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    Summary
    EudraCT Number:2018-001392-21
    Sponsor's Protocol Code Number:P018.000
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-09-25
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2018-001392-21
    A.3Full title of the trial
    A randomized trial to investigate the reset of humoral autoimmunity by combining belimumab with rituximab in severe systemic lupus erythematosus
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Synergetic B-cell immunomodulation in SLE – 2nd study
    A.4.1Sponsor's protocol code numberP018.000
    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 SponsorLeiden University Medical Center
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportLeiden University Medical Center
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLeiden University Medical Center
    B.5.2Functional name of contact pointDr. Y.K.O. Teng
    B.5.3 Address:
    B.5.3.1Street AddressAlbinusdreef 2
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333ZA
    B.5.3.4CountryNetherlands
    B.5.4Telephone number31715262148
    B.5.6E-maily.k.o.teng@lumc.nl
    D. IMP Identification
    D.IMP: 1
    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 belimumab or benlysta
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxoSmithKline
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    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 anti-CD20 B cell depletion with Truxima
    D.2.1.1.2Name of the Marketing Authorisation holderCelltrion Healthcare Hungary Kft
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nametruxima
    D.3.4Pharmaceutical form Concentrate for emulsion for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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 Yes
    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
    systemic lupus erythematosus
    E.1.1.1Medical condition in easily understood language
    systemic lupus erythematosus
    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 10042947
    E.1.2Term Systemic lupus erythematosus synd
    E.1.2System Organ Class 100000004859
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10029142
    E.1.2Term Nephritis systemic lupus erythematosus
    E.1.2System Organ Class 100000004857
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10042948
    E.1.2Term Systemic lupus erythematosus syndrome aggravated
    E.1.2System Organ Class 100000004859
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    In this study the primary objective is to assess long-term efficacy of the combination treatment of belimumab with rituximab (BLM+RTX) compared to standard of care with mycophenolate and steroids and the association with more effective and sustained B-cell depletion. The primary clinical efficacy parameter is treatment failure rate during the 2 year study period. The main functional and immunological parameter for autoreactive B-cells is the reduction of disease relevant autoantibodies, in particular anti-dsDNA autoantibodies, at 28 weeks after treatment.
    E.2.2Secondary objectives of the trial
    The evaluation of long-term effects of BLM+RTX with respect to clinical response correlated to immunological parameters in comparison to standard of care with mycophenolate+steroids; a.the sustained reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies at 28+104 weeks b.seroconversion of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies at 28+104 weeks c.the reduction of memory B-cells at 28+104 weeks d.the regression of excessive NET formation at 28+104 weeks e.the feasibility of the combination treatment with tapering of concomitant immunosuppression f.the safety of the combination treatment according to the Common toxicity Criteria developed by the National Cancer Institute g.the clinical response other than treatment failure;reduction in SLEDAI scores and no worsening of PGA, in case of lupus nephritis:the number of partial and complete renal responders, the number of moderate or severe flares and renal flares, time to treatment failure
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects enrolled in the study must meet the following inclusion criteria:
    1) Age 16 years,
    2) Have a clinical diagnosis of SLE according to the SLICC criteria 2012 (see appendix 1)
    3) Severe, active SLE disease (see also section 5.3.3.2.), defined as a situation in which 1 or more of the following criteria are met:
    a. SLEDAI (SLE Disease Activity Index) with 12 or more points
    b. New or worse SLE-related activity of major organs, i.e.: CNS-SLE (includes NPSLE), vasculitis, nephritis, pericarditis and/or myocarditis, myositis, thrombocytopenia < 60, hemolytic anemia < 4.4mmol/L (=7.0g/dL)
    c. high disease activity that requires or warrants induction treatment by switching to or increasing dosage of oral mycophenolate
    4) Persisting or progressive disease activity despite the use of conventional maintenance immunosuppressive treatment (e.g. mycophenolate or azathioprine)
    5) Positive for relevant SLE-specific autoantibodies defined as a situation in which 1 or more of the
    following criteria are met:
    a. ANA seropositivity, as defined by a positive ANA-titer ≥ 1:80, before and at screening :
    - Positive test results from 2 independent time points within the study screening period; OR
    - One positive historical test result and 1 positive result during the screening period. Historical
    documentation of a positive test of ANA (eg, ANA by HEp-2 titer, ANA by ELISA) must
    include the date of the test.
    b. Anti-DNA seropositivity, as defined by a positive anti-dsDNA serum antibody ≥ 30 IU/mL,
    before and at screening:
    - Positive test results from 2 independent time points within the study screening period.
    - One positive historical test result and 1 positive result during the screening period. Historical
    documentation of a positive test of anti-dsDNA (eg, anti-dsDNA by Farr assay or ELISA)
    must include the date of the test.
    6) Female subjects are eligible to enter the study if she is:
    - Not pregnant or nursing
    - Of non-child-bearing potential (i.e. after hyseterectomy, postmenopausal, bilateral ovariectomy or
    documented bilateral tubal ligation or other permanent female sterilization procedure)
    - Use of effective contraception:
    • 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 sterilisation (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.
    • Female subjects using mycophenolate mofetil (MMF) should be made aware that MMF affects
    the metabolism of oral contraceptives and may reduce their effectiveness. As such, women
    receiving MMF who are using oral contraceptives for birth control should employ an additional
    method (e.g., barrier method).
    E.4Principal exclusion criteria
    Subjects will be excluded from participation if they meet any of the following exclusion criteria:
    1) Active pregnancy, as proven by a positive urine beta-HCG test or a positive serum beta-HCG
    2) Significant hypogammaglobulinemia (IgG < 4.0 g/L) or an IgA deficiency (IgA < 0.1 g/L)
    3) Immunization with a live vaccine 1 month before screening
    4) Active infection at time of screening, as follows:
    - Hospitalization for treatment of infection within previous 60 days of day 0 of the study
    - Use of parenteral (intravenous of intramuscular) antibiotics ( including anti-bacterials, anti-virals,
    anti-fungals or anti-parasitic agents) within previous 60 days of day 0 of the study
    - Serological evidence of uncontrolled, active viral hepatitis defined as: patients positive for HbsAg
    test or HBcAb or a positive hepatitis C antibody not treated with antiviral medication
    5) Have a historically positive HIV test or test positive at screening for HIV
    6) Have a history of a primary immunodeficiency
    7) Have a neutrophil count of < 1.5x10E9/L
    8) Have a significant infection history that in the opinion of the investigator would make the
    candidate unsuitable for the study
    9) Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or
    murine proteins or monoclonal antibodies
    10) Have any other clinically significant abnormal laboratory value in the opinion of the investigator
    11) Have current drugs or alcohol abuse or dependence within 365 days prior to Day 0 of the study
    12) Have an active malignant neoplasm or one in the history of the last 5 years, except basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the uterine cervix treated locally and with no evidence of metastatic disease for 3 years
    13) Have evidence of serious suicide risk including any history of suicidal behavior in the last 6 months and/or any suicidal ideation in the last 2 months or who, in the investigator’s opinion, poses a significant suicide risk
    14) Have any other clinically significant abnormal laboratory value, any intercurrent significant medical or psychiatric illness that in the opinion of the investigator would make the candidate unsuitable for the study
    E.5 End points
    E.5.1Primary end point(s)
    With the above-described detailed evaluations, in order to assess the study’s primary endpoint, we will compare the treatment failure rate during the 2 years study period between the two treatment arms.
    E.5.1.1Timepoint(s) of evaluation of this end point
    week 104
    E.5.2Secondary end point(s)
    In order to assess the study’s main secondary endpoints, the percentage reduction in absolute serum levels of anti-dsDNA autoantibodies per patient at week 28 compared to baseline values.
    For other secondary endpointswe will:
    Ad a. A sustained reduction of serum levels of anti-dsDNA autoantibodies will be defined as the absence of a doubling of serum level on at least 2 consecutive visits or a seroconversion to positive on at least 2 consecutive visits

    Ad b. Seroconversion of anti-dsDNA autoantibodies will be defined by the immunofluorescence assay when changed from (strongly) positive to negative or to ‘weakly’ positive

    Ad c. The reduction of memory B-cells will be assessed by flowcytometry and quantified as the percentage reduction in absolute CD19+CD27+ memory B-cell counts

    Ad d. A sustained reduction of CD19+CD27+ memory B-cell will be defined as the absence of an increase in their absolute number on flowcytometry on at least 2 consecutive visits

    Ad e. A regression in excessive NET formation will be quantified by an in-house established assay where ‘normal’ amount of NET formation is assessed by serum from normal human subjects. The regression in sera from SLE patients is calculated in relation to the negative control of normal human serum, as described by the assay.

    Ad f. A sustained regression of excessive NET formation will be defined as the absence of a doubling of NET formation on at least 2 consecutive visits
    Ad g & h. Feasibility and safety of combination treatment will be assessed by monitoring the occurrence of hypogammaglobulinemia, infectious events and allergic events

    Ad i. Clinical responses will be evaluated.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Relevant study parameters will be evaluated after 28 weeks, 60 weeks and 104 weeks
    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 Yes
    E.6.13.1Other scope of the trial description
    Immunological secondairy endpoints to assess whether a combination treatment of belimumab with rituximab will lead to the improvement of pivotal, SLE-specific autoimmune phenomena compared SLE patients treated with conventional immunosuppression
    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) 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) 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 concerned6
    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
    last visit of the last subject
    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 months0
    E.8.9.1In the Member State concerned 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: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    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 state30
    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)
    Treatment during the study is defined up to 100 weeks after which the treatment with belimumab can be continued or patients can be switched to another immunosuppressive regimen. This decision is left to the discretion of the treating physician. Patients will be followed up to 100 weeks after initiation of the study treatment regardless of the chosen follow-up treatment.
    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 Decision2018-09-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-09-06
    P. End of Trial
    P.End of Trial StatusOngoing
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