Pulse Versus Continuous Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitides

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Brief Title

Pulse Versus Continuous Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitides

Official Title

Randomized Trial of Intravenous Pulse Versus Oral Continuous Cyclophosphamide for Induction of Remission in Systemic ANCA-Associated Vasculitides

Brief Summary

      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.
    

Detailed Description

      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.
    

Study Phase

Phase 2/Phase 3

Study Type

Interventional


Primary Outcome

Disease free period, time from remission to relapse or study end.

Secondary Outcome

 Adverse events

Condition

ANCA Associated Systemic Vasculitis

Intervention

cyclophosphamide


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

160

Start Date

February 1998

Completion Date

April 2004


Eligibility Criteria

        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.
      

Gender

All

Ages

18 Years - 80 Years

Accepts Healthy Volunteers

No

Contacts

Kirsten de Groot, , 



Administrative Informations


NCT ID

NCT00430105

Organization ID

IC20-CT97-0019

Secondary IDs

BMH4-CT97-2328


Study Sponsor

Cambridge University Hospitals NHS Foundation Trust


Study Sponsor

Kirsten de Groot, Study Chair, Klinikum Offenbach GmbH, Germany


Verification Date

January 2007