Lupus Erythematosus, Systemic Clinical Trial
— SynBioSe-2Official title:
A Randomized Trial to Investigate the Reset of Humoral Autoimmunity by Combining Belimumab With Rituximab in Severe Systemic Lupus Erythematosus
In follow-up of the previous SynBioSe Study the present study is a randomized controlled trial designed to further investigate the long-term clinical and imunological efficacy of combination B-cell targeting by starting treatment with belimumab (anti-BAFF) followed by rituximab(anti-CD20) in lupus nephritis patients.
Status | Recruiting |
Enrollment | 70 |
Est. completion date | September 2025 |
Est. primary completion date | December 2023 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | Inclusion Criteria: 1. Have a clinical diagnosis of SLE according to the SLICC criteria 2012 2. Severe, active SLE disease defined as a situation in which 1 or more of the following criteria are met: 1. SLEDAI-2K (SLE Disease Activity Index) with 12 or more points 2. 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) 3. high disease activity that requires or warrants induction treatment by switching to or increasing dosage of oral mycophenolate 3. New, persisting or progressive disease activity despite the use of conventional maintenance immunosuppressive treatment (e.g. mycophenolate or azathioprine) 4. Positive for relevant SLE-specific autoantibodies defined as a situation in which 1 or more of the following criteria are met: 1. 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. 2. 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. 5. Female subjects are eligible to enter the study if she is: - Not pregnant or nursing - Of non-child-bearing potential (i.e. after hysterectomy, postmenopausal, bilateral ovariectomy or documented bilateral tubal ligation or other permanent female sterilization procedure) - in agreement to not become pregnant (if female subjects of childbearing potential) and therefore must be sexually inactive by abstinence or use contraceptive methods with a failure rate of < 1%. 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 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 |
Country | Name | City | State |
---|---|---|---|
Netherlands | University Medical Center Groningen | Groningen | |
Netherlands | Leiden University Medical Center | Leiden | |
Netherlands | Radboud University Medical Center | Nijmegen | |
Netherlands | HagaZiekenhuis | The Hague |
Lead Sponsor | Collaborator |
---|---|
Leiden University Medical Center | Dutch Kidney Foundation, GlaxoSmithKline |
Netherlands,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Treatment failure rate | The treatment failure rate will be measured at 104 weeks in both treatment arms with the hypothesis that lower treatment failure rates will be obtained in the RTX+BLM arm. | 2 years | |
Secondary | Change of disease relevant auto-antibodies present at baseline, in particular anti-dsDNA | All disease relevant auto-antibodies will be measured at 28 weeks and compared to baseline with the hypothesis that a better reduction will be obtained in the RTX+BLM arm. | 28 weeks | |
Secondary | Sustained change of autoantibody production | The sustained reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies | 2 years | |
Secondary | Seroconversion of disease relevant auto-antibodies | Seroconversion of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies | 2 years | |
Secondary | Change of memory B-cell numbers | The detection of (autoreactive) memory B-cells by standardized flowcytometry and in B-cell culture assays | 28 weeks | |
Secondary | Sustained change of memory B-cell numbers | The detection of (autoreactive) memory B-cells by standardized flowcytometry and in B-cell culture assays | 2 years | |
Secondary | Change of immune complex-mediated excessive neutrophil extracellular traps (NET) formation | The quantification of ex vivo NET induction with a 3-dimensional, confocal microscopy technique | 28 weeks | |
Secondary | Sustained change of immune complex-mediated excessive neutrophil extracellular traps (NET) formation | The quantification of ex vivo NET induction with a 3-dimensional, confocal microscopy technique | 2 years | |
Secondary | Evaluation of the renal response | The number of partial and complete renal responders in case of lupus nephritis | 2 years | |
Secondary | Evaluation of the clinical response by SLEDAI | Patients will be monitored at frequent timepoints by the The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), with a minimum score of 0 and a maximum score of 105, with a higher score indicating a higher disease activity | 2 years | |
Secondary | Evaluation of the clinical response by SLICC | SLICC damage score (System Lupus International Collaborating Clinics/American College of Rheumatology Damage Index for Systemic Lupus Erythematosus) will be assesed at baseline, one year and two years, with a minimum score of 0 and a maximum score of 47, with a higher score indicating more damage | 2 years | |
Secondary | Evaluation of the clinical response by QoL questionnaires | QoL questionnaires will be assessed at multiple time points by the SF-36 (ShortForm-36) questionnaire, with a minimum score of 0 and a maximum score of 100, with a higher score indicating a higher quality of life | 2 years | |
Secondary | Evaluation of the clinical response by the amount of moderate and severe flares. | Patients will be monitored at frequent timepoints | 2 years | |
Secondary | Evaluation of the clinical response by the ability to reduce concomitant immunosuppression without flares | Patients will be monitored at frequent timepoints | 2 years | |
Secondary | Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Patients will be monitored at frequent timepoints | 2 years |
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