A randomized trial to investigate the reset of humoral autoimmunity by combining belimumab with rituximab in severe systemic lupus erythematosus

Prior treatment

• Have current drugs or alcohol abuse or dependence within 365 days prior to Day 0 of the study
• 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
• Immunization with a live vaccine 1 month before screening
• 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

Other illness

• 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
• Have a historically positive HIV test or test positive at screening for HIV
• Have a history of a primary immunodeficiency
• Have a significant infection history that in the opinion of the investigator would make the candidate unsuitable for the study
• Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies

Lab values

• Active pregnancy, as proven by a positive urine beta-HCG test or a positive serum beta-HCG
• Have any other clinically significant abnormal laboratory value in the opinion of the investigator
• 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
• Significant hypogammaglobulinemia (IgG < 4.0 g/L) or an IgA deficiency (IgA < 0.1 g/L)
• Have a neutrophil count of < 1.5x10E9/L

• Adults with the age of 18 years and above
• Have a clinical diagnosis of SLE according to the SLICC criteria 2012
• Severe, active SLE disease, 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
• New, persisting or progressive disease activity despite the use of conventional maintenance immunosuppressive treatment (e.g. mycophenolate or azathioprine)
• 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.
• 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) - 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%. 16 Version: 10.0 Date: April 19, 2022 Therefore, these women must have a negative serum pregnancy test at screening, and agree to 1 of the following with respect to the 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 (Note: Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred lifestyle of the participant.) 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 Bilateral tubal occlusion (documentation in the CRF based on 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 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. • 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), resulting in two reliable forms of contraception being used simultaneously before starting study treatments, during therapy, and for 6 weeks after stopping therapy; unless abstinence is the chosen method of contraception