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    Summary
    EudraCT Number:2017-005034-36
    Sponsor's Protocol Code Number:CIDPRIT
    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:2020-11-04
    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 number2017-005034-36
    A.3Full title of the trial
    An Italian database-based randomized controlled trial with Rituximab in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
    Studio randomizzato controllato con rituximab in pazienti con poliradicoloneuropatia cronica infiammatoria demielinizzante (CIDP). Studio basato sul database italiano
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study evaluating the effect of rituximab in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
    Studio che valuta l'effetto del farmaco rituximab nei pazienti con poliradicoloneuropatia cronica infiammatoria demielinizzante (CIDP) in trattamento cronico con immunoglobuline
    A.3.2Name or abbreviated title of the trial where available
    A randomized controlled trial of rituximab in CIDP (CIDPRIT)
    Studio randomizzato controllato sulla efficacia di rituximab in CIDP (CIDPRIT)
    A.4.1Sponsor's protocol code numberCIDPRIT
    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 SponsorIRCCS ISTITUTO CLINICO HUMANITAS
    B.1.3.4CountryItaly
    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 supportAIFA - Italian Medicines Agency
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIRCCS Istituto Clinico Humanitas
    B.5.2Functional name of contact pointProf. Eduardo Nobile-Orazio
    B.5.3 Address:
    B.5.3.1Street AddressVia Manzoni 56
    B.5.3.2Town/ cityRozzano (MI)
    B.5.3.3Post code20089
    B.5.3.4CountryItaly
    B.5.4Telephone number0282242209
    B.5.5Fax number0282242298
    B.5.6E-maileduardo.nobile_orazio@humanitas.it
    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 MABTHERA - 1 FIALA 500 MG 50 ML
    D.2.1.1.2Name of the Marketing Authorisation holderROCHE REGISTRATION LIMITED
    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 nameRituximab
    D.3.2Product code [Rituximab]
    D.3.4Pharmaceutical form Concentrate 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 INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.2Current sponsor codeRituximab
    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: 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 TACHIPIRINA - 1000 MG COMPRESSE 8 COMPRESSE
    D.2.1.1.2Name of the Marketing Authorisation holderAZIENDE CHIMICHE RIUNITE ANGELINI FRANCESCO ACRAF SPA
    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
    D.3.2Product code [Paracetamolo]
    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.3.9.1CAS number 103-90-2
    D.3.9.2Current sponsor codeParacetamolo
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    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 SOLU MEDROL - 125 MG/2 ML POLVERE E SOLVENTE PER SOLUZIONE INIETTABILE 1 FLACONE A DOPPIA CAMERA DA 125 MG/2 ML
    D.2.1.1.2Name of the Marketing Authorisation holderPFIZER ITALIA S.R.L.
    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 nameMetilprednisolone sodio succinato
    D.3.2Product code [Metilprednisolone sodio succinato]
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    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 INNMETILPREDNISOLONE SODIO SUCCINATO
    D.3.9.1CAS number 83-43-2
    D.3.9.2Current sponsor codeMETILPREDNISOLONE
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number63
    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.2.1.1.1Trade name TRIMETON - 10 MG/1 ML SOLUZIONE INIETTABILE 5 FIALE 1 ML
    D.2.1.1.2Name of the Marketing Authorisation holderMSD ITALIA S.R.L.
    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 nameClorfenamina maleato
    D.3.2Product code [Clorfenamina maleato]
    D.3.4Pharmaceutical form Solution for injection
    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 INNCLORFENAMINA MALEATO
    D.3.9.1CAS number 132-22-9
    D.3.9.2Current sponsor codeCLORFENAMINA MALEATO
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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.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
    Chronic inflammatory demyelinating polyradiculoneuropathy
    Poliradicoloneuropatia cronica infiammatoria demielinizzante
    E.1.1.1Medical condition in easily understood language
    Chronic inflammatory demyelinating polyradiculoneuropathy
    Polineuropatia cronica infiammatoria demielinizzante
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10072650
    E.1.2Term CIDP
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10057645
    E.1.2Term Chronic inflammatory demyelinating polyradiculoneuropathy
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10057645
    E.1.2Term Chronic inflammatory demyelinating polyradiculoneuropathy
    E.1.2System Organ Class 10029205 - Nervous 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 of this study is to assess whether rituximab is effective in CIDP permitting to suspend immunoglobulin therapy without clinical worsening
    L'obiettivo primario dello studio ¿ valutare se nei pazienti con CIDP il trattamento con rituximab sia efficace nel prevenire il peggioramento della malattia dopo la sospensione di sei mesi di trattamento con immunoglobuline
    E.2.2Secondary objectives of the trial

    The secondary objective is to evaluate whether treatment with rituximab may improve the response to therapy compared to placebo in patients treated with immunoglobulins and whether it may allow delay of the mean worsening time after discontinuation of immunoglobulin therapy. The exploratory objectives are the correlation between the response to rituximab therapy and the clinical form of CIDP and the presence of antibody reactivity against Ranvier node antigens.
