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    Summary
    EudraCT Number:2019-004718-32
    Sponsor's Protocol Code Number:NL72607.041.20
    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:2021-10-18
    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 number2019-004718-32
    A.3Full title of the trial
    Upfront autologous hematopoietic stem cell transplantation versus immunosuppressive medication in early diffuse cutaneous systemic sclerosis: an international multicentre, open-label, randomized controlled trial
    Trapianto di cellule staminali ematopoietiche autologhe in anticipo rispetto alla terapia immunosoppressiva per la sclerosi sistemica cutanea diffusa precoce (UPSIDE): uno studio internazionale, multicentrico, in aperto, randomizzato e controllato – UPSIDE study
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Stem cell transplantation in diffuse cutaneous systemic sclerosis: upfront therapy or rescue therapy after failure of immunosuppressants?
    Trapianto di cellule staminali nella sclerosi sistemica cutanea diffusa: terapia iniziale o terapia di salvataggio dopo il fallimento degli immunosoppressori?
    A.3.2Name or abbreviated title of the trial where available
    UPSIDE study
    UPSIDE study
    A.4.1Sponsor's protocol code numberNL72607.041.20
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04464434
    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 SponsorUNIVERSITY MEDICAL CENTER UTRECHT
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportZonMW
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportDutch Arthritis Foundation
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Medical Centre Utrecht
    B.5.2Functional name of contact pointCoordinator UPSIDE trial
    B.5.3 Address:
    B.5.3.1Street AddressHeidelberglaan 100
    B.5.3.2Town/ cityUtrecht
    B.5.3.3Post code3584CX
    B.5.3.4CountryNetherlands
    B.5.6E-mailJ.Spierings@umcutrecht.nl
    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 Yes
    D.2.1.1.1Trade name cyclophosphamide
    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 nameEndoxan
    D.3.2Product code [L01AA01]
    D.3.4Pharmaceutical form Concentrate for solution for injection/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 INNCICLOFOSFAMIDE
    D.3.9.2Current sponsor code1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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: 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.2.1.1.1Trade name Mycophenolate mofetil
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    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 nameMycophenolate Mofetil
    D.3.2Product code [L04AA06]
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNACIDO MICOFENOLICO
    D.3.9.2Current sponsor code1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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 RoleComparator
    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 Granulokine
    D.2.1.1.2Name of the Marketing Authorisation holderAmgen Europe B.V.
    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 nameFilgrastim
    D.3.2Product code [L03AA02]
    D.3.4Pharmaceutical form Concentrate 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 INNFILGRASTIM
    D.3.9.2Current sponsor code1
    D.3.10 Strength
    D.3.10.1Concentration unit µg/ml microgram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    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: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 THYMOGLOBULINE - 5 MG/ML POLVERE PER CONCENTRATO PER SOLUZIONE PER INFUSIONE 1 FIALA DA 10 ML
    D.2.1.1.2Name of the Marketing Authorisation holderGENZYME EUROPE B.V.
    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 namethymoglobulin
    D.3.2Product code [L04AA04]
    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 INNIMMUNOGLOBULINA DI CONIGLIO ANTITIMOCITI UMANI
    D.3.9.2Current sponsor code1
    D.3.9.3Other descriptive nameTHYMOGLOBULINE
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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) Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Scleroderma is a rare, chronic disease of the immune system, blood vessels and connective tissue. It is an autoimmune condition, meaning that the immune system becomes overactive and attacks healthy tissue within the body. Hardening of the skin can be one of the first noticeable symptoms, as the body produces too much collagen. This excess of collagen can affect the skin, joints, tendons and internal organs. It causes scarring and stops the affected parts of the body from functioning normally.
    La sclerodermia è una malattia rara e cronica del sistema immunitario, dei vasi sanguigni e del tessuto connettivo. È una condizione autoimmune, il che significa che il sistema immunitario diventa iperattivo e attacca i tessuti sani all'interno del corpo. L'indurimento della pelle può essere uno dei primi sintomi evidenti, poiché il corpo produce troppo collagene. Questo eccesso di collagene può colpire la pelle, le articolazioni, i tendini e gli organi interni.
    E.1.1.1Medical condition in easily understood language
    Diffuse cutaneous systemic sclerosis is likely to affect the whole body, and there can be potentially serious complications involving the heart, lungs and kidneys.
    La sclerosi sistemica diffusa spesso causa danni cutanei che si diffondono a tutto il corpo, progredisce rapidamente. Le principali complicanze sono polmonare interstiziale e insufficienza renale.
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the optimal treatment strategy in early diffuse cutaneous systemic sclerosis (dcSSc): the effect of HSCT as upfront therapy compared with that of immunosuppressive medication in early dcSSc, with respect to survival and prevention of major organ failure (referred to as ‘event-free survival’ which is considered as primary endpoint), safety and the impact on skin thickening, visceral involvement, functional status, and quality of life
    Determinare la strategia di trattamento ottimale per il dcSSc precoce: l'effetto dell'HSCT come terapia iniziale rispetto ai farmaci immunosoppressivi nel dcSSc precoce in termini di sopravvivenza e di prevenzione dell'insufficienza d'organo grave (indicata come "sopravvivenza libera da eventi", che è considerata l'endpoint primario), sicurezza e impatto sull'ispessimento della pelle, coinvolgimento viscerale, stato funzionale e qualità della vita.
    E.2.2Secondary objectives of the trial
    Secondary Objectives:
    • Safety
    • Impact on skin thickening, visceral involvement, functional status, sexual functioning and quality of life
    • To determine cost-effectiveness of HSCT as upfront therapy compared to immunosuppressive medication and rescue HSCT
    • Biomarker substudies: To identify factors associated with response to treatment (including nailfold microscopy and skin biopsy characteristics, immune cell subsets).
    Gli obiettivi secondari sono di valutare:
    • Sicurezza
    • Impatto sull'ispessimento cutaneo, coinvolgimento viscerale, stato funzionale, funzionamento sessuale e qualità della vita
    • Determinare il rapporto costo-efficacia del trapianto come terapia iniziale rispetto ai farmaci immunosoppressivi e al trapianto di emergenza
    • Sottostudi sui biomarcatori: per identificare i fattori associati alla risposta al trattamento (compresi la microscopia delle pieghe ungueali e le caratteristiche della biopsia cutanea, sottogruppi di cellule immunitarie).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Life quality
    Version: v2.1
    Date: 13/05/2021
    Title: Quality of Life UPSIDE substudy
    Objectives: assess changes in quality of life after treatment

