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    Summary
    EudraCT Number:2021-001802-30
    Sponsor's Protocol Code Number:TMP-3001-2020-30
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-09-02
    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 number2021-001802-30
    A.3Full title of the trial
    Efficacy of belimumab to improve subclinical cardiovascular abnormalities
    using imaging endpoints with cardiac magnetic resonance in patients with
    systemic lupus erythematosus (BeCarma)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy of the drug Benlysta (active ingredient: belimumab) to improve cardiac abnormalities in patients with systemic lupus erythematosus (BeCarma)
    A.3.2Name or abbreviated title of the trial where available
    BeCarma
    A.4.1Sponsor's protocol code numberTMP-3001-2020-30
    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 SponsorFraunhofer Institut für Translationale Medizin und Pharmakologie (ITMP)
    B.1.3.4CountryGermany
    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 supportGlaxoSmithKline (GSK)
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportFraunhofer ITMP
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFraunhofer Institut für Translationale Medizin und Pharmakologie (ITMP)
    B.5.2Functional name of contact pointClinical Research
    B.5.3 Address:
    B.5.3.1Street AddressTheodor-Stern-Kai 7
    B.5.3.2Town/ cityFrankfurt am Main
    B.5.3.3Post code60596
    B.5.3.4CountryGermany
    B.5.4Telephone number+4969630180208
    B.5.5Fax number+496971047692
    B.5.6E-mailClinicalReseach@itmp.fraunhofer.de
    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 (GSK)
    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.3.4Pharmaceutical 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.3.11 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) 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Efficacy of belimumab to improve subclinical cardiovascular abnormalities using imaging endpoints with cardiac magnetic resonance in patients with systemic lupus erythematosus
    Wirksamkeit von Belimumab zur Verbesserung subklinischer kardiovaskulärer Anomalien anhand bildgebender Endpunkte mit kardialer Magnetresonanz bei Patienten mit systemischem Lupus erythematodes
    E.1.1.1Medical condition in easily understood language
    Efficacy of belimumab to improve cardiovascular abnormalities in patients with systemic lupus erythematosus
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    •To determine myocardial changes due to diffuse inflammatory involvement measured by T1 and T2 mapping and first pass perfusion imaging under maximal vasodilation in SLE patients with new initiation of belimumab or continued standard-of care therapy at W24 compared to BL
    E.2.2Secondary objectives of the trial
    Assess. of cardiovasc. risk factors and funct. (deform. and cardiac function (longitudinal strain, left ventricular (LV) volume and mass, ejection fraction, LGE, ECG, aortic stiffness (pulse wave velocity), myocardial triglyeride an creatine content (subgroup of patients)
    Assess.of cardiovas. risk factors and cardiac biomarkers measured in blood (lipids, triglycerides, VLDL, cholesterine, HDL, LDL, glucose, HbA1c, (apo)lipoproteine levels, hs-troponin T, NT-BNP, hsCRP)
    Assess. of antiphospholipid profile (lupus anticoagulant, anticardiolipin and anti-beta 2 GPI)
    Measurement of vital signs
    Assess. of cardiac echocardiography
    Determin. of SLE disease activity and damage (SLEDAI 2k, S2k Responder Index-50, SLICC damage index, CRP/ESR, PGA)
    Incidence of cardiovas. abnormalities
    PGIC
    LupusQoL
    Facit-Fatigue subscale
    CSSRS
    Compliance of belimumab/SLE
    Assess. of treatment changes
    Safety Parameters
    Rise in cardiac biomarkers/frequency of worsening of disease
    Subgroup analysis
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Proton magnetic resonance spectroscopy (1H-MRS) (optional)
    A subgroup of patients (of the university hospital Düsseldorf) will receive 1H-MRS for the detection of myocardial triglyceride and creatine content. 1H-MRS will be included in the CMR examinations at SCR, V4, V6 and V7. The duration of the CMR will be prolonged for 8 minutes. Study participants should be fasted for 4 hours prior examination. This is an optional assessment, i.e., patients can still participate in the study, if they do not perform this assessment
    Proton magnetic resonance spectroscopy (1H-MRS) (optional); Included in protocol Version 1.6 (only a subgroup of patients of the university hospital Düsseldorf(
    E.3Principal inclusion criteria
    1. Established diagnosis of SLE as per American College of Rheumatology revised classification criteria
    2. Stable disease (SLEDAI < 6 and no treatment change) over the last 12 weeks
    3. Cardiac abnormalities of recovery rate of T1 or T2 relaxation detected in CMR, measured in a midventricular SAX slice conservatively within the septal myocardium defined as follows:
    a. Native T1 ≥ 4SD: 1.5T 1050ms, 3.0T 1150 ms or
    b. Native T2 ≥ 4SD : 1.5T 50ms, 3.0T 40 ms
    4. If pericarditis is diagnosed:
    a. colchicine therapy will be started with a maximum of 0,5 mg once daily as indicated
    5. If concomitant cortisone treatment: stable dose (≤ 10 mg/day) within the last 2 weeks
    6. Patients with a BMI of 18-35 kg/m²
    7. Patients aged 18 - 75 years
    8. Written informed consent obtained prior to the initiation of any protocol-required procedures by the patient
    9. Willingness to comply to study procedures and study protocol
    E.4Principal exclusion criteria
    Main exclusion criteria
    1. Previous use of belimumab
    2. Contraindications for treatment with belimumab (e.g., hypersensitivity to IMP)
    3. Use of Rituximab and other B-cell-targeting therapies (e.g., anti-CD20 antibodies) within 12 months before BL
    4. Use of Cyclophosphamide within 90 days before BL
    5. Concomitant cortisone with dosages >10 mg/day
    6. Vaccination with live vaccine within 30 days prior to BL
    7. History of malignant neoplasm within 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
    8. Any other clinically significant abnormal laboratory value in the opinion of the investigator
    9. Any intercurrent significant medical or psychiatric illness that the investigator considers would make the candidate unsuitable for the study (e.g. severe depression)
    10. Clinically manifest cardiovascular symptoms, e.g.:
    o Severe congestive heart failure (NYHA III-IV), EF < 35%, AV block, Mobitz type II
    o Established severe ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease
    o History of bypass surgery or triple vessel disease, presence of flow limiting obstructive coronary artery disease, congenital or clinically relevant vavular heart disease
    11. Significant IgG deficiency (IgG level < 400 mg/dL)
    12. IgA deficiency (IgA level < 10 mg/dL)
    13. Renal disease with a current estimated GFR < 30 mL/min/1.73 m²
    14. Patients with a history of a major organ transplant (i.e., heart, lung, kidney, liver) or hematopoetic stem cell/marrow transplant within the last 5 years
    15. Patients with lupus nephritis
    16.Evidence of significant uncontrolled concomitant diseases or serious and/or uncontrolled diseases that are likely to interfere with the evaluation of the patient’s safety and of the study outcome
    17. History of primary immunodeficiency
    18. Current suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria), hospitalization for treatment of infection within 60 days before SCR, or use of parenteral (IV or IM) antiobiotics (anti-bacterial, antiviral, anti-fungal, or anti-parasitic agents) within 60 days before SCR
    19. History of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies
    20. History of or active status of Hepatitis (positive testing for HBsAG/HBcAb/Hepatitis C) and/or positive HIV test
    21. 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 poses a significant suicide risk
    22. Contraindications to contrast material-enhanced CV magnetic resonance (MR) imaging
    23. Current alcohol, drug or chemical abuse or dependence or within 1 year before SCR
    24. Males or females of reproductive potential as well as menopausal women not willing to use effective contraception for the duration of the study period (defined as PEARL index <1 - e.g. contraceptive pill, IUD, or true sexual abstinence within the last 4 weeks and the study period, bilateral tubal occlusion or male partner with vasectomy; also see chapter 7.4.4 for guidance)
    25. Current participation in another interventional clinical trial or participation within the last 3 months for non-biological IMPs and 12 months for biologic IMPs
    26. Lupus of the central nervous system
    27. Severe hyponatremia (sodium > 155 mmol/l)
    28. Moderate neutropenia: neutrophil count less than 1000µl (or defined as leukocytes less than 2000/µl if blood count is not further examined)
    29. Current severe infection (e.g. sepsis, pneumonia)
    30. Progressive multifocal leucencephalopathy

    For female subjects only:
    31. Positive pregnancy test at screening examination
    32. Pregnant or lactating women
    E.5 End points
    E.5.1Primary end point(s)
    •Treatment group difference in change in diffuse myocardial inflammation and myocardial blood flow using T1 and T2 mapping and first pass perfusion imaging at W24 compared to baseline
    E.5.1.1Timepoint(s) of evaluation of this end point
    •Primary endpoint will be analysed after 24 weeks (Visit 4)
    E.5.2Secondary end point(s)
    Secondary endpoints will be analysed at all available visits for both treatment groups.
    For all continuous endpoints, “changes” refer to the difference between the visit measurement and baseline (absolute and in %):
    •T1 and T2 values and change thereof compared to BL
    •Longitudinal strain and change thereof compared to BL
    •Left ventricular (LV) volume and mass and change thereof compared to BL
    •Ejection fraction and change thereof compared to BL
    •Late gadolinium enhancement (LGE) and change thereof compared to BL
    •Pulse wave velocity and change thereof compared to BL
    •Changes in values in cardiac echocardiography and ECG
    •Presence and extent of coronary artery calcification and soft plaques
    •SLEDAI-2k score and change to BL
    •Sledai-2k responder index-50 (S2k RI-50) and change to BL
    •Proportion of patients with partial and complete recovery according to Sledai-2k and S2k RI-50
    •SLICC score and change to BL
    •Proportion of patients that fulfil SLICC criteria (The SLICC criteria for SLE classification requires: 1) Fulfillment of at least four criteria, with at least one clinical criterion AND one immunologic criterion OR 2) Lupus nephritis as the sole clinical criterion in the presence of ANA or anti-dsDNA antibodies)
    •Physicians global assessment (PGA) and change to BL
    •Changes in cardiovascular risk factors and cardiac biomarkers in blood (lipids, triglycerides, VLDL, cholesterine, HDL, LDL, glucose, HbA1c, (apo)lipoproteine levels, hs-troponin T, NT-BNP) and CRP (+hsCRP) and ESR compared to BL
    •Blood pressure, heart rate and change thereof compared to BL
    •Patient global impression of change (PGIC/SGIC) score
    •Lupus Quality of Life score and change to BL
    •Facit-Fatigue subscale score and change to BL
    •CSSRS score and change to BL
    •Oral corticosteroid dose
    •Benlysta®/ SOC intake (empty syringes/pens) and patient diary information for drug accountability / compliance
    •Proportion of patients with a treatment change and proportion of patients who switch to rescue arm; reasons for change /switch
    •Previous SLE therapies for subgroup analyses using primary and other secondary endpoints

    Safety Data:
    •Frequency, seriousness and number of adverse events and adverse events of special interest
    •Frequency of worsening of disease (defined as a decreased PGA score) and proportion of patients with worsening of disease
    •Number of cardiovascular events and proportion of patients with at least one event
    •Incidence of cardiac abnormalities
    •Rise in cardiac biomarkers
    E.5.2.1Timepoint(s) of evaluation of this end point
    Statistical analysis will be performed after termination of the study, when the data review process of the data management is completed and all queries have been solveld.
    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 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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    SoC
    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 concerned3
    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
    data base lock, last site closure
    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 days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months4
    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: 51
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 state56
    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)
    Standard of care for the underlaying condition
    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 Decision2021-10-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-10-05
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2024-02-09
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