    L¿obiettivo secondario ¿ valutare se il trattamento con rituximab pu¿ migliorare la risposta alla terapia in confronto al placebo nei pazienti trattati con immunoglobuline e se pu¿ permetter di ritardare il tempio medio di peggioramento dopo la sospensione della terapia con immunoglobuline. Gli obiettivi esplorativi sono la correlazione tra la risposta alla terapia con rituximab e la forma clinica di CIDP e la presenza di reattivit¿ anticorpali contro antigeni del nodo di Ranvier
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Subject is = 18 years of age at Visit 1 (screening)
    - Subject has a documented diagnosis of definite or probable CIDP according to the EFNS/PNS criteria 2010 (Joint Task Force of the EFNS and the PNS, 2010)
    -. Subject has an Ig-dependency confirmed by clinical examination in the 12 months before screening and documented in medical history (ie, that a decrease or withdrawal of immunoglobulin was attempted that resulted in a clinically relevant decrease in function)
    - If the Ig dependency has been confirmed within 12 to 6 months before screening, the subject has to be on a stable dosage (not more than ±20% deviation) for SCIg or IVIg and a fixed interval for at least 3 months of either treatment, ie, once or twice weekly ±2 days for SCIg or every 2 to 8 weeks ±5 days for IVIg, respectively, for stability in functioning between dosing. If the Ig dependency has been confirmed within 6 months before Screening Visit, the stable dose and fixed interval is not required
    - Subject can take steroids at the maximum dosage equivalent to 12.5 mg/day of prednisone or 25 mg on alternate day or pulsed 400 mg/monthly of methylprednisolone as far as the dosage has been maintained stable (± 20%) in the previous 6 months. This treatment should be maintained unchanged during the sixmonth treatment period and the six-month follow-up period
    - Subject has adequate peripheral venous access
    - Female subjects of childbearing potential must have a negative serum pregnancy test and agree to use a highly effective method of birth control, during the study and for a period 12 months after their last dose of study drug
    - Male subject with a partner of childbearing potential must be willing to use an highly effective method of birth control when sexually active during the study and for 12 months after the final administration of rituximab/placebo.
    - Uomini e donne dell’età di almeno 18 anni all’inclusione che abbiamo firmato il consenso informato a partecipare allo studio
    - Diagnosi di CIDP definita o probabile secondo i criteri della EFNS/PNS del 2010
    - Soggetti con una dipendenza dalla terapia con immunoglobuline nei 12 mesi prima dello screening e documentato dalla storia clinica, nella quale un tentativo di riduzione o sospensione delle immunoglobuline è risultato in un peggioramento funzionale
    - Se la dipendenza dalle immunoglobuline è stata dimostrata tra i 6 e 12 mesi prima dello screening il paziente deve aver ricevuto un dosaggio stabile di immunoglobuline (con una variazioni di non più del ±20%) per le SCIg o IVIg e con un intervallo fisso tra le somministrazioni per al meno tre mesi per ciascun trattamento, tipo una o due volte alla settimana ±2 giorni per le SCIg o ogni 2-8 settimane ±5 giorni per le IVIg, per mantenere la stabilità funzionale tra le dosi. Se la dipendenza dalle immunoglobuline è stata confermata nei 6 mesi precedenti lo screening, la dose e l’intervallo fisso non sono richiesti
    - Il soggetto può assumere corticosteroidi al dosaggio massimo equivalente a 12.5 mg/die di prednisone oppure 25 mg a giorni alterni oppure 400 mg/mese di metilprednisolone sempre che il dosaggio sia rimasto stabile (±20%) nei 6 mesi precedenti. Questo dosaggio dovrà essere mantenuto costante per i sei mesi del trattamento e per i sei mesi successivi di follow-up
    - Soggetti con un adeguato accesso venoso periferico
    - Donne in età fertile con un test di gravidanza negativo e disponibili ad una contraccezione altamente efficace durante il periodo dello studio e nei dodici mesi successivi alla assunzione dell’ultima dose di rituximab/placebo
    - Uomini aventi una compagna in età fertile che siano disponibili ad assumere un sistema di contraccezione altamente efficace nei rapporti durante lo studio e nei dodici mesi successivi alla assunzione dell’ultima dose di rituximab/placebo.
    E.4Principal exclusion criteria
    - Subject has a current diagnosis or has a history of Type 1 or Type 2 diabetes mellitus
    - Subject with IgM paraproteinemia with anti-myelin associated glycoprotein antibodies
    - Subject has Multifocal Motor Neuropathy with conduction block (MMN)
    - Patient with a CIDP relapse or significant worsening of symptoms within 6 months of randomization
    - Clinical or known evidence of associated medical conditions that might cause neuropathy including but not limited to connective tissue disease, Lyme disease, cancer (with the exclusion of benign skin cancer), Castleman’s disease and systemic lupus erythematosus, malignant plasma cell dyscrasia, lymphoma,
    osteosclerotic myeloma, POEMS, or agents that may lead to neuropathy eg, amiodarone therapy
    - Female who is pregnant or lactating
    - Subjects has any medical condition (acute or chronic illness) or psychiatric condition that, in the opinion of the investigator, could harm the subject or would compromise the subject’s ability to participate in the study
    - Subject with congestive heart failure or a moderate or higher impairment of cardiac function
    - Subject has renal impairment defined as: serum creatinine > 1.4 mg/dL for females and 1.5 mg/dL for males
    - Subject has an absolute neutrophil count <4000/mm3, lymphocyte count < 800/mm3, platelet count <100,000/mm3
    - Subject has liver impairment defined as total or conjugated bilirubin >1.5 × upper limit of the normal (ULN) range, unless in context of Gilbert’s syndrome; aspartate aminotransferase (AST), alanine aminotransferase (ALT) >3 × ULN range; alkaline phosphatase (AP) >1.5 × ULN range; gammaglutamyl-transferase (GGT) >3 × ULN range
    - Subject has a history of chronic alcohol or drug abuse within the previous 12 months
    -. Subject has a history of clinically relevant ongoing chronic infections including but not limited to human immunodeficiency virus (HIV), hepatitis B, hepatitis C, active or latent tuberculosis or is tested positive for HIV (anti-HIV1 or anti-HIV2 antibodies) hepatitis B (HBsAG positive or HBcAb positive without HBsAb) or hepatitis C (HCV antibodies) at the screening visit
    - Subject has severe immunocompromission or a family history of primary immunodeficiency
    - Subject has a clinical relevant active infection (eg. sepsis, pneumonia, and abscess) or has had a serious infection (resulting in hospitalization or parenteral antibiotic treatment) within 6 weeks prior to the first dose of rituximab/placebo
    - Subject has an active neoplastic disease or history of neoplastic disease within 5 years of study entry (except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the uterine cervix which has been definitely treated with standard of care approaches)
    - Subject was treated with plasma exchange or immunoabsorption within 3 months of randomization, with immunosuppressive/chemotherapeutic medications including azathioprine, cyclophosphamide, cyclosporine, mycophenolate, etanercept, methotrexate within 6 months of randomization, other immunosuppressive medications (including mitoxantrone, alemtuzumab, cladribine, pimecrolimus , IPP- 201101) at any time; total lymphoid irradiation or hematopoietic stem cell transplantation at any time; any biological therapy within 12 months of randomization
    - Steroids at a dose superior to the equivalent dose of 12.5mg/day or 25 mg on alternate day of oral prednisone or of pulsed 400mg/month of intravenous or intravenous methylprednisolone
    - Subject has received a live vaccination within 8 weeks prior to the baseline visit or intend to have live vaccination during the course of the study or within 7 weeks following the final dose of rituximab/placebo
    - Subject has had prior treatment with rituximab in the 12 months before inclusion
    - History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.
