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    Summary
    EudraCT Number:2016-003050-32
    Sponsor's Protocol Code Number:205646
    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:2017-06-21
    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 number2016-003050-32
    A.3Full title of the trial
    A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-
    Controlled, 104-Week Study to Evaluate the Efficacy and Safety of Belimumab
    Administered in Combination with Rituximab to Adult Subjects with Systemic Lupus
    Erythematosus (SLE)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 Study to Evaluate the Efficacy and Safety of Belimumab
    Administered in Combination with Rituximab to Adult Subjects with Systemic Lupus
    Erythematosus (SLE) – BLISS-BELIEVE
    A.4.1Sponsor's protocol code number205646
    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 SponsorGlaxoSmithKline Research & Development Ltd
    B.1.3.4CountryUnited Kingdom
    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 supportGlaxoSmithKline LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline Research & Development Ltd
    B.5.2Functional name of contact pointGSK Clinical Support Help Desk
    B.5.3 Address:
    B.5.3.1Street AddressIron Bridge Road, Stockley Park West
    B.5.3.2Town/ cityUxbridge, Middlesex
    B.5.3.3Post codeUB11 1BT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44800 783 9733
    B.5.6E-mailGSKClinicalSupportHD@gsk.com
    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 MabThera (Rituximab)
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    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 nameMabThera (Rituximab)
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.4EV Substance CodeSUB12570MIG
    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 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) Yes
    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 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 (Belimumab)
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxoSmithKline (Ireland) Limited
    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 nameBenlysta (Belimumab)
    D.3.4Pharmaceutical form Solution for injection in pre-filled pen
    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.3.9.2Current sponsor codeGSK1550188
    D.3.9.3Other descriptive nameHGS1006, LymphoStat-B, monoclonal anti-BLyS, LSB, BENLYSTA
    D.3.9.4EV Substance CodeSUB25607
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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) Yes
    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 infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Systemic Lupus Erythematosus (SLE) or Lupus
    E.1.1.1Medical condition in easily understood language
    Lupus
    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 PT
    E.1.2Classification code 10042945
    E.1.2Term Systemic lupus erythematosus
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of belimumab and a single cycle of rituximab administered in a combination regimen to adult participants with SLE.
    E.2.2Secondary objectives of the trial
    To assess the safety and tolerability of belimumab and a single cycle of rituximab
    administered in a combination regimen to adult participants with SLE
    To assess the impact of belimumab and a single cycle of rituximab administered in a combination regimen to adult participants with SLE on PROs
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Participant must be ≥ 18 years of age at the time of signing the informed consent.
    2. Have a clinical diagnosis of SLE based on 4 or more of the 11 American College of
    Rheumatology (ACR) criteria.
    3. Have a screening SLEDAI-2K score ≥6 (This refers to the total score.
    Serological activity, i.e., anti-double
    stranded deoxyribonucleic acid [dsDNA]) positivity and/or hypocomplementemia is not required to be
    present in SLEDAI-2K assessment, but are scored if present).
    4. Have unequivocally positive autoantibody test results defined as an anti-nuclear (ANA) titer ≥ 1:80 and/or a positive anti-dsDNA ( ≥30 IU/mL) serum antibody test from 2 independent time points as follows:
    Positive test results from 2 independent time points within the study screening period. Screening results must be based on the study's central laboratory results
    OR
    One positive historical test result and 1 positive test result during the screening
    period.
    NOTE: Historical documentation of a positive test of ANA (e.g., ANA by HEp-2
    titer) and anti-dsDNA (e.g., anti-dsDNA by Farr assay) that must include the
    date and type of the test, the name of the testing laboratory and numerical reference range, whenever available. Only unequivocally positive values as defined in the laboratory's
    reference range are acceptable; borderline values will not be accepted.
    5. Are on a stable SLE treatment regimen consisting of any of the following
    medications (alone or in combination) for a period of at least 30 days prior to Day 1 (i.e., day of first dose of study treatment) with the exception that switching one agent for another of the same class for tolerability or availability reasons, which will be allowed within 30 days of Day 1.
    ∙Corticosteroids (prednisone or prednisone equivalent)
    ∙For those subjects on alternating daily doses of steroids, use the average of 2
    daily doses to calculate the average daily steroid dose.
    ∙Any immunosuppressant or immunomodulatory agents including methotrexate, azathioprine, leflunomide, mycophenolate (including mycophenolate mofetil, mycophenolate mofetil hydrochloride, and
    mycophenolate sodium), calcineurin inhibitors (e.g. tacrolimus, cyclosporine), sirolimus, cyclophosphamide, 6- mercaptopurine, mizoribine, or thalidomide. (Note: oral cyclophosphamide use is exclusionary in Germany)
    ∙Anti-malarials (e.g., hydroxychloroquine, chloroquine, quinacrine).
    ∙Non-steroidal anti-inflammatory drugs (NSAIDs).
    NOTES:
    Corticosteroids may be added as a new medication or their doses adjusted up to 30 days prior to Day 1.
    New SLE therapy other than corticosteroids must not be added within 60 days
    prior to Day 1.
    6. Male and/or female
    A female participant is eligible to participate if she is not pregnant (see Appendix 3 of the study protocol), not breastfeeding, and at least one of the following conditions applies:
    (i) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 (of the study protocol)
    OR
    (ii) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 (of the study protocol) during the treatment period and for at least 16 weeks after the last dose of belimumab, or at least 12 months after the last dose of rituximab or rituximab placebo, whichever is later.
    7. Capable of giving signed informed consent as described in Appendix 4 (of the study protocol) which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
    E.4Principal exclusion criteria
    1. Symptomatic herpes zoster within 3 months prior to screening.
    2. Evidence of active or latent tuberculosis (TB). Documentation may include medical history and examination, chest X-rays (posterior, anterior, and lateral), and TB testing
    3. Significant allergies to humanized monoclonal antibodies.
    4. History of hypersensitivity to belimumab and/or rituximab or known to have titers of human anti-mouse antibody or history of hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.
    5. Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years.
    6. Alanine transferase (ALT) >2x upper limit of normal (ULN).
    7. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is
    fractionated and direct bilirubin <35%).
    8. IgA deficiency (IgA level < 10 mg/dL).
    9. IgG < 250 mg/dL. (Note: <400 mg/dL for Germany only)
    10. Neutrophils < 1.5 x 10 to the power of 9
    11. Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
    12. Severe heart failure (New York Heart Association Class IV) or other severe,
    uncontrolled cardiac disease.
    13. QTc >450 msec or QTc >480 msec in participants with bundle branch block.
    14. Have a history of a major organ transplant or hematopoietic stem cell/marrow transplant.
    15. Have clinical evidence of significant unstable or uncontrolled acute or chronic
    diseases not due to SLE which, in the opinion of the principal investigator, could confound the results of the study or put the subject at undue risk.
    16. Have an acute or chronic infection requiring management as follows:
    Currently on any suppressive therapy for a chronic infection
    ∙Hospitalization for treatment of infection within 60 days of Day 1.
    ∙Have had infection requiring treatment with parenteral (IV or IM) antibiotics within 60 days of Day 1. Prophylactic anti-infective treatment is allowed.
    17. Have severe lupus kidney disease (defined by proteinuria >6 g/24 hour or equivalent using spot urine protein to creatinine ratio, or serum creatinine >2.5 mg/dL), or have severe active nephritis requiring induction therapy not permitted by protocol, or have required hemodialysis or high dose prednisone or equivalent (>100 mg/day) within 90 days of Day 1.
    18. Have severe active central nervous system (CNS) lupus (including seizures, psychosis, organic brain syndrome, cerebrovascular accident (CVA), cerebritis, or
    CNS vasculitis) requiring therapeutic intervention within 60 days of Day 1.
    19. Have a planned surgical procedure, laboratory abnormality, or condition that, in the opinion of the principal investigator, makes the subject unsuitable for the study.
    20. Have evidence of serious suicide risk, including any history of suicidal behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the C-SSRS in the last 2 months or who, in the investigator's opinion, pose a significant suicide risk.
    21. Have a history of an anaphylaxis reaction to parenteral administration of contrast agents, human or murine proteins, or monoclonal antibodies.
    22. Live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines during the screening period or during the study.
    23. Have received any of the following within 364 days of Day 1:
    ∙Belimumab.
    ∙Rituximab.
    ∙Abatacept.
    ∙Any B cell targeted therapy anti-Interferon alpha agents or anti-BLyS other than belimumab).
    ∙A biologic investigational agent other than B cell targeted therapy
    24. Have required 3 or more courses of systemic corticosteroids (e.g., IV pulse therapy or high dose oral treatment) within 364 days of Day 1. (Topical or inhaled steroids are permitted.)
    25. Have received any of the following within 90 days of Day 1:
    ∙Anti-TNF therapy
    ∙Interleukin-1 receptor antagonist
    ∙ Intravenous immunoglobulin
    ∙ High dose prednisone or equivalent
    ∙Plasmapheresis
    26. Have received any of the following within 60 days of Day 1:
    ∙A non-biologic investigational agent
    ∙Intravenous (IV) cyclophosphamide or oral cyclophosphamide and, for Germany only, oral cyclophosphamide
    ∙Any steroid injection
    27. Positive immunodeficiency virus (HIV) antibody test.
    28. Positive serology for Hepatitis B, defined as (i) HB surface antigen positive
    (HBsAg+) OR (ii) HB core antibody positive (HBcAb+).
    29. Positive Hepatitis C (HCV) antibody test.
    30. Have current drug or alcohol dependence, or a history of drug or alcohol abuse or dependence within 364 days prior to Day 1.
    See Study Protocol Section 6.2 for full list of exclusion critieria
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of participants with a state of disease control defined as a SLEDAI- 2K
    score ≤2, achieved without immunosuppressants and with corticosteroids at a prednisone equivalent dose of ≤5mg/day at Week 52. (Serological activity, i.e., anti-dsDNA positivity and/or hypocomplementemia, is scored in the SLEDAI-2K endpoint.)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 52
    E.5.2Secondary end point(s)
    Proportion of participants with a state of clinical remission defined as a Clinical
    SLEDAI-2K score =0, achieved without immuno-suppressants and with
    corticosteroids at a prednisone equivalent dose of 0 mg/day at Week 64. (Serological activity score, i.e., anti-dsDNA positivity and/or hypocomplementemia, is excluded from the Clinical SLEDAI-2K endpoint.)
    Proportion of participants with a state of disease control defined as a SLEDAI-2K
    score ≤2, achieved without immunosuppressants and withcorticosteroids at a prednisone equivalent dose of ≤5 mg/day at Week 104.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 64, Week 104
    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 Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group 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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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
    Brazil
    Canada
    Korea, Republic of
    Mexico
    Russian Federation
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days3
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days3
    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: 270
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 280
    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)
    At the end of the study, participants who wish to continue treatment with belimumab may do so by being prescribed commercially available belimumab.
    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 Decision2017-11-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-01-09
    P. End of Trial
    P.End of Trial StatusOngoing
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