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    Summary
    EudraCT Number:2016-001737-27
    Sponsor's Protocol Code Number:54767414AMY3001
    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:2021-06-17
    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 number2016-001737-27
    A.3Full title of the trial
    A Randomized Phase 3 Study to Evaluate the Efficacy and Safety of Daratumumab in Combination with Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared With CyBorD Alone in Newly Diagnosed Systemic AL Amyloidosis
    Uno Studio randomizzato di fase III per valutare l'efficacia e la sicurezza di daratumumab in combinazione a ciclofosfamide, bortezomib e Desametasone (CyBorD) rispetto a CyBorD in monoterapia in soggetti con diagnosi recente di amiloidosi sistemica AL.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Evaluate the Efficacy and Safety of Daratumumab in Combination With Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared to CyBorD Alone in Newly Diagnosed Systemic Amyloid Light-chain (AL) Amyloidosis
    Uno Studio per valutare l'efficacia e la sicurezza di daratumumab in combinazione a ciclofosfamide, bortezomib e Desametasone (CyBorD) rispetto a CyBorD in monoterapia in soggetti con diagnosi recente di amiloidosi sistemica AL.
    A.3.2Name or abbreviated title of the trial where available
    ANDROMEDA
    ANDROMEDA
    A.4.1Sponsor's protocol code number54767414AMY3001
    A.5.4Other Identifiers
    Name:AndromedaNumber:NA
    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 CILAG SPA
    B.4.2CountryItaly
    B.4.1Name of organisation providing supportJANSSEN CILAG INTERNATIONAL NV
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJANSSEN CILAG INTERNATIONAL NV
    B.5.2Functional name of contact pointCLINICAL REGISTRY GROUP
    B.5.3 Address:
    B.5.3.1Street AddressARCHIMEDESWEG 19
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031715242166
    B.5.5Fax number0031715242110
    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 coformulato con ialuronidasi umana ricombinante (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.3.8INN - Proposed INNDaratumumab
    D.3.9.1CAS number 945721-28-8
    D.3.9.2Current sponsor codeJnJ 54767414
    D.3.9.3Other descriptive nameHUMAX-CD38
    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
    AL Amyloidosis (Newly Diagnosed Systemic AL Amyloidosis)
    AL - amiloidosi - nuova diagnosi di amiloidosi sistemica
    E.1.1.1Medical condition in easily understood language
    Amyloidosis refers to a disease in which abnormally folded protein (amyloid) deposits in various organs and tissues in the body.
    l'amiloidosi si riferisce a una malattia in cui proteine con un folding errato si depositano nei diversi tessuti ed organi nell'organismo
    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 PT
    E.1.2Classification code 10002022
    E.1.2Term Amyloidosis
    E.1.2System Organ Class 10021428 - Immune system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to evaluate the efficacy of daratumumab plus CyBorD compared with CyBorD alone in the treatment of newly diagnosed AL amyloidosis patients
    daratumumab più CyBorD rispetto a CyBorD in monoterapia nel trattamento di pazienti con diagnosi recente di amiloidosi AL
    E.2.2Secondary objectives of the trial
    -To evaluate the clinically observable endpoints for major organ deterioration (MOD-PFS) following treatment with daratumumab in combination with CyBorD compared with CyBorD alone
    -To evaluate the following efficacy measures following treatment with daratumumab in combination with CyBorD compared with
    CyBorD alone:
    -- Progression-free survival (PFS)
    -- Organ response rate (OrRR)
    -- Overall survival (OS)
    -- Time and duration of response
    -To evaluate fatigue, mental functioning, and health-related quality of life following treatment with daratumumab in combination with CyBorD compared with CyBorD alone
    -To assess the safety and tolerability of daratumumab when administered in combination with CyBorD
    -To assess the pharmacokinetics of daratumumab and the immunogenicity of daratumumab and rHuPh20
    -To explore minimal residual disease status in amyloidosis patients as a surrogate for PFS and OS or as a biomarker for relapse
    - Valutare gli endpoint clinicamente osservabili di deterioramento degli organi vitali (MOD-PFS) dopo trattamento con daratumumab con CyBorD rispetto a CyBorD in monoterapia
    - Valutare le successive misure di efficacia a seguito del trattamento con daratumumab con CyBorD rispetto al trattamento con
    CyBorD in monoterapia:
    - Sopravvivenza senza progressione(PFS)
    - Frequenza di risposta degli organi (OrRR)
    - Sopravvivenza globale (OS)
    - Tempi e durata della risposta
    -Valutare affaticamento, funzionalità mentale e qualità della vita in termini di salute a seguito del trattamento con daratumumab
    con CyBorD rispetto al CyBorD in monoterapia
    - Determinare la sicurezza e la tollerabilità di daratumumab somministrato con CyBorD
    - Valutare farmacocinetica di daratumumab e l'immunogenicità di daratumumab e rHuPh20
    - Esaminare lo stato residuo minimo della malattia nei pazienti affetti da amiloidosi come surrogato di PFS e OS o come
    biomarcatore per la ricomparsa della malattia
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) 18y(or the legal age of consent in the jurisdiction in which the study is taking place) or older.
    2) Histopathological diagnosis of amyloidosis based on detection by immunohistochemistry and polarizing light microscopy of green birefringent material in congo red stained tissue specimens (in an organ other than bone marrow) or characteristic electron microscopy appearance
    Considerations for specific populations where other types of amyloidosis may be encountered:
    - For male subjects 70y or older who have cardiac involvement only, and subjects of African descent, MS typing of AL amyloid in a tissue biopsy is recommended to rule out other types of amyloidosis such as agerelated amyloidosis or ereditary amyloidosis (ATTR mutation)
    3) Measurable disease of amyloid light chain amyloidosis as defined by at least ONE of the following:
    -serum monoclonal protein major or =0.5 g/dL by PE (routine and immunofixation performed at central lab),
    -serum free light chain major or =5.0 mg/L with an abnormal kappa:lambda or the difference between involved and uninvolved free light chains (dFLC) major or =50 mg/ L.
    4) One or more organs impacted by AL amyloidosis according to consensus guidelines
    5) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2
    6) Pre-treatment lab values meeting the following criteria during the Screening Phase:
    a. Absolute neutrophil count major or =1.0 ×1000000000 /L;
    b. Hemoglobin level major or =8.0 g/dL (major or =5 mmol/L); red blood cell transfusion allowed until 7 days before randomization
    c. Platelet count major or =50 × 1000000000/L;
    d. ALT minor or =2.5 times the ULN;
    e. AST minor or =2.5 times the ULN
    f. Total bilirubin level minor or =1.5 × ULN except for subjects with Gilbert syndrome, in which case direct bilirubin minor or =2 × ULN
    g. Estimated glomerular filtration rate (eGFR) minor or =20 mL/min/1.73m2.
    Please note the eGFR is measured by using the CKD-epi equation
    7)Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception and one additional effective contraceptive method. Contraception must begin 4 w prior to dosing and continue for 1y after discontinuation of cyclophosphamide or 3m after discontinuation of daratumumab, whichever is longer.
    Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
    8) During the study and for 1 year after stopping cyclophosphamide or 3 months after receiving the last dose of daratumumab, whichever is longer, a woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
    9)A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control; eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository during and up to 4 months after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer. All men must also not donate sperm during the study and for 4 months after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer.
    10) A woman of childbearing potential must have a negative serum or urine pregnancy test result within 14 days prior to randomization.
    11) Each subject, or legally acceptable representative, must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF.
    1.Età =18y (o > età legale secondo giurisdizione del paese in cui si svolge lo studio).
    2.Diagnosi istopatologica di AL basata su rilevamento per IHC e microscopia in luce polarizzata di materiale birifrangente verde in campioni di tessuto con rosso Congo (in organo diverso da midollo osseo) o evidenza caratteristica via microscopia elettronica
    Considerazioni per popolazioni specifiche in cui è possibile riscontrare altri tipi di AL:
    per M=70y che presentano coinvolgimento solo cardiaco e i soggetti di origine africana, si consiglia tipizzazione dell'AL con SM in biopsia tissutale, per escludere altri tipi di AL, (senile o ereditaria (mutazione ATTR))
    3.malattia misurabile da AL a catena leggera definita da almeno UNO dei seguenti fattori:
    proteina monoclonale sierica maggiore o =0,5 g/dl mediante EP (di routine e immunofissazione c/o presso lab centrale);
    catene leggere libere sieriche maggiore o =5,0 mg/L con kappa:lambda anomalo o la differenza tra le catene leggere libere coinvolte e non (dFLC) maggiore o =50 mg/ dL
    4. Uno o più organi coinvolti dall'AL in base a linee guida di consenso
    5.Stato di prestazione ECOG (Eastern Cooperative Oncology Group) di 0, 1 o 2
    6.Valori degli esami clinici pretrattamento che soddisfano i seguenti criteri durante la fase di screening:
    a.conta assoluta dei neutrofili maggiore o = 1,0 x 109/l;
    b.emoglobina maggiore o =8,0 g/dl (maggiore o =5 mmol/l);
    c.conta piastrine maggiore o =50 × 109/l (trasfusione di piastrine è accettabile senza restrizioni durante screening)
    d.ALT minore o =2,5 volte l'ULN
    e.AST minore o =2,5 volte l'ULN
    f.bilirubina totale minore o =1,5 x ULN, eccetto soggetti con sindrome di Gilbert (in cui bilirubina diretta minore o =2 x ULN)
    g.eGFR maggiore o =20 ml/min/1,73m2. Si noti che l'eGFR viene misurato usando l'equazione CKDepi
    7.le donne potenzialmente fertili devono impegnarsi ad astenersi dai rapporti eterosessuali o a usare contemporaneamente 2 metodi contraccettivi affidabili, tra cui una forma di contraccezione altamente efficace e un ulteriore metodo contraccettivo efficace. La contraccezione deve iniziare 4w prima della terapia e continuare per 1y dopo la sospensione di ciclofosfamide o 3m dopo la sospensione di daratumumab, a seconda di quale di questi due periodi è il più lungo. Una contraccezione affidabile è indicata anche in presenza di una storia di infertilità, tranne se dovuta a isterectomia oppure ooforectomia bilaterale.
    8.Durante lo studio e per 1y dopo la sospensione di ciclofosfamide o 3m dopo l'ultima dose di daratumumab, a seconda di quale di questi due periodi è il più lungo, le donne devono acconsentire a non donare ovuli a scopo di riproduzione assistita.
    9.Gli uomini sessualmente attivi con donne potenzialmente fertili che non sono stati sottoposti a vasectomia devono acconsentire a usare un metodo contraccettivo a barriera, ad es. profilattico con schiuma/gel/pellicola/crema/supposta spermicida oppure la partner deve indossare un cappuccio occlusivo con schiuma/supposta spermicida durante la terapia e fino a 4m dopo la sospensione di ciclofosfamide o 3m dopo sospensione di daratumumab, a seconda di quale di questi due periodi è il più lungo. Gli uomini non potranno inoltre donare lo sperma per tutta la durata dello studio e per 4m dopo la sospensione del ciclofosfamide o 3m dopo la sospensione di daratumumab, a seconda di quale di questi due periodi è il più lungo.
    10.Le donne potenzialmente fertili devono presentare un test di gravidanza sul siero o sulle urine con risultato negativo nei 14gg precedenti la randomizzazione. Per i requisiti relativi alla fase di trattamento vedere lo schema Scadenze ed eventi programmati (Tab.1).
    11.Tutti i soggetti (o i rappresentanti legali) devono firmare il ICF indicante che hanno compreso lo scopo dello studio, le procedure e che intendono prendervi parte. I soggetti devono accettare ed essere in grado di conformarsi a quanto prescritto nell'ICF
    E.4Principal exclusion criteria
    1. Prior therapy for AL or MMY including medications that target CD38, except 160mg dexamethasone or equiv corticosteroid maximum exposure prior to random
    2.Previous or current diagnosis of symptomatic MMY, including lytic bone disease, plasmacytomas,=60% plasma cells in the bone marrow, or hypercalcemia
    3.significant cardiovascular conditions as below:
    a.NT-ProBNP >8500 ng/L
    b.NYHA classif. IIIB or IV heart failure
    c.Heart failure that in the opinion of the investigator is ischemic heart disease (prior myocardial infarction with documented history of cardiac enzyme elevation and ECG hanges)or uncorrected valvular disease and not primarily due to AL cardiomyopathy
    d.Inpatient admission to a H for unstable angina or infarction within the last 6m prior to first dose or percutaneous intervention with recent stent within 6m or coronary bypass within 6m
    e.congestive heart failure, cardiovascular-related hospitalizations within 4w prior to random
    f.history of sustained ventricular tachycardia or aborted ventricular fibrillation or AV nodal or SA nodal dysfunction for which a pacemaker/ICD is indicated but not placed (Subjects who do have a pacemaker/ICD are allowed)
    g.Screening 12-lead ECG showing a baseline QT as corrected by Fridericia's formula (QTcF) >500 msec.Subjects who have a pacemaker may be included regardless of calculated QTc
    h.Supine SBP <90 mm Hg, or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of >20 mmHg despite medical mngment (midodrine, fludrocortisones)in the absence of volume depletion
    4.Planned stem cell transplant in the first 6 cycles of therapy excluded.Stem cell collection in the 1st 6 cycles of protocol therapy is permitted
    5.History of malignancy (other than AL amyloidosis)within 3y before the date of random;
    6.COPD with a FEV in 1 sec (FEV1) <50% of predicted normal.FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of redicted normal
    7.Moderate/severe persistent asthma in the past 2y,currently has uncontrolled asthma of any classification.(subjects who currently have controlled intermittent asthma or controlled mild persistent asthma allowed)
    8.HIV+
    9.Any of the following: seropositive HBV or known seropositive HCV
    10.G2 sensory or G1 painful peripheral neuropathy
    11.Known hypersensitivity to bortezomib,boron or mannitol
    12.Concurrent medical condition or disease that is likely to interfere with procedures or results,or that in the opinion of the PI would constitute a hazard for particip
    13.Any form of non-AL,including wild type or mutated amyloidosis
    14.Known allergies,hypersensitivity,or intolerance to monoclonal antibodies or hum proteins,or their excip, or known sensitivity to ammalian-derived products
    15.Known or suspected of not being able to comply with protocol(alcoholism,drug dependency)or the subject has any condition for which,in the opinion of the PI, participation would not be in the interest of the subject or that could prevent, limit,or confound the protocol
    16. Woman pregnant or breast-feeding or planning to be pregnant while enrolled in this study or within 1y after discontinuation of cyclophosphamide or 3m following discontinuation of daratumumab,whichever is longer
    17.Received an invest drug (including invest vaccines) or used an invasive invest med device within 4w before Cycle1,Day 1
    18. Major surgery within 2w before Cycle1,Day1,or will not have fully recovered from surgery,or has surgery planned in the time the subject is expected to participate in the study or within 2w after the last dose of study drug administration. subjects with planned surgical procedures to be conducted under local anesthesia may participate.
    19.Subjects who are taking strong CYP3A4 inducers must discontinue their use at least 5 half-lives prior to the first dose of study treatment.
    1.già terapia per AL o MMY con farmaci sul CD38, (max 160 mg esametasone (o corticosteroide equiv)pre-randomizzazione
    2.Diagnosi di MMY sintomatico, (lisi ossea, plasmacitoma, cellule di plasma nel midollo osseo =60% o ipercalcemia)
    3.Condizioni cardiovascolari come segue:
    a.NT-ProBNP >8500 ng/l
    b. IC secondo New York Heart Association (NYHA) IIIB o IV
    c.IC alla base di cardiopatia ischemica (pregresso infarto con aumento degli enzimi cardiaci e alterazioni ECG) o valvulopatia non corretta e non primariamente attribuibile a cardiomiopatia dell'amiloide AL;
    d.Ricovero per angina instabile o infarto mioc o stent o bypass coronarico (tutti: entro 6 m dalla prima dose);
    e.insufficienza cardiaca congestizia, H per problema cardiovascolare entro 4w prerandomizzazione
    f.tachicardia ventricolare sostenuta o fibrillazione ventricolare abortita o AV o SA per cui è indicato ma non applicato un pacemaker/ICD (i soggetti con pacemaker/ICD sono ammessi
    g.ECG a 12 derivazioni allo screening con QT basale corretto per formula di Fridericia (QTcF)
    >500 msec. soggetti con pacemaker inclusi .
    h.PSS supina <90 mm Hg, ipotensione ortostatica sintomatica senza ipovolemia
    4.trapianti di cellule staminali nei primi 6 cicli di terapia del protocollo esclusi. La raccolta è permessa.
    5.tumore maligno (diverso dall'amiloidosi AL) sviluppato nei 3y precedenti la randomizzazione
    6.COPD con un FEV in 1 sec (FEV1)<50% del valore normale previsto. FEV1 per soggetti che si sospetta soffrano di COPD e i soggetti devono essere esclusi se FEV1 è <50% del valore normale previsto
    7.Asma persistente moderata o grave negli ultimi 2y o attuale asma non controllata di qualsiasi classificazione (soggetti che soffrono attualmente di asma intermittente controllata o asma persistente lieve controllata sono ammessi allo studio).
    8.HIV+
    9.9. Una delle seguenti condizioni :sieropositività per HBV+ sieropositività conosciuta per HCV.
    10.Neuropatia periferica sensoriale di g2 o neuropatia periferica dolorosa di g1
    11.Ipersensibilità nota a bortezomib, boro o mannitolo
    12.Condizione o patologia medica concomitante (ad es. infezione sistemica attiva) che può interferire con le procedure o i risultati dello studio o che potrebbe costituire rischio per la partecipazione allo studio.
    13.Qualsiasi forma di amiloidosi diversa dall'amiloidosi AL, inclusa l'amiloidosi "wild type" o mutata.
    14.Allergie, ipersensibilità o intolleranza nota agli anticorpi monoclonali, alle proteine umane o ai relativi eccipienti (consultare il Dossier dello sperimentatore) o sensibilità nota a prodotti di derivazione mammifera
    15.Certezza o sospetto che il soggetto non sia in grado di conformarsi al protocollo (alcolismo, dipendenza da farmaci) oppure che il soggetto presenti una condizione per la quale la partecipazione ne comprometterebbe il benessere) oppure potrebbe impedire, limitare o alterare le valutazioni specifiche del protocollo
    16.Soggetti in gravidanza o che allattano al seno o che prevedono di concepire un figlio durante l'arruolamento o entro 1y dopo la sospensione di ciclofosfamide o 3m dopo la sospensione di daratumumab, a seconda di quale di questi due periodi è il più lungo.
    17.Assunzione di un farmaco sperimentale (inclusi vaccini sperimentali) o utilizzo di un dispositivo medico sperimentale invasivo nelle 4w precedenti al gg 1 del Ciclo 1.
    18.Importante intervento chirurgico nelle 2w precedenti il gg1 del Ciclo 1, o mancata ripresa completa da un precedente intervento chirurgico oppure previsione di intervento chirurgico durante la partecipazione allo studio o nelle 2w successive all'ultima somministrazione del farmaco sperimentale. NB: soggetti con procedure chirurgiche programmate da effettuarsi in anestesia locale possono partecipare
    19. Soggetti che stanno assumendo forti induttori del CYP3A4 devono interromperne l’assunzione almeno 5 emivite prima della prima dose del trattamento sperimentale
    E.5 End points
    E.5.1Primary end point(s)
    overall complete hematologic response rate
    Tasso di risposta ematologico globale completo
    E.5.1.1Timepoint(s) of evaluation of this end point
    During cycles 1 through 6 every 28 days, then Cycle 7+ and during the observation phase Every 8 weeks until disease progression according to MOD-PFS criteria
    Durante il ciclo 1 fino al ciclo 6 ogni 28 giorni, poi ai cicli successivi al 7 e durante la fase di osservazione ogni 8 settimane, fino a progressione della patologie come da criteri MOD-PFS
    E.5.2Secondary end point(s)
    1.Major Organ Deterioration Progression-Free Survival (MOD-PFS). This is a composite endpoint of clinically observable endpoints and will be defined from andomization to any one of the following events whichever comes first: 1. Death 2. Clinical Manifestation of Cardiac Failure 3. Clinical Manifestation of Renal Failure: 4. Development of hematologic PD as per consensus guidelines.