    Other types of substudies
    Specify title, date and version of each substudy with relative objectives: Biomarker substudies, v2.1, date 13.05.2021
    - Immunoreconstitution, ATG levels and autoantibodies
    - Eicosanoids in systemic sclerosis
    - Inflammatory and fibrotic characteristics of the skin
    - Hand mobility
    - Microvascular changes
    - Cardiac scleroderma
    - Quality of Life

    Qualita' della vita
    Versione: v2.1
    Data: 13/05/2021
    Titolo: Qualità della vita Sottostudio UPSIDE
    Obiettivi: valutare i cambiamenti nella qualità della vita dopo il trattamento

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Sottostudi sui biomarcatori, v2.1, data 13.05.2021
    - Immunoricostituzione, livelli di ATG e autoanticorpi
    - Eicosanoidi nella sclerosi sistemica
    - Caratteristiche infiammatorie e fibrotiche della pelle
    - Mobilità della mano
    - Cambiamenti microvascolari
    - Sclerodermia cardiaca
    - Qualità della vita
    E.3Principal inclusion criteria
    In order to be eligible to participate in this study, a subject must be eligible for HSCT treatment and therefore meet all of the following criteria:
    1. Age between 18 and 65 years.
    2. Fulfilling the 2013 ACR-EULAR classification criteria for SSc

    3. Disease duration = 2 years (from onset of first non-Raynaud’s symptoms) and diffuse cutaneous disease with
    - mRSS = 15 and/or

    - clinically significant organ involvement as defined by either:
    a) respiratory involvement = i. DLCO and/or (F)VC = 85% (of predicted) and evidence of interstitial lung disease on HR-CT scan with clinically relevant obstructive disease and emphysema excluded. ii. Patients with a DCLO and/or FVC > 85%, but with a progressive course of lung disease: defined as relative decline of >10% in FVC predicted and/or TLC predicted, or >15% in DLCO predicted and evidence of interstitial lung disease on HR-CT scan with clinically relevant obstructive disease and emphysema excluded, within 12 months. Intercurrent infections excluded.
    b) renal involvement = any of the following criteria: hypertension (two successive BP readings of either systolic = 160 mm Hg or diastolic > 110 mm Hg, at least 12 hours apart), persistent urinalysis abnormalities (proteinuria, haematuria, casts), microangiopathic haemolytic anaemia, new renal insufficiency (serum creatinine > upper limit of normal); non-scleroderma related causes (e.g. medication, infection etc.) must be reasonably excluded.
    c) cardiac involvement = any of the following criteria: reversible congestive heart failure, atrial or ventricular rhythm disturbances such as atrial fibrillation or flutter, atrial paroxysmal tachycardia or ventricu-lar tachycardia, 2nd or 3rd degree AV block, pericardial effusion (not leading to hemodynamic problems), myo-carditis; non-scleroderma related causes must have been reasonably excluded.

