(COMBIVAS)
Research type
Research Study
Full title
A randomized, double blind, controlled mechanistic study of rituximab and belimumab combination therapy in PR3 ANCA-associated vasculitis
IRAS ID
229033
Contact name
Rachel Jones
Contact email
Sponsor organisation
Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge
Eudract number
2017-004645-24
Duration of Study in the UK
3 years, 6 months, 1 days
Research summary
Summary of Research
ANCA vasculitis is an auto-immune disease, a disorder when healthy tissue gets destroyed by the body’s own immune system. Current treatments target B cells, a type of white blood cell thought to be important in the process of the disease and can be effective in about 90% of patients.
In some patients, the effects of treatment can wear off and the disease can return, in around half of patients within 2 years of receiving treatment.
Belimumab is a drug currently used in SLE (systemic lupus erythematosus) which also targets B cells. There is reason to believe that it may work in ANCA vasculitis. The COMBIVAS trial will compare the effects of the combination of rituximab (a current treatment for ANCA vasculitis) plus belimumab with rituximab alone in patients with ANCA vasculitis. We will assess this by comparing the effect that the drugs are having on a certain protein in the blood (ANCA) that is produced by the B-cells, and compare the changes in the amount of different types of white blood cells in the blood, lymph glands and tissue from inside the nose. Blood and urine tests will also be done and information will also be collected on the activity of vasculitis and any side effects experienced throughout the trial. We will recruit both newly diagnosed and relapsing vasculitis patients into the trial. We plan to recruit at least 30 participants from 5 hospitals in England and Scotland. Patients will be randomly assigned to receive either rituximab plus belimumab or rituximab plus placebo. Both groups will also receive low dose steroids. The patient and investigators will not know if belimumab or the placebo is given. There is a one year treatment phase, followed by a one year follow up phase. Patients will be in the trial for approximately two years in total.Summary of Results
Who carried out the research? (including details of sponsor, funding and any competing interests) The trial was sponsored by Cambridge University Hospitals NHS Foundation Trust (CUH) and The University of Cambridge. The trial was funded by the MRC grant reference: MR/R502145/1 What public involvement there was in the study (how many people, what their relevant lived experience was, and what they did) The trial protocol was designed by the Trial Management Committee, which includes representatives from Cambridge University and Cambridge University Hospitals NHS Foundation Trust. The trial design was reviewed by external reviewers and by the funding panel as part of the application process for an MRC grant. GSK extensively reviewed the protocol before submission to the regulatory authorities.
8 participants (5 Vasculitis patients and 3 of their partners) took part in a patient and public involvement exercise. The panel discussed the Patient Information Sheet and the procedures planned for the study e.g. number of visits, biopsy procedures, drug administration.
Where and when the study took place. Who participated in the study?
The main site was Addenbrooke’s Hospital in Cambridge where 36 participants were recruited. Other recruiting sites include, Queen’s Medical Centre, Nottingham; Leicester General Hospital; and Hammersmith Hospital/Imperial College London. A total of 43 participants were consented and 35 enrolled into the trial.
Why was the research needed?
The research was needed as ANCA Associated Vasculitis (AAV) is an organ and life threatening multisystem autoimmune disease, where ANCA (Anti-neutrophil cytoplasmic antibodies) are strongly implicated in disease pathogenesis. B cell depletion with rituximab, and treatment with glucocorticoids, is associated with reduction in ANCA levels and clinical remission in AAV. However, patients with proteinase 3 (PR3) ANCA subtype and/or predominantly granulomatous disease have a lower remission rate after rituximab and glucocorticoids, with a high subsequent relapse risk of 50% by 13 months. There is a need for newer therapies to reduce the time to remission, to spare glucocorticoid use, and to promote long-lasting remission without risk of relapse. Scientific evidence suggests that dual B-cell targeted immunotherapy with both B cell depletion (i.e. rituximab) and B lymphocyte stimulator blockade (i.e. belimumab) may be more efficacious than targeting either mechanism alone.What were the main questions studied? What treatments or interventions did the participants take/receive?
This trial assessed compared how well belimumab worked in combination with Rituximab versus Rituximab alone.
Participants received 2 intravenous doses of 1000mg Rituximab plus either a weekly injection for 51 weeks of a placebo (not active) or of 200mg Belimumab.
The trial also compared how safe the treatments were and how effective the treatments were at stopping production of PR3 ANCA, which is an antibody that causes the disease and indicates whether the disease is active or not.What medical problems (adverse reactions) did the participants have?
18 serious adverse events were reported during the study, 10 in participants receiving rituximab plus placebo and 8 in participants receiving rituximab and belimumab.
Organ systems involved include, cardiac, gastro, infections, musculoskeletal, neoplasms (cancer), renal, respiratory, skin, vascular and injury.What happened during the study?
43 participants were assessed for eligibility and 35 participants were enrolled from 5 participating sites in the UK and randomised in a 1:1 ratio, 17 to the belimumab arm, 18 to the placebo arm. Of the 35 patients randomised, 32 (91%) completed follow up in the study. No participants were re-screened. 2 participants were withdrawn in the placebo arm; one had an incorrect diagnosis and the other was unblinded over concerns of a potential drug reaction. One participant in the Belimumab arm chose to withdraw from the study due to safety concerns during the COVID-19 pandemic.
What were the results of the study?
In this trial involving 35 patients with PR3 ANCA Associated Vasculitis, a trend in quicker time to PR3 ANCA negativity was observed and numerically fewer relapses occurred in the belimumab group. Rituximab-belimumab combination was associated with reduced time to remission and delayed reconstitution of B cells. These findings support further exploration of belimumab with rituximab as a combination biologic strategy for patients with AAV.
Analyses are still being finalised and will be published in due course and currently remain confidential.
How has this study helped patients and researchers?
Repeated Rituximab use for long term remission in ANCA Associated Vasculitis is associated with significant suppression of the immune system. The treatment strategy used in this trial combining a single course of rituximab with a different B cell therapy caused less suppression of the immune system but suggested that the combination may be beneficial in reducing ANCA vasculitis activity. This needs to be confirmed in a larger study and this is under consideration. If this combination therapy proves effective, it should reduce the long-term side effects for patients, particularly infections compared to long-term rituximab use.
Details of any further research planned
A larger clinical trial is being considered. Further ethics consent is being sought in order to retain the samples for further analyses.
Where can I learn more about this study?
Clinicaltrials.gov: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fclassic.clinicaltrials.gov%252Fct2%252Fshow%252FNCT03967925%2FNBTI%2Fi0y8AQ%2FAQ%2Fa8174c64-6455-4bf2-bf8a-65200c507e3a%2F2%2Ff7qwQPbsoN&data=05%7C02%7Ccambsandherts.rec%40hra.nhs.uk%7C065dcc2b0c8543d7923a08dd6df8316f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638787634922018236%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=b%2FB8MXnxvwzLLts6AoW4heQxUf5N9lEYZjRKMeo4EIE%3D&reserved=0
https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fcctu.org.uk%252Fportfolio%252Fvasculitis%252Ftrials-closed-to-recruitment-in-follow-up%252Fcombivas%2FNBTI%2Fi0y8AQ%2FAQ%2Fa8174c64-6455-4bf2-bf8a-65200c507e3a%2F3%2FqcZX-PwQD2&data=05%7C02%7Ccambsandherts.rec%40hra.nhs.uk%7C065dcc2b0c8543d7923a08dd6df8316f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638787634922031682%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=W%2BslaueBqVotZtToJ%2FeQOcpl6v6Wyyp2GjD9v6kwXUA%3D&reserved=0REC name
East of England - Cambridgeshire and Hertfordshire Research Ethics Committee
REC reference
18/EE/0275
Date of REC Opinion
9 Nov 2018
REC opinion
Further Information Favourable Opinion