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Rituximab and Belimumab Combination Therapy in PR3 Vasculitis (COMBIVAS)

Primary Purpose

ANCA Associated Vasculitis, Granulomatosis With Polyangiitis

Status
Active
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Belimumab
Rituximab
Prednisolone
Sponsored by
Rachel Jones
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for ANCA Associated Vasculitis focused on measuring proteinase 3

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Addenbrooke's Hospital
  • Glasgow Royal Infirmary
  • Imperial College London
  • Royal Free Hospital
  • Royal Freemann Hospital
  • Nottingham University Hospitals

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Belimumab

Belimumab placebo

Arm Description

Weekly 200mg SC injections of belimumab for 12 months

Weekly SC injections of belimumab placebo for 12 months

Outcomes

Primary Outcome Measures

Time to PR3 ANCA negativity
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
Measured by ELISA at various time points
Change from baseline of certain cell subsets
Measured by flow cytometry at various time points
Time to clinical remission
Measured by BVAS/WG
Incidence of serious adverse events (SAEs)
Hospitalisation or serious events

Full Information

First Posted
January 18, 2019
Last Updated
February 21, 2022
Sponsor
Rachel Jones
Collaborators
GlaxoSmithKline, Medical Research Council, Imperial College London, University College, London, Newcastle University, University of Glasgow, University of Cambridge
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1. Study Identification

Unique Protocol Identification Number
NCT03967925
Brief Title
Rituximab and Belimumab Combination Therapy in PR3 Vasculitis
Acronym
COMBIVAS
Official Title
A Randomised, Double Blind, Controlled Mechanistic Study of Rituximab and Belimumab Combination Therapy in PR3 ANCA-associated Vasculitis
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
February 1, 2019 (Actual)
Primary Completion Date
April 2023 (Anticipated)
Study Completion Date
November 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Rachel Jones
Collaborators
GlaxoSmithKline, Medical Research Council, Imperial College London, University College, London, Newcastle University, University of Glasgow, University of Cambridge

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
ANCA Associated Vasculitis, Granulomatosis With Polyangiitis
Keywords
proteinase 3

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
31 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Belimumab
Arm Type
Active Comparator
Arm Description
Weekly 200mg SC injections of belimumab for 12 months
Arm Title
Belimumab placebo
Arm Type
Placebo Comparator
Arm Description
Weekly SC injections of belimumab placebo for 12 months
Intervention Type
Drug
Intervention Name(s)
Belimumab
Other Intervention Name(s)
Benlysta
Intervention Description
Sub-cutaneous injection
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Truxima
Intervention Description
IV infusion 1g x 2
Intervention Type
Drug
Intervention Name(s)
Prednisolone
Other Intervention Name(s)
prednisone
Intervention Description
20mg prednisolone tapering dose
Primary Outcome Measure Information:
Title
Time to PR3 ANCA negativity
Description
ELISA analysis at different time points to determine when PR3 ANCA can no longer be detected
Time Frame
Analysed at 24 months
Secondary Outcome Measure Information:
Title
Proportion of participants with PR3 ANCA negativity
Description
Measured by ELISA at various time points
Time Frame
2 years
Title
Change from baseline of certain cell subsets
Description
Measured by flow cytometry at various time points
Time Frame
2 years
Title
Time to clinical remission
Description
Measured by BVAS/WG
Time Frame
2 years
Title
Incidence of serious adverse events (SAEs)
Description
Hospitalisation or serious events
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rachel B Jones
Organizational Affiliation
Addenbrookes Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Addenbrooke's Hospital
City
Cambridge
Country
United Kingdom
Facility Name
Glasgow Royal Infirmary
City
Glasgow
Country
United Kingdom
Facility Name
Imperial College London
City
London
Country
United Kingdom
Facility Name
Royal Free Hospital
City
London
Country
United Kingdom
Facility Name
Royal Freemann Hospital
City
Newcastle
Country
United Kingdom
Facility Name
Nottingham University Hospitals
City
Nottingham
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
33164993
Citation
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.
Results Reference
derived

Learn more about this trial

Rituximab and Belimumab Combination Therapy in PR3 Vasculitis

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