A pilot study examining the effect of abatacept in ANCA associated vasculitis (AAV)

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. In a randomized clinical trial, we previously
demonstrated that Methotrexate in combination with prednisolone was as
effective as cyclophosphamide and prednisolone. Relapse rate was, however,
unacceptable high in both arms of this study.
Abatacept is well tolerated in humans with a good safety profile. Abatacept is
now being increasingly used for other (non-ANCA) autoimmune conditions such as
lupus and rheumatoid arthritis.
ABAVAS has been designed to test the hypothesis that Abatacept leads to a
higher rate of sustained remission compared to standard therapies
(MTX/steroids) with an equal rate of adverse events and reduced
cyclophosphamide and prednisolon exposure as treatment for active,
non-life-threatening AASV.

Main objective:

To assess the relapse rate (defined by clinical and biochemical parameters)
over 24 months in patients with acute AAV presenting at first diagnosis of
relapse, after 12 months of treatment with abatacept in combination with
steroids and methotrexate or placebo in combination with steroids and
methotrexate.

Secondary objectives:

To assess the clinical efficacy of abatacept combined with MTX + steroids vs
placebo and MTX + steroids by measuring:
1. The sustained remission rate
2. Time to remission
3. The average steroid dosage at 6, 12, 18 and 24 months in abatacept and
placebo groups respectively
4. Time to ANCA megativity by immunofluorescence or negative anti PR3 or anti
MPO Ab test by ELISA
5. Proportion of patients defaulting to cyclophosphamide therapy
6. Proportion of patients unable to stick with trial protocol
7. Degree of chronic disease activity
8. Health related quality of life
9. Number of adverse events

Multinational, randomized, double-blind, placebo-controlled, two-arm parallel
design study of 24 months duration to the primary endpoint. This is an
exploratory study. Subjects will be randomized 1:1 to receive either abatacept
or placebo on top of MTX + CS for the first 12 months of the study and then be
maintained on MTX only.

In order to maximise recruitment in a short time period (12 months) 15-20
centres would be required. This realistically would require a pan-european
approach.

Intravenous injections of Abatacept or placebo will be given at day 1, 15, 29
at therafter each month for 12 months.
Dose: <60 kg: 500 mg
>60 to <100 kg: 750 mg
>100 kg: 1 gram

Yes, standard therapy with or without abatacept.
14 x intravenous injection

AAV are severe diseases that are treated with cyclophosphamide and prednisolon.
Side effects of this toxic therapy result in a lot of morbidity and even
sometimes mortality (around 10-20% of patients). Recently, we demonstrated in a
RCT that MTX in combination with corticosteroids is as effective as
cyclophosphamide/corticosteroids in mild forms of AAV. During this RCT,
however, relapse rate was unacceptable high in both arms of the study (70%
within 18 months). With Abatacept/MTX/Prednisolon we hope that a more stable
remission can be induced than with MTX/Prednisolon without increases of adverse
events. Abatacept has been proven to be safe in RA. Side effects that occur are
transfusion related. Theoretically also more infections can be induced by
abatacept.