Avacopan vs Reduced-dose Glucocorticoids in ANCA-associated Vasculitis (ARRIA)

Avacopan With Short-term Reduced-dose Glucocorticoids vs Reduced-dose Glucocorticoids Added to Rituximab on Remission Induction in ANCA-associated Vasculitis

The goal of this clinical trial is to learn if avacopan in combination with short-term (4 weeks) reduced-dose glucocorticoid and rituximab works to treat patients with newly-onset ANCA-associated vasculitis. It will also learn about the long-term safety of avacopan. The main questions it aims to answer are:

Is avacopan in combination with short-term reduced-dose glucocorticoid and rituximab as effective as the combination of 20 week reduced-dose glucocorticoid and rituximab in the proportion of the patients achieving remission? Does avacopan lower the relapse rate compared to the 6 monthly rituximab maintenance therapy? What medical problems do participants have when taking long-term avacopan?

Participants will:

Be treated with avacopan in combination with short-term (until 4 weeks) reduced-dose glucocorticoid and rituximab (at 0 week) or reduced-dose glucocorticoid (until 20 weeks) and rituximab (at 0, 26, 52 and 78 weeks).

Be assessed at 0, 4, 8, 16, 26, 52, 78 and 104 weeks regarding disease status (remission/relapse), disease activity by Birmingham Vasculitis Activity Score ver3, disease damage by Vasculitis Damage Index and adverse events.

The primary endpoint is remission rates at 26 weeks.

Study Overview

• Status: Recruiting
• Conditions: ANCA Associated Vasculitis (AAV)
• Intervention / Treatment: Drug: Prednisolone and rituximab; Drug: Avacopan, prednisolone and rituximab

Detailed Description

Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis is characterized by a small to medium-size vasculitis and the presence of ANCA. ANCA-associated vasculitis includes microscopic polyangiitis, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis. ANCA-associated vasculitis can be a life-threatening disease and the mortality is 80% at 1 year in untreated patients. In 2010s, standard therapies for remission induction of ANCA-associated vasculitis were the combination of high-dose glucocorticoids and either cyclophosphamide or rituximab. Although those therapies have high remission rates of 80-90%, mortality at 5 years is still high at 10-20% mainly due to treatments-related adverse events.

In the LoVAS trial (2021, JAMA), the combination of reduced-dose glucocorticoid and rituximab showed non-inferiority to high-dose glucocorticoid and rituximab in remission rates at 6 months. In addition, adverse events were dramatically less in the reduced-dose group than in the high-dose group.

In the ADVOCATE trial (2021, NEJM), the combination of avacopan, newly developed complement C5a inhibitor, and rituximab or cyclophosphamide showed non-inferiority to high-dose glucocorticoid and rituximab or cyclophosphamide in remission rates at 6 months. The avacopan group was allowed to use glucocorticoid within 1 month from the trial entry, and over 80% of patients used glucocorticoid indeed. Regarding adverse events, they were less in the avacopan group than in the glucocorticoid group.

Although both the reduced-dose glucocorticoid regimen in the LoVAS trial and the avacopan regimen in the ADVOCATE trial are effective and safe for patients with ANCA-associated vasculitis, there is no trial directly comparing both regimens at the moment. Thus, in this multicenter, open-label, randomized, non-ineriority, phase 4 trial, the investigators aim to investigate if the combination of avacoapn, short-term (4 weeks) reduced-dose glucocorticoid and rituximab is non-inferior to the combination of reduced-dose glucocorticoid (20 weeks) and rituximab. The investigators also compare safety profiles and disease relapse between the two groups. A total of 160 patients with new-onset ANCA-associated vasculitis (microscopic polyangiitis and granulomatosis with polyangiitis) will be recruited and randomized to the two treatments groups. The primary end point is remission rate at 26 weeks, and the patients will be followed until 104 weeks for assessing disease relapse and long-term safety.

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Shunsuke Furuta, MD, PhD; Phone Number: 5531 81+43-222-7171; Email: shfuruta@chiba-u.jp

Study Locations

• Japan
  • Chiba, Japan, 2600852
    • Recruiting
    • Chiba Aoba Municipal Hospital
    • Contact: Yoshihisa Kobayashi, MD, PhD; Phone Number: 81+043-227-1131; Email: yoshikoba7923@yahoo.co.jp
  • Chiba, Japan, 2608677
    • Recruiting
    • Chiba University
    • Contact: Shunsuke Furuta, MD, PhD; Phone Number: 5531 81+432227171; Email: shfuruta@chiba-u.jp
  • Nagasaki, Japan, 8528501
    • Recruiting
    • Nagasaki University
    • Contact: Atsushi Kawakami, MD, PhD; Phone Number: 81+095-819-7200; Email: atsushik@nagasaki-u.ac.jp
  • Okayama, Japan, 7008558
    • Recruiting
    • Okayama University
    • Contact: Yoshinori Matsumoto, MD, PhD; Phone Number: 81+086-235-7235; Email: ymatsumoto@okayama-u.ac.jp
  • Osaka, Japan, 5308480
    • Recruiting
    • Kitano Hospital
    • Contact: Tomomi Endo, MD; Phone Number: 81+06-6312-1221; Email: t-endou1106@kitano-hp.or.jp
  • Aichi
    • Toyoake, Aichi, Japan, 4701192
      • Not yet recruiting
      • Fujita Health University Hospital
      • Contact: Naotake Tsuboi, MD, PhD; Phone Number: 81+0562-93-2111; Email: nao-take@fujita-hu.ac.jp
  • Chiba
    • Asahi, Chiba, Japan, 2892511
      • Recruiting
      • Asahi General Hospital
      • Contact: ShinIchiro Kagami, MD, PhD; Phone Number: 81+0479-63-8111; Email: kagami@hospital-asahi.jp
    • Ichihara, Chiba, Japan, 2900003
      • Recruiting
      • Chiba Rosai Hospital
      • Contact: Tomohiro Tamachi, MD, PhD; Phone Number: 81+0436-74-1111; Email: tamachit@chiba-u.jp
    • Kamogawa, Chiba, Japan, 2968602
      • Recruiting
      • Kameda Medical Centre
      • Contact: Tomo Suzuki, MD; Phone Number: 81+04-7092-2211; Email: suzuki.tomo@kameda.jp
    • Narita, Chiba, Japan, 2868520
      • Recruiting
      • International University of Health and Welfare
      • Contact: Masayoshi Harigai, MD, PhD; Phone Number: 81+0476-35-5600; Email: mharigai@iuhw.ac.jp
    • Narita, Chiba, Japan, 2868523
      • Recruiting
      • Japanese Red Cross Narita Hospital
      • Contact: Masaki Hiraguri, MD; Phone Number: 81+0476-22-2311; Email: hiraguri@naritasekijyuji.jp
  • Gunma
    • Maebashi, Gunma, Japan, 3718511
      • Recruiting
      • Gunma University
      • Contact: Keijyu Hiromura, MD, PhD; Phone Number: 81+027-220-7111; Email: hiromura@gunma-u.ac.jp
  • Kagawa
    • Miki, Kagawa, Japan, 7610793
      • Recruiting
      • Kagawa University
      • Contact: Hiroaki Dobashi, MD, PhD; Phone Number: 81+087-898-5111; Email: dobashi.hiroaki@kagawa-u.ac.jp
  • Kanagawa
    • Kawasaki, Kanagawa, Japan, 2168511
      • Recruiting
      • St.Marianna University School of Medicine
      • Contact: Kimito Kawahata, MD, PhD; Phone Number: 81+044-977-8111; Email: kimito.kawahata@marianna-u.ac.jp
  • Miyagi
    • Sendai, Miyagi, Japan, 9808574
      • Recruiting
      • Tohoku Univerisity
      • Contact: Hiroshi Fujii, MD, PhD; Phone Number: 81+022-717-7000; Email: hfujii@med.tohoku.ac.jp
  • Saitama
    • Kawagoe, Saitama, Japan, 3508550
      • Recruiting
      • Saitama Medical University
      • Contact: Takahiko Kurasawa, MD, PhD; Phone Number: 81+049-228-3574; Email: t_kura@saitama-med.ac.jp
  • Tochigi
    • Mibu, Tochigi, Japan, 3210293
      • Recruiting
      • Dokkyo Medical University
      • Contact: Kei Ikeda, MD, PhD; Phone Number: 81+0282-86-1111; Email: k-ikeda847@dokkyomed.ac.jp
  • Tokyo
    • Bunkyoku, Tokyo, Japan, 1138431
      • Recruiting
      • Juntendo Univeristy
      • Contact: Naoto Tamura, MD, PhD; Phone Number: 81+03-3813-3111; Email: tnaoto@juntendo.ac.jp
    • Itabashi, Tokyo, Japan, 1738606
      • Recruiting
      • Teikyo University
      • Contact: Hajime Kono, MD, PhD; Phone Number: 81+03-3964-1211; Email: kono@med.teikyo-u.ac.jp
    • Mitaka, Tokyo, Japan, 1818611
      • Recruiting
      • Kyorin University
      • Contact: Yoshinori Komagata, MD, PhD; Phone Number: 81+0422-47-5511; Email: komagata@ks.kyorin-u.ac.jp
    • Ota-ku, Tokyo, Japan, 1438541
      • Recruiting
      • Toho University
      • Contact: Toshihiro Nanki, MD, PhD; Phone Number: 81+03-3762-4151; Email: toshihiro.nanki@med.toho-u.ac.jp
  • Yamanashi
    • Chuo-shi, Yamanashi, Japan, 4093898
      • Recruiting
      • Yamanashi University
      • Contact: Daiki Nakagomi, MD, PhD; Phone Number: 81+055-273-3113; Email: dnakagomi@yamanashi.ac.jp

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Provision of written informed consent by a patient or a surrogate decision maker
2. Age=>18 years
3. New clinical diagnosis of ANCA-associated vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis) consistent with the 2012 Chapel Hill consensus definitions and 2022 EULAR/ACR classification criteria
4. Positive test by ELISA, CLEIA or FEIA 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 less than 15ml/min) or alveolar hemorrhage (oxygen inhalation more than 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. History of 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)-use within the past 6 months
11. Past history of medication of avacopan
12. Patients can not take avacopan and prednisolone orally
13. Other conditions, in the investigator's opinion, inappropriate for the trial entry

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Glucocorticoid group; Prednisolone will be commenced with dose of 0.5mg/kg/day and will be tapered and off within 5 months. If a patient fails to achieve BVAS=0 or normalization of CRP levels or normalization of ANCA levels, an investigator can keep 5mg/day of prednisolone and postpone the procedure of stopping prednisolone. Patients will also receive rituximab (375mg/m2/w x4). During remission maintenance phase (6-24 months),, patients will receive rituximab (500mg/body) every 6 months as remission maintenance therapy. In the case of inadequate response to the combination therapy of prednisolone and rituximab, additional administration of prednisolone 20mg/day (less than 2 weeks) can be allowed as the rescue therapy. During remission maintenance phase, in the case of minor relapse, additional administration of prednisolone 20mg/day (less than 2 weeks) can be allowed as the rescue therapy. Minor relapse is defined as relapse with no major BVAS item.	Drug: Prednisolone and rituximab; Patients in the glucocorticoid arm will be treated with reduced-dose prednisolone and rituximab.
Experimental: Avacopan group; Prednisolone will be commenced with dose of 0.5mg/kg/day and will be tapered and off within 1 months. Patients will also receive avacopan (60mg/day) and rituximab (375mg/m2/w x4). During remission maintenance phase (6-24 months), patients will receive avacopan (60mg/day) as remission maintenance therapy until the trial end. In the case of inadequate response to the combination therapy of avacopan, prednisolone and rituximab, additional administration of prednisolone 20mg/day (less than 2 weeks) can be allowed as the rescue therapy. During remission maintenance phase, in the case of minor relapse, additional administration of prednisolone 20mg/day (less than 2 weeks) can be allowed as the rescue therapy. Minor relapse is defined as relapse with no major BVAS item.	Drug: Avacopan, prednisolone and rituximab; Patients in the avacoapn group will be treated with avacoapn, short-term reduced-dose prednisolone and rituximab.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportions of patients achieving remission	Remission is defined as BVAS (Birmingham vasculitis activity score)=0 and less than 5mg/day of prednisolone.	26 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival, relapse and end-stage renal disease	Assessed by Kaplan-Meier curves.	26 and 104 weeks
Accumulative dose of glucocorticoids	Accumulative dose of glucocorticoids during the study period	26 and 104 weeks
Birmingham Vasculitis Activity Score (BVAS) version 3	BVAS is a scoring system for assessing the disease activity of vasculitis.	26 and 104 weeks
Vasculitis Damage Index (VDI)	VDI is a scoring system for assessing irreversible disease damage due to vasculitis.	104 weeks
Short-Form 36 (SF-36)	SF-36 is a scoring system for assessing patient QOL.	26 and 104 weeks
Serious adverse event (SAE)	Event numbers and proportions of patients with one or more SAEs.	26 and 104 weeks
Proportions of the patients with new onset diabetes mellitus	Diabetes mellitus requiring drug treatments	26 and 104 weeks
Proportions of the patients with new onset hypertension	Hypertension requiring drug treatments	26 and 104 weeks
Proportions of the patients with new onset hyperlipidemia	Hyperlipidemia requiring drug treatments	26 and 104 weeks
Proportion of the patients with new onset bone fracture, bone density	Bone density is assessed at lumber spines.	104 weeks
Number of infections, proportions of the patients with infection	Infections requiring drug treatments	26 and 104 weeks
Number of serious infections, proportions of the patients with serious infection	Serious infections are serious events among infections requiring drug treatments.	26 and 104 weeks
Proportions of the patients with liver dysfunction	Liver dysfunction >= grade 3 liver dysfunction (CTCAE)	26 and 104 weeks
Proportions of the patients with new onset malignancies	Malignancies diagnosed after the trial entry	26 and 104 weeks
Sustained remission without taking prednisolone at 104 weeks	Remission is defined as BVAS (Birmingham vasculitis activity score)=0 and less than 5mg/day of prednisolone.	104 weeks
Proportions of patients achieving remission without the rescue therapy	Remission is defined as BVAS (Birmingham vasculitis activity score)=0 and less than 5mg/day of prednisolone.	26 weeks
Sustained remission without taking prednisolone at 104 weeks and the rescue therapy during the trial period	Remission is defined as BVAS (Birmingham vasculitis activity score)=0 and less than 5mg/day of prednisolone.	104 weeks
Proportions of patients treated with the rescue therapy	Details of the rescue therapy are written in the section of "Arms and Interventions".	26 and 104 weeks

Collaborators and Investigators

• Sponsor: Chiba University
• Collaborators: Kissei Pharmaceutical Co., Ltd.; International University of Health and Welfare
• Investigators: Principal Investigator: Masayoshi Harigai, MD, PhD, International University of Health and Welfare

Publications and helpful links

General Publications

• Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, Flores-Suarez LF, Gross WL, Guillevin L, Hagen EC, Hoffman GS, Jayne DR, Kallenberg CG, Lamprecht P, Langford CA, Luqmani RA, Mahr AD, Matteson EL, Merkel PA, Ozen S, Pusey CD, Rasmussen N, Rees AJ, Scott DG, Specks U, Stone JH, Takahashi K, Watts RA. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013 Jan;65(1):1-11. doi: 10.1002/art.37715. No abstract available.
• Mukhtyar C, Lee R, Brown D, Carruthers D, Dasgupta B, Dubey S, Flossmann O, Hall C, Hollywood J, Jayne D, Jones R, Lanyon P, Muir A, Scott D, Young L, Luqmani RA. Modification and validation of the Birmingham Vasculitis Activity Score (version 3). Ann Rheum Dis. 2009 Dec;68(12):1827-32. doi: 10.1136/ard.2008.101279. Epub 2008 Dec 3.
• Exley AR, Bacon PA, Luqmani RA, Kitas GD, Gordon C, Savage CO, Adu D. Development and initial validation of the Vasculitis Damage Index for the standardized clinical assessment of damage in the systemic vasculitides. Arthritis Rheum. 1997 Feb;40(2):371-80. doi: 10.1002/art.1780400222.
• Hellmich B, Sanchez-Alamo B, Schirmer JH, Berti A, Blockmans D, Cid MC, Holle JU, Hollinger N, Karadag O, Kronbichler A, Little MA, Luqmani RA, Mahr A, Merkel PA, Mohammad AJ, Monti S, Mukhtyar CB, Musial J, Price-Kuehne F, Segelmark M, Teng YKO, Terrier B, Tomasson G, Vaglio A, Vassilopoulos D, Verhoeven P, Jayne D. EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update. Ann Rheum Dis. 2024 Jan 2;83(1):30-47. doi: 10.1136/ard-2022-223764.
• Suppiah R, Robson JC, Grayson PC, Ponte C, Craven A, Khalid S, Judge A, Hutchings A, Merkel PA, Luqmani RA, Watts RA; DCVAS INVESTIGATORS. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for microscopic polyangiitis. Ann Rheum Dis. 2022 Mar;81(3):321-326. doi: 10.1136/annrheumdis-2021-221796. Epub 2022 Feb 2.
• Robson JC, Grayson PC, Ponte C, Suppiah R, Craven A, Judge A, Khalid S, Hutchings A, Watts RA, Merkel PA, Luqmani RA; DCVAS Investigators. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for granulomatosis with polyangiitis. Ann Rheum Dis. 2022 Mar;81(3):315-320. doi: 10.1136/annrheumdis-2021-221795. Epub 2022 Feb 2.
• Furuta S, Nakagomi D, Kobayashi Y, Hiraguri M, Sugiyama T, Amano K, Umibe T, Kono H, Kurasawa K, Kita Y, Matsumura R, Kaneko Y, Ninagawa K, Hiromura K, Kagami SI, Inaba Y, Hanaoka H, Ikeda K, Nakajima H; LoVAS Collaborators. Effect of Reduced-Dose vs High-Dose Glucocorticoids Added to Rituximab on Remission Induction in ANCA-Associated Vasculitis: A Randomized Clinical Trial. JAMA. 2021 Jun 1;325(21):2178-2187. doi: 10.1001/jama.2021.6615.
• Jayne DRW, Merkel PA, Schall TJ, Bekker P; ADVOCATE Study Group. Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med. 2021 Feb 18;384(7):599-609. doi: 10.1056/NEJMoa2023386. Erratum In: N Engl J Med. 2024 Jan 25;390(4):388. doi: 10.1056/NEJMx230010.

Helpful Links

• English version of the protocol is now preparing and will be shown in the above website.

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2024
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): September 30, 2028

Study Registration Dates

• First Submitted: September 22, 2024
• First Submitted That Met QC Criteria: September 22, 2024
• First Posted (Actual): September 25, 2024

Study Record Updates

• Last Update Posted (Actual): May 4, 2025
• Last Update Submitted That Met QC Criteria: May 1, 2025
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: microscopic polyangiitis; ANCA-associated vasculitis; avacopan; granulomatosis with polyangiitis
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Autoimmune Diseases; Immune System Diseases; Skin Diseases; Skin Diseases, Vascular; Systemic Vasculitis; Vasculitis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antirheumatic Agents; Protective Agents; Neuroprotective Agents; Methylprednisolone Acetate; Rituximab; Prednisolone; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate
• Other Study ID Numbers: CRB0097-24

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified participant data
• IPD Sharing Time Frame: After publishing the report regarding all the pre-defined trial data.
• IPD Sharing Access Criteria: Data requests should be sent to Dr Shunsuke Furuta at shfuruta@chiba-u.jp or Dr Masayoshi Harigai at mharigai@iuhw.ac.jp. The requests should be assessed and permitted according to the individual purposes of the requests.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Study Data/Documents

1. Study Protocol
   Information comments: Regarding deidentified patient data, please request to Dr Shunsuke Furuta at shfuruta@chiba-u.jp or Dr Masayoshi Harigai at mharigai@iuhw.ac.jp after publishing pre-defined trial results.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No