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    Summary
    EudraCT Number:2021-000037-14
    Sponsor's Protocol Code Number:NEOD001-301
    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:2021-11-26
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2021-000037-14
    A.3Full title of the trial
    A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Birtamimab Plus Standard of Care vs. Placebo
    Plus Standard of Care in Mayo Stage IV Subjects with Light Chain (AL) Amyloidosis
    Uno studio di fase 3, randomizzato, multicentrico, in doppio cieco, controllato con placebo, sull’efficacia e sulla sicurezza di birtamimab più terapia standard rispetto a placebo più terapia standard in soggetti con amiloidosi da catene leggere (AL) stadio Mayo IV
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Global Phase 3 Double-Blind, Placebo-Controlled study to assess Efficacy and Safety of Birtamimab Plus Standard of Care vs. Placebo Plus Standard
    of Care in Mayo Stage IV Subjects with Light Chain (AL) Amyloidosis
    Uno studio globale di fase 3, in doppio cieco, controllato con placebo, per valutare l’efficacia e la sicurezza di birtamimab più terapia standard rispetto a placebo più terapia standard in soggetti con amiloidosi da catene leggere (AL) stadio Mayo IV
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberNEOD001-301
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04973137
    A.5.4Other Identifiers
    Name:INDNumber:146070
    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 SponsorProthena Biosciences Limited
    B.1.3.4CountryIreland
    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 supportProthena Biosciences Limited
    B.4.2CountryIreland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationProthena Biosciences Limited
    B.5.2Functional name of contact pointRegulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address77 Sir John Rogerson's Quay, Block C
    B.5.3.2Town/ cityGrand Canal Docklands, Dublin 2
    B.5.3.3Post codeD02 T804
    B.5.3.4CountryIreland
    B.5.4Telephone number000000
    B.5.5Fax number000000
    B.5.6E-mailregaffairs@prothena.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/3/13/1100
    D.3 Description of the IMP
    D.3.1Product nameBirtamimab
    D.3.2Product code [Birtamimab]
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBIRTAMIMAB
    D.3.9.1CAS number 1608108-91-3
    D.3.9.2Current sponsor codebirtamimab
    D.3.9.3Other descriptive nameHumanized IgG1 kappa antiamyloid
    D.3.9.4EV Substance CodeSUB198016
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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.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 Yes
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameparacetamolo Zentiva Italia
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form Tablet
    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 INNPARACETAMOLO
    D.3.9.2Current sponsor codeNA
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product 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 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 Yes
    D.2.1.1.1Trade name Bortezomib Accord
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare S.L.U. (MA n.: EU/1/15/1019/001)
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBortezomib Accord
    D.3.2Product code [Bortezomib Accord]
    D.3.4Pharmaceutical form Powder for 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 INNBORTEZOMIB
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameBortezomib D-mannitol
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3500
    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 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 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 Yes
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameZirtec
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form Tablet
    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 INNCETIRIZINA DICLORIDRATO
    D.3.9.2Current sponsor codeNA
    D.3.9.3Other descriptive nameNA
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 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 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: 5
    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 Yes
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAciclin
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form Tablet
    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 INNACICLOVIR
    D.3.9.2Current sponsor codeNA
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number200 to 400
    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 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 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 placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    AL amyloidosis involves a hematologic disorder caused by clonal plasma cells that produce misfolded immunoglobulin light chains.
    Overproduction of misfolded light chains results in both soluble, aggregated forms of light chains and insoluble, fibrillar deposits of
    abnormal AL protein (amyloid), in the tissues and organs. This can cause a range of symptoms and organ dysfunction including cardiac, renal, and
    hepatic dysfunction, gastrointestinal involvement and neuropathy and macroglossia
    l'amiloidosi da catene leggere (AL) coinvolge un disordine ematologico causato dalle cellule clonali del plasma che producono le catene leggere misfolded dell'immunoglobulina.
    La sovrapproduzione di catene leggere misfolded produce sia forme solubili, aggregati di catene leggere che depositi fibrillari insolubili di proteina AL anormale (amiloide), nei tessuti e negli organi.
