Synergetic B-cell immunomodulation in SLE

• Register: EUCTR
• Last refreshed on: 30 April 2019
• Main ID: EUCTR2014-000488-42-NL
• Date of registration: 09/05/2014
• Prospective Registration: Yes
• Primary sponsor: Leiden University Medical Center
• Public title: Synergetic B-cell immunomodulation in SLE
• Scientific title: The SYNBioSe Study A proof-of-concept study involving synergetic B-cell imunnomodulation in patients with refractory systemic lupus erythematosus - SynBiose
• Date of first enrolment: 12/05/2014
• Target sample size: 15
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-000488-42
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Netherlands

Contacts

• Name: Teng
• Affiliation: Leiden University Medical Center

• Name: Teng
• Affiliation: Leiden University Medical Center

Key inclusion & exclusion criteria

Inclusion criteria:
4.1. Inclusion criteria
Subjects enrolled in the study must meet the following inclusion criteria:
1) age 18 years,
2) ACR diagnosis of SLE (1997 revised criteria, see appendix 1)
3) Severe SLE flare at screening (see also section 5.2.3.2.), defined as a situation in which 1 or more of the following criteria are met:
- Increase in SLEDAI (SLE Disease Activity Index) with 12 or more points
- New or worse SLE-related activity of major organs, i.e.: CNS-SLE (includes NPSLE), vasculitis, nephritis, pericarditis and/or myocarditis, myositis, trombocytopenia < 60, hemolytic anemia < 4.4mmol/L (=7.0g/dL).
4) Refractory disease, defined as persisting or progressive disease activity (SLEDAI > 6 points) despite conventional immunosuppressive treatment and 1 or more of the following criteria:
- failure of the initial induction treatment at six months, for which a switch to another induction therapy regime has already been carried out;
- intolerance or contraindication for cyclophosphamide and mycophenolate mofetil (MMF);
- exceeding a cumulative dose of 15 gram of cyclophosphamide;
- a second relapse within two years after start of the initial induction therapy
- a relative contraindication for high-dose oral or intravenous (iv) prednisone, such as avascular osteonecrosis, previous psychosis on corticosteroids, osteoporosis and/or severe obesity (BMI =35 kg/m2).
5) 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.
6) 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.
7) Immune-complex mediated complement usage, as defined by:
- a low C3 serum level = 0.9 g/L; OR
- a low C4 serum level = 95 mg/L; OR
- a reduced activation of the classical pathway < 75%
8) Use of effective contraception

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 15
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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 B-cell depletion (peripheral B-cell counts < 60x10E6)
3) Significant hypogammaglobulinemia (IgG < 8.0 g/L)
4) Immunization with a live vaccine 1 month before screening
5) Active infection at time of screening, as follows:
- Hospitalization for treatment of infection within previous 2 months 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 2 months of day 0 of the study



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

Health Condition(s) or Problem(s) studied

Systemic lupus erythematosus
MedDRA version: 17.0 Level: LLT Classification code 10025139 Term: Lupus erythematosus systemic System Organ Class: 100000004859

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

Intervention(s)

Trade Name: rituximab
Product Name: Rituximab
Pharmaceutical Form: Infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Current Sponsor code: Teng-001
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2000-

Trade Name: Benlysta
Product Name: Belimumab
Pharmaceutical Form: Infusion
INN or Proposed INN: BELIMUMAB
CAS Number: 356547-88-1
Current Sponsor code: Teng-001
Concentration unit: mg/kg milligram(s)/kilogram
Concentration type: equal
Concentration number: 10-

Primary Outcome(s)

Secondary Objective: Secondary goals are to evaluate clinical improvement, reduction of circulating immune complexes, safety and feasibility.

Primary end point(s): In this proof-of-concept study the primary objective is to assess whether a combination treatment of rituximab and belimumab will lead to a sustained reduction of pathogenic autoantibodies and thereby inhibition of NET formation. Therefore, the primary endpoints are:
- a sustained reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies, at 24 weeks after treatment start
- an inhibition of the formation of NETs at 24 weeks after treatment start

Main Objective: In this proof-of-concept study the primary objective is to assess whether a combination treatment ofrituximab (anti-CD20) and belimumab (anti-BAFF) will lead to a sustained reduction of pathogenic autoantibodies and thereby inhibition of NET formation, which portentially forms the basis of a new therapeutic approach in severe SLE.

Timepoint(s) of evaluation of this end point: at 24 weeks

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 4 weeks (short term), 24 weeks (intermediate term) and 104 weeks (long-term).

Secondary end point(s): The main secondary objective is to evaluate the effects of long-term B-cell depletion which will involve assessments of the clinical response correlated with immunological parameters. To this end, the relevant study parameters will be evaluated after 4 weeks (short term), 24 weeks (intermediate term) and 104 weeks (long-term). The secondary endpoints measured at these times are:
- the effects on the reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies
- the inhibition of the formation of NETs
- seroconversion of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies
- the normalization of complement usage, i.e. C3/C4 levels and C1Q-binding

Other secondary objectives are to evaluate:
- the safety and feasibility of the combination treatment according to the WHO toxicity criteria
- the clinical response of refractory SLE patients upon long-term B-cell depletion by:
* a reduction in SLEDAI scores, no new BILAG A involvement and the SLE responder index
* in case of lupus nephritis: the number of partial and complete renal responders
* the number of moderate or severe flares and renal flares

Secondary ID(s)

Teng-001

Source(s) of Monetary Support

Leiden University Medical Center

Ethics review

Status: Approved
Approval date:
Contact: