Clinical trial NCT06611696: Avacopan vs Reduced-dose Glucocorticoids in ANCA-associated Vasculitis
Official title: Avacopan With Short-term Reduced-dose Glucocorticoids vs Reduced-dose Glucocorticoids Added to Rituximab on Remission Induction in ANCA-associated Vasculitis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: ANCA Associated Vasculitis (AAV)
Keywords: microscopic polyangiitis
granulomatosis with polyangiitis
avacopan
ANCA-associated vasculitis
Lead sponsor: Chiba University
Sponsor class: OTHER
Collaborators: name: Kissei Pharmaceutical Co., Ltd.
name: International University of Health and Welfare
First posted: 2024-09-25
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: Inclusion Criteria:

1. Provision of written informed consent by a patient or a surrogate decision maker
2. Age=\&amp;gt;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\&amp;#39;s opinion, inappropriate for the trial entry

Primary outcomes:
measure: Proportions of patients achieving remission
timeFrame: 26 weeks
Secondary outcomes:
measure: Sustained remission without taking prednisolone at 104 weeks
timeFrame: 104 weeks
measure: Survival, relapse and end-stage renal disease
timeFrame: 26 and 104 weeks
measure: Accumulative dose of glucocorticoids
timeFrame: 26 and 104 weeks
measure: Birmingham Vasculitis Activity Score (BVAS) version 3
timeFrame: 26 and 104 weeks
measure: Vasculitis Damage Index (VDI)
timeFrame: 104 weeks
measure: Short-Form 36 (SF-36)
timeFrame: 26 and 104 weeks
measure: Serious adverse event (SAE)
timeFrame: 26 and 104 weeks
measure: Proportions of the patients with new onset diabetes mellitus
timeFrame: 26 and 104 weeks
measure: Proportions of the patients with new onset hypertension
timeFrame: 26 and 104 weeks
measure: Proportions of the patients with new onset hyperlipidemia
timeFrame: 26 and 104 weeks
measure: Proportion of the patients with new onset bone fracture, bone density
timeFrame: 104 weeks
measure: Number of infections, proportions of the patients with infection
timeFrame: 26 and 104 weeks
measure: Number of serious infections, proportions of the patients with serious infection
timeFrame: 26 and 104 weeks
measure: Proportions of the patients with liver dysfunction
timeFrame: 26 and 104 weeks
measure: Proportions of the patients with new onset malignancies
timeFrame: 26 and 104 weeks
measure: Proportions of patients achieving remission without the rescue therapy
timeFrame: 26 weeks
measure: Sustained remission without taking prednisolone at 104 weeks and the rescue therapy during the trial period
timeFrame: 104 weeks
measure: Proportions of patients treated with the rescue therapy
timeFrame: 26 and 104 weeks
Other outcomes:
Locations:
city: Toyoake
country: Japan
facility: Fujita Health University Hospital
state: Aichi
city: Asahi
country: Japan
facility: Asahi General Hospital
state: Chiba
city: Ichihara
country: Japan
facility: Chiba Rosai Hospital
state: Chiba
city: Kamogawa
country: Japan
facility: Kameda Medical Centre
state: Chiba
city: Narita
country: Japan
facility: International University of Health and Welfare
state: Chiba
city: Narita
country: Japan
facility: Japanese Red Cross Narita Hospital
state: Chiba
city: Maebashi
country: Japan
facility: Gunma University
state: Gunma
city: Miki
country: Japan
facility: Kagawa University
state: Kagawa
city: Kawasaki
country: Japan
facility: St.Marianna University School of Medicine
state: Kanagawa
city: Sendai
country: Japan
facility: Tohoku Univerisity
state: Miyagi
city: Kawagoe
country: Japan
facility: Saitama Medical University
state: Saitama
city: Mibu
country: Japan
facility: Dokkyo Medical University
state: Tochigi
city: Bunkyoku
country: Japan
facility: Juntendo Univeristy
state: Tokyo
city: Itabashi
country: Japan
facility: Teikyo University
state: Tokyo
city: Mitaka
country: Japan
facility: Kyorin University
state: Tokyo
city: Ota-ku
country: Japan
facility: Toho University
state: Tokyo
city: Chuo-shi
country: Japan
facility: Yamanashi University
state: Yamanashi
city: Chiba
country: Japan
facility: Chiba Aoba Municipal Hospital
city: Chiba
country: Japan
facility: Chiba University
city: Nagasaki
country: Japan
facility: Nagasaki University
city: Okayama
country: Japan
facility: Okayama University
city: Osaka
country: Japan
facility: Kitano Hospital
Study officials:
affiliation: International University of Health and Welfare
name: Masayoshi Harigai, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.