Synergetic B-cell Immunomodulation in SLE - 2nd Study.

NCT03747159 | Active Not Recruiting Phase 3

• 1 other identifier: NL65720.058.18
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

Lupus Erythematosus, Systemic

Keywords

systemic lupus erythematosus; lupus nephritis; systemic autoimmune disease; glomerulonephritis; autoimmune glomerulonephritis; membranoproliferative glomerulonephritis; renal insufficiency; renal failure

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (14)

• Change of disease relevant auto-antibodies present at baseline, in particular anti-dsDNA

  28 weeks

• Sustained change of autoantibody production

  2 years

• Seroconversion of disease relevant auto-antibodies

  2 years

• Change of memory B-cell numbers

  28 weeks

• Sustained change of memory B-cell numbers

  2 years

Study Arms (2)

BLM+RTX treatment arm

EXPERIMENTAL

Intervention 1 Belimumab injection: subcutaneous weekly injections with 200mg belimumab (BML) for the duration of the entire study period of two years. Intervention 2 Rituximab infusion: Two intravenously infusions of 1000mg rituximab (RTX) at week 4 and week 6 after the start of belimumab. Intervention 3: Standard of care: induction therapy with three intravenously infusions methylprednisolone of 1000mg (or 500mg if weight is below 60kg), oral prednisolone 60mg with a quick tapering scheme to reach 5mg in 10 weeks and mycofenolate mofetil start dosis 500mg twice daily with maximum dosis of 2000mg twice daily depending on tolerance and area under curve (AUC) aimed at 60mg\*hour/L.

Drug: Belimumab Injection

Standard of Care treatment arm

NO INTERVENTION

Intervention 1: Standard of care: induction therapy with three intravenously infusions methylprednisolone of 1000mg (or 500mg if weight is below 60kg), oral prednisolone 60mg with a quick tapering scheme to reach 5mg in 10 weeks and mycofenolate mofetil start dosis 500mg twice daily with maximum dosis of 2000mg twice daily depending on tolerance and area under curve (AUC) aimed at 60mg\*hour/L. Optional intervention: (if patients flare or are non-responders on mycofenolate mofetil + prednisolone) : Two intravenously infusions of 1000mg rituximab at week 4 and week 6 after the start of belimumab.

Interventions

Belimumab Injection DRUG

Weekly injection of belimumab prior to two infusions of rituximab with continuation of the belimumab as maintenance therapy

Also known as: Benlysta subcutaneous injection of 200mg

BLM+RTX treatment arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• SLEDAI-2K (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, thrombocytopenia \< 60, hemolytic anemia \< 4.4mmol/L (=7.0g/dL)
• 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:
• 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.
• 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

You may not qualify if:

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

Sponsors & Collaborators

• Leiden University Medical Center: lead
• Dutch Kidney Foundation: collaborator
• GlaxoSmithKline: collaborator

Study Sites (4)

University Medical Center Groningen

Groningen, 9713 GZ, Netherlands

Location

Leiden University Medical Center

Leiden, 2333 ZC, Netherlands

Location

Radboud University Medical Center

Nijmegen, 6525 GA, Netherlands

Location

HagaZiekenhuis

The Hague, 2545 AA, Netherlands

Location

Related Publications (2)

• Arends EJ, Zlei M, Tipton CM, Cotic J, Osmani Z, de Bie FJ, Kamerling SWA, van Maurik A, Dimelow R, Gregan YI, Fox NL, Rabelink TJ, Roth DA, Sanz I, van Dongen JJM, van Kooten C, Teng YKO. Disruption of memory B-cell trafficking by belimumab in patients with systemic lupus erythematosus. Rheumatology (Oxford). 2024 Sep 1;63(9):2387-2398. doi: 10.1093/rheumatology/keae286.

  PMID: 38775637 DERIVED

• van Schaik M, Arends EJ, Soonawala D, van Ommen E, de Leeuw K, Limper M, van Paassen P, Huizinga TWJ, Toes REM, van Kooten C, Rotmans JI, Rabelink TJ, Teng YKO. Efficacy of belimumab combined with rituximab in severe systemic lupus erythematosus: study protocol for the phase 3, multicenter, randomized, open-label Synbiose 2 trial. Trials. 2022 Nov 12;23(1):939. doi: 10.1186/s13063-022-06874-w.

  PMID: 36371234 DERIVED

MeSH Terms

Conditions

Lupus Erythematosus, Systemic; Lupus Nephritis; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Renal Insufficiency

Interventions

belimumab

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Nephritis; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Study Officials

• Dr. Y.K.O. Teng, MD, PhD

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr. Y.K.O. Teng, Nephrologist

Model Details: Multi-center

Study Record Dates

• First Submitted: October 12, 2018
• First Posted: November 20, 2018
• Study Start: October 1, 2018
• Primary Completion: June 7, 2024
• Study Completion (Estimated): June 7, 2026
• Last Updated: October 17, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

NL (4)