Synergetic B-cell immunomodulation in SLE – 2nd study

• Register: EUCTR
• Last refreshed on: 20 April 2020
• Main ID: EUCTR2018-001392-21-NL
• Date of registration: 25/09/2018
• Prospective Registration: Yes
• Primary sponsor: Leiden University Medical Center
• Public title: Synergetic B-cell immunomodulation in SLE – 2nd study
• Scientific title: A randomized trial to investigate the reset of humoral autoimmunity by combining belimumab with rituximab in severe systemic lupus erythematosus
• Date of first enrolment: 25/09/2018
• Target sample size: 30
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-001392-21
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Netherlands

Contacts

• Name: Dr. Y.K.O. Teng
• Affiliation: Leiden University Medical Center

• Name: Dr. Y.K.O. Teng
• Affiliation: Leiden University Medical Center

Key inclusion & exclusion criteria

Inclusion criteria:
Subjects enrolled in the study must meet the following inclusion criteria:
1) Age 16 years,
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 (=7.0g/dL)
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
Exclusion criteria:
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



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

systemic lupus erythematosus
MedDRA version: 21.1 Level: LLT Classification code 10042947 Term: Systemic lupus erythematosus synd System Organ Class: 100000004859
MedDRA version: 20.0 Level: LLT Classification code 10029142 Term: Nephritis systemic lupus erythematosus System Organ Class: 100000004857
MedDRA version: 21.1 Level: LLT Classification code 10042948 Term: Systemic lupus erythematosus syndrome aggravated System Organ Class: 100000004859

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Intervention(s)

Trade Name: belimumab or benlysta
Pharmaceutical Form: Solution for solution for injection

Trade Name: anti-CD20 B cell depletion with Truxima
Product Name: truxima
Pharmaceutical Form: Concentrate for emulsion for infusion

Primary Outcome(s)

Primary end point(s): With the above-described detailed evaluations, in order to assess the study’s primary endpoint, we will compare the treatment failure rate during the 2 years study period between the two treatment arms.

Secondary Objective: The evaluation of long-term effects of BLM+RTX with respect to clinical response correlated to immunological parameters in comparison to standard of care with mycophenolate+steroids; a.the sustained reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies at 28+104 weeks b.seroconversion of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies at 28+104 weeks c.the reduction of memory B-cells at 28+104 weeks d.the regression of excessive NET formation at 28+104 weeks e.the feasibility of the combination treatment with tapering of concomitant immunosuppression f.the safety of the combination treatment according to the Common toxicity Criteria developed by the National Cancer Institute g.the clinical response other than treatment failure;reduction in SLEDAI scores and no worsening of PGA, in case of lupus nephritis:the number of partial and complete renal responders, the number of moderate or severe flares and renal flares, time to treatment failure

Timepoint(s) of evaluation of this end point: week 104

Main Objective: In this study the primary objective is to assess long-term efficacy of the combination treatment of belimumab with rituximab (BLM+RTX) compared to standard of care with mycophenolate and steroids and the association with more effective and sustained B-cell depletion. The primary clinical efficacy parameter is treatment failure rate during the 2 year study period. The main functional and immunological parameter for autoreactive B-cells is the reduction of disease relevant autoantibodies, in particular anti-dsDNA autoantibodies, at 28 weeks after treatment.

Secondary Outcome(s)

Secondary end point(s): In order to assess the study’s main secondary endpoints, the percentage reduction in absolute serum levels of anti-dsDNA autoantibodies per patient at week 28 compared to baseline values.
For other secondary endpointswe will:
Ad a. A sustained reduction of serum levels of anti-dsDNA autoantibodies will be defined as the absence of a doubling of serum level on at least 2 consecutive visits or a seroconversion to positive on at least 2 consecutive visits

Ad b. Seroconversion of anti-dsDNA autoantibodies will be defined by the immunofluorescence assay when changed from (strongly) positive to negative or to ‘weakly’ positive

Ad c. The reduction of memory B-cells will be assessed by flowcytometry and quantified as the percentage reduction in absolute CD19+CD27+ memory B-cell counts

Ad d. A sustained reduction of CD19+CD27+ memory B-cell will be defined as the absence of an increase in their absolute number on flowcytometry on at least 2 consecutive visits

Ad e. A regression in excessive NET formation will be quantified by an in-house established assay where ‘normal’ amount of NET formation is assessed by serum from normal human subjects. The regression in sera from SLE patients is calculated in relation to the negative control of normal human serum, as described by the assay.

Ad f. A sustained regression of excessive NET formation will be defined as the absence of a doubling of NET formation on at least 2 consecutive visits
Ad g & h. Feasibility and safety of combination treatment will be assessed by monitoring the occurrence of hypogammaglobulinemia, infectious events and allergic events

Ad i. Clinical responses will be evaluated.

Timepoint(s) of evaluation of this end point: Relevant study parameters will be evaluated after 28 weeks, 60 weeks and 104 weeks

Secondary ID(s)

P018.000

Source(s) of Monetary Support

Leiden University Medical Center

Ethics review

Status: Approved
Approval date: 06/09/2018
Contact: