Rituximab and Belimumab Combination Therapy in PR3 COMBIVAS

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Brief Title

Rituximab and Belimumab Combination Therapy in PR3 Vasculitis

Official Title

A Randomised, Double Blind, Controlled Mechanistic Study of Rituximab and Belimumab Combination Therapy in PR3 ANCA-associated Vasculitis

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
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Time to PR3 ANCA negativity

Secondary Outcome

 Proportion of participants with PR3 ANCA negativity

Condition

ANCA Associated Vasculitis

Intervention

Belimumab

Study Arms / Comparison Groups

 Belimumab
Description:  Weekly 200mg SC injections of belimumab for 12 months

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

31

Start Date

February 1, 2019

Completion Date

November 2023

Primary Completion Date

April 2023

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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Rachel B Jones, , 

Location Countries

United Kingdom

Location Countries

United Kingdom

Administrative Informations


NCT ID

NCT03967925

Organization ID

206852


Responsible Party

Sponsor-Investigator

Study Sponsor

Rachel Jones

Collaborators

 GlaxoSmithKline

Study Sponsor

Rachel B Jones, Principal Investigator, Addenbrookes Hospital


Verification Date

February 2022