    - Diagnosi corrente o storia di diabete mellito di tipo 1 o 2
    - Soggetti con gammopatia monoclonale IgM con anticorpi anti-MAG
    - Soggetti con neuropatia motoria multifocale
    - Importante ricaduta o peggioramento della CIDP nei sei mesi precedenti l’inclusione
    - Evidenza clinica o anamnestica di altre patologie che possano causare la neuropatia ivi incluse ma non limitate a malattie del connettivo, malattia di Lyme, neoplasia (con la esclusione di neoplasia benigne della cute), malattia di Castleman, lupus sistemico eritematoso, discrasia plasmacellulare maligna, linfoma, mieloma osteosclerotico, POEMS, o uso di sostanze che possano aver causato la neuropatia, quali amiodarone
    - Donne in gravidanza o in allattamento attivo o che pianificano una gravidanza durante il periodo dello studio
    - Evidenza di altre patologie cliniche o psichiatriche che, a parere dell’esaminatore, possano interferire con la partecipazione del paziente allo studio o la valutazione della risposta alla terapia
    - Paziente con scompenso cardiaco congestizio o con moderata insufficienza cardiaca
    - Paziente con insufficienza renale, definite come valori di creatininemia =1.4 mg/dL per le donne e =1.5 mg/dL per gli uomini
    - Pazienti con conta di leucociti <4000/mm3, linfociti < 800/mm3, e piastrine <100000/mm3
    - Pazienti con compromissione epatica definita come valori di bilirubina coniugata > 1,5 i valori superiori della norma, se non nell’ambito di un ittero di Gilbert; aspartatoamino transferasi (AST) o alaninaamino transferasi (ALT) > 3 volte il limite superiore della norma, fosfatasi alcalina superiore a 1,5 i valori superiori della norma, gammaglutamiltransferasi (gammGT) >3 volte i limiti superiori della norma
    - Paziente con uso cronico di alcol o stupefacenti negli ultimi 12 mesi
    - Paziente con storia clinicamente rilevante di infezione cronica attiva ivi compreso ma non limitata a infezione da virus dell’immunodeficienza acquisita (HIV), epatite B, epatite C, tubercolosi attiva o latente, o risulta essere positivo al test per HIV (anticorpi anti-HIV1 o anti-HIV2), epatite B (positività HBsAg o HBcAb senza positività per HBsAb), o epatite C (HCAb) alla visita di screening
    - Il soggetto ha una immunocompromissione severa o una storia famigliare di immunodeficienza primaria
    - Storia di infezione importante risultante in una ospedalizzazione o in un trattamento con antibiotici per via sistemica nelle sei settimane precedenti la prima infusione di rituximab/placebo
    - Paziente con neoplasia in atto o una storia di neoplasia nei cinque anni precedenti lo screening escluse carcinoma da cellule basali o squamose della cute e carcinoma in sito della cervice uterine che siano state adeguatamente trattate in modo definitivo
    - Pazienti trattati con plasmaferesi o con immuno assorbimento negli ultimi tre mesi, con immunosoppressori o chemioterapici inclusi azatioprina, ciclofosfamide, ciclosporina, micofenolato, etanercept, metotressato negli ultimi 6 mesi prima dello screening o altri immunosoppressore tra cui mitoxantrone, alemtuzumab, cladribina, pimecrolimus , IPP-201101 in qualsiasi momento, trapianto di cellule staminali o irradiazione totale linfoide in qualsiasi momento o con qualsiasi terapia biologica negli ultimi 12 mesi
    - Corticosteroidi orali al dosaggio superiore all’equivalente di 12,5 mg al giorno o 25 mg/die alterni di prednisone, o 400 mg al mese di metilprednisolone in vena a bolo
    - Soggetti sottoposti a vaccinazione con vaccini viventi nelle 8 settimane precedenti lo screening o che intendano sottoporsi a vaccinazione con vaccini vivi nel corso dello studio o nelle 7 settimane successive all’ultima dose di rituximab placebo
    - Soggetti che abbiamo ricevuto il Rituximab nei 12 mesi precedenti lo screening
    - Soggetti con ipersensibilità a qualsiasi dei prodotti usati nello studio o a farmaci di simile composizione chimica.
    E.5 End points
    E.5.1Primary end point(s)
    To determine the efficacy of rituximab compared to placebo in reducing the proportion of patients with CIDP who worsen by at least one point in the INCAT score or two-points in the MRC sum-score or four points in the R-ODS score within six months after suspension of the treatment with immunoglobulins
    Differenza nella percentuale dei pazienti trattati con rituximab o placebo che peggiorano di un punto della scala INCAT o di due punti della scala di forza MRC o di quattro punti della scala RODs nei sei mesi successivi alla sospensione della terapia con immunoglobuline
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint will be evaluated at month 12 after the start of treatment with rituximab
    L'endpoint primario sarà valutato a 12 mesi dall'inizio del trattamento con rituximab
    E.5.2Secondary end point(s)
    To determine whether the treatment with rituximab to IVIg or SCIg in patients with CIDP may improve the disability (INCAT score and R-ODS score) and impairment (MRC sums-core for muscle strength) compared to placebo; To determine the efficacy of rituximab compared to placebo in reducing the number of patients with CIDP who worsen by at least one point in the INCAT score, two-points in the MRC sum-score or four points in the R-ODS score within 12 months and 18 months after suspension of the treatment with immunoglobulins; To determine the proportion of patients who suspend the treatment with rituximab or placebo for adverse events or for voluntary reasons or who develop adverse events in the 12 months following the start of treatment with rituximab; To compare the mean time for patients with CIDP treated with rituximab or placebo to worsen by at least one point in the INCAT score, two-points in the MRC sum-score or four points in the R-ODS score after suspension of the treatment with immunoglobulins; To determine whether the association of rituximab to IVIg or SCIg in patients with CIDP may improve compared to placebo the quality of life of the patients determined by SF-36 score after 6, 12, 18 and 24 months from the start of treatment with rituximab; Exploratory endpoint: To determine the difference between patients treated with rituximab or placebo in the mean variation of motor conduction block, negative distal CMAP amplitude, motor conduction velocity, distal and F-wave latencies in the two most relevant nerve between at the baseline and months 6, 12 and 24.; Exploratory endpoints: - To correlate the response to therapy with rituximab with the clinical form of typical or atypical CIDP - To correlate the response to therapy with rituximab in patients with CIDP with the presence of antibody reactivities against proteins at the node of Ranvier (contactin 1 and neurofascin 155)
    Differenza tra i pazienti trattati con rituximab e placebo nei punteggi delle scale INCAT, R_ODS e MRC; Differenza nella percentuale dei pazienti trattati con rituximab o placebo che peggiorano di un punto della scala INCAT o di due punti della scala di forza MRC o di quattro punti della scala RODs nei 12 mesi e 18 mesi successivi alla sospensione della terapia con immunoglobuline; Differenza nella percentuale di pazienti che interrompono il trattamento con rituximab o placebo per effetti collaterali o per sospensione volontaria o che sviluppano tali effetti nei 12 mesi successivi al trattamento con rituximab; Differenza nel tempo mediano intercorrente tra la sospensione della terapia con immunoglobuline e la comparsa di peggioramento di un punto della scala INCAT o di due punti della scala di forza MRC o di quattro punti della scala RODs tra i pazienti trattati con rituximab o placebo; Differenza tra i pazienti trattati con rituximab o con placebo nel miglioramento della qualit¿ della vita secondo la scala SF-36 dopo 6, 12, 18 e 24 mesi dall¿inizio del trattamento con rituximab; Endpoint esplorativo: Differenza tra i pazienti trattati con rituximab o con placebo nella variazione media, nei due nervi scelti come emblematici, dei parametri blocco di conduzione, area negativa del CMAP distale, velocit¿ di conduzione, latenza distale, latenza dell¿onda F, alla fine del 6°, del 12° e del 24° mese, rispetto alla valutazione eseguita al basale; Endpoint esplorativi: - Differenza nella risposta alla terapia in termini di percentuale di pazienti che non peggiorano tra la forma tipica e atipica di CIDP - Differenza nella risposta alla terapia in termini di percentuale di pazienti che non peggiorano a 12 e 24 mesi e la presenza o assenza di anticorpi contro le proteine del nodo di Ranvier (contactina 1 e neurofascina 155)
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 6, 12, 18 and 24 months from the start of treatment with rituximab; The endpoint will be evaluated at months 18 and 24 after the start of treatment with rituximab; The endpoint will be assessed during the 12 months following the start of treatment with rituximab; The endpoint will be evaluated after 12 months from the start of treatment with rituximab; The endpoint will be evaluated after 6, 12, 18 and 24 months from the start of treatment with rituximab; The endpoint will be assessed at months 6,12 and 24 after the visit at the screening; The endpoints will be evaluated at the end of the study
    Al termine dei mesi 6, 12, 18 e 24 dopo l'inizio del trattamento con rituximab; L'endpoint sarà valutato ai mesi 18 e 24 dopo l'inizio del trattamento con rituximab; L'endpoint sar¿ valutato durante i 12 mesi successivi all''inizio del trattamento con rituximab; L'endpoint sar¿ valutato dopo 12 mesi dall'inizio del trattamento con rituximab; L'endpoint sar¿ valutato dopo 6, 12, 18 e 24 mesi dall¿inizio del trattamento con rituximab; L'endpoint sarà valutato al mese 6, 12 e 24 dopo la visita basale; Gli endpoint saranno valutati alla fine dello studio
    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 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 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 concerned11
    E.8.5The trial involves multiple Member States No
    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 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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years3
    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: 36
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 60
    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 will be monitored and treated according to local clinical practice
    I pazienti saranno seguiti e trattati in accordo alla pratica clinica locale
    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 Decision2018-05-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-04-17
    P. End of Trial
    P.End of Trial StatusOngoing
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