    2.Progression-free survival (PFS) is defined as the time from the date of randomization to the date of first documentation of hematologic disease progression, or organ
    (cardiac, renal, or liver) progression, or death due to any cause, whichever occurs first according to central laboratory results and judged by international consensus guidelines. For those subjects who are still alive and have not yet progressed, the subject's data will be censored at the last disease assessment.
    3.Organ response rate (OrRR) for kidney, heart, liver is defined as the proportion of baseline organ involved subjects who achieve organ response in each corresponding
    organ
    4.Overall survival (OS) is measured from the date of randomization to the date of the subject's death. If the subject is alive or the vital status is unknown, then the subject's data will be censored at the date the subject was last known to be alive
    5.Improvement in fatigue is defined as the change from baseline in the EORTC QLQ-C30 Fatigue scale score, improvement in mental functioning is defined as the change
    from baseline in the SF-36v2 MCS, and improvement in health-related quality of life is defined as change from baseline in the EORTC QLQ-C30 Global Health Status scale score
    6.Time to next treatment (TNT) defined as the time from the date of randomization to the start date of subsequent AL amyloidosis (nonprotocol). Death due to PD prior to subsequent therapy is considered as an event. Otherwise, TNT is censored at the date of death or the last date known to be alive
    7.Hematologic VGPR or better rate is defined as the proportion of subjects who achieve hematologic CR or VGPR. -Time to complete hematologic response (or VGPR or
    better) is defined as the time between the date of randomization and the first efficacy evaluation at which the subject has met all criteria for hematologic CR (or VGPR or better). For subjects without a hematologic CR (or VGPR or better), data will be censored either at the date of progressive disease or, in the absence of progressive disease, at the last disease assessment
    8.Duration of complete hematologic response (or VGPR or better) is defined as the time between the date of initial documentation of CHR (or VGPR or better) to the
    date of first documented evidence of hematologic progressive disease. For subjects who have not progressed, data will be censored at the last disease assessment
    9.Time to organ response is defined as the time between the date of randomization and the first efficacy evaluation at which the subject has each corresponding organ
    response. For subjects without organ response, data will be censored either at the date of the corresponding organ progressive disease or, in the absence of organ progressive disease, at the last disease assessment
    10.Duration of organ response is defined as the time between the date of initial documentation of each corresponding organ response to the date of first documented
    evidence of the corresponding organ progressive disease. For subjects who have not had organ progression, data will be censored at the last disease assessment
    1.Sopravvivenza senza progressione da deterioramento maggiore degli organi (MOD.PFS); questo è un endpoint composto da una serie di endpoint osservabili clinicamente, e viene definito come tempo dalla randomizzazione al verificarsi di uno qualsiasi dei sequenti eventi: 1) morte 2) manifestazione clinica di insufficienza cardiaca; 3) manifestazione clinica di insufficienza renale; 4) progressione ematologica della malattia come da linee guida del consenso.
    2.la sopravvivenza senza progressione (PFS) viene definita come il tempo dalla randomizzazione alla data della prima evidenza di progressione della malattia ematologia, o progressione di organo (cuore, rene, fegato); o morte per qualsiasi causa, qualsiasi evento accada prima, in base ai laboratori centralizzati e giudicati in base alle linee guida normalmente accettate.
    3.l'Organ Response Ratio (OrRR) per rene, cuore e fegato è definito come la proporzione dei soggetti con coinvolgimento di organi al tempo 0 (baseline) che ottengono risposta positiva in ogni organo corrispondente
    4.la sopravvivezna globale (OS) viene misurata dalla data della randomizzazione alla data della morte del soggetto; se il soggetto al termine della rilevazione è vivo o il suo status non è noto, i suoi dati verranno bloccati alla data in cui era certo che il soggetto fosse ancora vivo
    5."Aumento dell'affaticamento" è definito come la variazione dal tempo 0 (baseline) EORTC QLQC30 Fatigue scale score; il miglioramento mentale è definito come il cambiamento da tempo 0 (baseline) nel questionario SF-36v2 MCS; miglioramento nella qualità della vita legata alla salute è definita come il cambiamento dal tempo 0 (baseline) nel questionario EORTC QLQ-C30 Global Health Status scale
    6.il tempo al prossimo trattamento (TNT) viene definito come il tempo dalla data della randomizzazione all'inizio del successivo trattamento per amiloidosi; la morte dovuta a progressione da malattia prima della successiva terapia viene considerata un evento; in caso contrario, TNT è chiusa alla data di morte dell'ultima o all'ultima data in cui il soggetto era vivo
    7.il VGPR ematologico è definito come la proporzione di soggetti che raggiungono CR o VGPR ematologico; - il tempo alla completa risposta ematologica (o VGPR) è definito come il tempo intercorso tra la randomizzazione e la prima evidenza di efficacia in cui il soggetto ha soddisfatto tutti i criteri di CR ematologico (o VGPR). per soggetti senza CR o VGPR, i dati verranno censurati o alla data di progressione della malattia o, in caso di assenza di progressione, all'ultima valutazione della
    malattia
    8.la durata della risposta ematologica completa è definita come il tempo tra la data della documentazione iniziale del CHR alla data della prima evidenza documentata di progressione ematologica. per i soggetti che non hanno avuto progressione, i dati saranno censurati all'ultima valutazione della malattia;
    9.il tempo alla risposta dell'organo è definito come il tempo tra la randomizzazione e la prima valutazione di efficacia alla quale il soggetto abbia avuto una risposta in ogni organo coinvolto; per i soggetti che non hanno avuto risposta, i dati saranno censurati alla data della corrispondente progressione di patologia nell'organo, o, in sua assenza, all'ultima valutazione della patologia
    10.la durata della risposta dell'organo è definita come il tempo tra la data dell'evidenza iniziale di risposta in organo corrispondente e l'evidenza della progressione della malattia nell'organo; per soggetti che non hanno avuto progressione i dati verranno censurati all'ultima valutazione della malattia
    E.5.2.1Timepoint(s) of evaluation of this end point
    During cycles 1 through 6 every 28 days, then Cycle 7+ and during the observation phase Every 8 weeks until disease progression according to MOD-PFS criteria
    Durante il ciclo 1 fino al ciclo 6 ogni 28 giorni, poi ai cicli successivi al 7 e durante la fase di osservazione ogni 8 settimane, fino a progressione della patologie come da criteri MOD-PFS
    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 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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    terapia standard
    standard therapy
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA71
    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
    Korea, Republic of
    Mexico
    Turkey
    United States
    Belgium
    Denmark
    France
    Germany
    Greece
    Hungary
    Italy
    Netherlands
    Poland
    Romania
    Spain
    Sweden
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of study is defined to be 5 years after the last subject is randomized. Please see Protocol Section 17.9.1
    la fine dello studio è definita come 5 anni dopo che l'ultimo soggetto è stato randomizzato
    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 months0
    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 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: 56
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 314
    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 state22
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 220
    F.4.2.2In the whole clinical trial 370
    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)
    Subjects will be instructed that study drug will not be available to them after they have completed/discontinued treatment and that they should return to their primary physician to determine standard ofcare (Prot Sect 9.1.5).Patients receiving daratumumab and who continue to benefit from the study treatment when study is over will have the option to continue on daratumumab treatment for a max of 2 year from the start of the study.Sponsor plans to provide study medication to these patients
    i soggetti saranno istruiti che il f. non sarà disponibile per loro dopo il completamento o la discontinuazione del trattamento, e che torneranno alla loro medico di base per determinare lo standard of care. i Pz che ricevono daratumumab e che continueranno a beneficiare del trattamento di studio quando lo studio sarà terminato avranno la possibilità di continuare ad assumere daratumumab per al massimo 2y dopo l'inizio dello studio. lo sponsor programma di fornire il f. di studio a questi pz
    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 Decision2018-03-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-01-11
    P. End of Trial
    P.End of Trial StatusOngoing
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