    Vedere EN nella sezione sottostante
    E.1.1.1Medical condition in easily understood language
    Light chain (AL) amyloidosis is a blood disorder, which causes progressive organ damage as a result of the misfolding of proteins. This
    disease can produce a range of symptoms and organ dysfunction
    l'amiloidosi da catene leggere è un disordine del sangue, che causa progressivo danno degli organi come risultato del mal ripiegamento delle proteine. vedere EN sezione sottostante
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10036673
    E.1.2Term Primary 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
    To evaluate the efficacy of birtamimab plus standard of care compared to placebo plus standard of care when administered intravenously in Mayo
    Stage IV subjects with AL amyloidosis by assessing time to all-cause mortality.
    Valutare l’efficacia di birtamimab più terapia standard rispetto al placebo più terapia standard quando somministrato per via endovenosa in soggetti con amiloidosi AL in stadio Mayo IV valutando il tempo alla mortalità per qualsiasi causa.
    E.2.2Secondary objectives of the trial
    To evaluate birtamimab plus standard of care compared to placebo plus standard of care on the following:
    • Change from baseline to Month 9 in health-related quality of life using the Short Form-36 questionnaire Version 2 (SF-36v2)
    • Change from baseline to Month 9 in the 6-Minute Walk Test (6MWT) distance
    Valutare birtamimab più terapia standard rispetto al placebo più la terapia standard nei seguenti parametri:
    • variazione dal basale al Mese 9 nella qualità della vita correlata alla salute utilizzando il questionario del Modulo breve a 36 voci, Versione 2 (SF-36v2);
    • variazione dal basale al Mese 9 nella distanza percorsa durante il Test del cammino in 6 minuti (6MWT).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Aged =18 years
    2.Newly diagnosed and AL amyloidosis treatment naive
    3.Bone marrow demonstrating clonal plasma cells
    4.Confirmed diagnosis of AL amyloidosis by the following:
    -Histochemical diagnosis of amyloidosis determined by polarizing light
    microscopy of green birefringent material in Congo red-stained tissue
    specimens OR characteristic electron microscopy appearance
    AND
    -Confirmatory immunohistochemistry OR mass spectroscopy of AL
    amyloidosis
    5.Confirmed diagnosis of AL amyloidosis by mass spectrometry or
    immunoelectron microscopy of amyloid material in tissue biopsy if the
    subject meets any of the following:
    -Is black or African American
    -Is over 75 years of age with concurrent monoclonal gammopathy
    -Has a history of familial amyloidosis and has concurrent monoclonal
    gammopathy
    OR
    -If the subject meets any of the above 3 conditions and has
    echocardiographic evidence of amyloidosis, biopsy-proven amyloidosis
    with a monoclonal gammopathy and no tissue is available for mass
    spectrometry or immunoelectron microscopy, the subject must have
    gene sequencing consistent with transthyretin (TTR) wild type (e.g., no
    TTR mutation present) AND must score 0 in technetium-99m-3,3-
    diphosphono-1,2 propanodicarboxylic acid (99mTc DPD),
    hydroxymethylenediphosphonate (99mTc HMDP), or pyrophosphate
    (99mTc PYP) scintigraphy
    6.Cardiac involvement as defined by all of the following:
    -Past documented or presently noted clinical signs and symptoms
    supportive of a diagnosis of heart failure in the setting of a confirmed
    diagnosis of AL amyloidosis in the absence of an alternative explanation
    for heart failure
    -Either an endomyocardial biopsy demonstrating AL amyloidosis or an
    echocardiogram demonstrating a mean left ventricular wall thickness at
    diastole >12 mm in the absence of other causes (e.g., severe
    hypertension, aortic stenosis), which would adequately explain the
    degree of wall thickening
    7.Confirmed Mayo Stage IV as defined by:
    -NT-proBNP =1800 pg/mL and
    -Troponin-T >0.03 ng/mL and
    -dFLC =18 mg/dL
