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    Summary
    EudraCT Number:2013-003295-12
    Sponsor's Protocol Code Number:15022013
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-10-28
    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 number2013-003295-12
    A.3Full title of the trial
    Combination Therapy Interferon Alpha + JAK1-2 Inhibitor in The Ph-Negative Chronic Myeloid Neoplasms
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Kombinationsbehandling med Interferon og JAK1-2 Hæmmer i behandlingen af Ph-Negativ Myeloprolifertiv Cancer
    A.4.1Sponsor's protocol code number15022013
    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 SponsorRoskilde University Hospital
    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 supportNovartis
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRoskilde Hospital
    B.5.2Functional name of contact pointMads Emil Bjørn
    B.5.3 Address:
    B.5.3.1Street AddressKoegevej 7-13
    B.5.3.2Town/ cityRoskilde
    B.5.3.4CountryDenmark
    B.5.4Telephone number004526223678
    B.5.6E-mailhans.hasselbalch@dadlnet.dk
    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.2.1.1.1Trade name Jakavi
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis
    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 Information not present in EudraCT
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameJakavi
    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.3.9.3Other descriptive nameRUXOLITINIB
    D.3.9.4EV Substance CodeSUB32273
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10 to 40
    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) Information not present in EudraCT
    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.2.1.1.1Trade name Pegasys 135 microgram
    D.2.1.1.2Name of the Marketing Authorisation holderRoche
    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.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEGINTERFERON ALFA-2A
    D.3.9.1CAS number 198153-51-4
    D.3.9.4EV Substance CodeSUB16452MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number45
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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: 3
    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.2.1.1.1Trade name PegIntron 50 microgram
    D.2.1.1.2Name of the Marketing Authorisation holderMSD
    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.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.3Other descriptive namePEGINTERFERON ALFA-2B
    D.3.9.4EV Substance CodeSUB12549MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    E.1.1.1Medical condition in easily understood language
    Polycythemia vera

    Hyperproliferativ myelofibrosis
    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 18.1
    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 18.1
    E.1.2Level LLT
    E.1.2Classification code 10036061
    E.1.2Term Polycythemia vera
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10053134
    E.1.2Term Osteomyelofibrosis
    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
    Primary Objectives
    1. To describe the effect of combination therapy with IFN-alpha (Pegasys, PegIntron) and JAK1-2-inhibitor treatment (ruxolitinib) evaluated by hematological parameters (Hb, hematocrit, white blood cell count, platelet count, LDH, reduction in JAK2V617-mutation allele burden) and quality of life score, which indirectly will also reflect the remission of the IFN-alpha-induced side effects
    E.2.2Secondary objectives of the trial
    Secondary Objectives
    1. To investigate whether additional treatment with JAK1-2-inhibitor (ruxolitinib) to patients who show intolerance (due to adverse events) during treatment with interferon-alpha (IFN-alpha) (Pegasys, PegIntron) can improve the efficacy based on individual contribution of the two agents regarding that the JAK1-2 inhibitor through its very potent anti-inflammatory efficacy profile may dampen the impact of the systemic inflammatory response mediated by IFN-alpha.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    3.1 Inclusion Criteria
    1. Male or female patients> 18 years.
    2. Patients with early prefibrotic myelofibrosis /post-ET myelofibrosis , PV, Post-PV myelofibrosis or hyperproliferative PMF according to WHO classification.
    3. Active disease defined by one or more of the following criteria, at some time before study enrollment and accordingly not necessarily at the time or weeks before enrollment :
    a) Need for venesection (hematocrit> 0.42 in females and > 0.45 in males)
    b) White blood cell counts > 10 MIA/L in the absence of infection / inflammation.
    c) Platelet count> 400 MIA/L in the absence infection / inflammation.
    d) Hypermetabolic symptoms such as weight loss (> 10% within 6 months), night sweats and subfebrilia (temperature> 38 º C for more than 2 weeks without signs of infection)
    e) Pruritus
    f) Symptomatic splenomegaly
    g) Presence of previous thrombosis.

    E.4Principal exclusion criteria
    3.2 Exclusion Criteria
    1. Childbearing potential patients without a negative pregnancy test prior to initiation of study drug and / or non-acceptance of the use of effective contraceptive methods *
    2. Other active malignancy within the past 5 years (except basal cell carcinoma of the skin).
    3. ECOG function scores> / = 3
    4. Serum creatinine more than 2 x ULN
    5. Total serum bilirubin greater than 1.5 x ULN
    6. Plasma ALT more than 3 x ULN
    7. Former psychiatric disorder (depression diagnosed by a psychiatrist)
    8. Uncontrolled metabolic disease.
    9. Severe heart disease (heart failure NYHA class 3-4).
    10. Severe myelosuppression. (leucocyte count<1.5 Mill/L, Platelet count<100)
    11. Chronic hepatitis with decompensated cirrhosis.
    12. Chronic hepatitis in patients who have been or recently (within 6 months) has been treated with immunosuppressive drugs with the exception of corticosteroid treatment.
    13. Epilepsy and / or other serious CNS disorders.
    14. Known hypersensitivity to recombinant interferon (Pegasys or PegIntron) and JAKAVI, or to one or more of these preparations .
    * Spiral, birth control pills, implants, transdermal patch, vaginal ring or transdermal injection.
    Sterile / infertile subjects are exempt from the use of contraception. In order to be considered sterile or infertile, one must generally be surgically sterilized (vasectomy, bilateral tubectomy, hysterectomy or ovariectomy) or be postmenopausal, defined as absent menstruation for at least 12 months before study enrollment.
    E.5 End points
    E.5.1Primary end point(s)
    ENDPOINTS
    Objective Endpoint related to objective
    To describe the effect of combination therapy with IFN-alpha (Pegasys, PegIntron) and JAK1-2-inhibitor treatment (ruxolitinib) Change in hematological parameters (Hb, hematocrit, white blood cell count, platelet count, LDH, reduction in JAK2V617-mutation allele burden) and
    Change in quality of life score from baseline (MPN-SAF)

    To investigate whether additional treatment with JAK1-2-inhibitor (ruxolitinib) to patients who show intolerance (due to adverse events) during treatment with interferon-alpha (IFN-alpha) (Pegasys, PegIntron) can improve the efficacy based on individual contribution of the two agents regarding that the JAK1-2 inhibitor through its very potent anti-inflammatory effect profile may dampen the systemic inflammatory response mediated by IFN-alpha. Difference in number of IFN-related adverse events compared to matched group in the Dahlia study

    The compliance to the treatment, as measured by the number of patients who discontinue ruxolitinib/IFN for AE, and the safety of the treatment, as measured by the number and the type of SAE during Ruxolitinib/IFN alpha treatment.
    To investigate whether additional treatment with JAK1-2-inhibitor (ruxolitinib) to patients who exhibit lack of efficacy of treatment (IFN-alpha) (Pegasys, PegIntron) can establish / re-establish treatment response regarding that the JAK1-2 inhibitor through its very potent anti-inflammatory effect profile may reduce / eliminate the systemic inflammation response - mediated by IFN-alpha and MPN disease per se – and thereby potentially may facilitate the inhibition of clonal expansion (by down-regulation of inflammatory cytokines - TNF-alpha 2, IL-6 etc. - and perhaps through an enhancement of IFN-alpha's effects on the immune cells of interest for intact "Tumor Immune Surveillance "(for example, NK cells, dendritic cells, cytotoxic T cells, regulatory T cells)
    Number of patients with complete hematological response compared to matched group in DAHLIA study
    To investigate whether combination therapy with JAK1-2 inhibitor results in elimination of interferon antibodies (IFN-ab) and thus induction of efficacy in treatment refractory patients with evidence of antibody formation to recombinant interferon Level of interferon antibodies (IFN-ab) compared to baseline

    E.5.1.1Timepoint(s) of evaluation of this end point
    Study end (LPLV): February 2019
    E.5.2Secondary end point(s)
    ENDPOINTS
    Objective Endpoint related to objective
    To describe the effect of combination therapy with IFN-alpha (Pegasys, PegIntron) and JAK1-2-inhibitor treatment (ruxolitinib) Change in hematological parameters (Hb, hematocrit, white blood cell count, platelet count, LDH, reduction in JAK2V617-mutation allele burden) and
    Change in quality of life score from baseline (MPN-SAF)

    To investigate whether additional treatment with JAK1-2-inhibitor (ruxolitinib) to patients who show intolerance (due to adverse events) during treatment with interferon-alpha (IFN-alpha) (Pegasys, PegIntron) can improve the efficacy based on individual contribution of the two agents regarding that the JAK1-2 inhibitor through its very potent anti-inflammatory effect profile may dampen the systemic inflammatory response mediated by IFN-alpha. Difference in number of IFN-related adverse events compared to matched group in the Dahlia study

    The compliance to the treatment, as measured by the number of patients who discontinue ruxolitinib/IFN for AE, and the safety of the treatment, as measured by the number and the type of SAE during Ruxolitinib/IFN alpha treatment.
    To investigate whether additional treatment with JAK1-2-inhibitor (ruxolitinib) to patients who exhibit lack of efficacy of treatment (IFN-alpha) (Pegasys, PegIntron) can establish / re-establish treatment response regarding that the JAK1-2 inhibitor through its very potent anti-inflammatory effect profile may reduce / eliminate the systemic inflammation response - mediated by IFN-alpha and MPN disease per se – and thereby potentially may facilitate the inhibition of clonal expansion (by down-regulation of inflammatory cytokines - TNF-alpha 2, IL-6 etc. - and perhaps through an enhancement of IFN-alpha's effects on the immune cells of interest for intact "Tumor Immune Surveillance "(for example, NK cells, dendritic cells, cytotoxic T cells, regulatory T cells)
    Number of patients with complete hematological response compared to matched group in DAHLIA study
    To investigate whether combination therapy with JAK1-2 inhibitor results in elimination of interferon antibodies (IFN-ab) and thus induction of efficacy in treatment refractory patients with evidence of antibody formation to recombinant interferon Level of interferon antibodies (IFN-ab) compared to baseline

    E.5.2.1Timepoint(s) of evaluation of this end point
    Study end (LPLV): February 2019
    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 No
    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 No
    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 Yes
    E.8.1.7.1Other trial design description
    Single group non-randomized combination study
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    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 No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    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: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 state50
    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)
    None
    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 Decision2013-10-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-09-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-05-15
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