Clinical trial NCT02994927: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: ANCA-Associated Vasculitis
Keywords: ANCA-associated vasculitis
complement
vasculitis
C5aR
avacopan
CCX168
MPA
GPA
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2016-12-16
Enrollment: 331
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Percentage of Subjects Achieving Disease Remission at Week 26
timeFrame: Week 26
measure: Percentage of Subjects Achieving Sustained Disease Remission at Week 52
timeFrame: Week 52
Secondary outcomes:
measure: Subject Incidence of Treatment-emergent SAEs, AEs, and Withdrawals Due to AEs
timeFrame: From day 1 throughout the study period (day 421/week 60)
measure: Glucocorticoid-induced Toxicity as Measured by Change From Baseline Over the First 26 Weeks in the GTI
timeFrame: Baseline, Week 13 and 26
measure: 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
timeFrame: Week 4
measure: 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
timeFrame: Baseline, Week 26 and 52
measure: Percentage of Subjects and Time to Experiencing a Relapse After Previously Achieving Remission at Week 26 in the Study
timeFrame: Week 52
measure: Percentage of Subjects and Time to Experiencing a Relapse After Previously Achieving BVAS=0 at Any Time During the Treatment Period
timeFrame: Week 52
measure: In Subjects With Renal Disease at Baseline (Based in the BVAS Renal Component), the Change in eGFR From Baseline Over 52 Weeks
timeFrame: Baseline, Week 26 and 52
measure: 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
timeFrame: Baseline, Week 4, 26 and 52
measure: 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
timeFrame: Baseline, Week 26 and 52
measure: Change in the VDI From Baseline Over 52 Weeks, Including the Week 26 and Week 52 Time Points
timeFrame: Baseline, Week 26 and 52
measure: Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (1/5)
timeFrame: Baseline, Week 26 and 52
measure: Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (2/5)
timeFrame: Baseline, Week 26 and 52
measure: Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (3/5)
timeFrame: Baseline, Week 26 and 52
measure: Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (4/5)
timeFrame: Baseline, Week 26 and 52
measure: Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Hematology (5/5)
timeFrame: Baseline, Week 26 and 52
measure: Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Serum Chemistry (1/2)
timeFrame: Baseline, Week 26 and 52
measure: Change From Baseline and Shifts From Baseline in All Safety Laboratory Parameters - Serum Chemistry (2/2)
timeFrame: Baseline, Week 26 and 52
measure: Change From Baseline in Vital Signs (1/5)
timeFrame: Baseline, Week 26 and 52
measure: Change From Baseline in Vital Signs (2/5)
timeFrame: Baseline, Week 26 and 52
measure: Change From Baseline in Vital Signs (3/5)
timeFrame: Baseline, Week 26 and 52
measure: Change From Baseline in Vital Signs (4/5)
timeFrame: Baseline, Week 26 and 52
measure: Change From Baseline in Vital Signs (5/5)
timeFrame: Baseline, Week 26 and 52
measure: Number of Subjects With Clinically Significant ECG Changes From Baseline
timeFrame: From day 1 throughout the study period (day 421/week 60)
measure: 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
timeFrame: From day 1 throughout the study period (day 421/week 60)
measure: Certain Safety Endpoints of Interest: Infections, Hepatic System Abnormalities, WBC Count Decreases, and Hypersensitivity
timeFrame: From day 1 throughout the study period (day 421/week 60)
measure: Number of Subjects Experiencing a Relapse After Previously Achieving BVAS=0 During the Study
timeFrame: From day 1 throughout the study period (day 421/week 60)
Other outcomes:
Locations:
city: Huntsville
country: United States
facility: Clinical Trial Site
state: Alabama
city: Phoenix
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country: Czechia
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city: Aalborg
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country: Germany
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country: Hungary
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country: Hungary
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city: Cork
country: Ireland
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country: Ireland
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country: Italy
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country: Italy
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country: Italy
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country: Italy
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country: Italy
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city: Torino
country: Italy
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country: Italy
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city: Aichi
country: Japan
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country: Japan
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country: Japan
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country: Japan
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country: Japan
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country: Japan
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country: Japan
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country: Japan
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country: Japan
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city: Tokyo
country: Japan
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city: Toyama
country: Japan
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country: Japan
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city: Groningen
country: Netherlands
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city: Leiden
country: Netherlands
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city: Rotterdam
country: Netherlands
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city: Christchurch
country: New Zealand
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city: Dunedin
country: New Zealand
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city: Grafton
country: New Zealand
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city: Hamilton
country: New Zealand
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city: Takapuna
country: New Zealand
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city: Nordbyhagen
country: Norway
facility: Clinical Trial Site
city: Oslo
country: Norway
facility: Clinical Trial Site
city: Tromsø
country: Norway
facility: Clinical Trial Site
city: Badalona
country: Spain
facility: Clinical Trial Site
city: Barcelona
country: Spain
facility: Clinical Trial Site
city: Burela
country: Spain
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city: Lleida
country: Spain
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city: Madrid
country: Spain
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city: San Sebastián
country: Spain
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city: Linköping
country: Sweden
facility: Clinical Trial Site
city: Lund
country: Sweden
facility: Clinical Trial Site
city: Stockholm
country: Sweden
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city: Uppsala
country: Sweden
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city: Örebro
country: Sweden
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city: Basel
country: Switzerland
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city: Bern
country: Switzerland
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city: Fribourg
country: Switzerland
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city: Lausanne
country: Switzerland
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city: St. Gallen
country: Switzerland
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city: Zürich
country: Switzerland
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city: Aberdeen
country: United Kingdom
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city: Basildon
country: United Kingdom
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city: Birmingham
country: United Kingdom
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city: Bristol
country: United Kingdom
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city: Cambridge
country: United Kingdom
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city: Canterbury
country: United Kingdom
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city: Cardiff
country: United Kingdom
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city: Carshalton
country: United Kingdom
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city: Dorchester
country: United Kingdom
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city: Dudley
country: United Kingdom
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city: Exeter
country: United Kingdom
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city: Glasgow
country: United Kingdom
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city: Inverness
country: United Kingdom
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city: Kirkcaldy
country: United Kingdom
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city: Leeds
country: United Kingdom
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city: Leicester
country: United Kingdom
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city: Liverpool
country: United Kingdom
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city: London
country: United Kingdom
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city: Manchester
country: United Kingdom
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city: Newcastle
country: United Kingdom
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city: Nottingham
country: United Kingdom
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city: Oxford
country: United Kingdom
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city: Reading
country: United Kingdom
facility: Clinical Trial Site
city: Salford
country: United Kingdom
facility: Clinical Trial Site
city: Westcliff-on-Sea
country: United Kingdom
facility: Clinical Trial Site
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.