    8.Planned first-line chemotherapy contains bortezomib administered subcutaneously weekly
    9.Adequate bone marrow reserve, hepatic function, and renal function,
    as demonstrated by:
    -Absolute neutrophil count =1.0 × 10e9/L
    -Platelet count =75 × 10e9/L
    -Hemoglobin =9 g/dL
    -Total bilirubin = 2 × the upper limit of normal (ULN)
    -Aspartate aminotransferase (AST)/serum glutamic oxaloacetic
    transaminase =3 × ULN
    -Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase
    =3 × ULN
    -Alkaline phosphatase (ALP) =5 × ULN (except for subjects with
    hepatomegaly and isozymes specific to liver, rather than bone)
    -Estimated glomerular filtration rate (eGFR) =30 mL/min/1.73 m2 as
    estimated by the Chronic Kidney Disease Epidemiology Collaboration equation
    10.Seated systolic blood pressure (BP) 90 to 180 mmHg
    11.Distance walked during each Screening 6MWT is >30 meters and
    <550 meters
    12.Women of childbearing potential (WOCBP) must have 2 negative
    pregnancy tests during Screening, the second within 24 hours prior to
    the first administration of study drug, and must agree to use highly
    effective physician-approved contraception from Screening to 90 days
    following the last study drug administration
    13.Male subjects must be surgically sterile or must agree to use highly
    effective physician approved contraception from Screening to 90 days
    following the last study drug administration
    14.Ability to understand and willingness to sign an informed consent
    form prior to initiation of any study procedures
    1. Età =18 anni
    2. Nuova diagnosi di amiloidosi AL naïve al trattamento
    3. Evidenza di plasmacellule clonali nel midollo osseo
    4. Diagnosi di amiloidosi AL confermata da quanto segue:
    • diagnosi istochimica di amiloidosi determinata mediante microscopia a luce polarizzata di materiale verde birifrangente in campioni di tessuto sottoposti a colorazione con rosso Congo OPPURE aspetto caratteristico al microscopio elettronico
    E
    • immunoistochimica OPPURE spettroscopia di massa che conferma l’amiloidosi AL.
    5. Diagnosi confermata di amiloidosi AL mediante spettrometria di massa o microscopia immunoelettronica del materiale amiloide nella biopsia tissutale, a condizione che il soggetto soddisfi una qualsiasi delle seguenti condizioni:
    • è nero o afro-americano;
    • ha più di 75 anni e presenta gammopatia monoclonale concomitante;
    • presenta un’anamnesi di amiloidosi familiare e soffre di gammopatia monoclonale concomitante;
    OPPURE
    • se il soggetto soddisfa una qualsiasi delle 3 condizioni di cui sopra e presenta evidenza ecocardiografica di amiloidosi, amiloidosi comprovata da biopsia con una gammopatia monoclonale e non vi è del tessuto disponibile per la spettrometria di massa o la microscopia immunoelettronica, il soggetto deve disporre di un risultato del sequenziamento genico coerente con transtiretina (TTR) wild-type (per es., nessuna mutazione di TTR presente) E deve ottenere un punteggio pari a 0 alla scintigrafia con tecnezio-99m-acido 3,3-difosfono-1,2 propanodicarbossilico (99mTc-DPD), idrossimetilenedifosfonato (99mTc-HMDP) o pirofosfato (99mTc-PYP).
    6. Coinvolgimento cardiaco definito da tutti i seguenti fattori:
    • segni e sintomi clinici precedentemente documentati o attualmente riscontrati a supporto di una diagnosi di insufficienza cardiaca nel contesto di una diagnosi confermata di amiloidosi AL in assenza di una spiegazione alternativa che giustifichi l’insufficienza cardiaca;
    • una biopsia endomiocardica che dimostri la presenza di amiloidosi AL o un ecocardiogramma che dimostri uno spessore medio della parete ventricolare sinistra alla diastole >12 mm in assenza di altre cause (per es. ipertensione grave, stenosi aortica) che spiegherebbe adeguatamente il grado di ispessimento della parete.
    7. Conferma dello stadio Mayo IV, come definito da:
    • pro-peptide cerebrale natriuretico N-terminale (NT-proBNP) =1.800 pg/ml;
    • troponina-T >0,03 ng/ml e
    • differenza tra catene leggere libere coinvolte e non coinvolte (dFLC) =18 mg/dl.
    8. La chemioterapia di prima linea prevista contiene bortezomib somministrato per via sottocutanea una volta alla settimana
    9. Riserva di midollo osseo, funzionalità epatica e funzionalità renale adeguate, come dimostrato da:
    • conta assoluta dei neutrofili =1,0 × 109/l;
    • conta piastrinica =75 × 109/l;
    • emoglobina =9 g/dl;
    • bilirubina totale =2 x limite superiore della norma (ULN);
    • aspartato aminotransferasi/transaminasi glutammico-ossalacetica sierica =3 × ULN;
    • alanina aminotransferasi/transaminasi glutammica piruvica sierica =3 × ULN;
    • fosfatasi alcalina =5 × ULN (eccetto per i soggetti con epatomegalia e isoenzimi specifici per il fegato, piuttosto che per le ossa);
    • velocità di filtrazione glomerulare stimata =30 ml/min/1,73 m2 calcolata mediante l’equazione della Collaborazione per l’epidemiologia nella malattia renale cronica.
    10. Pressione sanguigna sistolica in posizione seduta da 90 a 180 mmHg
    11. Distanza percorsa durante ogni test 6MWT di screening compresa tra =30 metri e =550 metri
    12. Le donne in età fertile devono risultare negative a 2 test di gravidanza durante lo screening, il secondo dei quali eseguito nelle 24 ore precedenti la prima somministrazione del farmaco in studio e devono accettare di utilizzare metodi contraccettivi altamente efficaci approvati dal medico dallo screening fino a 90 giorni successivi all’ultima somministrazione del farmaco in studio
    13 e 14 vedere EN nella sezione sottostante
    E.4Principal exclusion criteria
    1.Non-AL amyloidosis
    2.NT-proBNP >8500 pg/mL
    3.Meets the International Myeloma Working Group (IMWG) definition of
    multiple myeloma
    *Note that subjects who meet the IMWG definition of symptomatic
    multiple myeloma with signs and/or symptoms attributable only to
    associated amyloidosis are potentially eligible upon approval of the
    Sponsor.
    4.Subject is eligible for and plans to undergo ASCT or organ transplant
    during the study
    5.Symptomatic orthostatic hypotension that in the medical judgment of
    the Investigator would interfere with the subject's ability to safely
    receive treatment or complete study assessments
    6.Myocardial infarction, uncontrolled angina, severe uncontrolled
    ventricular arrhythmias, or ECG evidence of acute ischemia, within 6
    months prior to the Month 1-Day 1 Visit
    7.Severe valvular stenosis (e.g., aortic or mitral stenosis with a valve
    area <1.0 cm2) or severe congenital heart disease
    8.ECG evidence of acute ischemia or active conduction system
    abnormalities with the exception of any of the following:
    -First degree AV-block
    -Second degree AV-block Type 1 (Mobitz Type 1 / Wenckebach type)
    -Right or left bundle branch block
    -Atrial fibrillation with a controlled ventricular rate (uncontrolled [>110
    bpm] ventricular rate is not allowed [determined by an average of 3
    beats in Lead II or 3 representative beats if Lead II is not representative
    of the overall ECG])
    9.Peripheral neuropathy assessed as National Cancer Institute-Common
    Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 2 with pain,
    Grade 3, or Grade 4
    10.Subject is receiving oral or intravenous antibiotics, antifungals, or
    antivirals within 1 week of Month 1-Day 1 with the exception of
    prophylactic oral agents
    11.Prior treatment with hematopoietic growth factors, transfusions of
    blood or blood products within 1 week of Month 1-Day 1
    12.Prior radiotherapy within 4 weeks of Month 1-Day 1
    13.Major surgery within 4 weeks of Month 1-Day 1 or planned major
    surgery during the study
    14.Active malignancy with the exception of any of the following:
    -Adequately treated basal cell carcinoma, squamous cell carcinoma, or in
    situ cervical cancer
    -Adequately treated Stage I cancer from which the subject is currently in
    remission and has been in remission for 2 years
    -Low-risk prostate cancer with Gleason score <7 and prostate specific
    antigen <10 ng/mL
    -Any other cancer from which the subject has been disease-free for =2
    years
    15.History of severe allergy to any of the components of birtamimab
