Avacopan vs reduced-dose glucocorticoids ANCA-associated vasculitis; non-inferiority study

JRCT ID: jRCTs031240416

Registered date:18/11/2024

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Newly onset microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA)
• Date of first enrollment: 18/11/2024
• Target sample size: 160
• Study type: Interventional

Intervention(s)

Candidates of the study subjects take screening tests after giving their consent, and if they are judged to be eligible, they are registered in this study. While awaiting screening test results, methylprednisolone 500 mg/day x 3 days or less (steroid pulse) is allowed by judgement of attending physician. Upon enrollment, the enrolled study subjects are randomly assigned into "low-dose glucocorticoid plus rituximub group (GC group)" or "avacopan, short-term low-dose glucocorticoid plus rituximub group (avacopan group) in ratio of 1:1, and receive remission-induction therapy according to the assigned group. From the day of enrollment (=the day of assignment) or the next day, the administration of predonisolone and avacopan is initiated (the initiation day is defined as day 1). In the GC group, if the study subjects received GC during the screening period (for a maximm of 7 days), the first day of predonisolone administration after the assignment is defined as the day 1. The first administration of rituximub is conducted within day 1 to day 7. The study subjects who achive remission at week 26 by the remission-induction theraphy are moved to remission-maintainance therapy immidiately. The study subjects who do not achive remission at week 26 discontinue the participation in this study , and do not move to the remission-maintainance therapy.

<Screening period (within a week before enrollment)>
While awaiting screening test results, methylprednisolone 500 mg/day x 3 days or less (steroid pulse) is allowed by judgement of attending physician. If oral GC or prednisolone 0.5mg/kg/day or less was administered at another hospital, department, etc. prior to giving their consent, the study subjects are allowed to continue the GC for up to 7 days, including the screening period.

<Remission-induction period (week 0 - 26)>
- The study subjects assigned to the avacopan group take both avacopan 60 mg/min2 and prednisolone from the day 1. In addition, rituximab 375 mg/m2/w x 4 times intravenous injections is initiated within the day 1-7 (rituximab BSs are also allowed). Pre-medication for rituximab includes oral antipyretic analgesics and antihistamines and methylprednisolone 125 mg intravenous injections for the first dose. The second and subsequent doses are according to the method of each medical institution.
- The study subjects assigned to the GC group take prednisolone from the day 1. In addition, rituximab 375 mg /m2/w x 4 intravenous injection is initiated within the day 1-7 (rituximab BSs are also allowed). The second and subsequent doses are according to the method of each medical institution.

<Remission-maintainance period (week 26-104)>
The study subjects who achive remission at week 26 by the remission-induction theraphy are moved to remission-maintainance therapy.
- The study subjects assigned to the avacopan group continue to receive avacopan 60 mg/min2.
- The study subjects assigned to the GC group receive retuximan 500 mg/body intravenously at week 26, 52, and 78 (plus/minus 30 days are allowed for each observation point). If prednisolone is continued in the GC group at week 26, the dose is reduced on the same basis in the remission-induction period. The discontinuation step of prednisolone is initiated by week 30 at the latest.

<Rescue therapy>
Despite the treatment mentioned above, 1) if the major item dose not improve or stabilize within 4 weeks after the initiation of the study, or 2) if mild relapse is observed, rescue therapy with a maximum of prednisolone equivalent to 20 mg/day (for 2 weeks or less) is allowed.

Outcome(s)

• Primary Outcome: Proportion of patients who achieve remission at week 26 (including patients who received rescue treatment defined in the protocol and achieve remission at week 26). Remission is defined as achievement of BVAS ver.3 score of zero (or 1 or less in case of minimally invasive and persistent) and use of oral prednisolone of 5mg/day or less.

Secondary Outcome

<Secondary outcomes for efficacy>
- Proportion of patients who achieve oral prednisolone of 0mg/day and remain in remission at week 104
- Proportion of patients who achieve remission without rescue treatmet at week 26
- Proportion of patients who achieve oral prednisolone of 0mg/day and remain in remission without rescue treatmet at week 104
- Proportion and time to death, recurrence, and ESKD. Recurrence is defined as new appearance or re-appearance of one or more items of BVAS ver.3 after remission, regardless of re-administration or dose up of prednisolone.
- Cumulative dose of GC at week 26 or 104
- Proportion of patients who experienced rescue treatment till week 26 or 104
- Disease activity assessed by BVAS ver.3 at week 26 or 104
- Irreversible disorder assessed by VDI at week 104
- Health-related QOL assessed by SF-36 at week 26 or 104

<Secondary outcomes for safety>
- Number of severe adverse events and proportion of patients who experienced the severe adverse events till week 26 or 104
- Proportion of patients with new onset of diabetes, hypertension, and dyslipidemia requiring treatment till week 26 or 104
- Proportion of patients with pathological bone fracture and lumber spine bone density at week 104
- Number of infection requiring oral or transvenous administation of antibiotics, antivirals, or antimycotics and proportion of patients who experienced the infection till week 26 or 104
- Number of severe infection requiring oral or transvenous administation of antibiotics, antivirals, or antimycotics and proportion of patients who experienced the severe infection till week 26 or 104
- Number of hepatic disorder of grade 3 or higher and proportion of patients who experienced the hepatic disorder till week 26 or 104
- Number of malignant tumor of grade 3 or higher and proportion of patients who experienced the malignant tumor till week 26 or 104

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

Patients who meet all of the following criteria are included in this study:
1) Patients who give their consent in written form by themselves or their legal representatives
2) Patients who are 18 years or older at giving their consent
3) Patients who are newly dignosed with microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA), consistent with the Chapel Hill consensus conference (CHCC) definition, and who meet the MPA or GPA classification criteria of EULAR/ACR 2022
4) Patients who are positive in MPO-ANCA or PR3-ANCA at diagnosis by either of ELISA, CLEIA, or FEIA

Exclude criteria

Patients who fall into any of the following criteria are excluded from participating in the study:
1) Patients who initiated treatment for ANCA-associated vasculitis (GC, immunosuppressive agents, or molecular target agents) *1
2) Patients with glomerulonephritis and with eGFR of less than 15ml/min/1.73m2, or with complication of pulmonary alveolar hemorrhage requiring oxygen administration of 2L/min or more
3) Patients with comorbidity of other systemic autoimmune diseases *2
4) Patients with HIV infection, current infection or history of HBV or HCV *3
5) Patients who wish to have a baby, current pregnant, or current breastfeeding
6) Patients with history of malignant tumor within 5 years before giving their consent *4
7) Patients with history of active tuberculosis within a year before giving their consent
8) Patients with history of severe allergy or anaphylaxis by treatment with monoclonal antibodies
9) Patients with comorbidity which may require GC, immunosuppressive agents, biopharmaceuticals, plasmapheresis, or high-dose intravenous immunoglobulin *5
10) Patients who received treatment with biopharmaceuticals targeted B-cell within 6 months before giving their consent (eg. rituximab, belimumab)
11) Patients with history of use of avacopan
12) Patients who cannot receive oral administration of avacopan and prednisolone at the initiation of the study *6
13) Patients with other conditions by which responsible investigator or subinvestigator judge to be inappropriate to conduct this study safely

*1. Oral GC administration is allowed up to 7 days including the screening period if prednisolone equivalent of 0.5mg/kg/day or less is administered at another hospital or department before giving their consent. Patients with prior pulmonary lesions treated by antifibrotic agents (nintedanib, pirfenidone) can participate in this study, but with other treatments (eg. immunosuppressive agents) cannot participate in this study.
*2. Patients with rheumatoid arthritis without severe internal organ lesion, or patients with scleroderma or Sjogren's syndrome without treatment with GC can participate in this study.
*3. Patients with HBs negative, or HBs or HBc positive and HBV-DNA negative can participate in this study under monitoring of HBV-DNA.
*4. Patients with intramucosal carcinoma that is judged to be curatively resected can participate in this study.
*5. Patients with well-controlled bronchial asthma without oral GC can participate in this study (inhaled steroids are allowed).
*6. If the drugs can be administered through a gastric tube, it is also considered as the patients can receive them orally.

Related Information

• Primary Sponsor: Harigai Masayoshi
• Source(s) of Monetary Support: Kissei Pharmaceutical Co., Ltd.