The ENDURRANCE-1 Study. ;Exploring durable remission with rituximab in ANCA associated vasculitis

AAV is a systemic autoimmune disease characterized by capillaritis or
small-vessel vasculitis and the most severe manifestations are kidney failure,
lung hemorrhage or cerebritis. Current (inter-)national guidelines recommend,
in addition to steroid therapy, to use either cyclophosphamide or rituximab as
remission induction therapy and azathioprine or rituximab as maintenance
therapy1,2. As such, the guidelines do not provide a clear answer as to which
is the optimal treatment strategy for AAV patients. Also, because rituximab is
a relatively expensive, biological treatment, the widespread use of this
effective and safe drug is hampered in the Netherlands. Nevertheless, the
pathophysiology of AAV is closely associated with levels of anti-neutrophil
cytoplasmic autoantibodies (ANCA) against proteinase-3 (PR3) or myeloperoxidase
(MPO)3. As such, B-cell depletion with Rituximab (RTX) is successfully applied
as induction and maintenance treatment in ANCA-associated vasculitis (AAV)
patients4-6. Moreover, there is accumulating data that long-term safety profile
of rituximab might outperform cyclophosphamide7. However, because rituximab is
a relatively expensive, biological treatment, the widespread use of this
effective and safe drug is hampered in the Netherlands. This is mostly due to
the fact that the optimal treatment strategy for using RTX in AAV patients is
much debated and not yet well established8.

Remission induction therapy
Both RTX and high-dose cyclophosphamide combined with steroids are effective
remission induction therapies in AAV patients1,2. A previous randomized
controlled study on remission-induction therapy compared rituximab followed by
placebo with high-dose oral cyclophosphamide followed by azathioprine
maintenance treatment. Both treatment strategies were equivalent with respect
to duration of complete remission, frequency of relapses and severity of
relapses9. A few studies have investigated the clinical effects of combining
RTX with low-dose cyclophosphamide as a remission induction treatment strategy.
In an uncontrolled cohort the combination of RTX with six low-dose infusions of
cyclophosphamide (CycLowVas study) achieved clinical remission and a favorable
immunological state quickly (i.e. median of 20 weeks) with low relapse rates.10
Similar positive observations were seen in two other uncontrolled cohorts.11,12
From a safety perspective, rates of infection and hypogammaglobulinaemia were
comparable with other studies including a recent analysis of AAV patients
retreated with rituximab multiple times10,11. Also, no excess of malignancies
was observed, in keeping with a recent retrospective analysis that suggested
patients with AAV treated with rituximab have a comparable risk of malignancy
with the general population7. Taken together, RTX combined with
cyclophosphamide is a promising novel treatment strategy in AAV patients. 10,11.

Tailoring Rituximab as Maintenance therapy
When embarking upon RTX induction treatment for AAV, there is a strong
immunological rationale for combining RTX with cyclophosphamide based on their
differential effect across the B-cell lineage. RTX depletes precursors of
autoantibody-producing cells, but has little direct effect on ANCA-producing
plasmablasts and plasma cells that do not express CD20.13 Previous studies have
already demonstrated that induction treatment with RTX alone frequently (up to
75% of patients) necessitates re-treatment with RTX (as maintenance treatment)
to control disease activity and prevent (early) severe disease flares14-17. As
a direct consequence of the need for repetitive RTX treatment as maintenance
therapy to prevent disease flares, a fixed (6 monthly) re-dosing regimen with
RTX was demonstrated to be superior to the usual, standard of care maintenance
treatment with azathioprine 18,19. However, a fixed re-dosing regimen with RTX
can be appreciated as a relapse-preventive strategy at the cost of potential
overtreatment. Therefore, very recently a *tailored* re-dosing regimen (based
upon ANCA levels and B-cell repopulation) with RTX had equivalent efficacy as a
relapse-prevention strategy while it avoided overtreatment and reduced overall
treatment costs20.
Taken together all the recent evidence from high-quality trials on RTX
treatment for AAV patients has demonstrated that *tailored* maintenance
treatment with RTX is effective to achieve durable remission. Nevertheless,
tailoring RTX re-treatment on the basis of immunological parameters directly
implicates that the induction treatment can beneficially affect these
immunological parameters in AAV patients. Consequently, if re-treatment
rituximab infusions is guided by B-cell- and ANCA-levels it can be hypothesized
that less *tailored* infusions are needed as a maintenance treatment compared
to the current standard of care.

ENDURRANCE: Exploring durable remission with RTX in AAV
Based on these most recent insights in AAV treatment, the present study will be
the first study to directly compare RTX with low-dose cyclophosphamide to
current standard of care with RTX alone in AAV patients with respect to their
potency to reduce the cumulative number of tailored rituximab retreatments
needed to maintain clinical remission over two years.

This study has been transitioned to CTIS with ID 2023-507868-39-00 check the CTIS register for the current data.

In this randomized study the primary objective is to demonstrate a clinical
significant reduction of RTX retreatments in AAV patients receiving combination
RTX with cyclophosphamide remission-induction therapy as compared to RTX alone.

Secondary objectives are:
- to assess the safety parameters of each treatment arm including adverse
events according to WHO toxicity criteria, time to immune reconstitution and
recording of infectious events
- to assess quality of life by assessing patient-reported outcome measurements
- to assess durable immunological responses of each treatment arm including
time to an ANCA negative test, percentage of patients that reach seroconversion
of ANCA to negative, time to ANCA return, percentage of patients that have ANCA
return during follow-up, time to B-cell depletion and duration of B-cell
depletion
- to assess clinical responses in each arm including BVAS scores, clinical
biomarkers of disease activity and number of relapses.

The study is designed as an open-label, multicenter, 1:1 randomized,
prospective study between RTX with cyclophosphamide and RTX alone. The duration
of the study is 104 weeks during which AAV patients will be evaluated for the
number of RTX infusions needed to maintain clinical remission over 2 years,
tailored by B-cell and ANCA status and clinical status.

In addition to standard of care corticosteroid therapy, AAV patients will be
randomized to receive either standard induction therapy with 2 infusions of RTX
1000 mg or induction therapy combining 2 infusions of RTX 1000 mg RTX with 6
infusions of low dose intravenous cyclophosphamide 500mg. Thereafter, as part
of standard of care patients will receive tailored RTX re-treatment as
maintenance therapy.

A potential, but thus far uncertain, benefit lies in the rationale that
combination treatment could result in a better more prolonged clinical
improvement of the patient*s AAV disease based upon previous uncontrolled
studies and our own single center experience. Also, patients participating in
the study will be able to taper their concomitant immunosuppression to zero
while intensively monitored for receiving tailored rituximab infusions as
maintenance treatment. Lastly, long-term immunosuppressive treatment is
associated with (cumulative) toxicity and long- term increased risk for
infections or malignancies which is reduced in patients treated with rituximab.
The risks related to study participation lies predominantly in the side effect
profile of the described treatments and a minor risk with the intravenous
access needle necessary for rituximab and cylcophosphamide infusions.