A randomised study of rituximab and belimumab sequential therapy in PR3 ANCA-associated vasculitis (COMBIVAS): design of the study protocol
Abstract Background Sequential B cell-targeted immunotherapy with BAFF antagonism (belimumab) and B cell depletion (rituximab) may enhance B cell targeting in ANCA-associated vasculitis (AAV) through several mechanisms. Methods Study design: COMBIVAS is a randomised, double-blind, placebo-controlled...
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| Format: | Article |
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BMC
2023-03-01
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| Series: | Trials |
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| Online Access: | https://doi.org/10.1186/s13063-023-07218-y |
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| author | Mark E. McClure Seerapani Gopaluni James Wason Robert B. Henderson Andre Van Maurik Caroline C.O. Savage Charles D. Pusey Alan D. Salama Paul A. Lyons Jacinta Lee Kim Mynard David R. Jayne Rachel B. Jones on behalf the COMBIVAS investigators |
| author_facet | Mark E. McClure Seerapani Gopaluni James Wason Robert B. Henderson Andre Van Maurik Caroline C.O. Savage Charles D. Pusey Alan D. Salama Paul A. Lyons Jacinta Lee Kim Mynard David R. Jayne Rachel B. Jones on behalf the COMBIVAS investigators |
| author_sort | Mark E. McClure |
| collection | DOAJ |
| description | Abstract Background Sequential B cell-targeted immunotherapy with BAFF antagonism (belimumab) and B cell depletion (rituximab) may enhance B cell targeting in ANCA-associated vasculitis (AAV) through several mechanisms. Methods Study design: COMBIVAS is a randomised, double-blind, placebo-controlled trial designed to assess the mechanistic effects of sequential therapy of belimumab and rituximab in patients with active PR3 AAV. The recruitment target is 30 patients who meet the criteria for inclusion in the per-protocol analysis. Thirty-six participants have been randomised to one of the two treatment groups in a 1:1 ratio: either rituximab plus belimumab or rituximab plus placebo (both groups with the same tapering corticosteroid regimen), and recruitment is now closed (final patient enrolled April 2021). For each patient, the trial will last for 2 years comprising a 12-month treatment period followed by a 12-month follow-up period. Participants: Participants have been recruited from five of seven UK trial sites. Eligibility criteria were age ≥ 18 years and a diagnosis of AAV with active disease (newly diagnosed or relapsing disease), along with a concurrent positive test for PR3 ANCA by ELISA. Interventions: Rituximab 1000 mg was administered by intravenous infusions on day 8 and day 22. Weekly subcutaneous injections of 200 mg belimumab or placebo were initiated a week before rituximab on day 1 and then weekly through to week 51. All participants received a relatively low prednisolone (20 mg/day) starting dose from day 1 followed by a protocol-specified corticosteroid taper aiming for complete cessation by 3 months. Outcomes: The primary endpoint of this study is time to PR3 ANCA negativity. Key secondary outcomes include change from baseline in naïve, transitional, memory, plasmablast B cell subsets (by flow cytometry) in the blood at months 3, 12, 18 and 24; time to clinical remission; time to relapse; and incidence of serious adverse events. Exploratory biomarker assessments include assessment of B cell receptor clonality, B cell and T cell functional assays, whole blood transcriptomic analysis and urinary lymphocyte and proteomic analysis. Inguinal lymph node and nasal mucosal biopsies have been performed on a subgroup of patients at baseline and month 3. Discussion This experimental medicine study provides a unique opportunity to gain detailed insights into the immunological mechanisms of belimumab-rituximab sequential therapy across multiple body compartments in the setting of AAV. Trial registration ClinicalTrials.gov NCT03967925. Registered on May 30, 2019. |
| first_indexed | 2024-04-09T22:39:48Z |
| format | Article |
| id | doaj.art-de0d5603a4e24992b66dd2efe0d957ae |
| institution | Directory Open Access Journal |
| issn | 1745-6215 |
| language | English |
| last_indexed | 2024-04-09T22:39:48Z |
| publishDate | 2023-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Trials |
| spelling | doaj.art-de0d5603a4e24992b66dd2efe0d957ae2023-03-22T12:17:42ZengBMCTrials1745-62152023-03-0124111310.1186/s13063-023-07218-yA randomised study of rituximab and belimumab sequential therapy in PR3 ANCA-associated vasculitis (COMBIVAS): design of the study protocolMark E. McClure0Seerapani Gopaluni1James Wason2Robert B. Henderson3Andre Van Maurik4Caroline C.O. Savage5Charles D. Pusey6Alan D. Salama7Paul A. Lyons8Jacinta Lee9Kim Mynard10David R. Jayne11Rachel B. Jones12on behalf the COMBIVAS investigatorsVasculitis and Lupus Clinic, Cambridge University HospitalsVasculitis and Lupus Clinic, Cambridge University HospitalsPopulation Health Sciences Institute, Newcastle UniversityGlaxoSmithKlineGlaxoSmithKlineGlaxoSmithKlineDepartment of Immunology and Inflammation, Imperial College LondonUCL Centre for Nephrology, Royal Free HospitalDepartment of Medicine, University of CambridgeDepartment of Medicine, University of CambridgeDepartment of Medicine, University of CambridgeVasculitis and Lupus Clinic, Cambridge University HospitalsVasculitis and Lupus Clinic, Cambridge University HospitalsAbstract Background Sequential B cell-targeted immunotherapy with BAFF antagonism (belimumab) and B cell depletion (rituximab) may enhance B cell targeting in ANCA-associated vasculitis (AAV) through several mechanisms. Methods Study design: COMBIVAS is a randomised, double-blind, placebo-controlled trial designed to assess the mechanistic effects of sequential therapy of belimumab and rituximab in patients with active PR3 AAV. The recruitment target is 30 patients who meet the criteria for inclusion in the per-protocol analysis. Thirty-six participants have been randomised to one of the two treatment groups in a 1:1 ratio: either rituximab plus belimumab or rituximab plus placebo (both groups with the same tapering corticosteroid regimen), and recruitment is now closed (final patient enrolled April 2021). For each patient, the trial will last for 2 years comprising a 12-month treatment period followed by a 12-month follow-up period. Participants: Participants have been recruited from five of seven UK trial sites. Eligibility criteria were age ≥ 18 years and a diagnosis of AAV with active disease (newly diagnosed or relapsing disease), along with a concurrent positive test for PR3 ANCA by ELISA. Interventions: Rituximab 1000 mg was administered by intravenous infusions on day 8 and day 22. Weekly subcutaneous injections of 200 mg belimumab or placebo were initiated a week before rituximab on day 1 and then weekly through to week 51. All participants received a relatively low prednisolone (20 mg/day) starting dose from day 1 followed by a protocol-specified corticosteroid taper aiming for complete cessation by 3 months. Outcomes: The primary endpoint of this study is time to PR3 ANCA negativity. Key secondary outcomes include change from baseline in naïve, transitional, memory, plasmablast B cell subsets (by flow cytometry) in the blood at months 3, 12, 18 and 24; time to clinical remission; time to relapse; and incidence of serious adverse events. Exploratory biomarker assessments include assessment of B cell receptor clonality, B cell and T cell functional assays, whole blood transcriptomic analysis and urinary lymphocyte and proteomic analysis. Inguinal lymph node and nasal mucosal biopsies have been performed on a subgroup of patients at baseline and month 3. Discussion This experimental medicine study provides a unique opportunity to gain detailed insights into the immunological mechanisms of belimumab-rituximab sequential therapy across multiple body compartments in the setting of AAV. Trial registration ClinicalTrials.gov NCT03967925. Registered on May 30, 2019.https://doi.org/10.1186/s13063-023-07218-yANCAVasculitisRituximabBelimumab |
| spellingShingle | Mark E. McClure Seerapani Gopaluni James Wason Robert B. Henderson Andre Van Maurik Caroline C.O. Savage Charles D. Pusey Alan D. Salama Paul A. Lyons Jacinta Lee Kim Mynard David R. Jayne Rachel B. Jones on behalf the COMBIVAS investigators A randomised study of rituximab and belimumab sequential therapy in PR3 ANCA-associated vasculitis (COMBIVAS): design of the study protocol Trials ANCA Vasculitis Rituximab Belimumab |
| title | A randomised study of rituximab and belimumab sequential therapy in PR3 ANCA-associated vasculitis (COMBIVAS): design of the study protocol |
| title_full | A randomised study of rituximab and belimumab sequential therapy in PR3 ANCA-associated vasculitis (COMBIVAS): design of the study protocol |
| title_fullStr | A randomised study of rituximab and belimumab sequential therapy in PR3 ANCA-associated vasculitis (COMBIVAS): design of the study protocol |
| title_full_unstemmed | A randomised study of rituximab and belimumab sequential therapy in PR3 ANCA-associated vasculitis (COMBIVAS): design of the study protocol |
| title_short | A randomised study of rituximab and belimumab sequential therapy in PR3 ANCA-associated vasculitis (COMBIVAS): design of the study protocol |
| title_sort | randomised study of rituximab and belimumab sequential therapy in pr3 anca associated vasculitis combivas design of the study protocol |
| topic | ANCA Vasculitis Rituximab Belimumab |
| url | https://doi.org/10.1186/s13063-023-07218-y |
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