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

Subjects enrolled in the study must meet the following inclusion criteria:
1) Adults with the age of 18 years and above,
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
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).

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