    4. Written Informed consent
    Pazienti di età compresa tra 18 e 65 anni con una diagnosi stabilita di dcSSc secondo i criteri ACR/EULAR. La durata della malattia dei pazienti (senza sintomi di Raynaud) deve essere = 2 anni e avere un mRSS = 15 (aspetto cutaneo diffuso) e/o un coinvolgimento d'organo clinicamente significativo (cardiaco e polmonare).
    E.4Principal exclusion criteria
    A potential subject who meets any of the following criteria will be excluded from participation in this study:
    1. Pregnancy (confirmed by positive pregnancy test) or unwillingness to use adequate contraception during study
    2. Concomitant severe disease =
    a) respiratory:
    - pulmonary hypertension: a resting mean pulmonary artery pressure (mPAP) > 25 mmHg (byright heart
    catheterisation),
    - DLCO < 40% predicted or
    - respiratory failure as defined by the primary endpoint (see 8.1)
    b) renal: creatinine clearance < 40 ml/min (measured or estimated)
    c) cardiac: clinical evidence of refractory congestive heart failure; LVEF < 45% by cardiac echo or cardiac
    MR; chronic atrial fibrillation necessitating oral anticoagulation; uncontrolled ventricular
    arrhythmia; pericardial effusion with hemodynamic consequences (10)
    d) liver failure as defined by a sustained 3-fold increase in serum transaminase or bilirubin, or a Child-
    Pugh score C
    e) psychiatric disorders including active drug or alcohol abuse
    f) concurrent neoplasms or myelodysplasia, leading to exclusion of cyclo-
    phosphamide, mycophenolate mofetil or autologous stem cell transplantation in routine clinical practice.
    g) bone marrow insufficiency defined as leukocytopenia < 4.0 x 109/L, thrombocytopenia < 50
    x 109/L, anaemia < 8 gr/dL, CD4+ T lymphopenia < 200 x 106/L
    h) uncontrolled hypertension (systolic blood pressure >150mmHg despite medication)
    Blood pressure needs to be controlled prior to inclusion
    i) uncontrolled acute or chronic infection, including HIV, HTLV-1,2 positivity, leading to exclusion of cyclo-
    phosphamide, mycophenolate mofetil or autologous stem cell transplantation in routine clinical practice.
    Infection needs to be treated/controlled prior to inclusion.
    j) ZUBROD-ECOG-WHO Performance Status Scale > 2 (Appendix C)
    k) Known hypersensitivity to any of the study drug constituents

    3. Previous treatments with immunosuppressants > 6 months including MMF, methotrexate, azathioprine, rituxi-mab, tocilizumab, glucocorticosteroids.

    4. Previous treatments with TLI, TBI or alkylating agents including CYC.

    5. Significant exposure to bleomycin, tainted rapeseed oil, vinyl chloride, trichlorethylene or silica;

    6. eosinophilic myalgia syndrome; eosinophilic fasciitis.

