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    Summary
    EudraCT Number:2012-005259-18
    Sponsor's Protocol Code Number:PROUD-PV
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-06-27
    Trial results View 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 ConcernedCzechia - SUKL
    A.2EudraCT number2012-005259-18
    A.3Full title of the trial
    A randomized, open-label, multicenter, controlled, parallel arm, phase III study assessing the efficacy and safety of AOP2014 vs. Hydroxyurea in patients with Polycythemia Vera
    Otevřená multicentrická randomizovaná kontrolovaná studie fáze 3 s paralelními rameny hodnotící účinnost a bezpečnost AOP2014 ve srovnání s hydroxyureou u pacientů s polycytemií vera
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A randomized, open-label, multicenter, controlled, parallel arm, phase III
    study assessing the efficacy and safety of AOP2014 vs. Hydroxyurea in
    patients with Polycythemia Vera
    A.3.2Name or abbreviated title of the trial where available
    PROUD-PV
    A.4.1Sponsor's protocol code numberPROUD-PV
    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 SponsorAOP Orphan Pharmaceuticals AG
    B.1.3.4CountryAustria
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAOP Orphan Pharmaceuticals AG
    B.4.2CountryAustria
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAOP Orphan Pharmaceuticals AG
    B.5.2Functional name of contact pointmichael.zoerer@aoporphan.com
    B.5.3 Address:
    B.5.3.1Street AddressWilhelminenstrasse 91/IIf
    B.5.3.2Town/ cityVienna
    B.5.3.3Post code1160
    B.5.3.4CountryAustria
    B.5.4Telephone number43015037224446
    B.5.5Fax number4301503724465
    B.5.6E-mailmichael.zoerer@aoporphan.com
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/11/932
    D.3 Description of the IMP
    D.3.1Product namePegylated proline-interferon alpha-2b
    D.3.2Product code AOP2014
    D.3.4Pharmaceutical form Solution for injection
    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 INNPEGylated Proline-interferone alpha-2b recombinant
    D.3.9.1CAS number 1335098-50-4
    D.3.9.2Current sponsor codePEG-P-INFa-2b; P1101
    D.3.9.3Other descriptive namePEGINTERFERON ALFA-2B
    D.3.9.4EV Substance CodeSUB12549MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    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: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Hydrea
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb AB
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    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 Capsule, hard
    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 INNHYDROXYCARBAMIDE
    D.3.9.1CAS number 127-07-1
    D.3.9.4EV Substance CodeSUB08076MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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
    Polycythemia Vera
    Polycytemie vera
    E.1.1.1Medical condition in easily understood language
    Polycythemia Vera, a myeloproliferative disease of blood forming cells
    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 17.1
    E.1.2Level LLT
    E.1.2Classification code 10036061
    E.1.2Term Polycythemia vera
    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
    To compare the efficacy of AOP2014 vs. HU in terms of disease response rate in both HU naïve and currently treated patients, diagnosed with Polycythemia Vera.
    E.2.2Secondary objectives of the trial
    To further assess efficacy in the two treatment arms, safety, QoL and change of JAK-2 allelic burden
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Optional bone marrow samplings (one at screening prior the first study drug dose, and another one after completion of the 12 month period) taken and sent for central evaluation will be setup within the PROUD-PV study. Patients may decline participation in the bone marrow sub study, while remaining on the main study protocol
    E.3Principal inclusion criteria
    1. 18 years or older

    2. Diagnosis of Polycythemia Vera according to the WHO 2008 criteria with the mandatory presence of JAK2V617F mutation as the major disease criterion.
    3. For previously cytoreduction untreated patients – documented need of cytoreductive treatment (any of the following criteria):
    -age >60 years at the planned day of the first drug administration
    -at least one previous well documented major cardiovascular PV-related event (see appendix 6 for definitions), except bleeding and PV-related thromboembolic complications in the abdominal area, see excl. criterion 7) in the medical history
    -poor tolerance (defined as a phlebotomy/ procedure-related adverse event causing significant adverse impact on the patient and limiting ability to apply phlebotomy with the intention to keep Hct <45%) or frequent need of phlebotomy (more than one phlebotomy within last three months prior entering the study, while each of these phlebotomies was performed to reduce Hct level from >45%, or if one phlebotomy was not able to reduce Hct level to <45% for the next three months following phlebotomy)
    -progressive splenomegaly (de novo appearance of a palpable spleen, or appearance of the symptoms, related to the enlarged spleen, e.g. pain, early satiety etc., with confirmed size increase)
    -platelet counts greater than 1000 x 109/L (for two measurements within one week)
    -leukocytosis (WBC>10 x 109/L for two measurements within one week)
    4. For patients currently treated or pre-treated with HU, all of the following criteria:
    -being non responders (as defined by the response criteria for primary endpoint in this protocol)
    -total HU treatment duration shorter than three years
    -no documented resistance or intolerance as defined by modified Barosi et al, 2009 criteria
    5. Hospital Anxiety and Depression Scale (HADS) score 0-7 on both subscales
    6. Patients with a HADS score of 8-10 inclusive on either or both of the subscales may be eligible following psychiatric assessment
    7. Signed written informed consent
    E.4Principal exclusion criteria
    1.Any systemic cytoreduction for PVin the medical history prior to study entry with the exception of HU for shorter than 3 years (see respective inclusion criterion)
    2.Any contraindication to any of the IMPs (pegylated interferon or hydroxyurea) or their excipients
    3.Any systemic exposure to a non-pegylated or pegylated interferon alpha in the medical history
    4.Documented autoimmune disease at screening or in the medical history
    5.Clinically relevant pulmonary infiltrates, pneumonia, and pneumonitis at screening
    6. Infections with systemic manifistation, e.g. hepatitis B, hepatitis C, or HIV at screening
    7.Known, PV-related thromboembolic complications in the abdominal area (e.g. portal vein thrombosis, Budd-chiari syndrome)
    8.Any investigational drug less than 6 weeks prior to the first dose of study drug or not recovered from effects of prior administration of any investigational agent
    9.History or presence of depression requiring treatment with antidepressant
    10.HADS score equal to or above 11 on either or both of the subscales
    11.Any risk of suicide at screening or previous suicide attempts
    12.Any significant morbidity or abnormality which may interfere with the study participation
    13.Pregnancy and breast-feeding females of reproductive potential and males not using effective means of contraceptionNote: women of childbearing potential not using effective contraceptive methods are not eligible for the study. A woman of childbearing potential is defined as any female who has experienced menarche and who is not postmenopausal or permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy) (according to MHRA guidance, see references).
    14.History of active substance or alcohol abuse within the last year
    15.Evidence of severe retinopathy (e.g. cytomegalovirus retinitis, macular degeneration) or clinically relevant ophthalmological disorder (due to diabetes mellitus or hypertension)
    16.Thyroid dysfunction(clinical symptoms of thyroid hyper- or hypofunction) not adequately controlled
    17.Patients tested positively with TgAb (autoantibodies to thyroglobulin) and / or TPOAb (autoantibodies to thyroid peroxidase) at screening
    18.History of major organ transplantation
    19.History of uncontrolled severe seizure disorder
    20.Leukocytopenia at the time of screening
    21.Thrombocytopenia at the time of screening
    22.History of malignant disease, including solid tumours and hematological malignancies (except basal cell and squamous cell carcinomas of the skin and carcinoma in situ of the cervix that have been completely excised and are considered cured) within the last 3 years
    E.5 End points
    E.5.1Primary end point(s)
    • Primary efficacy endpoint:
    - Disease response rate at 12 months defined as hematocrit <45% without phlebotomy (at least 3 months since last phlebotomy), platelets 400 x109/l , leukocytes 10x 109 /L (all three lab parameters measured by blinded central lab), and normal spleen size (by imaging, central, blinded assessment)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Month 12
    E.5.2Secondary end point(s)
    • Secondary efficacy endpoints
    - Disease response rate at 6 months, based on hematological parameters only, defined as hematocrit <45% without phlebotomy (at least 3 months since last phlebotomy), platelets <400 x109/L, leukocytes <10 x109/L (all three lab parameters measured by blinded central lab) for the formal interim analysis,
    - Disease response rate at 6 months, defined as hematocrit <45% without phlebotomy (at least 3 months since last phlebotomy), platelets <400 x109/L, leukocytes <10 x 109/L (all three lab parameters measured by blinded central lab), and normal spleen size (by imaging, local ultrasonography measurement).
    - Disease response rates at months 3 and 9 months (spleen size measurements and hematological parameters coming from local measurements)
    - Time to first disease response
    - Disease response duration
    - Number of phlebotomies performed (per protocol, a phlebotomy has to be performed any time the patient’s hematocrit is higher than 45%)
    - Hematocrit change from baseline to last patient visit
    - Leukocytes change from baseline to last patient visit
    - Platelets change from baseline to last patient visit
    - Erythrocytes change from baseline to last patient visit
    - Spleen size from baseline to last patient visit
    - Disease-related symptoms (microvascular disturbances, pruritus, headache)
    -
    • Safety evaluation
    - Incidence, causality and intensity of adverse events according to common terminology criteria for adverse events (CTCAE 4.0)
    - Events leading to dose reduction or permanent treatment discontinuation. Adverse events of special interest (see section 7.3.9)
    • Quality of Life (EQ-5D)
    • Change of JAK-2 allelic burden over time
    E.5.2.1Timepoint(s) of evaluation of this end point
    Months 3,6,9
    and change over time as well as time to response
    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 Yes
    E.6.4Safety Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA38
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Bulgaria
    Czech Republic
    France
    Germany
    Hungary
    Italy
    Poland
    Romania
    Russian Federation
    Slovakia
    Spain
    Ukraine
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial 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: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 140
    F.4.2.2In the whole clinical trial 256
    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)
    The patients having benefit from AOP2014 treatment at the end of the 12 months core phase of the study will enter the long term extension study to collect additional relevant efficacy and safety data.
    Patients who had received Hydroxyurea will complete the study after 12 months treatment.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4 Investigator Network to be involved in the Trial: 2
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-08-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-07-24
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-04-08
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