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Low-dose Glucocorticoid Vasculitis Induction Study (LoVAS)

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ClinicalTrials.gov Identifier: NCT02198248
Recruitment Status : Recruiting
First Posted : July 23, 2014
Last Update Posted : January 31, 2019
Sponsor:
Collaborator:
National Hospital Organization Chiba East Hospital
Information provided by (Responsible Party):
Shunsuke Furuta, Chiba University

Tracking Information
First Submitted Date  ICMJE July 18, 2014
First Posted Date  ICMJE July 23, 2014
Last Update Posted Date January 31, 2019
Actual Study Start Date  ICMJE October 2014
Estimated Primary Completion Date September 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 21, 2014)
Proportion of the patients achieving remission [ Time Frame: 6 months ]
Remission; BVAS ver.3=0 (or 1 with only one minor and persistent BVAS item) and prednisolone <10mg/day
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02198248 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 27, 2014)
  • Time to remission [ Time Frame: assessed at 1, 2, 4 and 6 months ]
  • Overall survival, disease free survival, time to end-stage renal disease, time to the first serious adverse event [ Time Frame: 0-24 months ]
  • Proportions of death, relapse, end-stage renal disease and the composite of these [ Time Frame: at 6 and 24 months ]
  • Proportions of severe relapse [ Time Frame: at 24 months ]
  • Birmingham Vasculitis Activity Score (BVAS) version 3 [ Time Frame: assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months ]
    BVAS is a scoring system for assessing disease activity of vasculitis
  • Vasculitis Damage Index (VDI) [ Time Frame: assessed at 0, 6, 12, 18 and 24 months ]
    VDI is a scoring system for assessing irreversible disease damage due to vasculitis
  • Short-Form 36 (SF-36) [ Time Frame: assessed at 0, 6, 12, 18 and 24 months ]
    SF-36 is a scoring system for assessing patient QOL.
  • Patient global assessment (visualised analogue scale) [ Time Frame: assessed at 0, 6, 12, 18 and 24 months ]
  • Accumulative dose of glucocorticoids [ Time Frame: assessed at 6 and 24 months ]
  • Numbers of events of adverse events/serious adverse events, proportions of the patients with adverse events/serious adverse events [ Time Frame: at 6 and 24 months ]
  • Proportions of the patients with new onset diabetes mellitus [ Time Frame: at 6 and 24 months ]
  • Proportion of the patients with new onset insomnia [ Time Frame: at 6 and 24 months ]
  • Proportion of the patients with new onset bone fracture, bone density [ Time Frame: at 6 and 24 months ]
  • Number of infections, proportions of the patients with infection [ Time Frame: at 6 and 24 months ]
  • Proportions of the patients with new onset hypertension [ Time Frame: at 6 and 24 months ]
  • Proportions of the patients with new onset hyperlipidemia [ Time Frame: at 6 and 24 months ]
  • Proportions of patients achieving remission and discontinuance of glucocorticoids [ Time Frame: at 6 and 24 months ]
    Remission is BVAS ver3=0 and prednisolone <10mg/day.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 21, 2014)
  • Time to remission [ Time Frame: assessed at 1, 2, 4 and 6 months ]
  • Overall survival, disease free survival, time to end-stage renal disease, time to the first serious adverse event [ Time Frame: 0-24 months ]
  • Proportions of death, relapse, end-stage renal disease and the composite of these [ Time Frame: at 6 and 24 months ]
  • Proportions of severe relapse [ Time Frame: at 24 months ]
  • Birmingham Vasculitis Activity Score (BVAS) version 3 [ Time Frame: assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months ]
    BVAS is a scoring system for assessing disease activity of vasculitis
  • Vasculitis Damage Index (VDI) [ Time Frame: assessed at 0, 6, 12, 18 and 24 months ]
    VDI is a scoring system for assessing irreversible disease damage due to vasculitis
  • Short-Form 36 (SF-36) [ Time Frame: assessed at 0, 6, 12, 18 and 24 months ]
    SF-36 is a scoring system for assessing patient QOL.
  • Patient global assessment (visualised analogue scale) [ Time Frame: assessed at 0, 6, 12, 18 and 24 months ]
  • Accumulative dose of glucocorticoids [ Time Frame: assessed at 6 and 24 months ]
  • Numbers of events of adverse events/serious adverse events, proportions of the patients with adverse events/serious adverse events [ Time Frame: at 6 and 24 months ]
  • Proportions of the patients with new onset diabetes mellitus [ Time Frame: at 6 and 24 months ]
  • Proportion of the patients with new onset insomnia [ Time Frame: at 6 and 24 months ]
  • Proportion of the patients with new onset bone fracture, bone density [ Time Frame: at 6 and 24 months ]
  • Number of infections, proportions of the patients with infection [ Time Frame: at 6 and 24 months ]
  • Proportions of the patients with new onset hypertension [ Time Frame: at 6 and 24 months ]
  • Proportions of the patients with new onset hyperlipidemia [ Time Frame: at 6 and 24 months ]
Current Other Pre-specified Outcome Measures
 (submitted: July 21, 2014)
  • Serum immunoglobulin levels [ Time Frame: assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months ]
  • Peripheral blood B cell counts [ Time Frame: assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months ]
  • serum MPO-/PR3-ANCA levels measured by ELISA [ Time Frame: assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months ]
    MPO-ANCA and PR3-ANCA are disease specific autoantibodies binding neutrophil cytoplasmic antigen.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Low-dose Glucocorticoid Vasculitis Induction Study
Official Title  ICMJE Low-dose Glucocorticoids Plus Rituximab Versus High-dose Glucocorticoids Plus Rituximab for Remission Induction in ANCA-associated Vasculitis; a Multicentre, Open Label, Randomised Control Trial
Brief Summary

Previous reports suggested conventional immunosuppressants such as cyclophosphamide could not reduce glucocorticoid dose in remission induction in ANCA-associated vasculitis because of lower remission rate and higher relapse rate. However those reports didn't include rituximab.

B cell depletion therapy by rituximab is a new strategy for remission induction in ANCA-associated vasculitis. The RAVE and RITUXVAS trial (NEJM 2010, both) showed high-dose glucocorticoid plus rituximab had roughly the same efficacy and safety as high-dose glucocorticoid plus IV-cyclophosphamide. In addition, recent retrospective observational studies reported low-dose glucocorticoid plus rituximab led to re-induction in severe relapsing ANCA-associated vasculitis.

Thus, the investigators aim to investigate whether rituximab can reduce glucocorticoid dose in induction remission in ANCA-associated vasculitis (to show non-inferiority for efficacy between low-dose and high-dose glucocorticoid plus rituximab). Participants will be randomised to the "low-dose glucocorticoid plus rituximab" or the high-dose glucocorticoid plus rituximab" groups. Primary endpoint is proportion of remission at 6 months, then data regarding relapse and long-term safety will be collected until 24 months.

The study has been designed by the principal and coordinating investigators. It will include 140 participants from 18 hospitals in Japan. It is funded by Chiba University Hospital and Chiba East Hospital.

Detailed Description ANCA (anti-neutrophil cytoplasmic antibody)-associated vasculitis is characterised by small vessel vasculitis and presence of autoantibodies, ANCA. It can be a life-threatening disease with renal/respiratory failure. Current standard therapy in induction remission for ANCA-associated vasculitis is combination of high-dose glucocorticoid and IV-cyclophosphamide. This regimen is effective (remission rate; 80-90%), but often cause various glucocorticoid-related side effects. Especially, infection is related to death. Thus a new regimen reducing glucocorticoid dose is required.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
  • Microscopic Polyangiitis
  • Wegener Granulomatosis
Intervention  ICMJE
  • Drug: Rituximab
    Patients will be administered rituximab (375mg/m2/w x4 infusions) for reducing glucocorticoid dose in remission induction phase.
    Other Name: Rituxan
  • Drug: Glucocorticoids

    "Low-dose" group commenced 0.5mg/kg/day, then taper and stop within 6 months following pre-defined schedule.

