Clinical Trial Details
— Status: Active, not recruiting
Administrative data
NCT number |
NCT03967925 |
Other study ID # |
206852 |
Secondary ID |
|
Status |
Active, not recruiting |
Phase |
Phase 2
|
First received |
|
Last updated |
|
Start date |
February 1, 2019 |
Est. completion date |
November 2023 |
Study information
Verified date |
February 2022 |
Source |
Cambridge University Hospitals NHS Foundation Trust |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial 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.
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