Rituximab and Belimumab Combination Therapy in PR3 Vasculitis (COMBIVAS)

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ClinicalTrials.gov Identifier: NCT03967925

Recruitment Status : Active, not recruiting

First Posted : May 30, 2019

Last Update Posted : March 8, 2022

Sponsor:

Collaborators:

GlaxoSmithKline

Medical Research Council

Imperial College London

University College, London

Newcastle University

University of Glasgow

University of Cambridge

Information provided by (Responsible Party):

Rachel Jones, Cambridge University Hospitals NHS Foundation Trust

Study Description

Brief Summary:

Mechanistic study to assess whether dual B-cell immunotherapy by co-administration of rituximab and belimumab will result in improvements in biological endpoints, functional outcomes and clinical status compared to rituximab with placebo.

Condition or disease	Intervention/treatment	Phase
ANCA Associated Vasculitis Granulomatosis With Polyangiitis	Drug: Belimumab Drug: Rituximab Drug: Prednisolone	Phase 2

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Detailed Description:

AAV is an organ and life threatening multisystem autoimmune disease, where ANCA are strongly implicated in disease pathogenesis, causing neutrophil activation and endothelial damage. 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 (42% vs 9% failure rate compared to other subtypes) 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 as anti-CD20) and B lymphocyte stimulator (BLyS) blockade (i.e. belimumab) may be more efficacious than targeting either mechanism alone. Therefore, this mechanistic trial will assess whether dual B-cell immunotherapy by co-administration of rituximab and belimumab will result in improvements in mechanistic endpoints, functional outcomes and clinical status compared to rituximab with placebo.

The efficacy of B cell therapy depends on depletion of pathogenic B cells and the regulated reconstitution of the B cell compartment. Response to rituximab is associated with peripheral blood B cell depletion, but this is incomplete on high resolution FACS and at the disease tissue level in ANCA vasculitis patients. Early relapse is associated with a failure to become ANCA negative by 6 months, a failure of tissue B cell depletion (including PR3 specific B cells), a high proportion of memory B cells before rituximab treatment and early peripheral B cell reconstitution with a predominant memory phenotype.

Combining B cell depleting therapy (rituximab) with BLyS antagonism (belimumab) may enhance B cell targeting in AAV through several mechanisms: belimumab reduces both CD20+ and CD20- plasmablast populations in SLE patients hence combination therapy may impact a broader B cell population than targeting CD20 alone. High BLyS levels in tissue niches may also retain B cells and protect against depletion by rituximab. As observed in the BLISS studies, belimumab is associated with an early rise in peripheral blood memory B cells, possibly due to mobilisation from lymphoid tissue. Studies on tissue B cell depletion and BLyS in pre-clinical models support the concept of combining anti-CD20 and BLyS targeting and assessing tissue depletion in lymph node biopsies as well as in blood. High BLyS levels during B cell reconstitution post rituximab can promote return of autoreactive B cell resulting in more severe flares. Regulation of BLyS levels post depletion is thought to set a higher stringency for B cell reconstitution, selecting out autoreactive B cells and would directly target any BLyS driven rebound effect.

Rituximab will be dosed at Days 8 and 22, after initiation of belimumab and discontinuation of baseline immunosuppressants. Dosing at Day 8 and Day 22 is justified by: a) separation of start times for belimumab and rituximab, thereby allowing for observation of safety events which may be attributable to starting treatment with the individual agents, and b) evidence that belimumab may mobilise B cells into the periphery making them available targets for anti-CD20 treatment, therefore, starting belimumab prior to rituximab may allow more efficient peripheral B cell depletion by rituximab. Continuing belimumab therapy for 52 weeks ensures that anti-BLyS activity continues during the critical timeframe of B cell reconstitution post rituximab (median time 8.5 to 12.6 months) reducing the potential for high levels of BLyS during this time. Assessments during follow-up after completion of beliumumab / belimumab-placebo therapy allow assessment of whether immunological and clinical remission is maintained once B cell reconstitution has taken place.

