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

Amgen331 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

331

Conditions

ANCA-Associated Vasculitis

Interventions

AvacopanDRUG

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.

PrednisoneDRUG

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.

Eligibility

Sex: ALLMin age: 12 Years

Medical Language ↔ Plain English

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

Locations (198)

Outcomes

Primary Outcomes

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).

Time frame: 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.

Time frame: Week 52

Secondary Outcomes

Subject Incidence of Treatment-emergent SAEs, AEs, and Withdrawals Due to AEs

AEs=Adverse events SAEs=Serious adverse events TEAE=Treatment-emergent adverse event

Time frame: 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).

Time frame: Baseline, Week 13 and 26

Data from ClinicalTrials.gov

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Orally or intravenously administered

RituximabBIOLOGICAL

Intravenously administered

AzathioprineDRUG

Orally administered

Clinical Trial Site

Huntsville, Alabama, United States

Clinical Trial Site

Phoenix, Arizona, United States

Clinical Trial Site

Phoenix, Arizona, United States

Clinical Trial Site

Los Angeles, California, United States

Clinical Trial Site

Santa Monica, California, United States

Clinical Trial Site

Aurora, Colorado, United States

Clinical Trial Site

Washington D.C., District of Columbia, United States

Clinical Trial Site

Daytona Beach, Florida, United States

Clinical Trial Site

Tampa, Florida, United States

Clinical Trial Site

Atlanta, Georgia, United States

...and 188 more locations

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).

Time frame: 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).

Time frame: 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: 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).

Time frame: 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: 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).

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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).

Time frame: Baseline, Week 26 and 52

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)

BMI=Body Mass Index

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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: 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).

Time frame: From day 1 throughout the study period (day 421/week 60)