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Article ; Online: Pharmacokinetic Evaluation of the CYP3A4 and CYP2C9 Drug-Drug Interaction of Avacopan in 2 Open-Label Studies in Healthy Participants.

Miao, Shichang / Bekker, Pirow / Armas, Danielle / Lor, Mary / Han, Yanyan / Webster, Kenneth / Trivedi, Ashit

Clinical pharmacology in drug development

2024 Volume 13, Issue 5, Page(s) 517–533

Abstract: Avacopan, a complement 5a receptor (C5aR) antagonist approved for treating severe active antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, was evaluated in 2 clinical drug-drug interaction studies. The studies assessed the impact of ... ...

Abstract	Avacopan, a complement 5a receptor (C5aR) antagonist approved for treating severe active antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, was evaluated in 2 clinical drug-drug interaction studies. The studies assessed the impact of avacopan on the pharmacokinetics (PK) of CYP3A4 substrates midazolam and simvastatin and CYP2C9 substrate celecoxib, and the influence of CYP3A4 inhibitor itraconazole and inducer rifampin on the PKs of avacopan. The results indicated that twice-daily oral administration of 30 mg of avacopan increased the area under the curve (AUC) of midazolam by 1.81-fold and celecoxib by 1.15-fold when administered without food, and twice-daily oral administration of 30 or 60 mg of avacopan increased the AUC of simvastatin by approximately 2.6-3.5-fold and the AUC of the active metabolite β-hydroxy-simvastatin acid by approximately 1.4-1.7-fold when co-administered with food. Furthermore, the AUC of avacopan increased by approximately 2.19-fold when co-administered with itraconazole and decreased by approximately 13.5-fold when co-administered with rifampin. These findings provide critical insights into the potential drug-drug interactions involving avacopan, which could have significant implications for patient care and treatment planning. (NCT06207682).
MeSH term(s)	Humans ; Drug Interactions ; Male ; Adult ; Cytochrome P-450 CYP3A/metabolism ; Cytochrome P-450 CYP2C9/metabolism ; Rifampin/pharmacology ; Rifampin/administration & dosage ; Rifampin/pharmacokinetics ; Itraconazole/pharmacology ; Itraconazole/administration & dosage ; Itraconazole/pharmacokinetics ; Simvastatin/pharmacokinetics ; Simvastatin/administration & dosage ; Simvastatin/adverse effects ; Female ; Healthy Volunteers ; Young Adult ; Cytochrome P-450 CYP3A Inhibitors/pharmacology ; Cytochrome P-450 CYP3A Inhibitors/administration & dosage ; Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics ; Area Under Curve ; Midazolam/pharmacokinetics ; Midazolam/administration & dosage ; Food-Drug Interactions ; Administration, Oral ; Middle Aged
Chemical Substances	Cytochrome P-450 CYP3A (EC 1.14.14.1) ; Cytochrome P-450 CYP2C9 (EC 1.14.13.-) ; Rifampin (VJT6J7R4TR) ; Itraconazole (304NUG5GF4) ; Simvastatin (AGG2FN16EV) ; CYP2C9 protein, human (EC 1.14.13.-) ; CYP3A4 protein, human (EC 1.14.14.55) ; Cytochrome P-450 CYP3A Inhibitors ; Midazolam (R60L0SM5BC)
Language	English
Publishing date	2024-02-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649010-9
ISSN	2160-7648 ; 2160-763X
ISSN (online)	2160-7648
ISSN	2160-763X
DOI	10.1002/cpdd.1389
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Article: ANCA Associated Vasculitis Subtypes: Response [Letter].

Merkel, Peter A / Jayne, David R W / Bekker, Pirow

Journal of inflammation research

2022 Volume 15, Page(s) 5161–5162

Language	English
Publishing date	2022-09-09
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2494878-0
ISSN	1178-7031
ISSN	1178-7031
DOI	10.2147/JIR.S385293
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Article ; Online: The impact of treatment with avacopan on health-related quality of life in antineutrophil cytoplasmic antibody-associated vasculitis: a post-hoc analysis of data from the ADVOCATE trial.

Strand, Vibeke / Jayne, David R W / Horomanski, Audra / Yue, Huibin / Bekker, Pirow / Merkel, Peter A

The Lancet. Rheumatology

2023 Volume 5, Issue 8, Page(s) e451–e460

Abstract: Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is characterised by inflammation and destruction of small to medium sized blood vessels. In the previously reported ADVOCATE study, a phase 3 double-blind, double-dummy ... ...

Abstract	Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is characterised by inflammation and destruction of small to medium sized blood vessels. In the previously reported ADVOCATE study, a phase 3 double-blind, double-dummy randomised controlled trial of patients with newly diagnosed or relapsing ANCA-associated vasculitis, the oral selective complement 5a receptor inhibitor avacopan was shown to be non-inferior with regard to remission induction at week 26 and superior with regard to sustained remission at week 52, compared with a prednisone taper in a standard of care regimen. In this Article, we report an in-depth analysis of prespecified and exploratory patient-reported outcomes from the ADVOCATE study, measuring health-related quality of life and health utilities. Methods: We did a post-hoc analysis of patient-reported outcome data from the ADVOCATE study (NCT02994927) of patients with newly diagnosed or relapsing ANCA-associated vasculitis. We analysed summary scores and individual domain scores for the prespecified health-related quality of life outcomes from ADVOCATE, which were evaluated at weeks 26 and 52 by use of the Medical Outcomes Survey 36-Item Short Form Health Survey (SF-36) version 2, the EuroQol 5-Dimensions 5-Levels Questionnaire (EQ-5D-5L), and the EQ-5D health utility measure, assessed in the modified intention-to-treat population. We also calculated the Short Form 6 Dimension (SF-6D) score as an additional health utility measure. We evaluated the proportion of patients who reported scores that met or exceeded minimum clinically important differences in health-related quality of life, and we compared scores to normative values (age-specific and sex-specific scores from healthy populations from the USA matched to the protocol population). We also evaluated the proportion of patients who reported scores that met or exceeded minimum important difference in health utility scores. Findings: 331 patients were enrolled in the ADVOCATE trial, of whom 166 were in the avacopan group and 165 were in the prednisone standard of care group. In the avacopan group, the mean age was 61·2 years (SD 14·6), 98 (59%) of 166 patients were men, 68 (41%) were women, and 138 (83%) were White; in the prednisone group, the mean age was 60·5 years (14·5), 88 (54%) of 164 patients were men, 76 (46%) were women, and 140 (85%) were White. Patients treated with avacopan received approximately 2500 mg less median total prednisone up to week 52. Least squares means difference from baseline in physical component summary scores were significantly greater in patients in the avacopan group compared with those in the prednisone group at weeks 26 and 52, as well as in five of eight SF-36 domains at week 26 and two of eight SF-36 domains at week 52. The proportion of patients reporting scores equal to or greater than normative values was higher in the avacopan group than in the prednisone group across all SF-36 domains at both week 26 and 52, although the differences were not statistically significant with the exception of the role physical and vitality domains at week 26. Least squares means change from baseline in EQ-5D-5L visual analogue scale, EQ-5D health utility scores, and SF-6D health utility scores were significantly greater at week 52 in the avacopan group compared with the prednisone group. Interpretation: Patients with ANCA-associated vasculitis who received avacopan reported statistically significant and clinically meaningful improvements in health-related quality of life at 26 and 52 weeks and in health utility EQ-5D and SF-6D scores at 52 weeks. These patient-reported outcomes complement investigator assessments and support the efficacy of avacopan in patients with ANCA-associated vasculitis with use of lower prednisone doses. Funding: ChemoCentryx.
MeSH term(s)	Female ; Humans ; Male ; Middle Aged ; Aniline Compounds ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy ; Antibodies, Antineutrophil Cytoplasmic ; Nipecotic Acids ; Prednisone/therapeutic use ; Quality of Life ; Double-Blind Method
Chemical Substances	Aniline Compounds ; Antibodies, Antineutrophil Cytoplasmic ; avacopan (O880NM097T) ; Nipecotic Acids ; Prednisone (VB0R961HZT)
Language	English
Publishing date	2023-07-24
Publishing country	England
Document type	Randomized Controlled Trial ; Clinical Trial, Phase III ; Journal Article
ISSN	2665-9913
ISSN (online)	2665-9913
DOI	10.1016/S2665-9913(23)00092-9
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Article ; Online: Reduced-Dose vs High-Dose Glucocorticoids Added to Rituximab and Remission Induction in ANCA-Associated Vasculitis.