    "High-dose" group commenced 1.0mg/kg/day, then taper to 10mg/day within 6 months following pre-defined schedule.

    Other Names:
    • Predonine
    • Prednisolone
Study Arms  ICMJE
  • Experimental: Low-dose glucocorticoid

    Prednisolone will be commenced with dose of 0.5mg/kg/day and will be tapered and off within 6 months. If a patient fails to achieve BVAS=0, an investigator can postpone the procedure of stopping prednisolone (prednisolone 5mg/day x 2 weeks, 4mg/day x 2 weeks, 3mg/day x 4 weeks, 2mg/day x 4 weeks, 1mg/day x 4 weeks, then off prednisolone). Once starting the procedure, prednisolone must be off after 16 weeks. Patients will also receive rituximab (375mg/m2/w x4).

    After achieving remission, patients will be receive rituximab (1g/body or 0.5g/bodyx2) every 6 months as remission maintenance therapy.

    Interventions:
    • Drug: Rituximab
    • Drug: Glucocorticoids
  • Active Comparator: High-dose glucocorticoid

    Prednisolone will be commenced with dose of 1.0mg/kg/day and will be tapered to 10mg/day within 6 months. Patients will also receive rituximab (375mg/m2/w x4).

    After achieving remission, patients will be receive rituximab (1g/body or 0.5g/bodyx2) every 6 months as remission maintenance therapy. There's no limitation by the protocol regarding further prednisolone tapering.

    Interventions:
    • Drug: Rituximab
    • Drug: Glucocorticoids
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 21, 2014)
140
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2021
Estimated Primary Completion Date September 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Provision of written informed consent by a patient or a surrogate decision maker
  2. Age=>20 years
  3. New clinical diagnosis of ANCA-associated vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis or renal limited ANCA-associated vasculitis) consistent with the 2012 Chapel Hill consensus definitions
  4. Positive test by ELISA for proteinase 3-ANCA or myeloperoxidase-ANCA

Exclusion Criteria:

  1. Prior treatment for ANCA-associated vasculitis before trial entry
  2. ANCA-associated vasculitis related glomerulonephritis (eGFR<15ml/min) or alveolar hemorrhage (oxygen inhalation >2L/min)
  3. Presence of another multisystem autoimmune disease
  4. Known infection with HIV; a past or current history of hepatitis B virus or hepatitis C virus infection
  5. Desire to bear children, pregnancy or lactating
  6. History of malignancy within the past 5 years or any evidence of persistent malignancy
  7. Ongoing or recent (last 1 year) evidence of active tuberculosis
  8. Severe allergy or anaphylaxis to monoclonal antibody therapy
  9. Any concomitant condition anticipated to likely require oral systemic glucocorticoids, immunosuppressants, biologics, plasma exchange or IVIg
  10. Any biological B cell depleting agent (such as rituximab or belimumab) within the past 6 months
  11. Other conditions, in the investigator's opinion, inappropriate for the trial entry
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Shunsuke Furuta, M.D., Ph.D +81 43-222-7171 ext 5531 shfuruta@chiba-u.jp
Listed Location Countries  ICMJE Japan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02198248
Other Study ID Numbers  ICMJE G25051
UMIN000014222 ( Registry Identifier: UMIN-CTR )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Shunsuke Furuta, Chiba University
Study Sponsor  ICMJE Chiba University
Collaborators  ICMJE National Hospital Organization Chiba East Hospital
Investigators  ICMJE
Principal Investigator: Hiroshi Nakajima, M.D., Ph.D Chiba University Hospital
PRS Account Chiba University
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP