Pulse Versus Continuous Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitides
Pulse Versus Continuous Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitides
A comparison of intermittent pulsed cyclophosphamide to daily oral cyclophosphamide for the
 treatment of ANCA-associated systemic vasculitides with kidney involvement.

 Performed by the European Vasculitis Study group.
The primary, ANCA-associated systemic vasculitides (AASV), including Wegener's granulomatosis
 and microscopic polyangiitis, are progressive, multisystem, autoimmune diseases which respond
 to immunosuppressive therapy. Their treatment with corticosteroids and cytotoxic drugs has
 been standardised in a first wave of studies (ECSYSVASTRIAL project), but limitations of such
 regimens include only partial efficacy and appreciable treatment-related toxicity.

 The present trial, CYCLOPS, aims to reduce the cumulative exposure to immunosuppressive drugs
 by administering cyclophosphamide (CYC) as intermittent pulses. The potential benefit of
 using CYC in this way for AASV has been demonstrated in preliminary, smaller studies.
 Patients with previously untreated AASV and, "generalised", but not life threatening, disease
 with renal involvement, will be randomised to either continuous oral CYC or intermittent
 pulse CYC. CYC will be continued until three months after remission has been achieved, with a
 minimum CYC total duration of six months and maximum duration of twelve months; both limbs
 will then receive the same maintenance regimen of azathioprine and prednisolone.

 The study will last 18 months. The primary end-point is the disease-free period, taken as the
 period of time from remission until relapse or study end; secondary end-points are adverse
 effects, cumulative damage and immunosuppressive drug exposure. 160 patients will be
 required.
Inclusion Criteria:

 1. A new diagnosis of WG, MP or renal-limited vasculitis (RLV) (appendix 5). Patients not
 previously treated with cytotoxic drugs will be permitted.

 2. Renal involvement attributable to active WG, MP or RLV with at least one of the
 following:

 -  elevated serum creatinine between 150 and 500 umol/l.

 -  biopsy demonstrating necrotizing glomerulonephritis.

 -  red cell casts.

 -  haematuria with >30 red blood cells/high powered field and proteinuria > 1g/24hr.

 3. ANCA positivity or confirmatory histology or both (appendix 5). ANCA positivity
 requires a typical CANCA pattern by indirect immunofluorescence (IIF), (preferably
 confirmed by anti-PR3 ELISA), or the presence of PR3-ANCA or MPO-ANCA determined by
 ELISA, PANCA requires confirmation by anti-MPO ELISA [6]. (Central review of ANCA
 serology and histology will be performed).

 4. Age 18-80 years.

 Exclusion Criteria:

 1. More than two weeks treatment with cyclophosphamide (CYC) or other cytotoxic drug
 within previous year or with oral corticosteroids (OCS) for more than 4 weeks. If the
 patient has received >1.0g of methyl-prednisolone prior to the study start, discuss
 with trial co-ordinator.

 2. Co-existence of another multisystem autoimmune disease, e.g. SLE.

 3. Hepatitis Be antigen positive or Hepatitis C antibody positive.

 4. Known HIV positivity (HIV testing will not be a requirement for this trial).

 5. Serum creatinine > 500umol/l (consider MEPEX trial).

 6. Immediately life-threatening organ manifestations (e.g. lung haemorrhage or dialysis
 dependence).

 7. Previous malignancy (usually exclude unless agreed with trial co-ordinator).

 8. Pregnancy or inadequate contraception if female.

 9. Anti-GBM antibody positivity.