Belimumab after B Cell depletion therapy as a new treatment for patients with systemic lupus erythematosus (SLE)
| ISRCTN | ISRCTN47873003 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN47873003 |
| EudraCT/CTIS number | 2015-005543-14 |
| Secondary identifying numbers | 32235 |
- Submission date
- 28/11/2016
- Registration date
- 28/11/2016
- Last edited
- 10/02/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Musculoskeletal Diseases
Plain English Summary
Background and study aims
Systemic lupus erythematosus (SLE) is a long-term (chronic) disease which causes widespread inflammation (swelling) in the body. SLE occurs when the immune system attacks the body’s own cells (autoimmune disease). A person’s genes alongside other factors such as diet have been connected with the development and progression of the disease. B cell depletion therapy (normally rituximab) is used as part of standard of care in patients where their lupus is active. B cell depletion therapy removes a type of immune cell called B cells from the body. B cells can cause disease in lupus patients. Although patients respond to B cell depletion therapy the disease can quickly return. This is likely to be because a chemical (also known as a stimulating factor) called BAFF increases in the body once treatment ends, and switches the lupus back on. Belimumab is a drug that stops BAFF from working and has been shown to work in patients with lupus. The aim of this study is to investigate the safety and effectiveness of Belimumab in treating SLE.
Who can participate?
Men and women aged between 18-75 years old with systemic lupus erythematosus (SLE).
What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group receive Belimumab through a drip at two week intervals for the first three doses and then at four week intervals until 52 weeks. Those in the second group receive normal saline (salt water) through a drip according to the same schedule. After 52 weeks, participants in both groups provide blood samples and complete questionnaires in order to find out how effective the belimumab treatment is compared to the placebo (dummy) treatment.
What are the possible benefits and risks of participating?
The benefits of participating include study patients having a regular review of their Lupus by an experienced Lupus specialist and information collected from this study will help improve the treatment of lupus. As Belimumab has not been given after drugs like rituximab in a research study it is not known if this is a safe combination. It is also possible that the risks of cancer, infections and effects on mood (feeling anxious or depressed) could be increased when both Belimumab and rituximab are administered close together. The most common side effects that happen during or soon after a belimumab dose are nausea, diarrhoea, and fever.
Where is the study run from?
University College London Hospital (lead centre) and 14 other NHS hospitals in England (UK)
When is the study starting and how long is it expected to run for?
September 2016 to December 2020
Who is funding the study?
1. Versus Arthritis (formerly known as Arthritis Research UK)
2. GlaxoSmithKline foundation (UK)
3. University College London Biomedical Research Centre (UK)
Who is the main contact?
1. Ms Felecia Ikeji (public)
f.ikeji@ucl.ac.uk
2. Professor Michael Ehrenstein
m.ehrenstein@ucl.ac.uk
Contact information
Public
University College London
Comprehensive Clinical Trials Unit
Gower Street
London
WC1E 6BT
United Kingdom
| Phone | +44 20 7679 6163 |
|---|---|
| f.ikeji@ucl.ac.uk |
Scientific
University College London Hospital
253 Euston Road
London
NW1 2BU
United Kingdom
| Phone | +44 20 3447 9035 |
|---|---|
| m.ehrenstein@ucl.ac.uk |
Study information
| Study design | Multicentre phase II randomised double blind placebo-controlled clinical trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| Scientific title | Safety and efficacy of Belimumab After B cell depletion therapy in systemic LUPUS erythematosus |
| Study acronym | BEAT LUPUS |
| Study hypothesis | This study aims to find out whether a drug called Belimumab when used after B cell depletion therapy is safe and effective in reducing systemic lupus erythematosus (lupus) disease activity. |
| Ethics approval(s) | London - Hampstead Research Ethics Committee, 07/07/2016, ref: 16/LO/1024 |
| Condition | Systemic lupus erythematosus |
| Intervention | Participants are randomised to one of two groups. Intervention group: Patients will recieve Belimumab according to the standard dosage regime of infusions of 10mg/kg at 2 week intervals for the first 3 doses and at 4 week intervals thereafter up until week 52. Control group: Patients will receive the same volume of normal saline infusions (0.9% saline) at the same time points as the active treatment group. In total the treatment period (Belimumab or placebo) will be 52 weeks, with 16 weeks of further follow up. Each patient will therefore be enrolled in the study for 68 weeks in total. |
| Intervention type | Other |
| Primary outcome measure | Anti dsDNA-antibody levels are measured using blood sample testing at week -4 (baseline) and 52 weeks. |
| Secondary outcome measures | Current secondary outcome measures as of 26/03/2019: 1. Anti-dsDNA antibody levels at 24 weeks. 2. Proportion of participants with any adverse events by 52 weeks. 3. Proportion of participants with any serious adverse events by 52 weeks. 4. Proportion of participants with any infections by 52 weeks. 5. Proportion of participants with a severe disease flare (defined as one BILAG A or two B flares) by 52 weeks. 6. Proportion of participants with a severe or a moderate disease flare (defined one BILAG B flare accompanied by an increase in concomitant lupus medication - glucocorticoids, Mycophenolate, Azathioprine, or Methotrexate) by 52 weeks. 7. Time to severe disease flare. 8. Proportion of participants with a severe disease flare by 24 weeks. 9. SLEDAI 2000 at 52 weeks. 10. Subject Global Assessment of Disease Activity (SGADA) at 52 weeks. 11. C3 levels at 52 weeks. 12. Immunoglobulin levels at 52 weeks. 13. Cumulative steroid dose from randomisation to 52 weeks. 14. Proportion of participants decreasing steroid dose at randomisation by 50% without experiencing a severe flare, or if below 10mg/day at randomisation reducing dose to 5mg/day or less at 52 weeks. 15. Lupus Quality of Life (Lupus QoL), SF-36 at 52 weeks 16. Average EQ-5D from randomisation to 52 weeks. 17. C-SSRS (Columbian Suicide Severity Rating Scale) to assess suicidality risk at 52 weeks. Previous secondary outcome measures: 1. Anti-dsDNA antibody levels are measured using Blood sample testing at 24 and 68 weeks 2. Proportion of patients with any adverse events is measured by reviewing patient notes, blood sample testing, SLEDAI 2000 questionnaire, SLICC index and BILAG 2004 at week -4 , week 0, week 2 and every 4 weeks until week 68 3. Proportion of patients with any infections is measured by reviewing patient notes, blood sample testing, SLEDAI 2000 questionnaire, SLICC index, BILAG 2004” at week -4 , week 0, week 2 and every 4 weeks until week 68 4. Proportion of patients with any disease flare (defined as 1 BILAG A or 2 BILAG B flares) is measured by BILAG 2004 at week -4, week 0, week 2 and every 4 weeks until week 68 5. Time to disease flare (defined as 1 BILAG A or 2 BILAG B flares) is measured by BILAG 2004 at week -4 , week 0, week 2 and every 4 weeks until week 68 6. Proportion of patients with a BILAG A or 2 BILAG B flares is measured by BILAG 2004 at 24, 52 and 68 weeks 7. SLEDAI 2000 is measured by “SLEDAI 2000 at 52 weeks 8. Systemic lupus erythematosus disease activity is measured using Subject Global Assessment of Disease Activity (SGADA) at 52 weeks 9. C3 is measured by blood sample testing at week -4 , week 0, week 2 and every 4 weeks until week 68 10. Immunoglobulin levels are measured by blood sample testing at week -4 , week 0, week 2 and every 4 weeks until week 68 11. BAFF (measurement of RNA from whole blood) is measured by blood sample testing at week -4 , week 0, week 12, week 28, week 52 and week 68 12. Cumulative steroid dose during treatment from randomisation is measured by reviewing patient notes at week -4 , week 0, week 2 and every 4 weeks until week 68 13. Proportion of patients decreasing their baseline steroid dose by 50% without flaring from randomisation, or if below 10mg/day at baseline reducing steroid dose to 5mg/day or who discontinue glucocorticoids with stable disease is measured by reviewing patient notes at week -4 , week 0, week 2 and every 4 weeks until week 68 14.How systemic lupus erythematosus effects quality of participants life” is measured using Lupus Quality of Life (Lupus QoL), SF-36 and EQ5D questionnaires at week -4 , week 0, week 2 and every 4 weeks until week 68 15. Suicidality risk is measured using the C-SSRS (Columbia suicide severity rating scale) at week -4 , week 0, week 2 and every 4 weeks until week 68 16. Kinetics of B cell repopulation, B and T cell phenotype and function during repopulation using Flow Cytometry at week -4 , week 0, week 12, week 28, week 52 and week 68 |
| Overall study start date | 12/09/2016 |
| Overall study end date | 03/12/2020 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 50; UK Sample Size: 50 |
| Total final enrolment | 52 |
| Participant inclusion criteria | Current inclusion criteria as of 08/08/2018: 1. Aged between 18 and 75 years 2. Patients with 4 or more criteria for SLE according to the American College of Rheumatology (ACR) 1997 criteria or SLICC 2012 criteria or biopsy proven lupus nephritis with one additional supportive test on at least two occasions (positive ANA, anti-dsDNA antibodies or anti-Sm antibodies) 3. History of anti-dsDNA antibodies detectable at least once in the past 5 years prior to screening the patient on the study protocol (ELISA test is preferable for Anti dsDNA antibody testing) 4. Patients are due to be treated with the first infusion of this cycle of B cell depletion therapy (Rituximab) 4-8 weeks before randomisation (week 0, see participant timeline). Previous use of Rituximab is allowed prior to this cycle. 5. No contraindications to the use of Belimumab 6. Ability to provide informed consent Previous inclusion criteria: 1. Aged between 18 and 75 years 2. Patients with 4 or more criteria for SLE according to the American College of Rheumatology (ACR) 1997 criteria or SLICC 2012 criteria or biopsy proven lupus nephritis with one additional supportive test on at least two occasions (positive ANA, anti-dsDNA antibodies or anti-Sm antibodies) 3. History of anti-dsDNA antibodies detectable at least once in the past taken within one year of screening the patient on the study protocol (ELISA test should be used for Anti dsDNA antibody testing) 4. Patients have received the first infusion of this cycle of B cell depletion therapy (Rituximab) 4-6 weeks before randomisation (week 0, see participant timeline). Previous use of Rituximab is allowed 5. No contraindications to the use of Belimumab 6. Ability to provide informed consent |
| Participant exclusion criteria | Current exclusion criteria as of 08/08/2018: 1. Severe “critical” SLE flare defined as BILAG A flare in CNS system or any SLE manifestation requiring more immunosuppression than allowed within the protocol in the physician's opinion 2. Pregnancy and/or Breast Feeding patients 3. At risk of pregnancy and unwilling to use an acceptable form of birth control contraception (see section 6.3.1.4) 4. Prior use of Belimumab, Atacicept or any biologic therapy (except Rituximab, but no other B cell depleting therapies) 5. Participation in any other interventional trial within the last 6 months 6. eGFR <30mls/min at screening 7. Active infections, including but not limited to: 7.1. Current or past infection with hepatitis B or C as defined by: 7.1.1. Hepatitis B surface antigen positive 7.1.2. Hepatitis B surface antibody positive and hepatitis B core antibody positive 7.1.3. Hepatitis C antibody positive 7.2. Historically positive HIV test or test positive at screening for HIV 7.3. Active TB. 8. Infection history: 8.1. Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria) 8.2. Hospitalization for treatment of infection within 60 days of Day 0 8.3. Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti parasitic agents) within 30 days of Day 0 9. Receipt of a live-attenuated vaccine within 3 months of week 0 (see participant timeline) 10. In the investigator’s opinion, patients that are at high risk for infection (including but not limited to in dwelling catheter, dysphagia with aspiration, decubitus ulcer, history of prior aspiration pneumonia or recurrent severe urinary tract infection) 11. IgG levels below 4.0 g/L, IgA level < 10 mg/dL (IgG and IgA test must be performed no more than 10 days before study drug commenced for the second inclusion/exclusion criteria assessment at week 0) 12. Primary immunodeficiency 13. History of malignant neoplasm within the last 5 years 14. History of cervical dysplasia CIN Grade III cervical high risk human papillomavirus or abnormal cervical cytology other than abnormal squamous cells of undetermined significance (ASCUS) within the past 3 years. The patient will be eligible after the condition has resolved (e.g., follow-up HPV test is negative or cervical abnormality has been effectively treated >1 year ago) 15. Severe, progressive, or uncontrolled renal, hepatic, haematological, gastrointestinal, pulmonary, cardiac, or neurological disease or, in the investigator’s opinion, any other concomitant medical condition or significant abnormal laboratory value that places the participant at risk by participating in this study with the exception of diseases or conditions related to active SLE 16. Comorbidities currently requiring systemic corticosteroid therapy 17. Evidence of serious suicide risk including any history of suicidal behaviour in the last 6 months and/or any suicidal ideation in the last 2 months or who in the investigator’s judgement, pose a significant risk 18. History of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies 19. Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within 364 days prior to Day 0 20. White blood cells (WBC) <1.5 x 10(9)/L, Neutrophils <1 x 10(9)/L measured up to 10 days before week 0 (study drug commenced) 21. A history of major organ transplant or hematopoietic stem/cell/marrow transport or renal transplant. Previous exclusion criteria: 1. Severe “critical” SLE flare defined as BILAG A flare in CNS system or any SLE manifestation requiring more immunosuppression than allowed within the protocol in the physician's opinion 2. Pregnancy and/or Breast Feeding patients 3. At risk of pregnancy and unwilling to use an acceptable form of birth control contraception (see section 6.3.1.4) 4. Prior use of Belimumab, Atacicept or any biologic therapy (except Rituximab, but no other B cell depleting therapies) 5. Participation in any other interventional trial within the last 6 months 6. eGFR <30mls/min at screening 7. Active infections, including but not limited to: 7.1. Current or past infection with hepatitis B or C as defined by: 7.1.1. Hepatitis B surface antigen positive 7.1.2. Hepatitis B surface antibody positive and hepatitis B core antibody positive 7.1.3. Hepatitis C antibody positive 7.2. Historically positive HIV test or test positive at screening for HIV 7.3. Active TB. 8. Infection history: 8.1. Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria) 8.2. Hospitalization for treatment of infection within 60 days of Day 0 8.3. Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti parasitic agents) within 60 days of Day 0 9. Receipt of a live-attenuated vaccine within 3 months of week 0 (see participant timeline) 10. In the investigator’s opinion, patients that are at high risk for infection (including but not limited to in dwelling catheter, dysphagia with aspiration, decubitus ulcer, history of prior aspiration pneumonia or recurrent severe urinary tract infection) 11. IgG levels below 4.0 g/L, IgA level < 10 mg/dL (IgG and IgA test must be performed no more than 10 days before study drug commenced for the second inclusion/exclusion criteria assessment at week 0) 12. Primary immunodeficiency 13. History of malignant neoplasm within the last 5 years 14. History of cervical dysplasia CIN Grade III cervical high risk human papillomavirus or abnormal cervical cytology other than abnormal squamous cells of undetermined significance (ASCUS) within the past 3 years. The patient will be eligible after the condition has resolved (e.g., follow-up HPV test is negative or cervical abnormality has been effectively treated >1 year ago) 15. Severe, progressive, or uncontrolled renal, hepatic, haematological, gastrointestinal, pulmonary, cardiac, or neurological disease or, in the investigator’s opinion, any other concomitant medical condition or significant abnormal laboratory value that places the participant at risk by participating in this study with the exception of diseases or conditions related to active SLE 16. Comorbidities currently requiring systemic corticosteroid therapy 17. Evidence of serious suicide risk including any history of suicidal behaviour in the last 6 months and/or any suicidal ideation in the last 2 months or who in the investigator’s judgement, pose a significant risk 18. History of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies 19. Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within 364 days prior to Day 0 20. White blood cells (WBC) <1.5 x 109/L, Neutrophils <1 x 109/L measured up to 10 days before week 0 (study drug commenced) |
| Recruitment start date | 16/02/2017 |
| Recruitment end date | 31/03/2019 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
London
NW1 2BU
United Kingdom
London
SE1 9RT
United Kingdom
Cambridge
CB2 0QQ
United Kingdom
Manchester
M13 9WL
United Kingdom
White City
London
W12 0HS
United Kingdom
London
NW3 2QG
United Kingdom
London
E1 1BB
United Kingdom
London
E11 1NR
United Kingdom
Southampton
SO16 6YD
United Kingdom
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
Leeds
LS7 4SA
United Kingdom
Birmingham
B15 2TH
United Kingdom
Doncaster
DN2 5LT
United Kingdom
Sheffield
S10 2JF
United Kingdom
Leicester
LE5 4PW
United Kingdom
Walsgrave
Coventry
CV2 2DX
United Kingdom
Birmingham
B18 7QH
United Kingdom
Sponsor information
Hospital/treatment centre
Gower Street
London
WC1E 6BT
England
United Kingdom
| Phone | +44 20 7679 6163 |
|---|---|
| ctu.beatlupus@ucl.ac.uk | |
"ROR" |
https://ror.org/02jx3x895 |
Funders
Funder type
Charity
Private sector organisation / Other non-profit organizations
- Location
- United Kingdom
Private sector organisation / Trusts, charities, foundations (both public and private)
- Alternative name(s)
- GSK
- Location
- United Kingdom
No information available
Results and Publications
| Intention to publish date | 03/12/2021 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal. |
| IPD sharing plan | Individual de-identified participant data that will underlie the results of the trial publication will be available from 6 months up to 36 months following the trial publication. This will be available to investigators whose proposed use of the data has been approved by an internal review committee identified for this purpose and whose aim is to achieve/analyse what is in the approved proposal. Proposals should be directed to cctu-enquiries@ucl.ac.uk. To gain access a Data Sharing Agreement (DSA) will be signed. Data will be shared by an appropriate secure facility and will be password protected. Participants have consented to sharing of pseudo-anonymised data. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | protocol | 16/12/2019 | 19/12/2019 | Yes | No |
| Statistical Analysis Plan | statistical analysis plan | 16/07/2020 | 20/07/2020 | No | No |
| Results article | results | 26/10/2021 | 27/10/2021 | Yes | No |
| Basic results | 01/12/2021 | 03/12/2021 | No | No | |
| Other publications | Exploratory analysis | 28/11/2022 | 10/02/2023 | Yes | No |
| HRA research summary | 28/06/2023 | No | No |
Additional files
Editorial Notes
10/02/2023: Publication reference added.
03/12/2021: The basic results of this trial have been uploaded as an additional file.
27/10/2021: Publication reference added.
21/01/2021: The following changes were made to the trial record:
1. The overall trial end date was changed from 31/03/2021 to 03/12/2020.
2. The intention to publish date was changed from 31/03/2022 to 03/12/2021.
27/10/2020: IPD sharing statement added.
19/10/2020: The following changes were made to the trial record:
1. The overall trial end date was changed from 31/10/2020 to 31/03/2021.
2. The intention to publish date was changed from 31/10/2021 to 31/03/2022.
20/07/2020: Publication reference added.
19/12/2019: Publication reference added.
02/07/2019: The following changes were made to the trial record:
1. The overall trial start date was changed from 21/01/2014 to 12/09/2016.
2. The recruitment start date was changed from 01/10/2016 to 16/02/2017.
03/04/2019: The total final enrolment number has been added.
28/03/2019: The condition has been changed from "Specialty: Musculoskeletal disorders, Primary sub-specialty: Other; UKCRC code/ Disease: Inflammatory and Immune System/ Certain disorders involving the immune mechanism" to "Systemic lupus erythematosus" following a request from the NIHR.
26/03/2019: The following changes were made to the trial record:
1. The funder name has been changed from Arthritis UK to Versus Arthritis.
2. The secondary outcomes have been changed.
23/01/2019: The following changes have been made to the trial record:
1. The recruitment end date has been changed from 31/12/2018 to 31/03/2019
2. The overall trial end date has been changed from 31/07/2020 to 31/10/2020
3. The intention to publish date has been changed from 31/07/2021 to 31/10/2021
08/08/2018: The following changes have been made:
1. The recruitment end date has been changed from 01/05/2018 to 31/12/2018.
2. The overall trial end date has been changed from 31/12/2019 to 31/07/2020.
3. The intention to publish date has been changed from 31/12/2020 to 31/07/2021.
4. The participant inclusion criteria have been changed.
5. The participant exclusion criteria have been changed.
6. Sandwell Hospital has been removed from the trial centres and Leicester General Hospital, University Hospitals Coventry & Warwickshire and City Hospital Birmingham have been added.
7. The trial website has been added.
01/12/2016: Verified study information with principal investigator.
