A Study to Evaluate Avacopan in Participants With ANCA-associated Vasculitis

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the long-term safety of avacopan in participants with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).

Official Title
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A Randomized, Double-blind, Placebo-controlled Phase 4 Clinical Trial to Evaluate the Long-term Safety and Efficacy of Avacopan in Subjects With Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis

Conditions
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Antineutrophil Cytoplasmic Antibody-associated Vasculitis

Intervention / Treatment
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* Drug: Avacopan
* Drug: Placebo
* Drug: Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants has provided informed consent before initiation of any study-specific activities/procedures. Newly diagnosed or relapse of granulomatosis with polyangiitis or microscopic polyangiitis, consistent with Chapel-Hill Consensus Conference definitions (Jennette et al, 2013), where treatment with cyclophosphamide or rituximab is needed. Age >/= 18 years (or >/= legal age within the country if it is older than 18 years). Positive test for anti-positive antiproteinase 3 or antimyeloperoxidase (current or historic) antibodies. At least 1 Birmingham Vasculitis Activity Score (BVAS) major item, at least 3 BVAS nonmajor items, or at least the 2 renal items of proteinuria and hematuria. eGFR 15 mL/min/1.73 m^2 (using Chronic Kidney Disease Epidemiology Collaboration equations). Exclusion Criteria Alveolar hemorrhage requiring invasive pulmonary ventilation support anticipated to last beyond the screening period of the study. Any other known multisystem autoimmune disease including eosinophilic granulomatosis with polyangiitis (Churg-Strauss), systemic lupus erythematosus, immunoglobulin A vasculitis (Henoch-Schönlein), rheumatoid vasculitis, Sjogren's syndrome, anti-glomerular basement membrane disease, or cryoglobulinemic vasculitis. Any medical condition requiring or expected to require continued use of immunosuppressive therapies, including corticosteroids that may cause confoundment with study assessments and study conclusions. Received dialysis or plasma exchange within 12 weeks before signing of the informed consent. Have had a kidney transplant. Malignancy except nonmelanoma skin cancers, cervical or breast ductal carcinoma in situ within the last 5 years before signing the informed consent. Acute or chronic, active hepatitis B virus or hepatitis C virus, or human immunodeficiency virus infection during screening. Positive test for active or latent tuberculosis during screening. White blood cell count < 3500/µL, neutrophil count < 1500/µL, or lymphocyte count < 500/µl. Evidence of clinically significant hepatic disease including prior diagnosis of cirrhosis. aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase >2.0 times the upper limit of normal (ULN). Total bilirubin > 1.5 times the ULN. A participant with documented Gilbert's syndrome with total bilirubin < 2 x ULN may be eligible. Active infection and/or infection requiring oral or intravenous (IV) antimicrobials within 4 weeks before signing of the informed consent. History of any clinically significant cardiovascular disease, such as symptomatic congestive heart failure, unstable angina, myocardial infarction or stroke, within 12 weeks before signing of the informed consent. Received cyclophosphamide (CYC) within 12 weeks before signing the informed consent; if on azathioprine, mycophenolate, or methotrexate at the time of screening, these drugs must be withdrawn before receiving the CYC or rituximab (RTX). Have been taking an oral daily dose of a glucocorticoid of more than 10 mg prednisone equivalent for more than 6 weeks continuously before signing of the informed consent. Received RTX or other B-cell depleting therapies within 52 weeks before signing of the informed consent or within 26 weeks before signing of the informed consent provided CD19 count > 0.01x10^9/L, or received any of the following within 12 weeks before signing the informed consent: antitumor necrosis factor treatment abatacept alemtuzumab IV immunoglobulin belimumab tocilizumab. Taking a strong or moderate inducer of the cytochrome P450 3A4 (CYP3A4) enzyme unless the strong or moderate CYP3A4 inducer can be changed to an alternative medicine at least 1 week before Day 1. Received an investigational drug within 30 days or within 5 half-lives (whichever is longer) before signing of the informed consent. Previously received avacopan without clinical benefit per the Investigator's opinion or received avacopan within 60 days before signing of the informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Avacopan + Standard of Care (SoC)<br>Avacopan 30 mg twice daily for 5 years + SoC background immunosuppressive therapy. | Drug: Avacopan<br>* Administered orally.<br>* Other names: CCX168;Drug: Standard of Care<br>* All participants will receive SoC background immunosuppressive therapy for induction and maintenance, at the discretion of the Investigator and as supported by current guidelines, product labels and local practices and informed by the individual participant's clinical condition, preferences, and values.<br>|
| Experimental: Group B: Avacopan/Placebo + SoC<br>Avacopan 30 mg twice daily for 1 year, followed by placebo twice daily for 4 years + SoC background immunosuppressive therapy. | Drug: Avacopan<br>* Administered orally.<br>* Other names: CCX168;Drug: Placebo<br>* Administered orally.<br>Drug: Standard of Care<br>* All participants will receive SoC background immunosuppressive therapy for induction and maintenance, at the discretion of the Investigator and as supported by current guidelines, product labels and local practices and informed by the individual participant's clinical condition, preferences, and values.<br>|
| Placebo Comparator: Group C: Placebo + SoC<br>Placebo twice daily for 5 years + SoC background immunosuppressive therapy. | Drug: Placebo<br>* Administered orally.<br>Drug: Standard of Care<br>* All participants will receive SoC background immunosuppressive therapy for induction and maintenance, at the discretion of the Investigator and as supported by current guidelines, product labels and local practices and informed by the individual participant's clinical condition, preferences, and values.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) |  | Up to Month 60 | 
| Percentage of Participants Experiencing Adverse Events of Special Interest |  | Up to Month 60 | 
| Percentage of Participants Experiencing Serious Adverse Events |  | Up to Month 60 | 
| Percentage of Participants Experiencing Adverse Events Leading to Withdrawal |  | Up to Month 60 | 
| Percentage of Participants Experiencing Adverse Events Leading to Death |  | Up to Month 60 | 
| Number of Participants Experiencing Clinical Significant Changes from Baseline in Vital Signs Measurements |  | Up to Month 60 | 
| Number of Participants Experiencing Clinical Significant Changes from Baseline in Hematology Assessments |  | Up to Month 60 | 
| Number of Participants Experiencing Clinical Significant Changes from Baseline in Serum Chemistry Assessments |  | Up to Month 60 | 
| Number of Participants Experiencing Clinical Significant Changes from Baseline in Urinalysis Assessments |  | Up to Month 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Group A and B Participants who Achieved Remission at Month 12: Time to Relapse in AAV Between Month 12 and Month 60 |  | Month 12 to Month 60 | 
| Group A and B Participants who Achieved Remission at Month 12: Percentage of Participants who Relapse After Achieving Remission at Month 12 |  | Month 12 to Month 60 | 
| Groups A and C: Percentage of Participants who Achieved Sustained Remission at Month 60 |  | Month 60 | 
| Group A and C Participants with Overt Renal Disease at Baseline: Change from Baseline to Month 60 in Estimated Glomerular Filtration Rate (eGFR) |  | Baseline and Month 60 | 
| Groups A and C: Change from Baseline to Month 60 in Short Form 36 Health Survey Version 2 (SF-36 v2) General Health Perception Score |  | Baseline and Month 60 | 
| Groups A and C: Change from Baseline to Month 60 in EuroQoL-5 Dimension 5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) |  | Baseline and Month 60 | 
| Percentage of Participants who Achieved Remission at Month 6 |  | Month 6 | 
| Groups A and C: Change from Baseline to Week 60 in Vasculitis Damage Index (VDI) |  | Baseline and Week 60 | 
| Groups A and C: Percentage of Participants with Composite Outcome of Initiation of Maintenance Dialysis, Kidney Transplantation, or Death |  | Up to Month 60 | 
| Percentage of Participants With Glucocorticoid Use |  | Up to Month 60 | 
| Percentage of Participants With Immunosuppressant Use |  | Up to Month 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Avacopan, ANCA-associated Vasculitis, AAV