    such as histidine/L histidine hydrochloride monohydrate, trehalose
    dehydrate, or polysorbate 20 or history of Grade =3 infusion-related AEs
    or hypersensitivity to another monoclonal antibody, or known
    hypersensitivity to diphenhydramine (or an equivalent H1 antihistamine)
    or acetaminophen (or its equivalent, paracetamol)
    16.Known or history of uncontrolled, active HIV, hepatitis B or hepatitis C, or SARS-CoV-2 infection
    17.Prior treatment with plasma cell-directed chemotherapy, birtamimab,
    daratumumab, 11 1F4, anti-serum amyloid P antibody, doxycycline for
    amyloid, or other investigational treatment directed at amyloid
    18.Treatment with another investigational agent within 30 days of
    Month 1-Day 1
    19.Women who are pregnant or lactating
    20.Any condition which could interfere with, or the treatment for which
    might interfere with, the conduct of the study or which would, in the
    opinion of the Investigator, unacceptably increase the subject's risk by
    participating in the study
    21.Subject is under legal custodianship
    22.History of epilepsy or seizure disorder with the exception of
    childhood febrile seizures
    23.Waldenström's macroglobulinemia and/or immunoglobulin M
    monoclonal gammopathy
    1. Amiloidosi non-AL
    2. NT-proBNP >8.500 pg/ml
    3. Soddisfacimento della definizione di mieloma multiplo secondo il Gruppo di lavoro internazionale per il mieloma (IMWG) (Appendice 3)
    *Si noti che i soggetti che soddisfano la definizione IMWG di mieloma multiplo sintomatico con segni e/o sintomi attribuibili solo all’amiloidosi associata sono potenzialmente idonei previa approvazione dello sponsor.
    4. Il soggetto è idoneo e prevede di sottoporsi a un ASCT o trapianto di organo durante lo studio
    5. Ipotensione ortostatica sintomatica che, secondo il giudizio medico dello sperimentatore, interferirebbe con la capacità del soggetto di ricevere in modo sicuro il trattamento o completare le valutazioni dello studio
    6. Infarto miocardico, angina non controllata, aritmie ventricolari gravi non controllate o evidenza elettrocardiografica (ECG) di ischemia acuta nei 6 mesi precedenti la visita del Mese 1-Giorno 1
    7. Stenosi valvolare grave (per es., stenosi aortica o mitralica con area valvolare <1,0 cm2) o grave cardiopatia congenita
    8. Evidenza ECG di ischemia acuta o anomalie attive del sistema di conduzione a eccezione di uno qualsiasi dei seguenti:
    • blocco atrio-ventricolare (AV) di primo grado;
    • blocco AV di secondo grado di tipo 1 (tipo Mobitz 1/tipo Wenckebach);
    • blocco di branca destra o sinistra;
    • fibrillazione atriale con una frequenza ventricolare controllata (non è consentita una frequenza ventricolare non controllata [>110 bpm; determinata da una media di 3 battiti nella derivazione II o 3 battiti rappresentativi se la derivazione II non è rappresentativa dell’ECG complessivo]).
    9. Neuropatia periferica valutata di Grado 2 con dolore, Grado 3 o Grado 4 secondo i Criteri terminologici comuni per gli eventi avversi del National Cancer Institute (NCI-CTCAE)
    10. Il soggetto sta ricevendo antibiotici, antifungini o antivirali per via orale o endovenosa entro 1 settimana dal Mese 1-Giorno 1, esclusi agenti profilattici per via orale
    11. Precedente trattamento con fattori di crescita ematopoietici, trasfusioni di sangue o emoderivati entro 1 settimana dal Mese 1-Giorno 1
    12. Precedente radioterapia entro 4 settimane dal Mese 1-Giorno 1
    13. Intervento di chirurgia maggiore entro 4 settimane dal Mese 1-Giorno 1 o intervento di chirurgia maggiore programmato durante lo studio
    14. Tumore maligno attivo, a eccezione di uno qualsiasi dei seguenti:
    • carcinoma basocellulare, carcinoma a cellule squamose o carcinoma in situ della cervice adeguatamente trattati;
    • tumore in stadio I adeguatamente trattato dal quale il soggetto è attualmente in remissione e lo è da 2 anni;
    • tumore della prostata a basso rischio con punteggio Gleason <7 e antigene prostatico specifico <10 ng/ml;
    • qualsiasi altro tumore dal quale il soggetto sia rimasto libero da malattia per =2 anni.
    15. Anamnesi di grave allergia a uno qualsiasi dei componenti di birtamimab, come istidina/L istidina cloridrato monoidrato, trealosio deidrato o polisorbato 20, oppure anamnesi di eventi avversi (EA) correlati all’infusione di grado =3 o ipersensibilità a un altro anticorpo monoclonale o ipersensibilità nota alla difenidramina (o un antistaminico H1 equivalente) o acetaminofene (o il suo equivalente paracetamolo)
    16. Infezione nota o anamnesi di infezione non controllata da virus dell’immunodeficienza umana (HIV), epatite B, epatite C o SARS-CoV-2 in fase attiva
    17. Precedente trattamento con chemioterapia mirata alle plasmacellule, birtamimab, daratumumab, 11-1F4, anticorpo anti-amiloide P sierica, doxiciclina per l’amiloide o altro trattamento sperimentale diretto all’amiloide
    18. Trattamento con un altro agente sperimentale entro 30 giorni dal Mese 1-Giorno 1
    19. Donne in gravidanza o che allattano al seno
    20, 21, 22 e 23 vedere EN nella sezione sottostante
    E.5 End points
    E.5.1Primary end point(s)
    Time to all-cause mortality
    tempo alla mortalità per qualsiasi causa.
    E.5.1.1Timepoint(s) of evaluation of this end point
    -Interim Efficacy Analysis will be conducted when approximately 50%
    (or 24) of the events have occurred
    -Primary Analysis - for all-cause mortality, all deaths occurring after the
    first infusion of study drug (i.e., Study Day 1) through the study's last
    subject last visit will be included.
    -Un’analisi ad interim sarà condotta quando si sarà verificato circa il 50% (o 24) degli eventi.
    -Analisi primaria - Per tutte le cause di mortalità, tutte le morti che si verificano dopo la
    prima infusione del farmaco di studio (cioè, Giorno di studio 1) fino all'ultima visita dell'ultimo paziente che sarà inclusa.
    E.5.2Secondary end point(s)
    •Change from baseline to Month 9 in the Physical Component Summary
    (PCS) score of the SF-36v2
    •Change from baseline to Month 9 in the 6MWT distance (meters)
    • Variazione dal basale al Mese 9 nel punteggio del Riassunto delle componenti fisiche (PCS) del questionario SF-36v2
    • Variazione dal basale al Mese 9 nella distanza (in metri) percorsa durante il test 6MWT
    E.5.2.1Timepoint(s) of evaluation of this end point
    from baseline until Month 9
    dal basale fino al mese 9
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA74
    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
    Czechia
    Denmark
    France
    Germany
    Greece
    Hungary
    Israel
    Italy
    Korea, Republic of
    Netherlands
    Poland
    Portugal
    Spain
    Taiwan
    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
    The study will end when approximately 47 primary endpoint events have occurred or at least 135 subjects have completed 9 months of
    treatment and EOT Visits have been completed for all subjects who remain on study at that time. Events are defined as deaths due to any
    cause.
    Lo studio terminerà quando si sono verificati circa 47 eventi primari o almeno 135 soggetti hanno completato 9 mesi di trattamento e le visite EOT sono state completate per tutti i soggetti che rimangono nello studio in quel momento. Gli eventi sono definiti come morti per qualsiasi causa.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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: 75
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 75
    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 state17
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 91
    F.4.2.2In the whole clinical trial 150
    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 the time of study completion, all subjects still on study (subjects still receiving study
    drug treatment [birtamimab or placebo], subjects who discontinue
    study drug early but agree to return for assessments after the ETD
    Visit, and subjects participating in the Vital Status Assessment Followup)
    may be considered for entry into an open-label extension study of
    birtamimab.
    Al momento del completamento dello studio, tutti i soggetti ancora in studio (soggetti che ancora ricevono il trattamento farmacologico in studio [birtamimab o placebo], soggetti che interrompono in anticipo il farmaco dello studio ma accettano di tornare per le valutazioni dopo la visita ETD, e soggetti che partecipano al follow up per la valutazione dello stato vitale possono essere presi in considerazione per l'immissione in uno studio di estensione in aperto di birtamimab.
    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 Decision2022-01-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-12-15
    P. End of Trial
    P.End of Trial StatusOngoing
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