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

• ClinicalTrials.gov Identifier: NCT02994927
• Recruitment Status: Completed
• First Posted: December 16, 2016
• Results First Posted: September 9, 2022
• Last Update Posted: January 29, 2024
• Sponsor: ChemoCentryx
• Information provided by (Responsible Party): ChemoCentryx

Tracking Information

• First Submitted Date: December 11, 2016
• First Posted Date: December 16, 2016
• Results First Submitted Date: May 19, 2022
• Results First Posted Date: September 9, 2022
• Last Update Posted Date: January 29, 2024
• Actual Study Start Date: March 15, 2017
• Actual Primary Completion Date: September 7, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 12, 2022)

• Percentage of Subjects Achieving Disease Remission at Week 26 [ Time Frame: 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).
• Percentage of Subjects Achieving Sustained Disease Remission at Week 52 [ Time Frame: 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.

Original Primary Outcome Measures (submitted: December 13, 2016)

• Remission [ Time Frame: 26 weeks ]
  The proportion of patients achieving disease remission assessed by Birmingham Vasculitis Activity Score (BVAS) at Week 26
• Sustained remission [ Time Frame: 52 weeks ]
  The proportion of patients achieving sustained disease remission assessed by BVAS at Week 52

Current Secondary Outcome Measures (submitted: September 19, 2022)

• Subject Incidence of Treatment-emergent SAEs, AEs, and Withdrawals Due to AEs [ Time Frame: From day 1 throughout the study period (day 421/week 60) ]
  AEs=Adverse events SAEs=Serious adverse events TEAE=Treatment-emergent adverse event
• Glucocorticoid-induced Toxicity as Measured by Change From Baseline Over the First 26 Weeks in the GTI [ Time Frame: 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).
• 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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).
• Percentage of Subjects and Time to Experiencing a Relapse After Previously Achieving BVAS=0 at Any Time During the Treatment Period [ Time Frame: 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).
• In Subjects With Renal Disease at Baseline (Based in the BVAS Renal Component), the Change in eGFR From Baseline Over 52 Weeks [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline, Week 26 and 52 ]
  BVAS=Birmingham Vasculitis Activity Score MCP-1=monocyte chemoattractant protein-1
• Change in the VDI From Baseline Over 52 Weeks, Including the Week 26 and Week 52 Time Points [ Time Frame: 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) [ Time Frame: Baseline, Week 26 and 52 ]
• Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (2/5) [ Time Frame: Baseline, Week 26 and 52 ]
• Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (3/5) [ Time Frame: Baseline, Week 26 and 52 ]
• Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (4/5) [ Time Frame: Baseline, Week 26 and 52 ]
• Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (5/5) [ Time Frame: Baseline, Week 26 and 52 ]
• Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Serum Chemistry (1/2) [ Time Frame: Baseline, Week 26 and 52 ]
• Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Serum Chemistry (2/2) [ Time Frame: Baseline, Week 26 and 52 ]
• Change From Baseline in Vital Signs (1/5) [ Time Frame: Baseline, Week 26 and 52 ]
• Change From Baseline in Vital Signs (2/5) [ Time Frame: Baseline, Week 26 and 52 ]
• Change From Baseline in Vital Signs (3/5) [ Time Frame: Baseline, Week 26 and 52 ]
• Change From Baseline in Vital Signs (4/5) [ Time Frame: Baseline, Week 26 and 52 ]
• Change From Baseline in Vital Signs (5/5) [ Time Frame: Baseline, Week 26 and 52 ]
  BMI=Body Mass Index
• Number of Subjects With Clinically Significant ECG Changes From Baseline [ Time Frame: From day 1 throughout the study period (day 421/week 60) ]
  Clinical significance was assessed by the individual reading of the ECGs ECG=Electrocardiogram
• 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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).

Original Secondary Outcome Measures (submitted: December 13, 2016)

• Adverse events coded by MedDRA [ Time Frame: 60 weeks ]
  Patient incidence of treatment-emergent serious adverse events, adverse events, and withdrawals due to adverse events
• Glucocorticoid-induced toxicity [ Time Frame: 26 weeks ]
  Glucocorticoid-induced toxicity as measured by the Glucocorticoid Toxicity Index
• Response rapidity [ Time Frame: 4 weeks ]
  Remission assessed by BVAS at week 4
• Health-related quality of life [ Time Frame: 52 weeks ]
  Change in health-related quality-of-life based on the Short Form-36 version 2 component and domain scores and the EuroQOL-5D-5L visual analogue scale (in mm) and index
• Estimated glomerular filtration rate (eGFR) [ Time Frame: 52 weeks ]
  Change from baseline in eGFR in mL/min/1.73^2
• Urinary albumin:creatinine ratio (UACR) [ Time Frame: 52 weeks ]
  Change from baseline in UACR in mg/g creatinine
• Urinary monocyte chemoattractant protein-1 (MCP-1):creatinine ratio [ Time Frame: 52 weeks ]
  Change from baseline in urinary MCP-1:creatinine ratio in pg/mg creatinine
• Vasculitis Damage Index [ Time Frame: 52 weeks ]
  Change from baseline in the Vasculitis Damage Index (VDI)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 3 Clinical Trial of CCX168 (Avacopan) in Patients With ANCA-Associated Vasculitis
• Official Title: 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
• 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 Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

This study was double-blind, double-dummy, i.e., placebo capsules were identical in appearance to the avacopan capsules, and prednisone capsules also had matching placebo capsules. To maintain the blind, multiple measures were taken (i.e., randomization code was not accessible to study personnel who had contact with study centers or who were involved in data management and analysis for the duration of the study).

Primary Purpose: Treatment

• Condition: ANCA-Associated Vasculitis

Intervention

• Drug: Avacopan

  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.
  Other Name: CCX168
• Drug: Prednisone

  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.
• Drug: Cyclophosphamide
  Orally or intravenously administered
• Biological: Rituximab
  Intravenously administered
• Drug: Azathioprine
  Orally administered

Study Arms

• Active Comparator: Prednisone group
  Avacopan-matching placebo plus cyclophosphamide/azathioprine or rituximab plus a full starting dose of prednisone.
  Interventions:

  • Drug: Prednisone
  • Drug: Cyclophosphamide
  • Biological: Rituximab
  • Drug: Azathioprine
• Experimental: Avacopan group
  Avacopan plus cyclophosphamide/azathioprine or rituximab plus prednisone-matching placebo.
  Interventions:

  • Drug: Avacopan
  • Drug: Cyclophosphamide
  • Biological: Rituximab
  • Drug: Azathioprine

Publications *

• Harigai M, Kaname S, Tamura N, Dobashi H, Kubono S, Yoshida T. Efficacy and safety of avacopan in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis: A subanalysis of a randomized Phase 3 study. Mod Rheumatol. 2023 Mar 2;33(2):338-345. doi: 10.1093/mr/roac037.
• Soulsby WD. Journal Club Review of "Avacopan for the Treatment of ANCA-Associated Vasculitis". ACR Open Rheumatol. 2022 Jul;4(7):558-561. doi: 10.1002/acr2.11412. Epub 2022 Feb 15.
• Jayne DRW, Merkel PA, Schall TJ, Bekker P; ADVOCATE Study Group. Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med. 2021 Feb 18;384(7):599-609. doi: 10.1056/NEJMoa2023386. Erratum In: N Engl J Med. 2024 Jan 25;390(4):388.
• Merkel PA, Jayne DR, Wang C, Hillson J, Bekker P. Evaluation of the Safety and Efficacy of Avacopan, a C5a Receptor Inhibitor, in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Treated Concomitantly With Rituximab or Cyclophosphamide/Azathioprine: Protocol for a Randomized, Double-Blind, Active-Controlled, Phase 3 Trial. JMIR Res Protoc. 2020 Apr 7;9(4):e16664. doi: 10.2196/16664.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 19, 2022): 331
• Original Estimated Enrollment (submitted: December 13, 2016): 300
• Actual Study Completion Date: November 1, 2019
• Actual Primary Completion Date: September 7, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Canada, Czechia, Denmark, France, Germany, Hungary, Ireland, Italy, Japan, Netherlands, New Zealand, Norway, Spain, Sweden, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT02994927
• Other Study ID Numbers: CL010_168; ADVOCATE ( Other Identifier: ChemoCentryx )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.
• URL: http://www.amgen.com/datasharing

• Current Responsible Party: ChemoCentryx
• Original Responsible Party: Same as current
• Current Study Sponsor: ChemoCentryx
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: MD; Amgen

• PRS Account: ChemoCentryx
• Verification Date: January 2024