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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Academisch Ziekenhuis Leiden, Academisch Ziekenhuis Leiden

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

4 Oct 2018 → ongoing

Decision date (initial)

2024-08-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-507867-20-00

EudraCT number

2018-001392-21

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

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.

Secondary objectives 12

1. The sustained reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies throughout 104 weeks of the study
2. Seroconversion of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies throughout 104 weeks of the study
3. The reduction of memory B-cells at 28 weeks after treatment start
4. The sustained reduction of memory B-cells throughout 104 week of the study
5. The regression of excessive NET formation at 28 weeks after treatment start
6. The sustained regression of excessive NET formation throughout 100 weeks of the study
7. The feasibility of the combination treatment with tapering of concomitant immunosuppression
8. The safety of the combination treatment according to the Common toxicity Criteria (CTC) developed by the National Cancer Institute (NCI)
9. The clinical response of SLE patients by a reduction in SLEDAI scores and no worsening of PGA
10. The clinical response of SLE patients by in case of lupus nephritis: the number of partial and complete renal responders
11. The clinical response of SLE patients by: the number of moderate or severe flares and renal flares
12. The clinical response of SLE patients by: time to treatment failure

Conditions and MedDRA coding

Lupus Erythematosus, Systemic

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Adults with the age of 18 years and above
2. Have a clinical diagnosis of SLE according to the SLICC criteria 2012
3. 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
4. New, 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) - 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

Exclusion criteria 14

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 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Treatment failure rate during the 2 years study period

Secondary endpoints 8

1. Reduction of disease relevant autoantibodies, in particular anti-dsDNA autoantibody production at 28 weeks
2. Total renal response rate at 28 weeks
3. Regression of immune complex-mediated excessive neutrophil extracellular traps (NET) formation at 28 weeks
4. Sustained, long-term B-cell depletion during 104 weeks
5. Sustained reduction of relevant anti-nuclear autoantibodies, including seroconversion during 104 weeks
6. Sustained regression of immune complex-mediated excessive neutrophil extracellular traps (NET) formation during 104 weeks
7. Safety and toxicity monitoring according to Common toxicity Criteria (CTC) developed by the National Cancer Institute (NCI) with the use of Common Terminology Criteria for Adverse Events (CTCAE)
8. Evaluate the reduction of concomitant immunosuppression and the number of moderate and severe flares during study follow-up

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Academisch Ziekenhuis Leiden

Sponsor organisation

Academisch Ziekenhuis Leiden

Address

Albinusdreef 2

City

Leiden

Postcode

2333 ZA

Country

Netherlands

Scientific contact point

Organisation

Academisch Ziekenhuis Leiden

Contact name

Y.K.O. Teng

Public contact point

Organisation

Academisch Ziekenhuis Leiden

Contact name

Y.K.O. Teng

Academisch Ziekenhuis Leiden

Sponsor organisation

Academisch Ziekenhuis Leiden

Address

P. O. Box 9600

City

Leiden

Postcode

2300 RC

Country

Netherlands

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications