Evaluation of Belimumab and Rituximab Combination Therapy in Patients with Severe Systemic Lupus Erythematosus
- Trial ID
- 2023-507867-20-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the long-term efficacy of the combination treatment of **belimumab** with **rituximab** compared to the standard of care with mycophenolate and steroids in patients with severe **Systemic Lupus Erythematosus** (SLE). This objective is clinically relevant as it aims to determine the association of this combination therapy with more effective and sustained B-cell depletion, which is crucial in managing SLE due to the role of B-cells in the pathogenesis of the disease.
Secondary objectives include:
- The sustained reduction and seroconversion of pathogenic autoantibodies, particularly anti-dsDNA autoantibodies, throughout 104 weeks of the study.
- The reduction and sustained reduction of memory B-cells at 28 weeks and throughout 104 weeks after treatment start.
- The regression and sustained regression of excessive NET formation at 28 weeks and throughout 100 weeks of the study.
- The feasibility of the combination treatment with tapering of concomitant immunosuppression.
- The safety of the combination treatment according to the Common Toxicity Criteria (CTC) developed by the National Cancer Institute (NCI).
- The clinical response of SLE patients by a reduction in SLEDAI scores, no worsening of PGA, the number of partial and complete renal responders in cases of lupus nephritis, the number of moderate or severe flares and renal flares, and the time to treatment failure.
Participants
The clinical trial involves participants diagnosed with **Systemic Lupus Erythematosus** (SLE), focusing on adults aged 18 years and above. Both male and female subjects are included, with no vulnerable populations selected. The study population was chosen based on specific inclusion criteria, such as having a clinical diagnosis of SLE according to the SLICC criteria 2012 and exhibiting severe, active SLE disease. Participants must also be positive for relevant SLE-specific autoantibodies. Lifestyle considerations, such as diet and physical activity, are not specified. The sponsor has not provided information regarding the total number of participants. The trial aims to assess the long-term efficacy of a combination treatment of belimumab with rituximab compared to standard care. Key inclusion criteria include the presence of high disease activity requiring induction treatment and the use of effective contraception for female participants of childbearing potential. The trial does not focus on any specific lifestyle habits or dietary restrictions.
Plans and Procedures
The clinical trial is designed to evaluate the long-term efficacy of a combination treatment involving **belimumab** and **rituximab** in patients with severe **systemic lupus erythematosus** (SLE). This is a randomized, double-blind, controlled trial comparing the combination therapy to the standard of care, which includes mycophenolate and steroids. The trial aims to assess the association of the combination treatment with more effective and sustained B-cell depletion. The study is expected to last approximately eight years, with an estimated recruitment start date in May 2018 and an anticipated end date in January 2026.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, clinical diagnosis of SLE, and disease activity. The trial includes multiple follow-up visits to monitor treatment efficacy and safety, with primary endpoints focusing on treatment failure rates over a two-year period. Secondary endpoints include the reduction of disease-relevant autoantibodies, total renal response rate, and sustained B-cell depletion over 104 weeks. Safety and toxicity will be monitored according to the Common Terminology Criteria for Adverse Events (CTCAE).
The expected length of participant involvement is up to 104 weeks, with conditions for early termination including significant adverse events or lack of compliance with the study protocol. Participants will be required to attend regular follow-up visits to assess the primary and secondary endpoints, with the end-of-study visit marking the conclusion of their participation. The trial is structured to ensure rigorous monitoring and evaluation of the combination therapy's impact on SLE, providing valuable insights into its potential as a treatment option.
Treatment
The clinical trial involves the administration of **Benlysta**, a 200 mg solution for injection in a pre-filled pen. The active substance in Benlysta is **belimumab**, a protein-based therapeutic agent. The pharmaceutical form is a solution for injection, and it is administered via **subcutaneous injection**. The maximum daily dose is 400 mg, with a total maximum dose of 400 mg over a treatment period of up to 100 days. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen. Benlysta is manufactured by GlaxoSmithKline (Ireland) Limited and is authorized for use in the European Union.
Another experimental medication used in the trial is **Truxima**, a 100 mg concentrate for solution for infusion. The active substance in Truxima is **rituximab**, also a protein-based therapeutic agent. This medication is provided in the form of a solution for infusion and is administered via **intravenous** route. The maximum daily dose is 1000 mg, with a total maximum dose of 2000 mg over a treatment period of up to 2 days. The administration of Truxima is carefully monitored to ensure proper dosing and participant compliance. Truxima is produced by Celltrion Healthcare Hungary Kft and is also authorized for use in the European Union.
In addition to the experimental treatments, the study includes a standard-of-care therapy consisting of mycophenolate and steroids. This comparator treatment serves as a control to evaluate the efficacy of the combination treatment of belimumab with rituximab. The study aims to assess the long-term efficacy of this combination treatment in achieving more effective and sustained B-cell depletion in patients with systemic lupus erythematosus (SLE).
Efficacy
Efficacy in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the **treatment failure rate** during the 2-year study period. Secondary endpoints include the reduction of disease-relevant autoantibodies, particularly anti-dsDNA autoantibody production at 28 weeks, and the total renal response rate at 28 weeks. Additionally, the trial will evaluate the regression of immune complex-mediated excessive neutrophil extracellular traps (NET) formation at 28 weeks, sustained long-term B-cell depletion during 104 weeks, and sustained reduction of relevant anti-nuclear autoantibodies, including seroconversion during 104 weeks. Other secondary endpoints involve sustained regression of immune complex-mediated excessive NET formation during 104 weeks, 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), and the evaluation of the reduction of concomitant immunosuppression and the number of moderate and severe flares during study follow-up.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adults with the age of 18 years and above
- 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: 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
- 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: 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.
- 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
- 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
- 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
- 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 The Netherlands | Not Recruiting | 01 May 2018 | — |
| Netherlands | — | — | 30 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Benlysta 200 mg solution for injection in pre-filled pen. | Test | SOLUTION FOR INJECTION IN PRE-FILLED PEN | SUBCUTANEOUS INJECTION | 400 | 100 | PRD5568800 |
Truxima 100 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 1000 | 2 | PRD5065907 |