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    Summary
    EudraCT Number:2016-001205-16
    Sponsor's Protocol Code Number:54767414SMM3001
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-15
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2016-001205-16
    A.3Full title of the trial
    A Phase 3 Randomized, Multicenter Study of Subcutaneous Daratumumab Versus Active Monitoring in Subjects with High-risk Smoldering Multiple Myeloma
    Uno studio multicentrico randomizzato di fase III che mette a confronto daratumumab per via sottocutanea rispetto al monitoraggio attivo in soggetti con mieloma multiplo smoldering ad alto rischio
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to compare the safety, effectiveness and pharmacokinetics (the way the body absorbs, distributes, and gets rid of a drug) of Daratumumab given through the subcutaneous route versus the active monitoring in patients with high risk smoldering multiple myeloma (precancerous form of blood cancer in the bone marrow)
    Uno studio clinico per confrontare la sicurezza, l'efficacia e la farmacocinetica (il modo in cui il corpo assorbe, distribuisce e elimina un farmaco) di Daratumumab somministrato per via sottocutanea rispetto al monitoraggio attivo nei pazienti con mieloma multiplo smoldering ad alto rischio (forma precancerosa di tumore del sangue nel midollo osseo
    A.3.2Name or abbreviated title of the trial where available
    A clinical study to compare the safety, effectiveness and pharmacokinetics (the way the body absorbs
    Uno studio clinico per confrontare la sicurezza, l'efficacia e la farmacocinetica (il modo in cui il
    A.4.1Sponsor's protocol code number54767414SMM3001
    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 SponsorJANSSEN CILAG INTERNATIONAL NV
    B.1.3.4CountryBelgium
    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 supportJanssen Research & Development, LLC
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportJanssen-Cilag International N.V.
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportJANSSEN CILAG SPA
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJanssen-Cilag International N.V.
    B.5.2Functional name of contact pointClinical Registry group
    B.5.3 Address:
    B.5.3.1Street AddressArchimedesweg 29
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31715242166
    B.5.5Fax number+31715242110
    B.5.6E-mailClinicalTrialsEU@its.jnj.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/3/13/1153
    D.3 Description of the IMP
    D.3.1Product nameDaratumumab co-formulated with recombinant human hyaluronidase (rHuPH20)
    D.3.2Product code [JnJ 54767414]
    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.3.9.1CAS number 945721-28-8
    D.3.9.2Current sponsor codeJnJ 54767414
    D.3.9.4EV Substance CodeSUB175772
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number120
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    Smoldering multiple myeloma
    Smoldering Mieloma multiplo
    E.1.1.1Medical condition in easily understood language
    Precancerous form of blood cancer in the bone marrow
    Forma pre-cancerosa del tumore del sangue nel midollo osseo
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    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
    The main objective of this study is to determine whether treatment with daratumumab administered subcutaneously (SC) prolongs progression-free survival (PFS) compared with active monitoring in subjects with high-risk smoldering multiple myeloma (SMM).
    L'obiettivo primario dello studio è stabilire se il trattamento con daratumumab somministrato per via sottocutanea (SC) prolunghi la sopravvivenza libera da progressione (PFS) rispetto al monitoraggio attivo in soggetti con mieloma multiplo smoldering (SMM) ad alto rischio
    E.2.2Secondary objectives of the trial
    -To demonstrate additional clinical benefit (ORR, duration of response, OS, etc) for subjects with high-risk SMM treated with daratumumab compared with active monitoring
    - To assess the safety profile of daratumumab in subjects with high-risk SMM
    - To assess the clinical characteristics of symptomatic MM following progression of disease after therapy with daratumumab
    - To evaluate the PK and immunogenicity of daratumumab administered SC in subjects with high-risk SMM
    - To evaluate the immunogenicity of rHuPH20 when administered in combination with daratumumab SC in subjects with high-risk SMM
    - To evaluate the effect of treatment with daratumumab on health-related quality of life (HRQoL)
    -Dimostrare il beneficio clinico aggiuntivo (tasso di risposta globale, durata della risposta, sopravvivenza globale, ecc.) per i soggetti con SMM ad alto rischio trattati con daratumumab rispetto al monitoraggio attivo
    -Valutare il profilo di sicurezza di daratumumab in soggetti con SMM ad alto rischio
    -Valutare le caratteristiche cliniche del mieloma multiplo (MM) sintomatico a seguito della progressione della malattia dopo la terapia con daratumumab
    -Valutare la farmacocinetica e l'immunogenicità di daratumumab somministrato per via SC in soggetti con SMM ad alto rischio
    -Valutare l'immunogenicità della ialuronidasi umana ricombinante (rHuPH20) somministrata in associazione a daratumumab SC in soggetti con SMM ad alto rischio
    -Valutare l'effetto del trattamento con daratumumab sulla qualità di vita (HRQoL)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Refer to protocol
    Each potential subject must satisfy all of the following criteria to be enrolled in the study:
    1. At least 18 years of age or at least the legal age of consent in the jurisdiction in which the study is taking place, whichever is the older age.
    2. Diagnosis of SMM for <= 5 years with measurable disease, defined as serum M protein >=10 grams per litre (g/L) or urine M protein >= 200 milligrams (mg)/24 hours or involved serum free light chain (FLC) >= 100 milligrams per litre (mg/L) and abnormal serum FLC ratio.
    3. Bone marrow plasma cells (BMPCs) >=10%; and
    At least 1 of the following;
    a.Serum M protein >=30 g/L,
    b.Immunoglobulin A (IgA) SMM,
    c.Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes,
    d.Serum involved: uninvolved FLC ratio >= 8 and < 100, or
    e.Clonal BMPCs >50% to <60% with measurable disease.
    4.Eastern cooperative oncology group (ECOG) performance status score of 0 or 1.
    5.Pretreatment clinical laboratory values: refer to protocol
    6.Must sign an informed consent form (ICF) or their legally acceptable representative must sign indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
    7.Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies. Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 1 method highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants], or partner's vasectomy). Contraception must begin 4 weeks prior to dosing. Highly effective contraception is indicated even where there has been a history of infertility, unless due to hysterectomy.
    8.A woman of childbearing potential must have a negative serum or urine pregnancy test at screening within 14 days prior to randomization.
    9.During the study and for 3 months after receiving the last dose of daratumumab, a woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
    10.Willing and able to adhere to the prohibitions and restrictions specified in the protocol.
    1.Età di almeno 18 anni oppure almeno maggiore età legale secondo la giurisdizione del paese in cui si svolge lo studio, a seconda dell'età più elevata.
    2.Diagnosi di SMM da <= 5 anni con malattia misurabile, definita come proteina M nel siero >=10 g/L o proteina M nell'urina >= 200 mg/24 ore oppure involved FLC nel siero >=100 mg/L e anomalia del rapporto FLC sierico.
    3.BMPC >=10%; e
    Almeno una delle seguenti condizioni:
    a.Proteina M nel siero >= 30 g/L,
    b.IgA SMM,
    c.Immunoparesi con riduzione di 2 isotipi di immunoglobulina non coinvolti,
    d.Coinvolgimento sierico: rapporto uninvolved FLC >= 8 e <100, oppure
    e.BMPC clonali da >50% a <60% con malattia misurabile.
    4.Punteggio del performance status ECOG pari a 0 o 1.
    5.I valori pre-trattamento degli esami clinici di laboratorio devono soddisfare i criteri riferiti nel protocollo
    6.I soggetti o i relativi rappresentanti legali autorizzati devono firmare un modulo di consenso informato (ICF) in cui indicano di aver compreso lo scopo dello studio e le relative procedure e di essere intenzionati a prendervi parte.
    7.Sia per gli uomini che per le donne, l'uso dei metodi contraccettivi deve avvenire in conformità alle regolamentazioni locali esistenti in materia per i soggetti che partecipano a studi clinici.
    Le donne potenzialmente fertili devono impegnarsi ad astenersi continuativamente dai rapporti sessuali o a utilizzare un metodo contraccettivo altamente efficace (legatura delle tube, dispositivo intrauterino, contraccettivo ormonale [pillola anticoncezionale, iniezioni, cerotti ormonali, anelli vaginali o impianti] o vasectomia del partner). La contraccezione deve iniziare 4 settimane prima della somministrazione. Una contraccezione altamente efficace è indicata anche in presenza di una storia di infertilità, tranne se dovuta a isterectomia.
    8.Le donne potenzialmente fertili devono avere il test di gravidanza sul siero o sulle urine con risultato negativo allo screening entro i 14 giorni precedenti alla randomizzazione.
    9.Durante lo studio e per i 3 mesi successivi all'ultima dose di daratumumab, le donne devono acconsentire a non donare ovuli (ovociti) a scopo di riproduzione assistita.
    10.Volontà e capacità di rispettare i divieti e le restrizioni specificati in questo protocollo.
    E.4Principal exclusion criteria
    1. Multiple myeloma, requiring treatment, defined by any of the following:
    a. Bone lesions (one or more osteolytic lesions on low-dose whole body computed tomography [LDCT], positron-emission tomography with computed tomography [PET-CT] or computed tomography [CT])
    b. Hypercalcemia (serum calcium >0.25 mmol/L [>1 mg/dL] higher than ULN or >2.75 mmol/L [>11 mg/dL])
    c. Renal insufficiency, preferably determined by creatinine clearance <40 mL/min measured or estimated using the modification of diet in renal disease (MDRD), or serum creatinine >177 micro mole per litre (µmol/L)
    d. Anemia, defined as hemoglobin <10 gram per deci litre (g/dL) or >=2 g/dL below lower limit of normal or both; transfusion support or concurrent treatment with erythropoietin stimulating agents is not permitted
    e. Clonal BMPC percentage >=60%
    f. Serum FLC ratio (involved:uninvolved) >=100 (The involved FLC must be >=100 mg/L)
    g. More than 1 focal lesion >=5 mm in diameter by magnetic resonance imaging (MRI)
    2. Primary systemic (immunoglobulin light chain) amyloidosis (AL)
    3. Exposure to any of the following:
    a. Prior exposure to daratumumab or prior exposure to other anti-CD38 therapies
    b. Prior exposure to approved or investigational treatments for SMM or
    MM (including but not limited to conventional chemotherapies, immunomodulatory agent [IMiDs], or proteasome inhibitor [PIs]). Stable standard dosing of bisphosphonate as indicated for osteoporosis is acceptable.
    c. Exposure to investigational drug (including investigational vaccines) or invasive investigational medical device for any indication within 4 weeks or 5 half-lives, whichever is longer, before Cycle 1, Day 1
    d. Ongoing treatment with corticosteroids with a dose >10 mg prednisone or equivalent per day at the time of randomization; or >280 mg cumulative prednisone dose or equivalent for any 4-week period in the year prior to randomization
    4. Received treatment for a malignancy (other than SMM) within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion, which is considered cured with minimal risk of recurrence within 3 years.
    5. Either of the following:
    a. Known or suspected chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal
    b. Moderate or severe persistent asthma within the past 2 years or currently has uncontrolled asthma of any classification (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study)
    6. Any of the following:
    a. Known to be seropositive for human immunodeficiency virus (HIV)
    b. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Local testing and results of hepatitis B serology (Includes HBsAg, anti-HBs, and anti-HBc) is required for all patients prior to randomization when this amendment 3 is implemented. Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [Anti-HBc] and/or antibodies to hepatitis B surface antigen [Anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (Anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR
    c. Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy)
    Please see the protocol for a complete list of the exclusion criteria
    1.Mieloma multiplo che richieda un trattamento, definito da uno qualsiasi dei seguenti elementi:
    a.Lesioni ossee (una o più lesioni osteolitiche emerse LDCT, alla PET-TC o alla TC).
    b.Ipercalcemia (calcio nel siero >0,25 mmol/L [> 1 mg/dL] superiore a ULN o >2,75 mmol/L [>11 mg/dL])
    c.Insufficienza renale, preferibilmente determinata da clearance della creatinina <40 mL/min misurata o stimata mediante (MDRD), oppure creatinina sierica >177 µmol/L.
    d.Anemia, definita come emoglobina <10 g/dL o >=2 g/dL sotto il limite inferiore della norma o entrambe; non è consentito il supporto trasfusionale o il trattamento concomitante con agenti stimolanti dell'eritropoietina.
    e.Percentuale di BMPC clonali >=60%.
    f.Rapporto FLC sierico (involved:uninvolved) >=100 (la FLC coinvolta deve essere >=100 mg/L).
    g.Più di 1 lesione focale con diametro >=5 mm misurata con risonanza magnetica.
    2.Amiloidosi sistemica primaria AL (catena leggera dell'immunoglobulina).
    3.Esposizione a una delle seguenti terapie:
    a.Precedente esposizione a daratumumab o precedente esposizione ad altre terapie anti-CD38.
    b.Precedente esposizione a terapie approvate o sperimentali per l'SMM o l'MM (compresi, a titolo esemplificativo, chemioterapie convenzionali, IMiD e PI). La somministrazione di bisfosfonato al dosaggio standard stabile indicato per l'osteoporosi è accettabile.
    c.Esposizione a un farmaco sperimentale (inclusi i vaccini sperimentali) o a un dispositivo medico sperimentale invasivo per qualsiasi indicazione entro le 4 settimane o le 5 emivite precedenti al Giorno1 del C1, a seconda del periodo più lungo.
    d.Trattamento in corso con corticosteroidi con dose >10 mg di prednisone o equivalente al giorno al momento della randomizzazione oppure dose cumulativa di prednisone >280 mg o equivalente per un qualsiasi periodo di 4 settimane avvenuto nell'anno precedente alla randomizzazione.
    4.Trattamento per una neoplasia maligna (diversa dall'SMM) entro i 3 anni precedenti alla data di randomizzazione (fanno eccez. i carcinomi a cellule squamose e basali della pelle, il carcinoma in situ della cervice o della mammella e altre lesioni non invasive) considerate curate con minimo rischio di recidiva entro 3 anni).
    Una delle seguenti patologie:
    a.Broncopneumopatia cronica ostruttiva (BPCO) nota o presunta con volume espiratorio forzato in 1 secondo (FEV1) <50% del valore normale previsto.
    b.Asma persistente moderato o grave negli ultimi due anni o attuale asma non controllato di qualsiasi classificazione (i soggetti che soffrono attualmente di asma intermittente controllato o asma persistente lieve controllato sono ammessi allo studio).
    Una delle seguenti condizioni:
    a.sieropositività nota al virus HIV
    b.Sieropositività al virus dell'epatite B (definita da un test positivo per l'antigene di superficie dell'epatite B [HBsAg]). Gli esami locali e i risultati della sierologia dell’epatite B (compresi HBsAg, anti-HBs e anti-HBc) sono richiesti per tutti i pazienti prima della randomizzazione una volta che viene implementato l’Eme. 3. Soggetti con infezione risolta (ovvero soggetti negati all’antigene di superficie dell’epatite B [HBsAg] ma positivi agli anticorpi contro l'antigene core dell'epatite B [anti-HBc] e/o anticorpi contro l'antigene di superficie dell'epatite B [anti-Hbs]) devono essere sottoposti a screening utilizzando la reazione a catena della polimerasi real-time (PCR) dei livelli di DNA del virus dell'epatite B (HBV). Coloro che sono positivi alla PCR saranno esclusi. ECCEZIONE:Soggetti con risultati sierologici indicativi di vaccinazione anti-HBV (positività anti-Hbs come unico marcatore sierologico) E una storia nota di vaccinazione anti-HBV precedente, non devono essere testati per DNA dell'HBV mediante PCR.
