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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 25, 2018
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.

Study Type : Interventional  (Clinical Trial)
Estimated 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
Study Start Date : October 2014
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : September 2020


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.



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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


Contacts
Contact: Shunsuke Furuta, M.D., Ph.D +81 43-222-7171 ext 5531 shfuruta@chiba-u.jp

Locations
Japan
Asahi General Hospital Recruiting
Asahi, Chiba, Japan
Contact: Shinichiro Kagami, M.D., Ph.D         
Principal Investigator: Shinichiro Kagami, M.D., Ph.D         
Teikyo University Medical Centre Not yet recruiting
Ichihara, Chiba, Japan
Contact: Noboru Hagino, M.D., Ph.D.         
Principal Investigator: Noboru Hagino, M.D., Ph.D.         
Kameda Medical Centre Recruiting
Kamogawa, Chiba, Japan
Contact: Shinji Motoshima, M.D., Ph.D.         
Principal Investigator: Shinsji Motoshima, M.D., Ph.D.         
Matsudo City Hospital Recruiting
Matsudo, Chiba, Japan
Contact: Tsuyoshi Umibe, M.D., Ph.D         
Principal Investigator: Tsuyoshi Umibe, M.D., Ph.D         
Saiseikai Narashino Hospital Recruiting
Narashino, Chiba, Japan
Contact: Yasushi Nawata, M.D., Ph.D         
Principal Investigator: Yasushi Nawata, M.D., Ph.D         
Japanese Red Cross Narita Hospital Recruiting
Narita, Chiba, Japan
Contact: Masaki Hiraguri, M.D., Ph.D         
Principal Investigator: Masaki Hiraguri, M.D., Ph.D         
Juntendo University Urayasu Hospital Recruiting
Urayasu, Chiba, Japan
Contact: Iwao Sekikawa, M.D., Ph.D         
Principal Investigator: Iwao Sekikawa, M.D., Ph.D         
Sub-Investigator: Shinji Morimoto, M.D., Ph.D         
Tokyo Women's Medical University Yachiyo Medical Center Not yet recruiting
Yachiyo, Chiba, Japan
Contact: Yohei Seto, M.D., Ph.D         
Principal Investigator: Yohei Seto, M.D., Ph.D         
Shimoshizu Hospital Recruiting
Yotsukaido, Chiba, Japan
Contact: Takao Sugiyama, M.D., Ph.D         
Principal Investigator: Takao Sugiyama, M.D., Ph.D         
University of Occupational and Environmental Health Recruiting
Kitakyushu, Fukuoka, Japan
Contact: Yoshiya Tanaka, MD, PhD         
Hokkaido University Recruiting
Sapporo, Hokkaido, Japan
Contact: Tatsuya Atsumi, MD, PhD         
Hitachinaka General Hospital Recruiting
Katsuta, Ibaragi, Japan
Contact: Taichi Hayashi, M.D., Ph.D         
Principal Investigator: Taichi Hayashi, M.D., Ph.D         
University of Tsukuba Recruiting
Tsukuba, Ibaragi, Japan
Contact: Takayuki Sumida, M.D., Ph.D         
Principal Investigator: Takayuki Sumida, M.D., Ph.D         
Sub-Investigator: Atsuhiro Kondo, M.D., Ph.D         
St. Marianna University School of Medicine Hospital Recruiting
Kawasaki, Kanagawa, Japan
Contact: Hidehiro Yamada, M.D., Ph.D.         
Contact: Mamiko Shimizu         
Yokohama City University Recruiting
Yokohama, Kanagawa, Japan
Contact: Yoshiaki Ishigatsubo, M.D., Ph.D         
Principal Investigator: Yoshiaki Ishigatsubo, M.D., Ph.D         
Sub-Investigator: Ryusuke Yoshimi, M.D., Ph.D         
Yokohama Rosai Hospital Recruiting
Yokohama, Kanagawa, Japan
Contact: Yasuhiko Kita, M.D., Ph.D         
Principal Investigator: Yasuhiko Kita, M.D., Ph.D         
Tohoku Recruiting
Sendai, Miyagi, Japan
Contact: Tomonori Ishii, MD, PhD         
Shinshu University Recruiting
Matsumoto, Nagano, Japan
Contact: Shuichi Ikeda, M.D., Ph.D.         
Contact: Yasuhiro Shimojima, M.D., Ph.D.         
Saitama Medical Center Recruiting
Kawagoe, Saitama, Japan
Contact: Kouichi Amano, M.D., Ph.D         
Principal Investigator: Kouichi Amano, M.D., Ph.D         
Sub-Investigator: Ryota Sakai, M.D., Ph.D         
Dokkyo Medical University Recruiting
Mibu, Tochigi, Japan
Contact: Kazuhiro Kurasawa, M.D., Ph.D         
Principal Investigator: Kazuhiro Kurasawa, M.D., Ph.D         
Sub-Investigator: Takayoshi Owada, M.D., Ph.D         
Teikyo University Recruiting
Itabashi, Tokyo, Japan
Contact: Hajime Kono, M.D., Ph.D         
Principal Investigator: Hajime Kono, M.D., Ph.D         
Sub-Investigator: Shunya Uchida, M.D., Ph.D         
Keio University Hospital Recruiting
Shinanomachi, Tokyo, Japan
Contact: Tsutomu Takeuchi, MD, PhD         
Akita University Recruiting
Akita, Japan
Contact: Atsushi Komatsuda, MD, PhD         
Chiba University Hospital Recruiting
Chiba, Japan, 260-8677
Contact: Shunsuke Furuta, M.D., Ph.D         
Sub-Investigator: Shunsuke Furuta, M.D., Ph.D         
Principal Investigator: Hiroshi Nakajima, M.D., Ph.D         
Sub-Investigator: Kei Ikeda, M.D., Ph.D         
Chiba Aoba Municipal Hospital Recruiting
Chiba, Japan
Contact: Yoshihisa Kobayashi, M.D., Ph.D         
Principal Investigator: Yoshihisa Kobayashi, M.D., Ph.D         
Chiba East Hospital Recruiting
Chiba, Japan
Contact: Ryutaro Matsumura, M.D., Ph.D         
Principal Investigator: Ryutaro Matsumura, M.D., Ph.D         
Fukushima Medical University Recruiting
Fukushima, Japan
Contact: Hiroshi Watanabe, M.D., Ph.D.         
Principal Investigator: Hiroshi Watanabe, M.D., Ph.D.         
Nagasaki University Recruiting
Nagasaki, Japan
Contact: Atsushi Kawakami, MD, PhD         
Niigata University Recruiting
Niigata, Japan
Contact: Ichiei Narita, Prof         
Principal Investigator: Ichiei Narita, M.D., Ph.D.         
Osaka University Recruiting
Osaka, Japan
Contact: Atsushi Kumanogoh, MD, PhD         
National Center for Global Health and Medicine Not yet recruiting
Tokyo, Japan
Contact: Akio Mimori, M.D., Ph.D         
Principal Investigator: Akio Mimori, M.D., Ph.D         
Sub-Investigator: Hiroshi Kaneko, M.D., Ph.D         
Sponsors and Collaborators
Chiba University
National Hospital Organization Chiba East Hospital
Investigators
Principal Investigator: Hiroshi Nakajima, M.D., Ph.D Chiba University Hospital

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Shunsuke Furuta, Associate Professor, Chiba University
ClinicalTrials.gov Identifier: NCT02198248     History of Changes
Other Study ID Numbers: G25051
UMIN000014222 ( Registry Identifier: UMIN-CTR )
First Posted: July 23, 2014    Key Record Dates
Last Update Posted: January 25, 2018
Last Verified: January 2018

Additional relevant MeSH terms:
Vasculitis
Systemic Vasculitis
Granulomatosis with Polyangiitis
Microscopic Polyangiitis
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Vascular Diseases
Cardiovascular Diseases
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
Rituximab
Prednisolone
Methylprednisolone Hemisuccinate
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Glucocorticoids
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents