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    Summary
    EudraCT Number:2020-004519-29
    Sponsor's Protocol Code Number:APHP180351
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-11
    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 ConcernedFrance - ANSM
    A.2EudraCT number2020-004519-29
    A.3Full title of the trial
    Multicenter randomized double-blind study comparing the efficacy and safety of belimumab in the treatment of non-infectious active cryoglobulinemia vasculitis compared to placebo
    TRIBECA STUDY (Treatment nd BElimumab in Cryoglobulinemia Associated vasculitis)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    TRIBECA STUDY (Treatment nd BElimumab in Cryoglobulinemia Associated vasculitis)
    A.4.1Sponsor's protocol code numberAPHP180351
    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 SponsorAssistance Publique - Hôpitaux de Paris / DRCI
    B.1.3.4CountryFrance
    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 supportGSK
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAssistance Publique - Hôpitaux de Paris / DRCI
    B.5.2Functional name of contact pointChef de projet
    B.5.3 Address:
    B.5.3.1Street AddressHôpital Saint-Louis, 1 av. Claude Vellefaux
    B.5.3.2Town/ cityPARIS
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.4Telephone number+33(0)1 44 84 17 35
    B.5.5Fax number+33(0)1 44 84 17 01
    B.5.6E-mailelodie.soler@aphp.fr
    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 BENLYSTA®
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxoSmithKline (Ireland) Limited
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBELIMUMAB
    D.3.9.1CAS number 356547-88-1
    D.3.9.4EV Substance CodeSUB25607
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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.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 injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Adult patients with non-infectious active cryoglobulinemia vasculitis.
    E.1.1.1Medical condition in easily understood language
    Adult patients with non-infectious active cryoglobulinemia vasculitis.
    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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10075624
    E.1.2Term Cryoglobulinaemic vasculitis
    E.1.2System Organ Class 100000004866
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10075623
    E.1.2Term Cryoglobulinemic vasculitis
    E.1.2System Organ Class 100000004866
    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 efficacy of belimumab compared to placebo in patients with non-infectious active cryoglobulinemia vasculitis.
    E.2.2Secondary objectives of the trial
    • Safety and tolerability of treatments as assessed by frequency and severity of adverse clinical events
    • Complete, partial (improvement in some but not all organs involved at baseline) and non clinical (no clinical improvement) response rate
    • Rate of complete renal response
    • Rate of cryoglobulinemia clearance
    • Rate of negativation of rheumatoid factor activity
    • Rate of normalization of C4 complement level
    • Early failure rate at W4 (non clinical response at W4)
    • Clinical relapse rate and the time to relapse between the two treatments groups,
    • Cumulative dose of corticosteroids received between the two treatments groups,
    • Evolution of gammaglobulin and of CD19+ B cells levels
    • Quality of life scores (SF-36) between the two treatment groups,
    • Rate of infections (severe or not) and other complications (lymphoma)
    • BVAS activity score
    • Immunomonitoring (deep immunophenotyping, and cytokines production)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Age > 18 years
    • Written inform consent
    • Active cryoglobulinemia vasculitis define by a clinically active vasculitis with skin, joint, renal, peripheral nerve, central neurological, digestive, pulmonary and/or cardiac involvement (no histological evidence needed if presence of purpura demonstrated), and history of positive cryoglobulinemia
    • Affiliated to National French social security system
    • Having received Rituximab as induction therapy within 6 weeks
    • Female subjects of childbearing potential must not become pregnant and so must be sexually inactive by abstinence or use contraceptive methods with a failure rate of < 1%.
    Therefore, these women must have a negative serum pregnancy test at inclusion visit, and confirmed monthly while in study, out to at least 4 months (5 half lives) post last dose and agree to 1 of the following:
    - - Complete abstinence from intercourse from 2 weeks prior to administration of the 1st dose of study agent until 16 weeks after the last dose of study agent (Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception)
    OR
    - - Consistent and correct use of 1 of the following acceptable methods of birth control for 1 month prior to the start of the study agent, during the study, and 16 weeks after the last dose of study agent
    o Oral contraceptive, either combined or progestogen alone
    o Injectable progestogen
    o Implants of levonorgestrel or etonogestrel
    o Estrogenic vaginal ring
    o Percutaneous contraceptive patches
    o Intrauterine device (IUD) or intrauterine system (IUS) with <1% failure rate as stated in the product label
    o Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject. For this definition, “documented” refers to the outcome of the investigator's/designee’s medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject’s medical records
    o Double barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository)
    These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring subjects understand how to properly use these methods of contraception.
    • HIV negative serology ; negative HBs Ag test and HBc Ab test; HCV negative serology or negative HCV RNA if positive HCV serology within 3 months before inclusion
    • Neutrophils (ANC) >1x109/L
    E.4Principal exclusion criteria
    • Patient with a vasculitis unrelated to cryoglobulinemia
    • Patient with non active cryoglobulinemia vasculitis,
    • Excluded concomitant medications:
    > 365 days Prior to Belimumab:
    o Any biologic investigational agent (e.g., abetimus sodium, anti CD40L antibody, BG9588/ IDEC 131)
    Investigational agent applies to any drug not approved for sale in the country in which it is being used
    > 180 Days Prior to Belimumab:
    o Intravenous cyclophosphamide
    > 30 Days Prior to Belimumab (or 5 half lives, whichever is greater)
    o Any non-biologic investigational agent
    Investigational agent applies to any drug not approved for sale in the country in which it is being use
    > Live vaccines within 30 days prior to baseline or concurrently with belimumab
    • Have a history of malignant neoplasm within the last 5 years, other than carcinoma in situ of the cervix or excised basal cell, squamous cell carcinoma of the skin or hemopathy
    • Have evidence of serious suicide risk including any history of suicidal behaviour in the last 6 months and/or any suicidal ideation in the last 2 months or who in the investigator's judgment, pose a significant suicide risk
    • Have a Progressive multifocal leukoencephalopathy
    • Have a history of a primary immunodeficiency
    • Have a significant IgG deficiency (IgG level < 400 mg/dL) and/or significant IgA deficiency (IgA level < 10 mg/dL)
    • Have a history of major organ transplant or hematopoietic stem cell/marrow transplant or renal transplant
    • Infection history:
    > Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus
    > Infection requiring hospitalization and/or use of parenteral (IV or IM) antibiotics (antibacterials, an tivirals, anti-fungals, or anti parasitic agents) within 60 days of the inclusion visi.
    • Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within 365 days prior to the inclusion visit
    • Have a historically positive HIV test
    • Hepatitis status:
    > Serologic evidence of current or past Hepatitis B (HB) infection based on the results of testing for HBsAg and HBcAb as follows:
    - Patients positive for HBsAg or HBcAb are excluded
    > Positive test for Hepatitis C RNA
    • Have a history of a hypersensitivity or an anaphylactic reaction to parenteral administration of Belimumab, corticosteroids or any excipients of the treatments administered during the study
    • If Women of Child Bearing Potential (WCBP) are included please see special instructions above
    • Pregnant or breast feeding women
    • Have any intercurrent significant medical or psychiatric illness that the investigator considers would make the candidate unsuitable for the study
    • Patients under legal protection or unable to consent
    • Participation to another interventional study
    E.5 End points
    E.5.1Primary end point(s)
    Complete clinical response rate of vasculitis symptoms at W25 with corticosteroid withdrawal (prednisone at 0 mg/day) at week (W) 12.
    E.5.1.1Timepoint(s) of evaluation of this end point
    W25
    E.5.2Secondary end point(s)
    - Safety and tolerability of treatments as assessed by frequency and severity of adverse clinical events from baseline to W25 and at W48
    - Complete, partial and non clinical response rate at W13, W25 and at W48.
    - Complete renal response rate at W13, W25 and W48 defined by : proteinuria <0.5g/24h or proteinuria/creatininuria <50 mg/mmol, disappearance of hematuria and glomerular filtration rate by MDRD > 60 ml/min/1.73 m².
    - Rate of cryoglobulinemia clearance, negativation of rheumatoid factor activity and of normalization of C4 complement level at W13, W25 and at W48,
    - Rate of early failures (non clinical response at W5),
    - Clinical relapse rate defined by de novo appearance or recurrence of a manifestation attributable to cryoglobulinemia vasculitis during 48 weeks of follow-up,
    - Rate and time to relapse from baseline to W48
    - Cumulative dose of prednisone at W25 and at W48,
    - Evolution of gammaglobulin and of CD19+ B levels from baseline to W48
    - Quality of life score SF-36 at baseline, W25 and W48,
    - Rate of infections (severe or not) and other complications during the 48 weeks of follow-up
    - BVAS activity score at baseline, W13, W25 and W48.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline, W13, W25 and W48.
    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 No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 concerned20
    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 No
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 8
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state48
    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)
    Normal treatment of non-infectious active cryoglobulinemia vasculitis
    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 Decision2021-03-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-02-08
    P. End of Trial
    P.End of Trial StatusOngoing
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