. Age < 60 years and
    b. No prior thrombosis and
    c. B-thrombocytes < 1500 x 109/l.
    5. Does not use statin or bisphosphonate.

    High-risk MPN patients
    1. WHO 2008 classified ET, PV or hyperproliferativ primary myelofibrosis (thrombocytosis and/or leukocytosis without anemia).
    2. Age > 18 years.
    3. Expected survival > 1 year.
    4. Fulfills criteria for high-risk MPN disease:
    a. Age > 60 years or
    b. Prior thrombosis or
    c. B-thrombocytes > 1500 x 109/l.
    5. Does not use statin or bisphosphonate.

    Reactive thrombocytosis and/or leukocytosis
    1. Referred on suspicion of MPNs. No suspicion of MPN disease.
    2. Age > 18 years.
    3. Expected survival > 1 year.
    4. Does not use statin.
    E.4Principal exclusion criteria
    General:
    1. Uncontrolled autoimmune or chronic inflammatory disease
    2. Different active cancer
    3. Pregnancy (in fertile women pregnancy must be ruled out by negative pregnancy test and safe contraceptive treatment must be used).

    Low-risk MPN:
    1. Contraindications against atorvastatin treatment
    a. Active lever disease or continuous elevated transaminases of unknown reasons
    b. Use of potent CYP3A4-inhibitors
    c. Use of gemfibrozil or ciclosporin
    d. Allergies against statins
    2. Contraindications against zoledronic acid treatment
    a. Severe renal failure (GFR < 35 ml/min/1,73m2)
    b. Allergies against bisphosphonates

    High-risk MPN:
    1. Contraindications against atorvastatin treatment.
    a. Active lever disease or continuous elevated transaminases of unknown reasons
    b. Use of potent CYP3A4-inhibitors
    c. Use of gemfibrozil or ciclosporin
    d. Allergies against statins
    2. Contraindications against zoledronic acid treatment
    a. Severe renal failure (GFR < 35 ml/min/1,73m2)
    b. Allergies against bisphosphonates
    3. Contraindications against interferon treatment
    a. Uncompensated lever cirrhosis, severely reduced lever function along with HIV-HCV infected patients with cirrhosis and Child-pugh > 6
    b. Severe cardiac disease
    c. Autoimmune hepatitis
    d. Abnormal TSH (must be corrected)
    e. Allergies against interferon

    Reactive thrombocytosis and/or leukocytosis
    1. Contraindications against atorvastatin treatment
    a. Active lever disease or continuous elevated transaminases of unknown reasons
    b. Use of potent CYP3A4-inhibitors
    c. Use of gemfibrozil or ciclosporin
    d. Allergies against statins
    E.5 End points
    E.5.1Primary end point(s)
    1. Inflammatory biomarkers: hsCRP, inflammatory cytokines, leukocytecount, plateletcount.
    E.5.1.1Timepoint(s) of evaluation of this end point
    baseline, 14 days, 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 months
    cytokine measurements baseline, 1, 3, 6 months.
    E.5.2Secondary end point(s)
    2. Hematological parameters: hgb, hct, erytrocytecount, MCV, differential count, reticulocytes, LDH and URAT
    3. Inflammatory parameters and coagulationhemostasis: Ferritin, fibrin D-dimer, ESR, fibrinogen.
    4. MPN related symptoms
    5. Number of phlebotomies and transfusions.
    6. The need for further cytoreductive treatment.
    7. Response rates
    8. Comparison of the bonemarrow after 3 years with pretreatment bone marrow.
    9. CALR and JAK2 mutationburden
    10. IgA, IgG, IgM
    11. Cholesterol levels
    12. YKL-40, myeloperoxidase, beta2-mikroglobulin.
    13. markers of for oxidative stress in urine 8-oxoGua, 8-oxoGuo og 8-oxod-Guo.
    14. Genexpressionsprofilering, next generation exomsekventering
    15. Immunecell studies
    16. ROTEM
    17. Insulin resistance
    18. EndoPat measurements
    19. Echocardiografi, heart CT, cerebral blood flow, ultrasound of neck vessels and eye examination
    20. Treatment sideeffects
    21. Quality of life questionnaires MPN-SAF, BFI og EORTIC QLQ C-30

    E.5.2.1Timepoint(s) of evaluation of this end point
    Endpoint 2, 3, 4, 5, 6, 20: baseline, 14 days, 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 months
    Endpoint 7: 6, 24, 36 months
    Endpoint 8: 36 months
    Endpoint 9: Baseline, 3, 6, 12, 15, 21, 24, 27, 33, 36 months
    Endpoint 10, 11, 12, 17: baseline, 1, 3, 4, 6, 36 months
    Endpoint 13, 14, 15: baseline, 1, 3, 6 months
    Endpoint 16: baseline, 1, 3, 36 months
    Endpoint 18: baseline, 1, 3 months
    Endpoint 19: baseline and 36 months
    Endpoint 21: baseline, 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    compared to "no-treatment" og interferon alone
    E.8.2.4Number of treatment arms in the trial5
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    last visit of the last subject after 3 years
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state100
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Treatment after the study has ended wille follow normal treatment guidelines. Patients treated with atorvastatin will have the option og continuing this treatment.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-06-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-12-20
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2021-05-27
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