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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
Sponsored by
Cambridge University Hospitals NHS Foundation Trust
About
Eligibility
Locations
Outcomes
Full info

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:

  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.

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

    First Posted
    January 31, 2007
    Last Updated
    January 31, 2007
    Sponsor
    Cambridge University Hospitals NHS Foundation Trust
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    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
    No
    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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