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    Summary
    EudraCT Number:2020-003233-38
    Sponsor's Protocol Code Number:WA41937
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-04
    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 number2020-003233-38
    A.3Full title of the trial
    A PHASE III, RANDOMIZED, OPEN-LABEL ACTIVE COMPARATOR-CONTROLLED MULTICENTER STUDY TO EVALUATE EFFICACY AND SAFETY OF OBINUTUZUMAB IN PATIENTS WITH PRIMARY MEMBRANOUS NEPHROPATHY
    STUDIO DI FASE III, RANDOMIZZATO, IN APERTO, CONTROLLATO VERSO TRATTAMENTO ATTIVO, MULTICENTRICO, VOLTO A VALUTARE L’EFFICACIA E LA SICUREZZA DI OBINUTUZUMAB IN PAZIENTI AFFETTI DA NEFROPATIA MEMBRANOSA PRIMITIVA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Evaluate Efficacy and Safety of Obinutuzumab in Patients with Primary Membranous Nephropathy
    STUDIO VOLTO A VALUTARE L’EFFICACIA E LA SICUREZZA DI OBINUTUZUMAB IN PAZIENTI AFFETTI DA NEFROPATIA MEMBRANOSA PRIMITIVA
    A.3.2Name or abbreviated title of the trial where available
    A Study to Evaluate Efficacy and Safety of Obinutuzumab in Patients with Primary Membranous Nephropa
    STUDIO VOLTO A VALUTARE L’EFFICACIA E LA SICUREZZA DI OBINUTUZUMAB IN PAZIENTI AFFETTI DA NEFROPATIA
    A.4.1Sponsor's protocol code numberWA41937
    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 SponsorF. HOFFMANN - LA ROCHE LTD.
    B.1.3.4CountrySwitzerland
    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 supportF. Hoffmann-La Roche Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF.Hoffmann-La Roche Ltd
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.6E-mailglobal.rochegenentechtrials@roche.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 Yes
    D.2.1.1.1Trade name Gazyvaro
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH EU/1/14/937/001
    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 nameObinutuzumab
    D.3.2Product code [RO5072759]
    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 INNOBINUTUZUMAB
    D.3.9.1CAS number 949142-50-1
    D.3.9.2Current sponsor codeRO5072759
    D.3.9.3Other descriptive nameOBINUTUZUMAB/ GA101
    D.3.9.4EV Substance CodeSUB32751
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 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 Prograf
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas PZN 03053793
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameTacrolimus
    D.3.2Product code [RO0485337]
    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 INNTACROLIMUS
    D.3.9.1CAS number 104987-11-3
    D.3.9.2Current sponsor codeRO0485337
    D.3.9.4EV Substance CodeSUB10797MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    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: 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 Prograf
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas - PZN 04228786
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameTacrolimus
    D.3.2Product code [RO0485337]
    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 INNTACROLIMUS
    D.3.9.1CAS number 104987-11-3
    D.3.9.2Current sponsor codeRO0485337
    D.3.9.4EV Substance CodeSUB10797MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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 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 Adoport
    D.2.1.1.2Name of the Marketing Authorisation holderSandoz BE356526
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    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 nameTacrolimus
    D.3.2Product code [RO0485337]
    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 INNTACROLIMUS
    D.3.9.1CAS number 104987-11-3
    D.3.9.2Current sponsor codeRO0485337
    D.3.9.4EV Substance CodeSUB10797MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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 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 Prograf
    D.2.1.2Country which granted the Marketing AuthorisationAustralia
    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 nameTacrolimus
    D.3.2Product code [RO0485337]
    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 INNTACROLIMUS
    D.3.9.1CAS number 104987-11-3
    D.3.9.2Current sponsor codeRO0485337
    D.3.9.4EV Substance CodeSUB10797MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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: 6
    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 Adoport
    D.2.1.1.2Name of the Marketing Authorisation holderSandoz BE356501
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    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 nameTacrolimus
    D.3.2Product code [RO0485337]
    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 INNTACROLIMUS
    D.3.9.1CAS number 104987-11-3
    D.3.9.2Current sponsor codeRO0485337
    D.3.9.4EV Substance CodeSUB10797MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    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: 7
    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 Prograf
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas AUST R 77280
    D.2.1.2Country which granted the Marketing AuthorisationAustralia
    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 nameTacrolimus
    D.3.2Product code [RO0485337]
    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 INNTACROLIMUS
    D.3.9.1CAS number 104987-11-3
    D.3.9.2Current sponsor codeRO0485337
    D.3.9.4EV Substance CodeSUB10797MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    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.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
    Primary Membranous Nephropathy (pMN)
    Nefropatia membranosa primitiva
    E.1.1.1Medical condition in easily understood language
    pMN is a kidney-specific, autoimmune glomerular disease that presents with increased protein in the urine associated with an injury in glomeruli
    pMN è una malattia glomerulare autoimmune specifica dei reni che si presenta con un aumento delle proteine nelle urine associato a una lesione nei glomeruli
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10027170
    E.1.2Term Membranous nephropathy
    E.1.2System Organ Class 100000004857
    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 obinutuzumab compared with tacrolimus on the basis of the proportion of patients who achieve a complete remission (CR) at Week 104
    valutare l’efficacia di obinutuzumab rispetto a tacrolimus sulla base della percentuale di pazienti che raggiungono una risposta completa (Complete Response, CR) alla Settimana 104.
    E.2.2Secondary objectives of the trial
    •To evaluate the efficacy of obinutuzumab compared with tacrolimus on the basis of the proportion of patients who achieve an overall remission at Week 104, CR at Week 76, relapse by Week 104, receive escape therapy by Week 104, achieve immunologic remission at Week 52, mean change in ankle circumference from baseline to Week 104, patients with >= 30% reduction in Estimated glomerular filtration rate (eGFR) from baseline to Week 104, mean change from baseline in the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Assessment of Physical Health scale at Week 104, mean change from baseline in the PROMIS Fatigue scale at Week 104 and duration of CR
    •To evaluate the safety of obinutuzumab compared with tacrolimus
    •To characterize the pharmacodynamic effects of obinutuzumab in pMN patients
    •To characterize the pharmacokinetics of obinutuzumab in the pMN population
    •To evaluate the immune response to obinutuzumab
    Per valutare l'efficacia di obinutuzumab rispetto a tacrolimus sulla base della percentuale di pazienti che raggiungono una remissione globale alla sett 104, CR alla settimana 76, recidiva entro la settimana 104, ricevono la terapia di fuga entro la sett 104, raggiungono la remissione immunologica alla settimana 52 , variazione media della circonferenza della caviglia dal basale alla sett 104, pazienti con riduzione>= 30% della velocità di filtrazione glomerulare stimata (eGFR) dal basale alla settimana 104, variazione media rispetto al basale nel sistema PROMIS globale Scala di valutazione della salute fisica alla sett 104, variazione media rispetto al basale nella scala PROMIS Fatigue alla settimana 104 e durata della CR • Valutare la sicurezza di obinutuzumab rispetto a tacrolimus • Caratterizzare gli effetti farmacodinamici di obinutuzumab nei pazienti con pMN • Caratterizzare la farmacocinetica di obinutuzumab nella popolazione pMN• Valutare la risposta immunitaria a obinutuzumab
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Age 18-75 years
    •Diagnosis of pMN according to renal biopsy prior to or during screening
    •Urinary protein-to-creatinine ratio (UPCR) >= 5 g from 24-hour urine collection despite best supportive care for >= 3 months prior to screening or UPCR >= 4 g despite best supportive care >= 6 months prior to screening
    •Systolic blood pressure <= 140 mmHg and diastolic blood pressure <= 90 mmHg at screening
    •eGFR >= 40 mL/min/1.73m2 or qualified endogenous creatinine clearance >= 40 mL/min based on 24-hour urine collection during screening
    •Patients who previously responded to calcineurin inhibitor (CNIs), rituximab, or alkylating agents with either a CR or partial remission and subsequently relapsed are eligible but require discontinuation of CNIs or alkylating agents for >= 6 months and rituximab for >= 9 months prior to screening
    •For women of childbearing potential: agreement to remain abstinent or use adequate contraception during the treatment period and for 18 months after the final dose of obinutuzumab and for 28 days after the final dose of tacrolimus
    •For men receiving tacrolimus: agreement to remain abstinent or use a condom, as defined below: With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 28 days after the final dose of tacrolimus to avoid exposing the embryo
    •For patients enrolled in the extended China enrollment phase at National Medical Products Administration-recognized sites: current resident of mainland China and of Chinese ancestry
    -Età compresa tra 18 e 75 anni al momento della sottoscrizione del modulo di consenso informato.
    -Capacità di rispettare il protocollo dello studio, a giudizio dello sperimentatore.
    -Diagnosi di pMN confermata da biopsia renale prima o durante la fase di screening.
    - UPCR >= 5 g su campione urinario delle 24 ore nonostante l’impiego della miglior terapia di supporto per >=3 mesi prima della fase di screening oppure UPCR >= 4 g nonostante l’impiego della miglior terapia di supporto per >= 6 mesi prima dello screening.
    -Pressione arteriosa sistolica <= 140 mmHg e diastolica <= 90 mmHg allo screening.
    - eGFR >= 40 mL/min/1.73m2 oppure idonea clearance della creatinina endogena >= 40 mL/min su campione urinario delle 24 ore durante lo screening.
    -I pazienti che hanno precedente risposto con una CR o PR alla terapia con CNI (CsA o tacrolimus), rituximab o agenti alchilanti e che sono successivamente recidivati, sono eleggibili purché la terapia con CNI o con agenti alchilanti sia stata interrotta per un periodo >= 6 mesi prima dello screening e la terapia con rituximab sia stata interrotta per un periodo >= 9 mesi prima dello screening.
    -Per le donne in età fertile: consenso a praticare l’astinenza dai rapporti eterosessuali o a fare uso di un adeguato metodo contraccettivo durante il periodo di trattamento, per 18 mesi dopo la somministrazione dell’ultima dose di obinutuzumab e per 28 giorni dopo la somministrazione dell’ultima dose di tacrolimus.
    -Per gli uomini in terapia con tacrolimus: consenso a praticare l’astinenza dai rapporti eterosessuali o a far uso di un profilattico, secondo quanto definito di seguito:
    Gli uomini con partner di sesso femminile in età fertile o in gravidanza dovranno praticare l’astinenza dai rapporti sessuali o usare il preservativo durante il periodo di trattamento e per 28 giorni dopo la somministrazione dell’ultima dose di tacrolimus, al fine di evitare l’esposizione dell’embrione al farmaco.
    -Per i pazienti coinvolti nell’estensione cinese della fase di arruolamento presso centri autorizzati dalla NMPA: attuale residenza nella Cina continentale e discendenza cinese
    E.4Principal exclusion criteria
    •Patients with a secondary cause of MN
    •Uncontrolled blood pressure, in the opinion of the investigator, during 3 months prior to screening
    •Evidence of >= 50% reduction in proteinuria during the previous 6 months prior to screening
    •Receipt of renal replacement therapy
    •Type 1 or 2 diabetes mellitus
    •Pregnant or breastfeeding, or intending to become pregnant during the study or within 18 months after the final dose of obinutuzumab or 28 days after the final dose of tacrolimus
    •History of resistance (no response) to CNIs or B-cell depleting antibodies
    •Receipt of previous therapies as follows:
    oTreatment with MMF or oral, intramuscular, or intravenous corticosteroids within 1 month prior to screening
    oAny B-cell depleting therapy such as rituximab, ocrelizumab, or ofatumumab within 9 months prior to screening
    oTreatment with cyclophosphamide or CNI within 6 months prior to screening
    oTreatment with any biologic therapy such as belimumab, ustekinumab, or anifrolumab within 6 months prior to screening
    oTreatment with an inhibitor of Janus-associated kinase, Bruton’s tyrosine kinase, or tyrosine kinase 2, including but not limited to tofacitinib, baricitinib, upadacitinib, filgotinib, ibrutinib, or fenebrutinib within 3 months prior to screening
    oTreatment with any investigational agent within 28 days of screening or 5 drug-elimination half-lives of the investigational drug, whichever is longer
    oReceipt of a live vaccine within 28 days prior to screening or during screening
    •Thrombocytopenia, anemia, and/or coagulopathy with high risk for clinically significant bleeding or organ dysfunction or requiring plasmapheresis, intravenous immunoglobulin, or acute blood product transfusions
    •Significant or uncontrolled medical disease which, in the investigator’s opinion, would preclude patient participation
    •Known HIV infection
    •Tuberculosis infection
    •Known active infection of any kind, excluding fungal infection of the nail beds
    •Any major episode of infection requiring hospitalization or treatment either with IV anti-infective treatments during the 2 months prior to or during screening or with oral anti-infective treatments during the 2 weeks prior to or during screening
    •History of serious recurrent or chronic infection, progressive multifocal leukoencephalopathy, cancer, carcinoma in situ, except non-melanomatous carcinomas of the skin that have been treated or excised and have resolved
    •Major surgery requiring hospitalization within the 4 weeks prior to screening
    •Current active alcohol or drug abuse or history of alcohol or drug abuse within 12 months prior to screening
    •Intolerance or contraindication to study therapies, including:
    oEvidence of intolerance or toxicity associated with tacrolimus prior to screening
    oHistory of severe allergic or anaphylactic reactions to monoclonal antibodies or known hypersensitivity to any component of the obinutuzumab infusion
    oIntolerance or contraindication to oral or IV corticosteroids and premedications
    oIntolerance or hypersensitivity to tacrolimus and its excipients
    oLack of peripheral venous access
    •Laboratory parameters
    oaspartate aminotransferase or alanine transaminase > 2.5 ×the upper limit of normal (ULN)
    oAmylase or lipase > 2 × ULN
    oNeutrophils < 1.5 × 103/micro L
    oCD19+ B cells < 5/micro L
    oPositive for hepatitis B surface antigen (HBsAg) at screening
    oPositive hepatitis C virus antibody at screening
    oHemoglobin < 9 g/dL
    oPlatelet count < 75,000/micro L
    oPositive serum human chorionic gonadotropin measured at screening
    -Causa secondaria di nefropatia membranosa-Pressione arteriosa non controllata, durante 3m prec alla fase scree.-Evidenza di una riduzione>= 50% della proteinuria nei 6m prec fase scree.-Terapia sostitutiva renale-Diabete mellito tipo 1 o 2 -Gravidanza o allattamento o intenzione di iniziare una gravidanza durante studio, nei 18m succes sommi ultima dose obinu o nei 28g succes sommi ultima dose di tacrolimus.-Positività anamnestica per resistenza a CNI o anticorpi inducenti la deplezione delle cellule B.Prec assunzione seguenti terapie:-tratt con MMF o corticosteroidi orali, intramuscolari o e.v. mese prec fase scree;-qualsiasi terapia di deplezione delle cell B, come rituximab, ocrelizumab od ofatumumab, nei 9m prec fase scree;-trattamento con ciclofosfamide o CNI nei 6m prec fase scree;-tratt con qualsiasi terapia biologica, come belimumab,ustekinumab o anifrolumab nei 6m prec la fase scree;-tratt con un inibitore della Janus chinasi, della tirosin-chinasi di Bruton o della tirosin-chinasi2, tra cui, tofacitinib,baricitinib,upadacitinib,filgotinib,ibrutinib o fenebrutinib nei 3m prec la fase scree;-tratt con qualsiasi farmaco sper nei 28g prec fase scree o nelle 5 emivite di eliminaz farmaco sper;-somminist di un vaccino vivo nei 28g prec fase scree o durante scree.Trombocitopenia, anemia e/o coagulopatia con alto rischio di sanguinamento o disfunzione organo significativa rilevanza clinica o necessitante plasmaferesi, IVIg o trasfusioni di prodotti ematici per fase acuta.-Patologia medica significativa o non controllata che,potrebbe precludere la partecipazione pz.-Infezione HIV.-Infezione da tubercolosi.-Se richiesto dalle normative locali o conformemente alla pratica clinica locale, in sede scree sarà eseguito test TBC latente.-Infezione nota di qualsiasi tipo in fase attiva, ad eccezione di infezione fungina del letto ungueale.- Qualsiasi episodio di infezione> che richieda ricovero ospedaliero oppure l’impiego di terapia antinfettiva e.v. durante scree o nei 2m ad esso prec o di terapia antinfettiva orale durante scree o nelle 2 sett ad esso prec.-Anamnesi di infezione grave, cronica o ricorrente.-Anamnesi di leucoencefalopatia multifocale progressiva.-Anamnesi di cancro, tra cui tumori solidi, neoplasie maligne ematologiche e carcinoma in situ, ad eccezione di casi di carcinoma cutaneo non melanomatoso trattati o escissi che sono andati incontro a risoluzione.-Procedura chirurgica> che richieda ricovero ospedaliero nelle 4 sett prec fase scree.-Abuso alcol o droghe attualmente attivo o anamnesi abuso alcol o droghe 12m prec fase scree.-Intolleranza o controindicazione alle terapie in studio, tra cui:-evidenza di intolleranza o tossicità associata a tacrolimus prima fase scree;-Anamnesi di gravi reazioni allergiche o anafilattiche agli anticorpi monoclonali oppure nota ipersensibilità a qualsiasi componente dell’infusione di obinu;-intolleranza a corticosteroidi e premedicazioni per via orale o e.v. oppure controindicazione al loro uso;-intolleranza o ipersensibilità a tacrolimus e ai suoi eccipienti;-assenza di accesso venoso periferico. Parametri di laboratorio- AST o ALT >2.5 volte il limite superiore di normalità;- amilasi o lipasi>2 volte l’ULN; neutrofili <1.5x103/microL;-cellule B CD19+< 5/microL;-positività per l’antigene di superficie dell’epatite B in sede di screening;ai pz negativi per HBsAg e positivi per l’anticorpo core epatite B con assenza di rilevabilità del DNA del virus epatite B sarà consentito l’ingresso nello studio ma dovranno essere sottoposti a monitoraggio periodico DNA HBV.-positività per gli anticorpi diretti contro virus epatite C in sede scree;I pz con risultato + test anticorpi epatite C e assenza di rilevabilità RNA HCV per almeno 12m dopo completamento terapia antivirale saranno considerati idonei studio ma dovranno sottoporsi a monitoraggio periodico RNA HCV.-emoglobina<9 g/dL;-conta piastrinica<75.000/microL;-sierologia positiva per gonadotropina corionica umana misurata in sede scree
    E.5 End points
    E.5.1Primary end point(s)
    1.The proportion of patients who achieve a CR at Week 104
    percentuale di pazienti con una risposta completa (Complete Response, CR) alla Settimana 104.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1.At Week 104
    alla Settimana 104
    E.5.2Secondary end point(s)
    1.The proportion of patients who achieve an overall remission at Week 104
    2.The proportion of patients who achieve CR at Week 76
    3.The proportion of patients who relapse by Week 104
    4.The proportion of patients who receive escape therapy by Week 104
    5.The proportion of patients who achieve immunologic remission at Week 52
    6.Mean change in ankle circumference from Baseline to Week 104
    7.The proportion of patients with >= 30% reduction in eGFR from baseline to Week 104
    8.Mean change from baseline in the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Assessment of Physical Health scale at Week 104
    9.Mean change from baseline in the PROMIS Fatigue scale at Week 104
    10.Duration of CR
    11.Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0
    12.Characterization of adverse events of special interest
    13.Change from baseline in targeted vital signs
    14.Change from baseline in targeted clinical laboratory test results
    15.Peripheral B-cell counts at specified timepoints
    16.Serum concentrations of obinutuzumab at specified timepoints
    17.Prevalence of anti-drug antibodies (ADAs) to obinutuzumab at baseline and incidence of ADAs during the study
    1.Percentuale di pazienti che raggiungono una remissione complessiva alla settimana 104
    2.Percentuale di pazienti che hanno raggiunto la CR alla settimana 76
    3. La percentuale di pazienti che recidivano entro la settimana 104
    4. La percentuale di pazienti che ricevono la terapia di fuga entro la settimana 104
    5. La percentuale di pazienti che raggiungono la remissione immunologica alla settimana 52
    6 Variazione media della circonferenza della caviglia dal basale alla settimana 104
    7.Percentuale di pazienti con riduzione> = 30% dell'eGFR dal basale alla settimana 104
    8 Cambiamento medio rispetto al basale nella scala di valutazione globale della salute fisica del sistema PROMIS (Patient-Reported Outcomes Measurement Information) alla settimana 104
    9 Variazione media rispetto al basale nella scala PROMIS Fatigue alla settimana 104
    10.Durata della CR
    11.Incidenza e gravità degli eventi avversi, con gravità determinata in base ai Criteri comuni di terminologia per gli eventi avversi del National Cancer Institute versione 5.0
    12.Caratterizzazione di eventi avversi di particolare interesse
    13. Cambiamento rispetto al basale nei segni vitali mirati
    14. Variazione rispetto al basale nei risultati dei test clinici di laboratorio mirati
    15. Conta dei linfociti B periferici in punti temporali specificati
    16 Concentrazioni sieriche di obinutuzumab a intervalli di tempo specificati
    17.Prevalenza degli anticorpi anti-farmaco (ADA) contro obinutuzumab al basale e incidenza di ADA durante lo studio
    E.5.2.1Timepoint(s) of evaluation of this end point
    1.At Week 104
    2.At Week 76
    3-4.At Week 104
    5.At Week 52
    6-9.From Baseline (Day 1) to Week 104
    10-12.Up to 9 years
    13-14.Baseline to 9 years
    15.Up to 9 years
    16.Open label: Baseline, Weeks 2, 4, 12, 24, 26, 36, 50, 52, 64, 76, 88, 104; Long-Term Follow-Up (LTFU): Week 117, 130, 143, 156, 169, 182, 195, 208, every 26 weeks thereafter (Q26W); escape treatment: Weeks 0, 2, 4,12, 24, 26, 36, 52, 64, 76, 88, 104, 130, 156, 182,208, Q26W (each assessment: unplanned visit, study discontinuation)
    17.Open label: Baseline, Weeks 2, 4, 12, 24, 26, 36, 50, 52, 64, 76, 88, 104; LTFU: Week 130, 156, 182, 208, Q26W; escape treatment: Weeks 0, 2, 4, 12, 24, 36, 52, 76, 104, 130, 156, 182,208, Q26W (each assessment: unplanned, safety follow up visit, study discontinuation)
    1 sett 104 2. sett 76 3-4. sett 104 5. sett 52 6-9 Dal basale (g1) alla sett 104 10-12, fino a 9 anni
    13-14. Baseline a 9 anni 15.Fino a 9 anni 16. Etichetta aperta: Baseline, sett 2, 4, 12, 24, 26, 36, 50, 52, 64, 76, 88, 104; Fu a lungo termine (LTFU): sett 117, 130, 143, 156, 169, 182, 195, 208, successivamente ogni 26 sett (Q26W); tratt di fuga: sett 0, 2, 4,12, 24, 26, 36, 52, 64, 76, 88, 104, 130, 156, 182,208, Q26W (ciascuna valutazione: visita non pianificata, interruzione dello studio) 17. Etichetta aperta: Basale, sett 2, 4, 12, 24, 26, 36, 50, 52, 64, 76, 88, 104; LTFU: Sett 130, 156, 182, 208, Q26W; tratt di fuga: sett 0, 2, 4, 12, 24, 36, 52, 76, 104, 130, 156, 182,208, Q26W (ciascuna valutazione: non pianificata, visita di fu di sicurezza, interruzione 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 No
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Tacrolimus
    Tacrolimus
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    Brazil
    Canada
    China
    Israel
    Peru
    Russian Federation
    Turkey
    Ukraine
    United States
    France
    Italy
    Poland
    Spain
    Argentina
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last Person Last Visit
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months2
    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: 119
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 21
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    If patients cannot read the consent or they have relatives with the legal ability to make medicial decisions for them, they would be abke to be included in the study.
    Se i pazienti non sono in grado di leggere il consenso o hanno parenti con la capacità legale di prendere decisioni mediche per loro, potrebbero essere inclusi nello studio.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 42
    F.4.2.2In the whole clinical trial 140
    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)
    The Sponsor will offer continued access to Roche IMP (obinutuzumab) free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product which can be found on
    http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
    Lo Sponsor offrirà l'accesso continuo a Roche IMP (obinutuzumab) gratuitamente ai pazienti idonei in conformità con la Roche Global Policy on Continued Access to Investigational Medicinal Product che può essere trovata su
    http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
    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 Decision2021-03-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-04-06
    P. End of Trial
    P.End of Trial StatusOngoing
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