ANCA Associated Vasculitis (AAV)
Conditions
Keywords
microscopic polyangiitis, granulomatosis with polyangiitis, avacopan, ANCA-associated vasculitis
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.
Interventions
DRUGAvacopan, prednisolone and rituximab
Patients in the avacoapn group will be treated with avacoapn, short-term reduced-dose prednisolone and rituximab.
DRUGPrednisolone and rituximab
Patients in the glucocorticoid arm will be treated with reduced-dose prednisolone and rituximab.
Sponsors
Kissei Pharmaceutical Co., Ltd.
International University of Health and Welfare
Chiba University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportions of patients achieving remission | 26 weeks | Remission is defined as BVAS (Birmingham vasculitis activity score)=0 and less than 5mg/day of prednisolone. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Survival, relapse and end-stage renal disease | 26 and 104 weeks | Assessed by Kaplan-Meier curves. |
| Accumulative dose of glucocorticoids | 26 and 104 weeks | Accumulative dose of glucocorticoids during the study period |
| Birmingham Vasculitis Activity Score (BVAS) version 3 | 26 and 104 weeks | BVAS is a scoring system for assessing the disease activity of vasculitis. |
| Vasculitis Damage Index (VDI) | 104 weeks | VDI is a scoring system for assessing irreversible disease damage due to vasculitis. |
| Short-Form 36 (SF-36) | 26 and 104 weeks | SF-36 is a scoring system for assessing patient QOL. |
| Serious adverse event (SAE) | 26 and 104 weeks | Event numbers and proportions of patients with one or more SAEs. |
| Proportions of the patients with new onset diabetes mellitus | 26 and 104 weeks | Diabetes mellitus requiring drug treatments |
| Proportions of the patients with new onset hypertension | 26 and 104 weeks | Hypertension requiring drug treatments |
| Sustained remission without taking prednisolone at 104 weeks | 104 weeks | Remission is defined as BVAS (Birmingham vasculitis activity score)=0 and less than 5mg/day of prednisolone. |
| Proportion of the patients with new onset bone fracture, bone density | 104 weeks | Bone density is assessed at lumber spines. |
| Number of infections, proportions of the patients with infection | 26 and 104 weeks | Infections requiring drug treatments |
| Number of serious infections, proportions of the patients with serious infection | 26 and 104 weeks | Serious infections are serious events among infections requiring drug treatments. |
| Proportions of the patients with liver dysfunction | 26 and 104 weeks | Liver dysfunction >= grade 3 liver dysfunction (CTCAE) |
| Proportions of the patients with new onset malignancies | 26 and 104 weeks | Malignancies diagnosed after the trial entry |
| Proportions of patients achieving remission without the rescue therapy | 26 weeks | Remission is defined as BVAS (Birmingham vasculitis activity score)=0 and less than 5mg/day of prednisolone. |
| Sustained remission without taking prednisolone at 104 weeks and the rescue therapy during the trial period | 104 weeks | Remission is defined as BVAS (Birmingham vasculitis activity score)=0 and less than 5mg/day of prednisolone. |
| Proportions of patients treated with the rescue therapy | 26 and 104 weeks | Details of the rescue therapy are written in the section of Arms and Interventions. |
| Proportions of the patients with new onset hyperlipidemia | 26 and 104 weeks | Hyperlipidemia requiring drug treatments |
Countries
Japan
Contacts
Primary ContactShunsuke Furuta, MD, PhD
Outcome results
None listed