A Phase 3 Clinical Trial of CCX168 (Avacopan) in Patients With ANCA-Associated Vasculitis

Study Overview
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Brief Summary
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The primary objective is to evaluate the efficacy of CCX168 (avacopan) to induce and sustain remission in patients with active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), when used in combination with cyclophosphamide followed by azathioprine, or in combination with rituximab.

Detailed Description
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Complement 5a and its receptor C5aR (CD88) are involved in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. This is a randomized, double-blind, active-controlled Phase 3 study to evaluate the safety and efficacy of the orally-administered, selective C5aR inhibitor CCX168 (avacopan) in inducing and sustaining remission in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated concomitantly with Rituximab or Cyclophosphamide/Azathioprine.

Official Title
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A Randomized, Double-Blind, Active-Controlled, Phase 3 Study to Evaluate the Safety and Efficacy of CCX168 (Avacopan) in Patients With ANCA-Associated Vasculitis Treated Concomitantly With Rituximab or Cyclophosphamide/Azathioprine

Conditions
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ANCA-Associated Vasculitis

Intervention / Treatment
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* Drug: Avacopan
* Drug: Prednisone
* Drug: Cyclophosphamide
* Biological: Rituximab
* Drug: Azathioprine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of granulomatosis with polyangiitis (Wegener's) or microscopic polyangiitis Male and female subjects, aged at least 18 years, with newly-diagnosed or relapsed associated vasculitis (AAV) where treatment with cyclophosphamide or rituximab is needed; where approved by Regulatory Agencies, adolescents (12-17 year old) may be enrolled Use of adequate contraception Positive test for anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO) At least 1 major item, or at least 3 non-major items, or at least the 2 renal items of proteinuria and hematuria on Birmingham Vasculitis Activity Score (BVAS) Estimated glomerular filtration rate ≥15 mL/minute/1.73 m^2 at screening Exclusion Criteria: Pregnant or breast-feeding Alveolar hemorrhage requiring pulmonary ventilation support at screening Any other known multi-system autoimmune disease Required dialysis or plasma exchange within 12 weeks prior to screening Have a kidney transplant Received cyclophosphamide within 12 weeks prior to screening; if on azathioprine, mycophenolate mofetil or methotrexate at the time of screening, these drugs must be withdrawn prior to receiving the cyclophosphamide or rituximab dose on Day 1 Received intravenous glucocorticoids, >3000 mg methylprednisolone equivalent, within 4 weeks prior to screening Have been taking an oral daily dose of a glucocorticoid of more than 10 mg prednisone-equivalent for more than 6 weeks continuously prior to screening Received rituximab or other B-cell antibody within 52 weeks of screening or 26 weeks provided B cell reconstitution has occurred (i.e., CD19 count > 0.01x10^9/L); received anti-tumor necrosis factor (TNF) treatment, abatacept, alemtuzumab, intravenous immunoglobulin (IVIg), belimumab, tocilizumab, or eculizumab within 12 weeks prior to screening For patients scheduled to receive cyclophosphamide treatment, urinary outflow obstruction, active infection (especially varicella zoster infection), or platelet count <50,000/μL before start of dosing Participated previously in a CCX168 study

Ages Eligible for Study
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Minimum Age: 12 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Prednisone group<br>Avacopan-matching placebo plus cyclophosphamide/azathioprine or rituximab plus a full starting dose of prednisone. | Drug: Prednisone<br>* Avacopan-matching placebo twice daily orally for 52 weeks (364 days): - Three avacopan-matching placebo capsules in the morning, preferably with food, and three in the evening, preferably with food, approximately 12 hours after the morning dose. Oral prednisone tapering regimen over 20 weeks (140 days): Prednisone 60 mg per day if the subject's body weight was ≥55 kg, or 45 mg per day if the subject's body weight was <55 kg, starting on Day 1 with tapering according to the protocol-specified schedule. Adolescents who weighed ≤37 kg started at a prednisone dose of 30 mg per day.<br>Drug: Cyclophosphamide<br>* Orally or intravenously administered<br>Biological: Rituximab<br>* Intravenously administered<br>Drug: Azathioprine<br>* Orally administered<br>|
| Experimental: Avacopan group<br>Avacopan plus cyclophosphamide/azathioprine or rituximab plus prednisone-matching placebo. | Drug: Avacopan<br>* Avacopan 30 mg twice daily orally for 52 weeks (364 days): - Three 10 mg avacopan capsules in the morning, preferably with food, and three in the evening, preferably with food, approximately 12 hours after the morning dose. Oral prednisone-matching placebo tapering regimen over 20 weeks (140 days): Prednisone-matching placebo capsules equivalent to 60 mg per day if the subject's body weight was ≥55 kg, or 45 mg per day if the subject's body weight was <55 kg, starting on Day 1 with tapering according to a protocol-specified schedule. Adolescents who weighed ≤37 kg started at a prednisone-matching placebo dose of 30 mg per day.<br>* Other names: CCX168;Drug: Cyclophosphamide<br>* Orally or intravenously administered<br>Biological: Rituximab<br>* Intravenously administered<br>Drug: Azathioprine<br>* Orally administered<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects Achieving Disease Remission at Week 26 | Disease remission at Week 26 was defined as: Achieving a BVAS of 0 as determined by the Adjudication Committee; No administration of glucocorticoids given for ANCA-associated vasculitis within 4 weeks prior to Week 26; No BVAS >0 during the 4 weeks prior to Week 26 (if collected for an unscheduled assessment). | Week 26 | 
| Percentage of Subjects Achieving Sustained Disease Remission at Week 52 | Sustained remission at Week 52 was defined as: Disease remission at Week 26 as defined above; Disease remission at Week 52 defined as a BVAS of 0 at Week 52 as determined by the Adjudication Committee and no administration of glucocorticoids for treatment of ANCA-associated vasculitis within 4 weeks prior to Week 52; No disease relapse between Week 26 and Week 52 as determined by the Adjudication Committee. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subject Incidence of Treatment-emergent SAEs, AEs, and Withdrawals Due to AEs | AEs=Adverse events SAEs=Serious adverse events TEAE=Treatment-emergent adverse event | From day 1 throughout the study period (day 421/week 60) | 
| Glucocorticoid-induced Toxicity as Measured by Change From Baseline Over the First 26 Weeks in the GTI | GTI-CWS=Glucocorticoid Toxicity Index Cumulative Worsening Score; GTI-AIS=Glucocorticoid Toxicity Index Aggregate Improvement Score; The Glucocorticoid Toxicity Index (GTI) was developed to score glucocorticoid toxicity. The GTI includes: the Cumulative Worsening Score (CWS) that captures cumulative toxicity, both permanent and transient, over the course of time (serves as a cumulative record of toxicity); and the Aggregate Improvement Score that captures both improvement and worsening of toxicity over time (serves as a record of both improving and worsening toxicity). Both scores range from 0 (best health) to 100 (worst health). | Baseline, Week 13 and 26 | 
| Percentage of Participants With BVAS of 0 at Week 4, Regardless of Whether the Subjects Received Glucocorticoids During This Period of Time and Based on Assessment by the Blinded AC | AC=Adjudication Committee; BVAS=Birmingham Vasculitis Activity Score; The BVAS form is divided into 9 organ-based systems, with each section including symptoms/signs that are typical of that particular organ involvement in systemic vasculitis. The clinician only scores features believed to be due to active vasculitis. Completion of the form provides a numerical score, which ranges from 0 (best health) to 63 (worst health). | Week 4 | 
| Change From Baseline Over 52 Weeks in Health-related Quality of Life as Measured by the Domains and Component Scores of the SF-36v2 and EQ-5D-5L VAS and Index | SF-36v2: Measure of health- related quality of life (Medical Outcomes Survey Short Form-36 version 2) EQ-5D-5L: EuroQuality of Life-5 Domains-5 Levels The SF-36v2 component scores and the EQ-5D-5L VAS score range from 0 (worst health) to 100 (best health). The EQ-5D-5L Index Score ranges from 0 (worst health) to 1 (best health). | Baseline, Week 26 and 52 | 
| Percentage of Subjects and Time to Experiencing a Relapse After Previously Achieving Remission at Week 26 in the Study | The median time to relapse was not estimable because of small number of relapsed subjects. A relapse was defined as occurrence of at least one major item in the BVAS, or three or more minor items in the BVAS, or one or two minor items in the BVAS recorded at two consecutive visits, after: having achieved remission at Week 26 (BVAS=0 and no glucocorticoids for ANCA-associated vasculitis within 4 weeks) or having achieved BVAS=0 at any time during the treatment period ANCA=anti-neutrophil cytoplasmic autoantibody; BVAS=Birmingham Vasculitis Activity Score; The BVAS form is divided into 9 organ-based systems, with each section including symptoms/signs that are typical of that particular organ involvement in systemic vasculitis. The clinician only scores features believed to be due to active vasculitis. Completion of the form provides a numerical score, which ranges from 0 (best health) to 63 (worst health). | Week 52 | 
| Percentage of Subjects and Time to Experiencing a Relapse After Previously Achieving BVAS=0 at Any Time During the Treatment Period | The median time to relapse was not estimable because of small number of relapsed subjects. A relapse was defined as occurrence of at least one major item in the BVAS, or three or more minor items in the BVAS, or one or two minor items in the BVAS recorded at two consecutive visits, after: having achieved remission at Week 26 (BVAS=0 and no glucocorticoids for ANCA-associated vasculitis within 4 weeks) or having achieved BVAS=0 at any time during the treatment period The Birmingham Vasculitis Activity Score (BVAS) form is divided into 9 organ-based systems, with each section including symptoms/signs that are typical of that particular organ involvement in systemic vasculitis. The clinician only scores features believed to be due to active vasculitis. Completion of the form provides a numerical score, which ranges from 0 (best health) to 63 (worst health). | Week 52 | 
| In Subjects With Renal Disease at Baseline (Based in the BVAS Renal Component), the Change in eGFR From Baseline Over 52 Weeks | Change from baseline in kidney function, as measured by eGFR (based on the MDRD equation), was measured in subjects with renal disease based on the BVAS renal component. eGFR=estimated glomerular filtration rate BVAS=Birmingham Vasculitis Activity Score MDRD=Modification of Diet in Renal Disease | Baseline, Week 26 and 52 | 
| In Subjects With Renal Disease and Albuminuria at Baseline (Based in the BVAS Renal Component), the Percent Change in UACR From Baseline Over 52 Weeks | BVAS=Birmingham Vasculitis Activity Score UACR=Urinary albumin:creatinine ratio | Baseline, Week 4, 26 and 52 | 
| In Subjects With Renal Disease at Baseline (Based in the BVAS Renal Component), the Percent Change in Urinary MCP-1:Creatinine Ratio From Baseline Over 52 Weeks | BVAS=Birmingham Vasculitis Activity Score MCP-1=monocyte chemoattractant protein-1 | Baseline, Week 26 and 52 | 
| Change in the VDI From Baseline Over 52 Weeks, Including the Week 26 and Week 52 Time Points | VDI=Vasculitis Damage Index; The VDI is comprised of 64 items of damage, grouped into 11 organ-based systems or categorizations. Damage is defined as the presence of non-healing scars and does not give any indication of current disease activity. Damage is also defined as having been present or currently present for at least 3 months. Completion of the form provides a numerical score, which ranges from 0 (best health) to 64 (worst health). | Baseline, Week 26 and 52 | 
| Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (1/5) |  | Baseline, Week 26 and 52 | 
| Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (2/5) |  | Baseline, Week 26 and 52 | 
| Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (3/5) |  | Baseline, Week 26 and 52 | 
| Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (4/5) |  | Baseline, Week 26 and 52 | 
| Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (5/5) |  | Baseline, Week 26 and 52 | 
| Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Serum Chemistry (1/2) |  | Baseline, Week 26 and 52 | 
| Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Serum Chemistry (2/2) |  | Baseline, Week 26 and 52 | 
| Change From Baseline in Vital Signs (1/5) |  | Baseline, Week 26 and 52 | 
| Change From Baseline in Vital Signs (2/5) |  | Baseline, Week 26 and 52 | 
| Change From Baseline in Vital Signs (3/5) |  | Baseline, Week 26 and 52 | 
| Change From Baseline in Vital Signs (4/5) |  | Baseline, Week 26 and 52 | 
| Change From Baseline in Vital Signs (5/5) | BMI=Body Mass Index | Baseline, Week 26 and 52 | 
| Number of Subjects With Clinically Significant ECG Changes From Baseline | Clinical significance was assessed by the individual reading of the ECGs ECG=Electrocardiogram | From day 1 throughout the study period (day 421/week 60) | 
| Number of Subjects Where a Relationship Between Avacopan/Placebo, Glucocorticoid Use, Cyclophosphamide, Rituximab, and Azathioprine or Mycophenolate Use to an AE Was Determined by the Investigator | AE=Adverse Event | From day 1 throughout the study period (day 421/week 60) | 
| Certain Safety Endpoints of Interest: Infections, Hepatic System Abnormalities, WBC Count Decreases, and Hypersensitivity | WBC=White Blood Cell TEAE=Treatment-Emergent Adverse Event | From day 1 throughout the study period (day 421/week 60) | 
| Number of Subjects Experiencing a Relapse After Previously Achieving BVAS=0 During the Study | BVAS=Birmingham Vasculitis Activity Score; A relapse was defined as occurrence of at least one major item in the BVAS, or three or more minor items in the BVAS, or one or two minor items in the BVAS recorded at two consecutive visits, after: having achieved remission at Week 26 (BVAS=0 and no glucocorticoids for ANCA-associated vasculitis within 4 weeks) or having achieved BVAS=0 at any time during the treatment period The BVAS form is divided into 9 organ-based systems, with each section including symptoms/signs that are typical of that particular organ involvement in systemic vasculitis. The clinician only scores features believed to be due to active vasculitis. Completion of the form provides a numerical score, which ranges from 0 (best health) to 63 (worst health). | From day 1 throughout the study period (day 421/week 60) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MPA, ANCA-associated vasculitis, complement, vasculitis, C5aR, avacopan, CCX168, GPA