A Phase 3 Clinical Trial of CCX168 (Avacopan) in Patients With ANCA-Associated Vasculitis (ADVOCATE)
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT02994927 |
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Recruitment Status :
Completed
First Posted : December 16, 2016
Results First Posted : September 9, 2022
Last Update Posted : September 7, 2023
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| ANCA-Associated Vasculitis | Drug: Avacopan Drug: Prednisone Drug: Cyclophosphamide Biological: Rituximab Drug: Azathioprine | Phase 3 |
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 (Clinical Trial) |
| Actual Enrollment : | 331 participants |
| 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 |
| 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 |
| Actual Study Start Date : | March 15, 2017 |
| Actual Primary Completion Date : | September 7, 2019 |
| Actual Study Completion Date : | November 1, 2019 |
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: Prednisone group
Avacopan-matching placebo plus cyclophosphamide/azathioprine or rituximab plus a full starting dose of prednisone.
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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):
Drug: Cyclophosphamide Orally or intravenously administered Biological: Rituximab Intravenously administered Drug: Azathioprine Orally administered |
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Experimental: Avacopan group
Avacopan plus cyclophosphamide/azathioprine or rituximab plus prednisone-matching placebo.
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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):
Other Name: CCX168 Drug: Cyclophosphamide Orally or intravenously administered Biological: Rituximab Intravenously administered Drug: Azathioprine Orally administered |
- 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.
- 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:
- 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).
- 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:
- 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).
- 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:
- 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).
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 12 Years and older (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02994927
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| Study Director: | MD | Amgen |
Documents provided by ChemoCentryx:
| Responsible Party: | ChemoCentryx |
| ClinicalTrials.gov Identifier: | NCT02994927 |
| Other Study ID Numbers: |
CL010_168 ADVOCATE ( Other Identifier: ChemoCentryx ) |
| First Posted: | December 16, 2016 Key Record Dates |
| Results First Posted: | September 9, 2022 |
| Last Update Posted: | September 7, 2023 |
| Last Verified: | August 2023 |
| Individual Participant Data (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 Statistical Analysis Plan (SAP) Informed Consent Form (ICF) 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 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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ANCA-associated vasculitis complement vasculitis C5aR |
avacopan CCX168 MPA GPA |
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Vasculitis Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis Vascular Diseases Cardiovascular Diseases Systemic Vasculitis Skin Diseases, Vascular Skin Diseases Autoimmune Diseases Immune System Diseases Prednisone Cyclophosphamide Rituximab Azathioprine Immunosuppressive Agents Immunologic Factors |
Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Myeloablative Agonists Antineoplastic Agents, Immunological Anti-Inflammatory Agents Glucocorticoids Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Antineoplastic Agents, Hormonal Antimetabolites Antimetabolites, Antineoplastic |