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

Primary Purpose

ANCA Associated Systemic Vasculitis, Wegener's Granulomatosis, Microscopic Polyangiitis

Status

Completed

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

cyclophosphamide

About this trial

This is an interventional treatment trial for ANCA Associated Systemic Vasculitis focused on measuring Vasculitis, ANCA, Wegener's granulomatosis, Renal vasculitis, Cyclophosphamide

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

A new diagnosis of WG, MP or renal-limited vasculitis (RLV) (appendix 5). Patients not previously treated with cytotoxic drugs will be permitted.
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.
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).
Age 18-80 years.

Exclusion Criteria:

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.
Co-existence of another multisystem autoimmune disease, e.g. SLE.
Hepatitis Be antigen positive or Hepatitis C antibody positive.
Known HIV positivity (HIV testing will not be a requirement for this trial).
Serum creatinine > 500umol/l (consider MEPEX trial).
Immediately life-threatening organ manifestations (e.g. lung haemorrhage or dialysis dependence).
Previous malignancy (usually exclude unless agreed with trial co-ordinator).
Pregnancy or inadequate contraception if female.
Anti-GBM antibody positivity.

Sites / Locations

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Adverse events

Vasculitis Damage Index

Cumulative exposure to cyclophosphamide

Full Information

NCT ID

NCT00430105

First Posted

January 31, 2007

Last Updated

January 31, 2007

Sponsor

Cambridge University Hospitals NHS Foundation Trust

1. Study Identification

Unique Protocol Identification Number

NCT00430105

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2007

Overall Recruitment Status

Completed

Study Start Date

February 1998 (undefined)

Primary Completion Date

undefined (undefined)

Study Completion Date

April 2004 (undefined)

3. Sponsor/Collaborators

Name of the Sponsor

Cambridge University Hospitals NHS Foundation Trust

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

ANCA Associated Systemic Vasculitis, Wegener's Granulomatosis, Microscopic Polyangiitis

Keywords

Vasculitis, ANCA, Wegener's granulomatosis, Renal vasculitis, Cyclophosphamide

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

160 (false)

8. Arms, Groups, and Interventions

Intervention Type

Drug

Intervention Name(s)

cyclophosphamide

Primary Outcome Measure Information:

Title

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

Secondary Outcome Measure Information:

Title

Adverse events

Title

Vasculitis Damage Index

Title

Cumulative exposure to cyclophosphamide

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: A new diagnosis of WG, MP or renal-limited vasculitis (RLV) (appendix 5). Patients not previously treated with cytotoxic drugs will be permitted. 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. 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). Age 18-80 years. Exclusion Criteria: 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. Co-existence of another multisystem autoimmune disease, e.g. SLE. Hepatitis Be antigen positive or Hepatitis C antibody positive. Known HIV positivity (HIV testing will not be a requirement for this trial). Serum creatinine > 500umol/l (consider MEPEX trial). Immediately life-threatening organ manifestations (e.g. lung haemorrhage or dialysis dependence). Previous malignancy (usually exclude unless agreed with trial co-ordinator). Pregnancy or inadequate contraception if female. Anti-GBM antibody positivity.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kirsten de Groot

Organizational Affiliation

Klinikum Offenbach GmbH, Germany

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Caroline OS Savage

Organizational Affiliation

University of Birmingham

Official's Role

Study Chair

12. IPD Sharing Statement

Citations:

PubMed Identifier

28592297

Citation

Morgan MD, Szeto M, Walsh M, Jayne D, Westman K, Rasmussen N, Hiemstra TF, Flossmann O, Berden A, Hoglund P, Harper L; European Vasculitis Society. Negative anti-neutrophil cytoplasm antibody at switch to maintenance therapy is associated with a reduced risk of relapse. Arthritis Res Ther. 2017 Jun 7;19(1):129. doi: 10.1186/s13075-017-1321-1.

Results Reference

derived

PubMed Identifier

19451574

Citation

de Groot K, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Gross WL, Luqmani R, Pusey CD, Rasmussen N, Sinico RA, Tesar V, Vanhille P, Westman K, Savage CO; EUVAS (European Vasculitis Study Group). Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009 May 19;150(10):670-80. doi: 10.7326/0003-4819-150-10-200905190-00004.

Results Reference

derived

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

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