    7. Poor compliance of the patient as assessed by the referring physicians.
    Un potenziale soggetto che soddisfi uno qualsiasi dei seguenti criteri sarà escluso dalla partecipazione a questo studio:
    1. Gravidanza (confermata da test di gravidanza positivo) o riluttanza a usare un'adeguata contraccezione durante lo studio
    2. Malattia grave concomitante =
    a) respiratorio:
    - ipertensione polmonare: una pressione arteriosa polmonare media a riposo (mPAP) > 25 mmHg (byright heart
    cateterizzazione),
    - DLCO < 40% previsto o
    - insufficienza respiratoria definita dall'endpoint primario (vedere 8.1)
    b) renale: clearance della creatinina < 40 ml/min (misurata o stimata)
    c) cardiaco: evidenza clinica di insufficienza cardiaca congestizia refrattaria; LVEF < 45% per eco cardiaco o cardiaco
    SIG; fibrillazione atriale cronica che richiede anticoagulante orale; ventricolare incontrollato
    aritmia; versamento pericardico con conseguenze emodinamiche (10)
    d) insufficienza epatica come definita da un aumento sostenuto di 3 volte delle transaminasi o della bilirubina sieriche, o un
    Pug punteggio C
    e) disturbi psichiatrici compreso l'abuso di droghe attive o alcol
    f) neoplasie o mielodisplasia concomitanti, che portano all'esclusione del ciclo-
    fosfamide, micofenolato mofetile o trapianto autologo di cellule staminali nella pratica clinica di routine.
    g) insufficienza midollare definita come leucocitopenia < 4,0 x 109/l, trombocitopenia < 50
    x 109/l, anemia < 8 gr/dl, linfopenia T CD4+ < 200 x 106/l
    h) ipertensione non controllata (pressione sistolica >150 mmHg nonostante i farmaci)
    La pressione sanguigna deve essere controllata prima dell'inclusione
    i) infezione acuta o cronica non controllata, inclusa la positività all'HIV, HTLV-1,2, che porta all'esclusione del ciclo-
    fosfamide, micofenolato mofetile o trapianto autologo di cellule staminali nella pratica clinica di routine.
    L'infezione deve essere trattata/controllata prima dell'inclusione.
    j) ZUBROD-ECOG-WHO Scala dello stato di prestazione > 2 (Appendice C)
    k) Ipersensibilità nota a uno qualsiasi dei componenti del farmaco in studio

    3. Precedenti trattamenti con immunosoppressori > 6 mesi inclusi MMF, metotrexato, azatioprina, rituximab, tocilizumab, glucocorticosteroidi.

    4. Trattamenti precedenti con TLI, TBI o agenti alchilanti incluso CYC.

    5. Esposizione significativa a bleomicina, olio di colza contaminato, cloruro di vinile, tricloroetilene o silice;

    6. sindrome mialgica eosinofila; fascite eosinofila.

    7. Scarsa compliance del paziente valutata dai medici di riferimento.
    E.5 End points
    E.5.1Primary end point(s)
    The main study parameter is event-free survival 2 year after randomisation
    Il principale parametro dello studio è la sopravvivenza libera da eventi a 2 anni dopo la randomizzazione/inizio del trattamento.
    E.5.1.1Timepoint(s) of evaluation of this end point
    In the first 2 years 3-monthly, year 2-5 annually.
    Nei primi 2 anni trimestrale, anno 2-5 annuale.
    E.5.2Secondary end point(s)
    Overall survival (OS), progression-free survival, number of participants who required rescue therapy (i.e. alternative treatment) due to treatment failure. Treatment-related mortality, treatment toxicity, and changes in mRSS, FVC, TLC and Dlco, nail fold microscopy, and cardiac MRI. The CRISS at 12 months. Safety and tolerability outcomes according to CTC criteria (CTCAE v5.0) and BMT-CTN classification (viral infections).
    Sopravvivenza globale (OS), sopravvivenza libera da progressione, numero di partecipanti che hanno richiesto una terapia di salvataggio (cioè il trattamento alternativo) a causa del fallimento del trattamento. Mortalità legata al trattamento, tossicità del trattamento e cambiamenti in mRSS, FVC, TLC e DLCO, microscopia delle pieghe delle unghie e RM cardiaca. Il CRISS a 12 mesi. Esiti di sicurezza e tollerabilità secondo i criteri CTC (CTCAE v5.0) e la classificazione BMT-CTN (infezioni virali).
    E.5.2.1Timepoint(s) of evaluation of this end point
    All abovementioned time points are measured at 6,12,18,21,24, 36, 48, 60m.
    Tutti i suddetti punti temporali sono misurati a 6,12,18,21,24, 36, 48, 60m.
    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 No
    E.6.4Safety No
    E.6.5Efficacy No
    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 Yes
    E.6.13.1Other scope of the trial description
    optimal timing of different treatment strategies
    treatment strategy
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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) Yes
    E.8.2.2Placebo No
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    after completion of the last visit of the last included patient.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years10
    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 years10
    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: 120
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3.2Women of child-bearing potential using contraception No
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 120
    F.4.2.2In the whole clinical trial 120
    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)
    Patients are treated according to usual care after participation in the trial.
    I pazienti sono trattati secondo le cure consuete dopo la partecipazione allo studio.
    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 Decision2022-02-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-02-09
    P. End of Trial
    P.End of Trial StatusOngoing
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