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    Summary
    EudraCT Number:2014-001394-13
    Sponsor's Protocol Code Number:C16021
    National Competent Authority:Croatia - MIZ
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-05-26
    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 ConcernedCroatia - MIZ
    A.2EudraCT number2014-001394-13
    A.3Full title of the trial
    A Phase 3, Randomized, Placebo-Controlled, Double-Blind Study of Oral Ixazomib
    Maintenance Therapy After Initial Therapy in Patients With Newly Diagnosed Multiple Myeloma Not Treated With Stem Cell Transplantation
    Treća faza randomiziranog, placebom kontroliranog, dvostruko slijepog ispitivanja održavanja liječenja iksazomibom za oralnu primjenu nakon početnog liječenja ispitanika s novodijagnosticiranim multiplim mijelomom neliječenim presađivanjem matičnih stanica
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to determine whether ixazomib as maintenance therapy has an effect on progression free survival and compared to placebo in patients with newly diagnosed multiple myeloma who have not been treated with stem-cell transplantation
    Ispitivanje sa svrhom utvrđivanja da li terapija održavanja iksazomibom ima učinka na preživljenje bez progresije bolesti u odnosu na primjenu placeba u bolesnika s novodijagnosticiranim multiplim mijelomom neliječenim presađivanjem matičnih stanica
    A.4.1Sponsor's protocol code numberC16021
    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 SponsorMillennium Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    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 supportMillennium Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMillennium Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointDrug Information Call Center
    B.5.3 Address:
    B.5.3.1Street Address40 Landsdowne Street
    B.5.3.2Town/ cityCambridge, MA
    B.5.3.3Post code02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number15107402412
    B.5.5Fax number18008816092
    B.5.6E-mailmedical@mlnm.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/3/11/899
    D.3 Description of the IMP
    D.3.1Product nameIxazomib Capsules 0.5 mg
    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 INNixazomib citrate
    D.3.9.1CAS number 1072833-77-2
    D.3.9.3Other descriptive nameIXAZOMIB
    D.3.9.4EV Substance CodeSUB121332
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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 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/3/11/899
    D.3 Description of the IMP
    D.3.1Product nameIxazomib Capsules 2.3 mg
    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 INNixazomib citrate
    D.3.9.1CAS number 1072833-77-2
    D.3.9.3Other descriptive nameIXAZOMIB
    D.3.9.4EV Substance CodeSUB121332
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.3
    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: 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 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/3/11/899
    D.3 Description of the IMP
    D.3.1Product nameIxazomib Capsules 3 mg
    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 INNixazomib citrate
    D.3.9.1CAS number 1072833-77-2
    D.3.9.3Other descriptive nameIXAZOMIB
    D.3.9.4EV Substance CodeSUB121332
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    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: 4
    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/3/11/899
    D.3 Description of the IMP
    D.3.1Product nameIxazomib Capsules 4 mg
    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 INNixazomib citrate
    D.3.9.1CAS number 1072833-77-2
    D.3.9.3Other descriptive nameIXAZOMIB
    D.3.9.4EV Substance CodeSUB121332
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 4
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Newly Diagnosed Multiple Myeloma Not Treated With Stem Cell Transplantation
    Novodijagnosticirani multipli mijelom neliječen presađivanjem matičnih stanica
    E.1.1.1Medical condition in easily understood language
    Cancer
    Rak
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10028228
    E.1.2Term Multiple myeloma
    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 determine the effect of ixazomib maintenance therapy on progression-free survival (PFS), defined as the time from randomization to progressive disease (PD) or death from any cause, compared with placebo, in patients with NDMM who have had a major response - defined as complete response (CR), very good partial response (VGPR), or partial response (PR) - to initial therapy and who have not undergone SCT
    Utvrditi učinak održavanja liječenja iksazomibom na preživljavanje bez pogoršanja bolesti, definirano kao vrijeme od randomizacije do pogoršanja bolesti ili smrti zbog bilo kojeg uzroka u usporedbi s placebom u ispitanika s novodijagnosticiranim multiplim mijelomom kod kojih je zabilježen snažan odgovorkoji se definira kao potpuni odgovor, vrlo dobar djelomičan odgovor ili djelomičan odgovor – na početno liječenje i kojima se nisu presađivale matične stanice.
    E.2.2Secondary objectives of the trial
    To determine the effect of ixazomib maintenance therapy on overall survival (OS) compared with placebo
    Utvrditi učinak održavanja liječenja iksazomibom na ukupno preživljavanje u usporedbi s placebom.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Adult male or female patients aged 18 years or older with a confirmed diagnosis of symptomatic NDMM according to standard criteria.
    2. Completed 6 to 12 months ( ±2 weeks) of initial therapy, during which the patient was treated to best response, defined as the best response maintained for 2 cycles after the M-protein nadir is reached.
    3. Documented major response (PR, VGPR, CR) according to the IMWG uniform response criteria, version 2011, after this initial therapy.
    4. Female patients who
    -Are postmenopausal for at least 1 year before the screening visit, OR
    -Are surgically sterile, OR
    - If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug, or
    - Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)
    Male patients, even if surgically sterilized (ie, status postvasectomy), who:
    -Agree to practice effective barrier contraception during the entire study
    Treatment period and through 90 days after the last dose of study drug, or
    -Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)
    5. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
    6. Complete documentation of the details of the initial therapy before randomization including cytogenetics and ISS is available.
    7. Eastern Cooperative Oncology Group Performance Status of 0 to 2
    8. Suitable venous access for the study-required blood sampling and consent for the specific amounts that will be taken.
    9. Patient is willing and able to adhere to the study visit schedule and other protocol requirements including blood sampling and bone marrow aspiration.
    10. Patients must meet the following clinical laboratory criteria at study entry:
    -Absolute neutrophil count (ANC) ≥1,000/mm3 without growth factor support and platelet count ≥ 75,000/mm3. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before randomization.
    -Total bilirubin ≤ 1.5 X the upper limit of the normal range (ULN).
    -Alanine aminotransferase and aspartate aminotransferase ≤ 3 X ULN.
    -Calculated creatinine clearance ≥ 30 mL/min (using the Cockroft-Gault equation
    1. Bolesnice i bolesnici stariji od 18 godina s potvrđenom dijagnozom novodijagnosticiranog multiplog mijeloma prema standardnim kriterijima (vidjeti poglavlje 15.1).
    2. Završenih 6 do 12 mjeseci ( 2 tjedna) početnog liječenja tijekom kojeg je bolesnik izliječen do najboljeg odgovora, definirano kao najbolji odgovor održan tijekom 2 ciklusa nakon dostizanja najniže razine M-proteina.
    3. Dokazani snažan odgovor (djelomičan odgovor, vrlo dobar djelomičan odgovor, potpuni odgovor) nakon tog početnog liječenja prema ujednačenim kriterijima odgovora Međunarodne radne skupine za mijelom, inačica iz 2011. godine.
    4. Bolesnice moraju:
    • biti u postmenopauzi najmanje 1 godinu prije posjeta za probir ili
    • biti kirurški sterilizirane ili
    • ako mogu zatrudnjeti, pristati istodobno koristiti 2 učinkovite metode kontracepcije od trenutka potpisivanja informiranog pristanka do 90. dana od zadnje doze ispitivanog lijeka ili
    • potpuno se suzdržavati od seksualnih odnosa, ako je to u skladu s njezinim odabranim i uobičajenim načinom života. (Povremena apstinencija [na primjer, kalendarska, ovulacijska, simptotermalna, postovulacijska metoda] i prekid snošaja nisu prihvatljive metode kontracepcije.).
    Bolesnici, čak i ako su kirurški sterilizirani (odnosno nakon vazektomije) moraju:
    • pristati koristiti učinkovitu barijernu metodu kontracepcije tijekom cijelog razdoblja ispitivanja i do 90. dana od primanja zadnje doze ispitivanog lijeka ili
    • pristati potpuno se suzdržavati od seksualnih odnosa, ako je to u skladu s njegovim odabranim i uobičajenim načinom života. (Povremena apstinencija [na primjer, kalendarska, ovulacijska, simptotermalna, postovulacijska metoda za partnericu] i prekid snošaja nisu prihvatljive metode kontracepcije.).
    5. Dobrovoljni pisani pristanak mora se dati prije provođenja bilo kojeg postupka povezanog s ispitivanjem koji nije dio redovne zdravstvene njege, uz razumijevanje da bolesnik u svakom trenutku može povući pristanak bez posljedica za buduću zdravstvenu skrb.
    6. Potpuna dokumentacija o pojedinostima početnog liječenja prije randomizacije, uključujući citogenetiku i međunarodni sustav stupnjevanja, mora biti dostupna.
    7. Opće stanje zdravlja prema ljestvici ECOG između 0 i 2 (vidjeti poglavlje 15.2).
    8. Pogodan pristup venama za uzimanje uzoraka krvi potrebnih za ispitivanje i pristanak na uzimanje potrebnih količina krvi.
    9. Bolesnik mora biti voljan i sposoban pridržavati se rasporeda posjeta iz ispitivanja i drugih zahtjeva iz plana ispitivanja, uključujući prikupljanje uzoraka krvi i aspiraciju koštane srži.
    10. U trenutku uključivanja u ispitivanje bolesnici moraju ispunjavati sljedeće kliničke laboratorijske kriterije:
    • apsolutni broj neutrofila  1.000/mm3 bez potpore faktorom rasta i broj trombocita  75.000/mm3. Transfuzija trombocita da bi se bolesnicima pomoglo u ispunjavanju kriterija podobnosti nije dopuštena tijekom 3 dana prije randomizacije;
    • ukupni bilirubin  1,5  gornja granica normale;
    • alanin aminotransferaza i aspartat aminotransferaza  3  gornja granica normale;
    • izračunati klirens kreatinina  30 ml/min (koristeći Cockroft-Gaultovu jednadžbu [poglavlje 15.3]).
    E.4Principal exclusion criteria
    1. Multiple myeloma that has relapsed after, or was not responsive to, initial therapy.
    2. Prior SCT.
    3. Radiotherapy within 14 days before randomization.
    4. Diagnosed or treated for another malignancy within 5 years before randomization or previous diagnosis with another malignancy. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
    5. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period.
    6. Major surgery within 14 days before randomization.
    7. Central nervous system involvement.
    8. Infection requiring IV antibiotic therapy or other serious infection within 14 days before randomization.
    9. Diagnosis of Waldenstrom’s macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome.
    10. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, uncontrolled congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
    11. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole), or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital) or use of St. John’s wort within 14 days before randomization.
    12. Ongoing or active infection, known human immunodeficiency virus positive, active hepatitis B or C infection
    13. Comorbid systemic illnesses or other severe concurrent disease that, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens (eg, PN that is Grade 1 with pain or Grade 2 or higher of any cause).
    14. Psychiatric illness/social situation that would limit compliance with study requirements.
    15. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
    16. Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or GI procedure that could interfere with the oral absorption or tolerance of treatment.
    17. Treatment with any investigational products within 30 days before randomization.
    1. Multipli mijelom koji je relapsirao nakon početnog liječenja ili na njega nije odgovarao.
    2. Prethodno presađivanje matičnih stanica.
    3. Zračenje u 14 dana prije randomizacije.
    4. Dijagnoza ili liječenje druge maligne bolesti u 5 godina prije randomizacije ili prethodna dijagnoza druge maligne bolesti. Bolesnici s nemelanomskim karcinomom kože ili karcinomom in situ bilo koje vrste mogu se uključiti ako im je napravljena potpuna resekcija.
    5. Bolesnice u laktaciji koje doje ili imaju pozitivan serumski test na trudnoću u razdoblju probira.
    6. Veća operacija u 14 dana prije randomizacije.
    7. Uključenost središnjeg živčanog sustava.
    8. Infekcija koju je potrebno liječiti intravenoznim antibioticima ili druga ozbiljna infekcija u 14 dana prije randomizacije.
    9. Dijagnoza Waldenstromove makroglobulinemje, sindroma POEMS (polineuropatija, organomegalija, endokrinopatija, monoklonska gamapatija i promjene na koži), leukemije plazma stanica, primarne amiloidoze, mijelodisplastičnog sindroma ili mijeloproliferativnog sindroma.
    10. Dokazi trenutačnog nekontroliranog kardiovaskularnog poremećaja, uključujući nekontroliranu hipertenziju, nekontrolirane srčane aritmije, nekontrolirano kongestivno zatajenje srca, nestabilnu anginu ili infarkt miokarda u prethodnih 6 mjeseci.
    11. Sistemsko liječenje jakim inhibitorima CYP1A2 (fluvoksamin, enoksacin, ciprofloksacin), jakim inhibitorima CYP3A (claritromicin, telitromicin, itrakonazol, vorikonazol, ketokonazol, nefazodon, pozakonazol) ili jakim induktorima CYP3A (rifampin, rifapentin, rifabutin, karbamazepin, fenitoin, fenobarbital) ili korištenje pripravaka od biljke ginkgo biloba ili gospine trave u 14 dana prije randomizacije.
    12. Tekuća ili aktivna infekcija, HIV-pozitivnost, aktivna infekcija hepatitisom B ili C.
    13. Istodobna sistemska bolest ili druga ozbiljna popratna bolesti koja prema mišljenju ispitivača čini bolesnika nepodobnim za uključivanje u ispitivanje ili bi znatno utjecala na pravilnu procjenu sigurnosti i toksičnosti propisanih načina liječenja (na primjer, periferna neuropatija stupnja 1 s bolovima ili stupnja 2 ili višega s bilo kojim uzrokom).
    14. Duševna bolest ili socijalno stanje koje bi ograničavalo usklađivanje sa zahtjevima ispitivanja.
    15. Poznata alergija na bilo koji od ispitivanih lijekova, njihovih analognih lijekova ili pomoćnih tvari u raznim formulacijama bilo kojeg ljekovitog sastojka.
    16. Nemogućnost gutanja oralnih lijekova, nemogućnosti ili nevoljnost za usklađivanje sa zahtjevima davanja lijeka ili gastrointestinalni postupak koji bi utjecao na apsorpciju oralnog lijeka ili podnošenje liječenja.
    17. Liječenje bilo kojim ispitivanim proizvodom u 30 dana prije randomizacije.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival, defined as the time from randomization to the first occurrence of PD, as evaluated by an independent review committee (IRC), or death from any cause, whichever occurs first

    Preživljenje bez progresije bolesti definirano kao vrijeme od randomizacije to prve pojave progresije, a evaluirano od strane Nezavisnog odbora ili do smrti neovisno od uzroka, što god nastupi prije
    E.5.1.1Timepoint(s) of evaluation of this end point
    first occurrence of PD
    Prva pojava progresije bolesti
    E.5.2Secondary end point(s)
    Overall survival, measured as the time of randomization to the date of death
    Ukupno preživljenje, od rdana randomizacije do dana smrti
    E.5.2.1Timepoint(s) of evaluation of this end point
    date of death
    Datum smrti
    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 Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) No
    E.8.2.2Placebo Yes
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA92
    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
    Argentina
    Australia
    Austria
    Belgium
    Brazil
    Canada
    Chile
    China
    Colombia
    Croatia
    Czech Republic
    Denmark
    France
    Germany
    Greece
    Hungary
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    Poland
    Portugal
    Russian Federation
    Serbia
    Singapore
    South Africa
    Spain
    Sweden
    Switzerland
    Taiwan
    Thailand
    Turkey
    United Kingdom
    United States
    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
    Zadnji posjet ispitanika koji je posljednji bio uključen u ispitivanje
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months7
    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: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 711
    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 state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 500
    F.4.2.2In the whole clinical trial 761
    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)
    After participation in the trial, if applicable, patients will be treated with the current standard therapy.
    Nakon završetka sudjelovanja u ispitivanju, bolesnici će biti liječeni standardnom terapijom
    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 Decision2015-05-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-04-30
    P. End of Trial
    P.End of Trial StatusOngoing
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