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

Phase 3

Completed

Conditions: ANCA-Associated Vasculitis

Interventions: Drug: Prednisone
Drug: Avacopan
Drug: Cyclophosphamide
Biological: Rituximab
Drug: Azathioprine

Registration Number: NCT02994927

Lead Sponsor: Amgen

Brief Summary: 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: 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.

Study acquired by Amgen and all disclosures were done by previous sponsor ChemoCentryx.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 331

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to screening; if on azathioprine, mycophenolate mofetil or methotrexate at the time of screening, these drugs must be withdrawn prior to receiving the cyclophosphamide or rituximab dose on Day 1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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Avacopan group	Cyclophosphamide	Avacopan plus cyclophosphamide/azathioprine or rituximab plus prednisone-matching placebo.
Prednisone group	Rituximab	Avacopan-matching placebo plus cyclophosphamide/azathioprine or rituximab plus a full starting dose of prednisone.
Avacopan group	Rituximab	Avacopan plus cyclophosphamide/azathioprine or rituximab plus prednisone-matching placebo.
Prednisone group	Prednisone	Avacopan-matching placebo plus cyclophosphamide/azathioprine or rituximab plus a full starting dose of prednisone.
Prednisone group	Cyclophosphamide	Avacopan-matching placebo plus cyclophosphamide/azathioprine or rituximab plus a full starting dose of prednisone.
Prednisone group	Azathioprine	Avacopan-matching placebo plus cyclophosphamide/azathioprine or rituximab plus a full starting dose of prednisone.
Avacopan group	Azathioprine	Avacopan plus cyclophosphamide/azathioprine or rituximab plus prednisone-matching placebo.
Avacopan group	Avacopan	Avacopan plus cyclophosphamide/azathioprine or rituximab plus prednisone-matching placebo.

Primary Outcome Measures

Name	Time	Method
Percentage of Subjects Achieving Sustained Disease Remission at Week 52	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.
Percentage of Subjects Achieving Disease Remission at Week 26	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).

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Vital Signs (1/5)	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)	Baseline, Week 26 and 52	BMI=Body Mass Index
Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (4/5)	Baseline, Week 26 and 52
Subject Incidence of Treatment-emergent SAEs, AEs, and Withdrawals Due to AEs	From day 1 throughout the study period (day 421/week 60)	AEs=Adverse events SAEs=Serious adverse events TEAE=Treatment-emergent adverse event
Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (2/5)	Baseline, Week 26 and 52
Percentage of Subjects and Time to Experiencing a Relapse After Previously Achieving BVAS=0 at Any Time During the Treatment Period	Week 52	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: 1. having achieved remission at Week 26 (BVAS=0 and no glucocorticoids for ANCA-associated vasculitis within 4 weeks) or 2. 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).
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	Week 4	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).
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	Baseline, Week 26 and 52	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).
Percentage of Subjects and Time to Experiencing a Relapse After Previously Achieving Remission at Week 26 in the Study	Week 52	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: 1. having achieved remission at Week 26 (BVAS=0 and no glucocorticoids for ANCA-associated vasculitis within 4 weeks) or 2. 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).
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 - Serum Chemistry (2/2)	Baseline, Week 26 and 52
Change From Baseline in Vital Signs (2/5)	Baseline, Week 26 and 52
Number of Subjects With Clinically Significant ECG Changes From Baseline	From day 1 throughout the study period (day 421/week 60)	Clinical significance was assessed by the individual reading of the ECGs ECG=Electrocardiogram
Glucocorticoid-induced Toxicity as Measured by Change From Baseline Over the First 26 Weeks in the GTI	Baseline, Week 13 and 26	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).
Change in the VDI From Baseline Over 52 Weeks, Including the Week 26 and Week 52 Time Points	Baseline, Week 26 and 52	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).
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 (5/5)	Baseline, Week 26 and 52
In Subjects With Renal Disease at Baseline (Based in the BVAS Renal Component), the Change in eGFR From Baseline Over 52 Weeks	Baseline, Week 26 and 52	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
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	Baseline, Week 4, 26 and 52	BVAS=Birmingham Vasculitis Activity Score UACR=Urinary albumin:creatinine ratio
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	Baseline, Week 26 and 52	BVAS=Birmingham Vasculitis Activity Score MCP-1=monocyte chemoattractant protein-1
Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Serum Chemistry (1/2)	Baseline, Week 26 and 52
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	From day 1 throughout the study period (day 421/week 60)	AE=Adverse Event
Certain Safety Endpoints of Interest: Infections, Hepatic System Abnormalities, WBC Count Decreases, and Hypersensitivity	From day 1 throughout the study period (day 421/week 60)	WBC=White Blood Cell TEAE=Treatment-Emergent Adverse Event
Number of Subjects Experiencing a Relapse After Previously Achieving BVAS=0 During the Study	From day 1 throughout the study period (day 421/week 60)	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: 1. having achieved remission at Week 26 (BVAS=0 and no glucocorticoids for ANCA-associated vasculitis within 4 weeks) or 2. 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).