    c.sieropositività nota al virus dell'epatite C(tranne in presenza di SVR, definita come aviremia almeno 12 sett dopo il completamento della terapia antivirale)
    v. protocollo per lista completa
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (PFS), defined as the time from the date of randomization to the date of initial documented progression to MM according to the international myeloma working group (IMWG) diagnostic criteria for MM or the date of death, whichever occurs first
    Sopravvivenza libera da progressione, definita come l’intervallo di tempo tra la data di randomizzazione e la data della prima progressione documentata a mieloma multiplo secondo i criteri diagnostici international Working Group (IMWG) per il MM o la data di morte, secondo quanto si verifica per primo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every 12 weeks until progressive disease
    Ogni 12 settimane fino a progressione di malattia
    E.5.2Secondary end point(s)
    1. Time to biochemical or diagnostic (SLiM-CRAB) progression defined as the earlier of time to the earlier of biochemical progression or diagnostic (SLiM-CRAB) progression 2. Overall response rate (ORR), defined as, the proportion of subjects with a PR or better as defined by the IMWG response criteria 3. Complete response (CR) rate, defined as, the proportion of subjects with a CR (or better) as defined by the IMWG response criteria 4. Time to first-line treatment for MM, defined as, the time from the date of randomization to the date of the first-line treatment for MM 5. Progression-free survival on first-line treatment for MM (PFS2), defined as, the time from the date of randomization to the date of documented progressive disease (PD) on the first-line treatment for MM or death, whichever comes first 6. Overall survival (OS), defined as, the time from the date of randomization to the date of death 7. Incidence of MM with adverse prognostic features, which include International Staging System Stage III (based on beta 2-microglobulin and albumin) and adverse cytogenetic characteristics 8. Serum daratumumab PK concentrations and parameters including minimum observed concentration (Cmin) and maximum observed concentration (Cmax) 9. Incidence of anti-daratumumab antibodies and anti-rHuPH20 antibodies 10. Change from baseline in global health status and emotional functioning scales of the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30, future perspective scale of the EORTC QLQ-MY20, and utility and visual analog scale of the European Quality of Life Five Dimensions Questionnaire (EQ-5D-5L) 11. Duration of response, defined as date of onset of first response until date of disease progression or death 12. Time to response, defined as the time from randomization until onset of first response Exploratory end point: 13. Identification of novel biomarkers in relation to PFS/OS
    1. tempo fino alla progressione biochimica o diagnostica (Slim-Crab) definita come il tempo più breve fino alla prima progressione biochimica o diagnostica 2. Entità della risposta globale (ORR) definita come la proporzione di soggetti con una risposta parziale o una risposta migliore come definito dai criteri IMWG 3. Entità della risposta completa definita come la proporzione di soggetti con una risposta completa o una risposta migliore come definito dai criteri IMWG 4. Tempo fino al trattamento di prima linea del MM, definito come l¿intervallo dalla data di randomizzazione alla data del trattamento di prima linea per il MM 5. Sopravvivenza libera da progressione per la prima linea di trattamento per il MM, definito come l'intervallo dalla data di rand. alla data della progressione di malattia documentata rispetto alla prima linea di trattamento per MM o morte, secondo quello che si verifica per primo 6. Sopravvivenza generale, definita come l'intervallo dalla data di rand. alla data di morte 7. Incidenza di MM con caratteristiche prognostiche sfavorevoli, che include l'International Staging System Stage III (che si basa su beta 2 microglobuline e albumina) e caratteristiche citogenetiche sfavorevoli 8. Concentrazione sierica e parametri citogenetici di dara. inclusi la minima concentrazione osservata (Cmin) e la massima concentrazione osservata (Cmax) 9. Presenza di anticorpi anti-dara e anti-rHuPH20 10. Modifica rispetto al basale della scala che valuta lo stato generale di salute ed emotivo dell¿European Organization for Research and Treatment of Cancer (EORTC), la scala della prospettiva futura del EORTC QLQ-MY20 e scala analoga dell'European Quality of Life Five Dimensions Questionnaire (EQ-5D-5L). 11. Durata della risposta, definita come l'intervallo di tempo che va dalla data di insorgenza della prima risposta fino alla data di progressione di malattia o morte 12. Tempo alla risposta, definita come l'intervallo dalla randomizzazione fino all¿inizio della prima risposta Endpoint esplorativo 13. identificazione di nuovi biomarcatori in relazione alla sopravvivenza libera da malattia e sopravvivenza generale.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1,2,3, 11 and 12. Every 12 weeks until progressive disease 4&5. Every 6 months after PD duration until end of study 6. Throughout study, and at least every 12 weeks until PD 7. During screening and at the time of PD 8. Pre dose on Cycle 1 Day 1, C3D1, C5D1, C7D1, C12D1, C24D1, and post dose C1D4, C3D4, and 28 (+/-3) days and 8 weeks after the last Daratumumab dose 9. Pre dose on C1D1, C3D1, C5D1, C7D1, C12D1, C24D1, and 28 (+/-3) days and 8 weeks after the last Daratumumab dose 10. C1D1, Week 12, 24, 60, then every year until the end of the the study or PD and then at Months 3, 6, 12, and 18 during post-PD follow-up 13. At screening, 24, 48, and 96 weeks post randomization, end of treatment and during progressive disease
    1,2,3, 11 e 12. Ogni 12 sett fino alla progressione della malattia. 4e5. Ogni 6 mesi dopo la durata della PD fino alla fine dello studio. 6. Durante lo studio, e almeno ogni 12 sett fino alla PD. 7. Durante lo screening e al momento della PD 8. prima della dose dei cicli 1 Day 1, C3D1, C5D1, C7D1, C12D1, C24D1, e dopo la dose dei cicli C1D4, C3D4, e 28 (+/-3) gg e 8 sett dopo l'ultima dose di Daratumumab 9. Prima della dose dei cicli C1D1, C3D1, C5D1, C7D1, C12D1, C24D1, e 28 (+/-3) gg e 8 sett dopo l'ultima dose di Daratumumab 10. C1D1, settimana 12, 24, 60, e poi ogni anno fino alla conclusione dello studio o alla PD e poi ai mesi 3, 6, 12, e 18 durante il follow-up dopo la PD 13. Allo screening, e alle sett 24, 48, e 96 dopo la randomizzazione, alla fine del trattamento e durante la PD.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity and Biomarker analyses
    Immunigeneticità e analisi dei biomarcatori
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Monitoraggio attivo


















    Active monitoring






















    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA68
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Brazil
    Canada
    China
    Israel
    Japan
    Mexico
    Russian Federation
    Turkey
    United States
    Belgium
    Denmark
    France
    Germany
    Greece
    Hungary
    Italy
    Netherlands
    Norway
    Poland
    Spain
    Sweden
    United Kingdom
    Czechia
    Argentina
    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
    The study is considered completed approximately 8 years after the first subject is randomized.








    Lo studio è considerato concluso approssimativamente 8 anni dopo la randomizzazione del primo paziente.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months0
    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: 216
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 144
    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 state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 168
    F.4.2.2In the whole clinical trial 360
    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)
    At investigator treatment discretion
    A discrezione dello Sperimentatore
    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 Decision2018-01-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-22
    P. End of Trial
    P.End of Trial StatusOngoing
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