A barrier to research of B cell targeted therapy has been the difficulty in obtaining sequential cells from sites where the immune dysregulation occurs or sites of inflammation. Therefore, the inclusion of both lymph node biopsies and nasal tissue biopsies in this trial will potentially permit direct characterisation of pathogenic cells at key sites, their microenvironment and, critically, the interaction of B cells with helper T cells, the primary drivers of the abnormal immune response

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	31 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Triple (Participant, Care Provider, Investigator)
Primary Purpose:	Treatment
Official Title:	A Randomised, Double Blind, Controlled Mechanistic Study of Rituximab and Belimumab Combination Therapy in PR3 ANCA-associated Vasculitis
Actual Study Start Date :	February 1, 2019
Estimated Primary Completion Date :	April 2023
Estimated Study Completion Date :	November 2023

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Granulomatosis with polyangiitis

MedlinePlus related topics: Vasculitis

Drug Information available for: Rituximab Belimumab

Genetic and Rare Diseases Information Center resources: ANCA-associated Vasculitis Granulomatosis With Polyangiitis

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Belimumab Weekly 200mg SC injections of belimumab for 12 months	Drug: Belimumab Sub-cutaneous injection Other Name: Benlysta Drug: Rituximab IV infusion 1g x 2 Other Name: Truxima Drug: Prednisolone 20mg prednisolone tapering dose Other Name: prednisone
Placebo Comparator: Belimumab placebo Weekly SC injections of belimumab placebo for 12 months	Drug: Rituximab IV infusion 1g x 2 Other Name: Truxima Drug: Prednisolone 20mg prednisolone tapering dose Other Name: prednisone

Outcome Measures

Primary Outcome Measures :

Time to PR3 ANCA negativity [ Time Frame: Analysed at 24 months ]
ELISA analysis at different time points to determine when PR3 ANCA can no longer be detected

Secondary Outcome Measures :

Proportion of participants with PR3 ANCA negativity [ Time Frame: 2 years ]
Measured by ELISA at various time points
Change from baseline of certain cell subsets [ Time Frame: 2 years ]
Measured by flow cytometry at various time points
Time to clinical remission [ Time Frame: 2 years ]
Measured by BVAS/WG
Incidence of serious adverse events (SAEs) [ Time Frame: 2 years ]
Hospitalisation or serious events

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Participants must be 18 of age

Have a diagnosis of AAV (granulomatosis with polyangiitis or microscopic polyangiitis)
Have PR3 ANCA positivity by ELISA at screening
Have active disease defined by one major or three minor disease activity items on BVAS/WG
Be capable of giving signed informed consent

Exclusion Criteria:

MPO ANCA or anti-GBM antibody positivity by ELISA at screening
Presence of pulmonary haemorrhage with hypoxia at screening
Estimated glomerular filtration rate (eGFR) <30 ml/min/1.73m2 at screening
Have an acute serious or chronic infection at screening
Have received any B cell targeted therapy within 364 days of Day 1
Have received any steroid injection (e.g., intramuscular [IM], intraarticular, or IV) within 60 days of Day 1 (unless given during or 14 days before screening period)
Have received >1.5mg methylprednisolone (IV) between 14 days prior to screening and Day 1 (including Day 1).
Have received oral prednisolone >10mg/day (or equivalent) on average over the 30 days prior to screening
Have undetectable peripheral blood B cells at screening
Have IgG <400mg/dl at screening

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03967925

Locations

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United Kingdom
Addenbrooke's Hospital
Cambridge, United Kingdom
Glasgow Royal Infirmary
Glasgow, United Kingdom
Imperial College London
London, United Kingdom
Royal Free Hospital
London, United Kingdom
Royal Freemann Hospital
Newcastle, United Kingdom
Nottingham University Hospitals
Nottingham, United Kingdom

Sponsors and Collaborators

Rachel Jones

GlaxoSmithKline

Medical Research Council

Imperial College London

University College, London

Newcastle University

University of Glasgow

University of Cambridge

Investigators

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Principal Investigator:	Rachel B Jones	Addenbrookes Hospital

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Serling-Boyd N, Wallace ZS. Management of primary vasculitides with biologic and novel small molecule medications. Curr Opin Rheumatol. 2021 Jan;33(1):8-14. doi: 10.1097/BOR.0000000000000756. Review.

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Responsible Party:	Rachel Jones, Consultant Nephrologist, Cambridge University Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier:	NCT03967925
Other Study ID Numbers:	206852
First Posted:	May 30, 2019 Key Record Dates
Last Update Posted:	March 8, 2022
Last Verified:	February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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Studies a U.S. FDA-regulated Drug Product:	No
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by Rachel Jones, Cambridge University Hospitals NHS Foundation Trust:


proteinase 3

Additional relevant MeSH terms:

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Granulomatosis with Polyangiitis Vasculitis Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis Vascular Diseases Cardiovascular Diseases Systemic Vasculitis Lung Diseases, Interstitial Lung Diseases Respiratory Tract Diseases Autoimmune Diseases Immune System Diseases Prednisone Prednisolone	Rituximab Belimumab Antineoplastic Agents, Immunological Antineoplastic Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Anti-Inflammatory Agents Glucocorticoids Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Antineoplastic Agents, Hormonal Immunosuppressive Agents

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