Jayne, David R W / Merkel, Peter A / Bekker, Pirow

JAMA

2021 Volume 326, Issue 15, Page(s) 1536

MeSH term(s)	Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy ; Glucocorticoids ; Humans ; Remission Induction ; Rituximab
Chemical Substances	Glucocorticoids ; Rituximab (4F4X42SYQ6)
Language	English
Publishing date	2021-10-19
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	2958-0
ISSN	1538-3598 ; 0254-9077 ; 0002-9955 ; 0098-7484
ISSN (online)	1538-3598
ISSN	0254-9077 ; 0002-9955 ; 0098-7484
DOI	10.1001/jama.2021.13873
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Article ; Online: Avacopan for the Treatment of ANCA-Associated Vasculitis. Reply.

Jayne, David R W / Merkel, Peter A / Bekker, Pirow

The New England journal of medicine

2021 Volume 384, Issue 21, Page(s) e81

MeSH term(s)	Aniline Compounds ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy ; Humans ; Nipecotic Acids
Chemical Substances	Aniline Compounds ; Nipecotic Acids ; avacopan (O880NM097T)
Language	English
Publishing date	2021-05-27
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	207154-x
ISSN	1533-4406 ; 0028-4793
ISSN (online)	1533-4406
ISSN	0028-4793
DOI	10.1056/NEJMc2104672
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Article ; Online: Avacopan for the Treatment of ANCA-Associated Vasculitis.

Jayne, David R W / Merkel, Peter A / Schall, Thomas J / Bekker, Pirow

The New England journal of medicine

2021 Volume 384, Issue 7, Page(s) 599–609

Abstract: Background: The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.: Methods: In this randomized, controlled trial, we assigned patients with ANCA-associated ... ...

Abstract	Background: The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Methods: In this randomized, controlled trial, we assigned patients with ANCA-associated vasculitis in a 1:1 ratio to receive oral avacopan at a dose of 30 mg twice daily or oral prednisone on a tapering schedule. All the patients received either cyclophosphamide (followed by azathioprine) or rituximab. The first primary end point was remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 (on a scale from 0 to 63, with higher scores indicating greater disease activity) at week 26 and no glucocorticoid use in the previous 4 weeks. The second primary end point was sustained remission, defined as remission at both weeks 26 and 52. Both end points were tested for noninferiority (by a margin of 20 percentage points) and for superiority. Results: A total of 331 patients underwent randomization; 166 were assigned to receive avacopan, and 165 were assigned to receive prednisone. The mean BVAS at baseline was 16 in both groups. Remission at week 26 (the first primary end point) was observed in 120 of 166 patients (72.3%) receiving avacopan and in 115 of 164 patients (70.1%) receiving prednisone (estimated common difference, 3.4 percentage points; 95% confidence interval [CI], -6.0 to 12.8; P<0.001 for noninferiority; P = 0.24 for superiority). Sustained remission at week 52 (the second primary end point) was observed in 109 of 166 patients (65.7%) receiving avacopan and in 90 of 164 patients (54.9%) receiving prednisone (estimated common difference, 12.5 percentage points; 95% CI, 2.6 to 22.3; P<0.001 for noninferiority; P = 0.007 for superiority). Serious adverse events (excluding worsening vasculitis) occurred in 37.3% of the patients receiving avacopan and in 39.0% of those receiving prednisone. Conclusions: In this trial involving patients with ANCA-associated vasculitis, avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52. All the patients received cyclophosphamide or rituximab. The safety and clinical effects of avacopan beyond 52 weeks were not addressed in the trial. (Funded by ChemoCentryx; ADVOCATE ClinicalTrials.gov number, NCT02994927.).
MeSH term(s)	Administration, Oral ; Aniline Compounds/adverse effects ; Aniline Compounds/therapeutic use ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy ; Azathioprine/administration & dosage ; Cyclophosphamide/administration & dosage ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Glucocorticoids/administration & dosage ; Glucocorticoids/adverse effects ; Humans ; Immunosuppressive Agents/administration & dosage ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Nipecotic Acids/adverse effects ; Nipecotic Acids/therapeutic use ; Prednisone/administration & dosage ; Prednisone/adverse effects ; Receptor, Anaphylatoxin C5a/antagonists & inhibitors ; Recurrence ; Remission Induction ; Rituximab/administration & dosage
Chemical Substances	Aniline Compounds ; C5AR1 protein, human ; Glucocorticoids ; Immunosuppressive Agents ; Nipecotic Acids ; Receptor, Anaphylatoxin C5a ; Rituximab (4F4X42SYQ6) ; Cyclophosphamide (8N3DW7272P) ; Azathioprine (MRK240IY2L) ; avacopan (O880NM097T) ; Prednisone (VB0R961HZT)
Language	English
Publishing date	2021-02-09
Publishing country	United States
Document type	Clinical Trial, Phase III ; Comparative Study ; Equivalence Trial ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	207154-x
ISSN	1533-4406 ; 0028-4793
ISSN (online)	1533-4406
ISSN	0028-4793
DOI	10.1056/NEJMoa2023386
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Article ; Online: Renal Recovery for Patients with ANCA-Associated Vasculitis and Low eGFR in the ADVOCATE Trial of Avacopan.

Cortazar, Frank B / Niles, John L / Jayne, David R W / Merkel, Peter A / Bruchfeld, Annette / Yue, Huibin / Schall, Thomas J / Bekker, Pirow

Kidney international reports

2023 Volume 8, Issue 4, Page(s) 860–870

Abstract: Introduction: In the 330-patient ADVOCATE trial of avacopan for the treatment of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, in which 81% of patients had renal involvement, estimated glomerular filtration rate (eGFR) increased ... ...

Abstract	Introduction: In the 330-patient ADVOCATE trial of avacopan for the treatment of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, in which 81% of patients had renal involvement, estimated glomerular filtration rate (eGFR) increased on average 7.3 ml/min per 1.73 m Methods: eGFR was determined at baseline and over the course of the trial. Changes in eGFR were compared between the 2 treatment groups. Results: In ADVOCATE, 27 of 166 patients (16%) in the avacopan group and 23 of 164 patients (14%) in the prednisone group had a baseline eGFR ≤20 ml/min per 1.73 m Conclusion: Among patients with baseline eGFR ≤20 ml/min per 1.73 m
Language	English
Publishing date	2023-02-03
Publishing country	United States
Document type	Journal Article
ISSN	2468-0249
ISSN (online)	2468-0249
DOI	10.1016/j.ekir.2023.01.039
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Article ; Online: Glucocorticoid Toxicity Index scores by domain in patients with antineutrophil cytoplasmic antibody-associated vasculitis treated with avacopan versus standard prednisone taper: post-hoc analysis of data from the ADVOCATE trial.

Patel, Naomi J / Jayne, David R W / Merkel, Peter A / Bekker, Pirow / Zhang, Yuqing / Yue, Huibin / Stone, John H

The Lancet. Rheumatology

2023 Volume 5, Issue 3, Page(s) e130–e138

Abstract: Background: The ADVOCATE trial, in which the complement C5a receptor inhibitor avacopan was compared with a standard prednisone taper in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, used the Glucocorticoid Toxicity ... ...

Abstract	Background: The ADVOCATE trial, in which the complement C5a receptor inhibitor avacopan was compared with a standard prednisone taper in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, used the Glucocorticoid Toxicity Index (GTI) to measure glucocorticoid toxicity change. We set out to do a post-hoc analysis of the ADVOCATE data to evaluate changes in individual GTI domains and their ability to differentiate treatment groups. Methods: The ADVOCATE trial was a phase 3, double-blind, double-dummy, randomised trial comparing oral avacopan (30 mg) twice daily for 52 weeks plus a prednisone-matching placebo for 20 weeks with oral prednisone tapered over 20 weeks plus an avacopan-matching placebo for 52 weeks in patients with ANCA-associated vasculitis. GTI data were collected within each of the included domains (BMI, blood pressure, glucose tolerance, lipid metabolism, glucocorticoid myopathy, skin toxicity, neuropsychiatric effects, and infections) at baseline, 13 weeks, and 26 weeks. In this post-hoc analysis, we calculated the cumulative worsening score (CWS) and aggregate improvement score (AIS) for each GTI domain, assessed to what extend each domain contributed to the GTI score, and which domains differentiated between the avacopan and prednisone groups. Differences in domain scores between the two groups were compared using Mantel-Haenszel χ Findings: Among the 330 patients included in the intention-to-treat population of the ADVOCATE trial, 321 (97%) had complete data at week 13 (160 in the avacopan group, and 161 in the prednisone group), and 307 (93%) had complete data at week 26 (154 in the avacopan group, and 153 in the prednisone group) and were assessed in this post-hoc study. In ADVOCATE, mean age in both groups was 61 years (61·2 years [SD 14·6] in the avacopan group; 60·5 years [14·5] in the prednisone group); 98 (59%) of 166 patients in the avacopan group were men and 68 (41%) were women; 88 (54%) of 164 patients in the prednisone group were men and 76 (46%) were women. 278 (84%) of 330 patients were White. The mean glucocorticoid use over 26 weeks was lower in the avacopan group than the prednisone group (1073 mg [SD 1669] vs 3192 mg [1174]). Significantly less glucocorticoid toxicity was observed in the avacopan group than the prednisone group by week 13 in four domains of the GTI (BMI, glucose tolerance, lipid metabolism, and skin toxicity), based on both the CWS and AIS. CWS values in the BMI, lipid metabolism, and skin toxicity domains were significantly lower in the avacopan group than the prednisone group at 26 weeks. No domain favoured the prednisone group for glucocorticoid toxicity reduction. 280 (91%) of 307 patients had glucocorticoid toxicity at 26 weeks. Blood pressure (35% in the avacopan group vs 25% in the prednisone group), infection (22% vs 24%), and lipid metabolism (20% vs 15%) contributed the most weight toward CWS values at 26 weeks. 128 (42%) of 307 patients had combinations of improvement and worsening in different domains at 26 weeks. Interpretation: Replacing a standard prednisone taper with avacopan in patients with ANCA-associated vasculitis reduced glucocorticoid toxicity in multiple GTI domains. For individual patients, glucocorticoid toxicity was often nuanced, improving in some domains while worsening in others. These findings emphasise the value of a composite measure of glucocorticoid toxicity that quantifies cumulative worsening and aggregate change directly. Funding: ChemoCentryx.
MeSH term(s)	Female ; Humans ; Male ; Middle Aged ; Aniline Compounds ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ; Antibodies, Antineutrophil Cytoplasmic ; Glucocorticoids/adverse effects ; Glucose ; Nipecotic Acids ; Prednisone/adverse effects ; Double-Blind Method
Chemical Substances	Aniline Compounds ; Antibodies, Antineutrophil Cytoplasmic ; avacopan (O880NM097T) ; Glucocorticoids ; Glucose (IY9XDZ35W2) ; Nipecotic Acids ; Prednisone (VB0R961HZT)
Language	English
Publishing date	2023-02-20
Publishing country	England
Document type	Randomized Controlled Trial ; Clinical Trial, Phase III ; Journal Article
ISSN	2665-9913
ISSN (online)	2665-9913
DOI	10.1016/S2665-9913(23)00030-9
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Article: C5a receptor inhibitor avacopan in immunoglobulin A nephropathy-an open-label pilot study.

Bruchfeld, Annette / Magin, Hasan / Nachman, Patrick / Parikh, Samir / Lafayette, Richard / Potarca, Antonia / Miao, Shichang / Bekker, Pirow

Clinical kidney journal

2022 Volume 15, Issue 5, Page(s) 922–928

Abstract: Background: Improvement of proteinuria as a marker for disease activity is associated with a better renal outcome in immunoglobulin A nephropathy (IgAN). Complement is an effector pathway in IgA-mediated kidney injury. Avacopan, a selective C5a receptor ...

Abstract	Background: Improvement of proteinuria as a marker for disease activity is associated with a better renal outcome in immunoglobulin A nephropathy (IgAN). Complement is an effector pathway in IgA-mediated kidney injury. Avacopan, a selective C5a receptor inhibitor, has previously shown efficacy in anti-neutrophil cytoplasmic antibody-associated vasculitis. The aim of this study was to evaluate the safety and efficacy of avacopan in patients with IgAN with persistent proteinuria despite a maximally tolerated dose of renin-angiotensin-aldosterone system blockade. The efficacy evaluation was based on the change in proteinuria. Methods: This open-label pilot trial enrolled adult patients with biopsy-proven IgAN, urinary protein:creatinine ratio (UPCR) >1 g/g creatinine and an estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m Results: A total of 10 of 15 screened patients entered the run-in period. Seven patients with a UPCR >1 g/g creatinine received avacopan. Six of seven patients had numerical improvement in the UPCR during the avacopan treatment period, three of whom had a numerical improvement of ∼50% at week 12. At week 24, five of seven patients still showed numerical improvement in the UPCR compared with baseline. The urinary monocyte chemoattractant protein-1:creatinine ratio decreased numerically 30% by week 8, possibly reflecting the anti-inflammatory activity of avacopan. Avacopan was well tolerated. There was one serious adverse event of unstable angina, which was deemed to be unrelated to avacopan. Conclusions: This short-term pilot study showed an improvement in the slope of the UPCR, with ∼50% improvement in three of seven patients with IgAN. Longer avacopan treatment duration may be indicated for maximal benefit.
Language	English
Publishing date	2022-01-24
Publishing country	England
Document type	Journal Article
ZDB-ID	2655800-2
ISSN	2048-8513 ; 2048-8505
ISSN (online)	2048-8513
ISSN	2048-8505
DOI	10.1093/ckj/sfab294
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Article: 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.

Merkel, Peter A / Jayne, David R / Wang, Chao / Hillson, Jan / Bekker, Pirow

JMIR research protocols

2020 Volume 9, Issue 4, Page(s) e16664

Abstract: Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a serious, often life-threatening disease. In new-onset disease or a relapse, the standard treatment is immunosuppressive therapy with glucocorticoids; these therapies are ... ...

Abstract	Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a serious, often life-threatening disease. In new-onset disease or a relapse, the standard treatment is immunosuppressive therapy with glucocorticoids; these therapies are associated with substantial short- and long-term toxicity. Complement component 5a (C5a) binding to C5a receptor (C5aR) may play a central role in the pathogenesis of ANCA-associated vasculitis. Avacopan is a novel, orally bioavailable, and highly selective antagonist of human C5aR. Avacopan does not interfere with the production of C5b or the membrane attack complex (ie, terminal complement complex) and does not block C5a binding to a second receptor, C5L2 (also called C5aR2), shown to be protective in antimyeloperoxidase glomerulonephritis. This trial will evaluate if avacopan replaces the need for chronic glucocorticoids in the treatment of ANCA-associated vasculitis. Objective: The aim of this study is to determine the proportions of patients in remission at week 26 and with sustained remission at week 52, defined as Birmingham Vasculitis Activity Score=0, and not taking glucocorticoids within the 4 weeks before week 26 and week 52, respectively. Methods: The Avacopan Development in Vasculitis to Obtain Corticosteroid elimination and Therapeutic Efficacy study is a randomized, double-blind, active-comparator (prednisone), 2-arm study evaluating the safety and efficacy of avacopan versus prednisone, administered in combination with other immunosuppressive therapy. Eligible subjects will have active disease requiring induction of remission. Subjects are stratified based on the type of immunosuppressive therapy, ANCA subtype, and new or relapsing disease. Target sample size is 300 patients, enrolled at over 200 sites globally. All authors and local ethics committees approved the study design. All patients will provide informed consent. Results: Enrollment of patients was completed in Q4 2018. Topline results are anticipated to be published by Q3 2020. Conclusions: Results will be released irrespective of whether the findings are positive or negative. Trial registration: ClinicalTrials.gov NCT02994927; https://clinicaltrials.gov/ct2/show/NCT02994927. International registered report identifier (irrid): DERR1-10.2196/16664.
Language	English
Publishing date	2020-04-07
Publishing country	Canada
Document type	Journal Article
ZDB-ID	2719222-2
ISSN	1929-0748
ISSN	1929-0748
DOI	10.2196/16664
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