An international, randomised, open label trial comparing a rituxmab based regimen with a standard cyclophosphamide/azathioprine regimen in the treatment of active, 'generalised' ANCA associated vasculitis

The ANCA associated vasculitides (AASV), namely Wegener*s granulomatosis,
microscopic polyangiitis, and renal limited vasculitis are autoimmune,
multi-system,
progressive diseases which untreated can lead to rapidly progressive renal
failure and death.
Randomised, prospective, clinical trials have demonstrated the efficacy of
immunosuppressive treatments for vasculitis and have defined treatment
protocols at different disease points. The current *gold standard* treatment
for active AASV with glomerulonephritis is cyclophosphamide with steroids.
However the standard treatment is associated with significant morbidity and
mortality, largely due to infections and malignancy with cumulative
cyclophosphamide dosing. Other effective treatments for AASV are being sought,
with safer side effect profiles. Rituximab is an anti CD20 chimeric monoclonal
antibody, which is used for the treatment of non-Hodgkin*s lymphoma (NHL). It
is well tolerated in humans with a good safety profile. Rituximab has been
shown in small series to induce remission in AASV and is now being increasingly
used for other (non-ANCA) autoimmune conditions such as lupus and rheumatoid
arthritis.
RITUXVAS has been designed to test the hypothesis that Rituximab leads to a
higher rate of sustained remission compared to standard therapies
(cyclophosphamide /azathioprine) with a lower rate of adverse events and
reduced cyclophosphamide exposure as treatments for active, *generalised* AASV.
We plan a randomised phase II/phase III trial to compare a rituximab based
regimen to standard of care. For the initial phase II part, 44 patients will be
randomised 3:1 to rituximab or control. Following this analysis, the trial may
be extended to a phase III stage. The trial will be conducted by 14 centres
from 8 countries.

To assess the rates of preliminary response and sustained remission of AASV
following rituximab (on the basis of former studies, 86% sustained remission
expected with rituximab compared to 75% in control group).
To assess safety of a rituximab regimen in terms of severe adverse events (in
patients receiving standard therapies, adverse advent rate is 45% at 2 years,
at least 50% of which are infection relapted. In comparison rituximab use is
only rarely associated with infections, therefore 22.5% adverse event rate
expected with rituximab compared to 45% at 2 years in control group).

Trial Overview


Entry
(Eligibility criteria)



Randomisation
(experimental limb 33:control limb 11)

Rituximab 375mg/m2 IV x4 IV Cyclophosphamide Cyclophosphamide 15mg/kg IV
x2 (minimum 3months, max
Methylprednisolone 1g IV 6 months).
Prednisolone PO Methylprednisolone 1gIV
Prednisolone PO


Remission/maintenance
Azathioprine 2mg/kg


2 years
Trial End


Analyses

6 weeks: Initial response evaluation

6 months: Efficacy and safety evaluation

24 months: Trial end and efficacy and safety evaluation

1.3 Rituximab
Rituximab is an anti CD 20 chimeric mouse/human monoclonal antibody, with human
IgG1 constant regions and murine light/heavy chain variable regions (7). CD 20
is a ligand which exists on developing B cells, excluding stem cells and plasma
cells. The role of the CD 20 ligand in nature is not fully understood, although
mediation of apoptosis has been suggested. The mechanisms by which rituximab
causes B cell depletion may involve complement induced B cell lysis, Fc
receptor mediated cytotoxic cell killing or the direct induction of B cell
apoptosis by rituximab.
Rituximab therapy correlates positively with B cell depletion and rituximab
levels. Different dosing regimens have been trialled. In patients with
systemic lupus erythematosus (SLE), the efficacy of rituximab is dependant upon
B cell depletion. 4 infusions of 375mg/m2 rituximab infusions (one per week for
four weeks) were required for this to occur (13,14). In 3 published reports
375mg/m2 has resulted in B cell depletion and clinical response in patients
with refractory vasculitis (10-13). On the basis of these results a dose of 4 x
375mg/m2 infusions will be used in RITUXVAS.
In RITUXVAS, 2 doses cyclophosphamide will still be administered with the 1st
and 3rd rituximab infusions, for two reasons. Firstly, the necrotising
cresentic glomerulonephritis associated with AASV progresses rapidly and the
therapeutic effect of rituximab is delayed. The use of cyclophosphamide/high
dose steroid, which are standard components of induction therapy, will allow
adequate immunosuppression in the early crucial treatment of AASV. Secondly,
human anti-chimeric antibody (HACA) formation has been reported in NHL, SLE,
and RA with varying frequencies, (4.3% of patients in RA (8)). The long term
implications of these antibodies are not known. However, the possibility of
anaphylactic reactions and rituximab resistance with further treatments exists.
Co-administration of an immunosuppressant effective in the treatment of
vasculitis is thus a logical approach to minimise HACA development.
Rituximab has now been used to treat 300,000 patients with NHL. Long-term
safety regarding carcinogenicity and fertility has yet to be established.
However, no major long-term adverse sequelae have been reported (1).
Up to 50% of patients receiving rituximab for an indication will develop
infusion reactions with symptoms including; fevers, chills, rigors, flushing,
throat irritation rash rhinitis fatigue headache, nausea, vomiting, urticaria,
angioedema, bronchospasm, myalgia, arthralgia, hypotension, hypertension and
exacerbation of angina or congestive cardiac failure. Later reactions include
diarrhoea, leucopenia, neutropenia, thrombocytopenia, anaemia, and infections
in 30%, which may or may not be drug related (investigators brochure).

ANCA geassocieerde vasculitides zijn ernstige aandoeningen. In verband met hoge
mortaliteit indien onbehandeld wordt al jaren een standaardtherapie gegeven met
cyclofosfamide en prednisolon. Deze standaardtherapie gaat gepaard met ernstige
bijwerkingen op de korte termijn (infecties en hematologische afwijkingen) en
op de langere termijn (infertiliteit en ontwikkeling van maligniteiten). Men is
naarstig op zoek naar therapieën met mindere bijwerkingen. In de huidige studie
wordt getest of rituximab cyclofosfamide sparend kan werken. Het nadeel van
rituximab lijkt beperkt. In de uitgebreide ervaring bij andere aandoeningen
zoals non-Hodgkin lymfoom en reumatoïde arthritis en uit de beperkte ervaring
bij vasculitis blijkt dat rituximab over het algemeen zeer goed verdragen
wordt. Behalve transfusie reacties is er theoretisch in ieder geval een risico
op infecties. Daarnaast kunnen er antistoffen tegen rituximab gemaakt worden
waardoor een enkele keer serumziekte kan optreden. Serumziekte is echter over
het algemeen ook passager en kan goed behandeld worden met corticosteroïden.