E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Newly Diagnosed Multiple Myeloma Not Treated With Stem Cell Transplantation |
Novodijagnosticirani multipli mijelom neliječen presađivanjem matičnih stanica |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main 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 odgovorkoji se definira kao potpuni odgovor, vrlo dobar djelomičan odgovor ili djelomičan odgovor – na početno liječenje i kojima se nisu presađivale matične stanice. |
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E.2.2 | Secondary 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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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]).
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E.4 | Principal 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.
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E.5 End points |
E.5.1 | Primary 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
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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 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
first occurrence of PD |
Prva pojava progresije bolesti |
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E.5.2 | Secondary end point(s) |
Overall survival, measured as the time of randomization to the date of death |
Ukupno preživljenje, od rdana randomizacije do dana smrti |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
date of death |
Datum smrti |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 92 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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 |
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E.8.7 | Trial 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
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LVLS |
Zadnji posjet ispitanika koji je posljednji bio uključen u ispitivanje |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |