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    Summary
    EudraCT Number:2014-000382-41
    Sponsor's Protocol Code Number:WA29330
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-12-09
    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 ConcernedGermany - PEI
    A.2EudraCT number2014-000382-41
    A.3Full title of the trial
    A randomized, double-blind, double-dummy active-comparator, multicenter study to evaluate the efficacy and safety of rituximab versus MMF in patients with pemphigus vulgaris
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Rituximab Versus Mycophenolate Mofetil in Patients With Pemphigus Vulgaris
    A.3.2Name or abbreviated title of the trial where available
    PEMPHIX
    A.4.1Sponsor's protocol code numberWA29330
    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 MABTHERA®
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    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 nameRituximab
    D.3.2Product code RO0452294/V02
    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 codeRO 0452294
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500mg/50ml
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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 CELLCEPT®
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    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 nameMycophenolate mofetil
    D.3.2Product code RO1061443/F02
    D.3.4Pharmaceutical form Film-coated 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 INNMycophenolate mofetil
    D.3.9.1CAS number 128794-94-5
    D.3.9.2Current sponsor codeRO1061443/F02
    D.3.9.4EV Substance CodeSUB03360MIG
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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 placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pemphigus Vulgaris (PV)
    E.1.1.1Medical condition in easily understood language
    Pemphigus Vulgaris (PV)
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10052802
    E.1.2Term Pemphigus vulgaris
    E.1.2System Organ Class 100000004858
    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 rituximab compared with MMF in achieving sustained complete remission, evaluated by the Pemphigus Disease Area Index (PDAI; see Section 3.4.1.1), and assessed at Week 52 in patients with moderate-to-severely active PV
    - To evaluate the safety of rituximab compared with MMF with a focus on adverse events and safety laboratory values.
    E.2.2Secondary objectives of the trial
    • To evaluate the efficacy of rituximab compared with MMF, as measured by the time to disease flare the duration of sustained complete remission, the total number of disease flares during the treatment period, and the time to initial sustained complete remission
    • To assess corticosteroid exposure over 52 wks
    • To assess the effect of rituximab compared with MMF on health-related quality of life (HRQoL), as measured by the Dermatology Life Quality Index
    • To assess the effect of rituximab compared with MMF on patients’ impression of PV symptoms, as measured by the Patient Global Impression of Change questionnaire
    • To assess the effect of rituximab compared with MMF on clinician impression of patients’ PV symptoms, as measured by the Clinician Global Impression of Change questionnaire
    • To evaluate corticosteroid-related adverse events in relation to corticosteroid exposure
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Age 18−75 years
    • Signed Informed Consent Form
    • First confirmed diagnosis of PV within the previous 24 months, based on the presence of: histological features of acantholysis via skin or mucosal biopsy and one of the following: tissue-bound IgG antibodies by direct immunofluorescence on the surface of affected epithelium or serological detection of serum Dsg3 autoantibodies against epithelial cell surface either by indirect immunofluorescence microscopy or by enzyme-linked immunosorbent assay
    • Presence of moderate to severely active disease, defined as overall PDAI activity score of ≥ 15
    • Receiving standard-of-care corticosteroids consisting of 60−120 mg/day PO prednisone or equivalent (1.0 − 1.5 mg/kg/day) and, in the judgment of the investigator, expected to benefit from the addition of immunosuppressive therapy
    • For women who are not postmenopausal (≥ 12 months of non−therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use two effective methods of contraception, including at least one method with a failure rate of < 1% per year, during the treatment period and for at least 12 months after the last dose of study treatment
    Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
    Barrier methods must always be supplemented with the use of a spermicide.
    Examples of contraceptive methods with a failure rate of < 1% per year(highly effective contraceptive methods) include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices.
    • For men (including those who have undergone a vasectomy): agreement to remain abstinent or use a condom during the treatment period and for at least 12 months after the last dose of study treatment and agreement to refrain from donating sperm during this same period
    Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
    In addition to male contraception, agreement to advise female partners of childbearing potential to use highly effective contraception during the study and for at least 12 months after the last dose of study treatment
    • Agreement to avoid excessive exposure to sunlight during study participation
    • Able to comply with the study protocol, in the investigator’s judgment
    E.4Principal exclusion criteria
    Diagnosis of pemphigus foliaceus or evidence of paraneoplastic pemphigus or other non-PV autoimmune blistering disease
    • History of a severe allergic or anaphylactic reaction to humanized or murine monoclonal antibodies, or known hypersensitivity to any component of rituximab
    • Known hypersensitivity or contraindication to MMF, mycophenolic acid, polysorbate, or oral corticosteroids
    • Lack of peripheral venous access
    • Pregnant or lactating, or intending to become pregnant during the study Women who are not postmenopausal (≥ 12 months of non−therapy-induced amenorrhea) or surgically sterile must have two negative result with a sensitivity of ≥ 25 mIU/mL: one from a serum pregnancy test at Day -8 to Day -10 of screening and another from an urine pregnancy test at Day 1 prior to randomization.
    • Participated in another interventional clinical trial within 28 days prior to randomization
    • Use of any investigational agent within 28 days or 5 elimination half-lives prior to randomization (whichever is the longer)
    • Significant cardiovascular or pulmonary disease (including obstructive pulmonary disease)
    Evidence of any new or uncontrolled concomitant disease that, in the investigator’s judgment, would preclude patient participation, including but not limited to nervous system, renal, hepatic, endocrine, malignant, or gastrointestinal disorders
    • Any concomitant condition that required treatment with oral or systemic corticosteroids within 12 weeks prior to randomization
    • Treatment with IV Ig, plasmapheresis, or other similar procedure within 8 weeks prior to randomization
    • Treatment with immunosuppressive medications (e.g., azathioprine, MMF) within 1 week prior to randomization
    • Treatment with cyclophosphamide within 12 weeks prior to randomization
    • History of or currently active primary or secondary immunodeficiency, including known history of HIV infection and other severe Immunodeficiency blood disorders
    • Known active infection of any kind (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV anti-infectives within 4 weeks prior to screening, or completion of oral anti-infectives within 2 weeks prior to randomization; entry into this study may be reconsidered once the infection has fully resolved.
    •History of or current cancer, including solid tumors, hematologic malignancies, and carcinoma in situ (except basal cell carcinoma and squamous cell carcinoma of the skin that have been excised and cured.)
    •Currently active alcohol or drug abuse, or history of alcohol or drug abuse within 24 weeks prior to screening
    •Major surgery within 4 weeks prior to randomization, excluding diagnostic surgery
    •Treatment with rituximab or a B cell-targeted therapy (e.g., anti-CD20, anti CD22, or anti-BLyS) within 12 months prior to randomization
    •Treatment with a live or attenuated vaccine within 28 days prior to randomization; it is recommended that a patient’s vaccination record and the need for immunization prior to study entry be carefully investigated.
    •Evidence of abnormal liver (AST, ALT) and pancreatic (amylase) enzymes or hematology laboratory values
    •Positive test results for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus (HCV) serology at screening
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy:
    Proportion of patients (excluding telemedicine patients)who achieve a sustained complete remission without experiencing an event that constitutes treatment failure, as measured at Week 52. Sustained complete remission is defined as achieving healing of lesions with no new active lesions (i.e., PDAI activity score of 0) while on 0 mg/day prednisone or equivalent, and maintaining this response for a total of at least 16 consecutive weeks, during the 52-week treatment period.

    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 52
    E.5.2Secondary end point(s)
    Efficacy:
    1. Time to disease flare
    2. Duration of sustained complete remission
    3. Total number of diseases flares during the treatment period
    4. Cumulative oral corticosteroid dose (prednisone or equivalent) over the treatment period
    5. Time to sustained complete remission
    6. Change in health-related quality of life (HRQoL), as measured by the Dermatology Life Quality Index (DLQI) score from baseline to Week 52
    7. Patients' impression of change in PV symptoms as measured by the
    Patients' Global Impression of Change (PGIC) score during the treatment
    period
    8. Clinician impression of change in patients’ PV symptoms as measured by the Clinician Global Impression of Change (CGIC) score during the treatment period

    Safety:
    9. Frequency of adverse events, including serious adverse events and adverse events leading to discontinuation
    10. Vital signs and clinical laboratory test results (including complete blood count and blood chemistry)
    11. Incidence of human anti-chimeric antibody (HACA)
    12. Circulating B cells, T cells, natural killer (NK) cells, plasma cells, and other leukocytes
    13. Plasma Ig levels (total Ig, IgG, IgM, and IgA)
    14 Corticosteroid-related adverse events in relation to coticosteroid exposure
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-8: From baseline to Week 52
    9-14: From baseline to Week 52 and upon study completion or early withdrawal #9, 11, 12 and 13 during the 48-week safety follow up period
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Quality of Life, optional biomarker analysis
    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) 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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Canada
    France
    Germany
    Israel
    Italy
    Spain
    Turkey
    Ukraine
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as the date when the last patient, last visit (LPLV) occurs. LPLV is expected to occur approximately 2 years after the last patient is enrolled, assuming a 52-week treatment period and a 48-week SFU period for the last patient.
    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 months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 32
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 41
    F.4.2.2In the whole clinical trial 132
    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 post-trial access to the study drug rituximab free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product, as outlined in the protocol (section 4.3.4 Post-Trial Access to Rituximab)
    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 Decision2014-12-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-06
    P. End of Trial
    P.End of Trial StatusOngoing
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