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

Microscopic Polyangiitis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00430105
• Other study ID #: IC20-CT97-0019
• Secondary ID: BMH4-CT97-2328IC
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: January 31, 2007
• Last updated: January 31, 2007
• Start date: February 1998
• Est. completion date: April 2004

Study information

• Verified date: January 2007
• Source: Cambridge University Hospitals NHS Foundation Trust
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 160
• Est. completion date: April 2004
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• ANCA Associated Systemic Vasculitis
• Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
• Microscopic Polyangiitis
• Systemic Vasculitis
• Vasculitis
• Wegener Granulomatosis
• Wegener's Granulomatosis

Intervention

Drug:
• cyclophosphamide

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Cambridge University Hospitals NHS Foundation Trust

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease free period, time from remission to relapse or study end.
Secondary	Adverse events
Secondary	Vasculitis Damage Index
Secondary	Cumulative exposure to cyclophosphamide