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Low-dose Glucocorticoid Vasculitis Induction Study (LoVAS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02198248
Recruitment Status : Active, not recruiting
First Posted : July 23, 2014
Last Update Posted : January 27, 2020
Sponsor:
Collaborator:
National Hospital Organization Chiba East Hospital
Information provided by (Responsible Party):
Shunsuke Furuta, Chiba University

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.


Condition or disease Intervention/treatment Phase
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis Microscopic Polyangiitis Wegener Granulomatosis Drug: Rituximab Drug: Glucocorticoids Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 140 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : October 2014
Actual Primary Completion Date : December 2019
Estimated Study Completion Date : June 2021


Arm Intervention/treatment
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.

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

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.

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




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Time to remission [ Time Frame: assessed at 1, 2, 4 and 6 months ]
  2. Overall survival, disease free survival, time to end-stage renal disease, time to the first serious adverse event [ Time Frame: 0-24 months ]
  3. Proportions of death, relapse, end-stage renal disease and the composite of these [ Time Frame: at 6 and 24 months ]
  4. Proportions of severe relapse [ Time Frame: at 24 months ]
  5. 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

  6. 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

  7. 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.

  8. Patient global assessment (visualised analogue scale) [ Time Frame: assessed at 0, 6, 12, 18 and 24 months ]
  9. Accumulative dose of glucocorticoids [ Time Frame: assessed at 6 and 24 months ]
  10. 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 ]
  11. Proportions of the patients with new onset diabetes mellitus [ Time Frame: at 6 and 24 months ]
  12. Proportion of the patients with new onset insomnia [ Time Frame: at 6 and 24 months ]
  13. Proportion of the patients with new onset bone fracture, bone density [ Time Frame: at 6 and 24 months ]
  14. Number of infections, proportions of the patients with infection [ Time Frame: at 6 and 24 months ]
  15. Proportions of the patients with new onset hypertension [ Time Frame: at 6 and 24 months ]
  16. Proportions of the patients with new onset hyperlipidemia [ Time Frame: at 6 and 24 months ]
  17. 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.


Other Outcome Measures:
  1. Serum immunoglobulin levels [ Time Frame: assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months ]
  2. Peripheral blood B cell counts [ Time Frame: assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months ]
  3. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02198248


Locations
Show Show 17 study locations
Sponsors and Collaborators
Chiba University
National Hospital Organization Chiba East Hospital
Investigators
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Principal Investigator: Hiroshi Nakajima, M.D., Ph.D Chiba University Hospital
Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Shunsuke Furuta, Associate Professor, Chiba University
ClinicalTrials.gov Identifier: NCT02198248    
Other Study ID Numbers: G25051
UMIN000014222 ( Registry Identifier: UMIN-CTR )
First Posted: July 23, 2014    Key Record Dates
Last Update Posted: January 27, 2020
Last Verified: January 2020
Additional relevant MeSH terms:
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Granulomatosis with Polyangiitis
Microscopic Polyangiitis
Vasculitis
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Vascular Diseases
Cardiovascular Diseases
Systemic Vasculitis
Lung Diseases, Interstitial
Lung Diseases
Respiratory Tract Diseases
Autoimmune Diseases
Immune System Diseases
Cerebral Small Vessel Diseases
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Prednisolone
Rituximab
Glucocorticoids
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Anti-Inflammatory Agents
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal