scholarly journals 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

10.2196/16664 ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. e16664 ◽  
Author(s):  
Peter A Merkel ◽  
David R Jayne ◽  
Chao Wang ◽  
Jan Hillson ◽  
Pirow Bekker
Keyword(s):  
Immunosuppressive Therapy ◽  
Membrane Attack Complex ◽  
Ethics Committees ◽  
Antineutrophil Cytoplasmic Antibody ◽  
Sustained Remission ◽  
Double Blind ◽  
C5a Receptor ◽  
Safety And Efficacy ◽  
Anca Associated Vasculitis ◽  
Orally Bioavailable

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

scholarly journals 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 (Preprint)

2019 ◽  
Author(s):  
Peter A Merkel ◽  
David R Jayne ◽  
Chao Wang ◽  
Jan Hillson ◽  
Pirow Bekker
Keyword(s):  
Immunosuppressive Therapy ◽  
Membrane Attack Complex ◽  
Ethics Committees ◽  
Antineutrophil Cytoplasmic Antibody ◽  
Sustained Remission ◽  
Double Blind ◽  
C5a Receptor ◽  
Safety And Efficacy ◽  
Anca Associated Vasculitis ◽  
Orally Bioavailable

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. CLINICALTRIAL ClinicalTrials.gov NCT02994927; https://clinicaltrials.gov/ct2/show/NCT02994927 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/16664

scholarly journals Pituitary dysfunction in patients with ANCA associated vasculitis: prevalence, presentation, and outcomes

2020 ◽  
Vol 11 ◽  
pp. 204062232093063
Author(s):  
Chunjia Li ◽  
Yu Zou ◽  
Xin Lu ◽  
Guochun Wang ◽  
Xiaoming Shu
Keyword(s):  
Immunosuppressive Therapy ◽  
Clinical Symptoms ◽  
Clinical Manifestations ◽  
Antineutrophil Cytoplasmic Antibody ◽  
Magnetic Resonance Images ◽  
Initial Symptom ◽  
Pituitary Fossa ◽  
Pituitary Dysfunction ◽  
Anca Associated Vasculitis ◽  
Positron Emission

Background: The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are rare multisystem autoimmune diseases characterized by inflammatory cell infiltration causing necrosis of small blood vessels. Pituitary involvement in AAV is poorly described. This study aimed to describe the prevalence, clinical characteristics, and outcomes of pituitary involvement in patients with AAV. Methods: A total of 150 patients diagnosed with AAV and hospitalized in the China–Japan Friendship Hospital between 2009 and 2019 were enrolled in this retrospective study. Patients diagnosed with pituitary involvement in AAV were selected for inclusion. Results: Three patients (2%) were identified with pituitary involvement. Two patients had positive ANCA titers, one with proteinase 3 positive and one with myeloperoxidase positive antibodies. Pituitary dysfunction presented as an initial symptom in one patient and developed over the course of the diseases in the other two patients. All three patients had abnormal hormones. Among them, two patients had an enlarged pituitary, shown by magnetic resonance images (MRIs), and one patient had a normal sized pituitary, shown by MRI, but presented with increased linear radioactivity uptake in the pituitary fossa by positron emission tomography-computed tomography. All patients were treated with corticosteroid and immunosuppressive therapy. Both pituitary dysfunction and vasculitis were in remission. Conclusion: Pituitary involvement is uncommon in AAV and it can occur at any point during AAV. The main clinical manifestations are central diabetes insipidus and panhypopituitarism. Immunosuppressive therapy could significantly alleviate clinical symptoms as well as pituitary imaging.

scholarly journals LB003A RANDOMIZED, DOUBLE-BLIND, ACTIVE CONTROLLED STUDY OF AVACOPAN IN ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY-ASSOCIATED VASCULITIS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
David Jayne ◽  
Peter Merkel ◽  
Huibin Yue ◽  
Thomas J Schall ◽  
Catherine Kelleher ◽  
...  
Keyword(s):  
Renal Disease ◽  
Cell Activation ◽  
Group Analysis ◽  
Controlled Study ◽  
Sustained Remission ◽  
Double Blind ◽  
C5a Receptor ◽  
Disease Remission ◽  
Severe Renal Disease ◽  
G Protein Coupled

Abstract Background and Aims Complement fragment C5a is strongly linked to the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The C5a receptor (C5aR), is a G protein-coupled receptor present on neutrophils. Avacopan (previously CCX168) is an orally-administered selective antagonist of C5aR which blocks C5a-induced cell activation. Two previous Phase 2 clinical trials provided evidence of effectiveness of avacopan in AAV. This Phase 3 study evaluated the efficacy and safety of avacopan for the treatment of AAV as well as the potential of avacopan to eliminate extensive use of glucocorticoids (GC) and GC-related toxicities. Method Eligible subjects were randomized 1:1 to receive either prednisone or avacopan in combination with either a) cyclophosphamide (oral or IV) followed by azathioprine or b) rituximab (four IV infusions). Randomization was stratified by the treatment regimen (rituximab, IV cyclophosphamide, or oral cyclophosphamide), ANCA serotype, and newly-diagnosed or relapsing disease. Treatment period was 52 weeks; primary efficacy endpoints were the proportion of subjects achieving disease remission at Week 26, and sustained disease remission at Week 52. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of zero and not taking glucocorticoids for AAV within 4 weeks prior to Week 26. Sustained remission was defined as being in remission at Week 26 and sustained through Week 52 without relapse. Change in estimated glomerular filtration rate (eGFR) from baseline to week 52 was a pre-specified secondary endpoint. Results 330 subjects were randomized and dosed: 166 in the avacopan and 164 in the prednisone groups. At Week 26, 72.3% subjects achieved remission in the avacopan compared to 70.1% in the prednisone group (p<0.0001 for non-inferiority). At Week 52, 65.7% subjects achieved sustained remission in the avacopan compared to 54.9% in the prednisone group achieving both non-inferiority and superiority to prednisone group (p=0.0066 for superiority of avacopan). The avacopan arm had a significant reduction in glucocorticoid-related toxicity compared to the prednisone arm as measured by the Glucocorticoid Toxicity Index of Cumulative Worsening Score (p=0.0002) and Aggregate Improvement Score (p=0.0082). In subjects with renal disease at baseline, the avacopan group (n=134) showed a mean increase in eGFR of 7.3 mL/min/1.73 m2 from baseline to week 52 as compared to 4.1 mL/min/1.73 m2 increase in the prednisone group (n=132) (p=0.029). A pre-specified sub-group analysis showed a greater difference in the avacopan sub-group with a baseline eGFR <30 (13.7 mL/min/1.73 m2 vs. 8.2 mL/min/1.73 m2; p<.005). Conclusion Treatment with avacopan resulted in remission in patients with AAV receiving rituximab or cyclophosphamide/azathioprine at a rate that was non-inferior to the active comparator prednisone at Week 26 and superior to prednisone in sustained remission at Week 52. A significant reduction in glucocorticoid-related toxicity was observed in the avacopan vs. prednisone arms. The increase in eGFR seen with avacopan was marked among subjects with more severe renal disease. The safety profile of avacopan was acceptable for use in patients with AAV. The ADVOCATE trial demonstrated avacopan is an effective treatment for patients with AAV.

scholarly journals Propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitis and agranulocytosis in a patient with Graves’ disease

2020 ◽  
Vol 2020 ◽  
Author(s):  
Maria Tomkins ◽  
Roxana Maria Tudor ◽  
Diarmuid Smith ◽  
Amar Agha
Keyword(s):  
Adverse Effect ◽  
Immunosuppressive Therapy ◽  
Antithyroid Drug ◽  
Antineutrophil Cytoplasmic Antibody ◽  
Organ Damage ◽  
Graves Disease ◽  
List Type ◽  
Drug Induced ◽  
End Organ Damage ◽  
Anca Associated Vasculitis

Summary This case is the first to describe a patient who experienced concomitant agranulocytosis and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis as an adverse effect of propylthiouracil treatment for Graves’ disease. A 42-year-old female with Graves’ disease presented to the emergency department (ED) with a 2-week history of fevers, night sweats, transient lower limb rash, arthralgia, myalgia and fatigue. She had been taking propylthiouracil for 18 months prior to presentation. On admission, agranulocytosis was evident with a neutrophil count of 0.36 × 109/L and immediately propylthiouracil was stopped. There was no evidence of active infection and the patient was treated with broad-spectrum antibodies and one dose of granulocyte colony-stimulation factor, resulting in a satisfactory response. On further investigation, ANCAs were positive with dual positivity for proteinase 3 and myeloperoxidase. There was no evidence of end-organ damage secondary to vasculitis, and the patient’s constitutional symptoms resolved completely on discontinuation of the drug precluding the need for immunosuppressive therapy. Learning points: Continued vigilance and patient education regarding the risk of antithyroid drug-induced agranulocytosis is vital throughout the course of treatment. ANCA-associated vasculitis is a rare adverse effect of antithyroid drug use. Timely discontinuation of the offending drug is vital in reducing end-organ damage and the need for immunosuppressive therapy in drug-induced ANCA-associated vasculitis. Similarities in the pathogenesis of agranulocytosis and drug-induced ANCA-associated vasculitis may offer insight into an improved understanding of vasculitis and agranulocytosis.

scholarly journals OP0011 A RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROLLED STUDY OF AVACOPAN IN ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA)-ASSOCIATED VASCULITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 8.1-8
Author(s):  
P. A. Merkel ◽  
D. Jayne ◽  
H. Yue ◽  
T. Schall ◽  
C. Kelleher ◽  
...  
Keyword(s):  
Adverse Events ◽  
Renal Disease ◽  
Cell Activation ◽  
Controlled Study ◽  
Sustained Remission ◽  
Research Support ◽  
Serious Adverse Events ◽  
C5a Receptor ◽  
Disease Remission ◽  
Anca Associated Vasculitis

Background:Complement fragment C5a is strongly linked to the pathogenesis of Anti-Neutrophil Cytoplasmic Antibody (ANCA)-associated vasculitis (AAV). C5a receptor (C5aR), present on neutrophils, is a G protein-coupled receptor for C5a. Avacopan (previously CCX168) is an orally-administered selective antagonist of C5aR which blocks C5a-induced cell activation. Two previous Phase 2 clinical trials provided evidence of effectiveness of avacopan in AAV and its potential to eliminate extensive use of glucocorticoids (GC) and GC-related toxicities.Objectives:This Phase 3 study evaluated the efficacy and safety of avacopan for the treatment of AAV.Methods:Eligible subjects were randomized 1:1 to receive either prednisone or avacopan in combination with either a) cyclophosphamide (oral or IV) followed by azathioprine or b) rituximab (four IV infusions). Randomization was stratified by the treatment regimen (rituximab, IV cyclophosphamide, or oral cyclophosphamide), ANCA serotype, and newly-diagnosed or relapsing disease. Treatment period was 52 weeks; primary efficacy endpoints were the proportion of subjects achieving disease remission at Week 26, and sustained disease remission at Week 52. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of zero and not taking glucocorticoids for AAV within 4 weeks prior to Week 26. Sustained remission was defined as being in remission at Week 26 and also subsequently in remission as defined above at Week 52. Any relapse of AAV between Weeks 26 and 52 was considered not achieving sustained remission.Results:330 subjects were randomized and dosed: 166 in avacopan and 164 in prednisone arms. At Week 26, 72.3% subjects achieved remission in the avacopan arm compared to 70.1% in the prednisone arm (p<0.0001 for non-inferiority). At Week 52, 65.7% subjects achieved sustained remission in the avacopan arm compared to 54.9% in the prednisone arm achieving both non-inferiority and superiority to prednisone arm (p=0.0066 for superiority of avacopan).The avacopan arm had a significant reduction in glucocorticoid-related toxicity compared to the prednisone arm as measured by the Glucocorticoid Toxicity Index (GTI) of Cumulative Worsening Score (p=0.0002) and Aggregate Improvement Score (p=0.0082).In subjects with renal disease at baseline, the avacopan arm showed a mean increase in estimated glomerular filtration rate (eGFR) of 7.3 mL/min/1.73 m2 from baseline to week 52 as compared to 4.0 mL/min/1.73 m2 increase in the prednisone arm (p=0.0259).Overall subject incidence of serious adverse events (SAEs) was generally consistent with previous AAV trials at 45.1% and 42.2% for prednisone and avacopan groups, respectively. Serious infections were 15.2% and 13.3%, serious hepatic adverse events 3.7% vs 5.4%, and SAEs of white blood cell count decreases were 4.9% vs 2.4% for prednisone and avacopan, respectively. No meningococcal infections were reported.Conclusion:Avacopan treatment resulted in remission in AAV patients receiving rituximab or cyclophosphamide/azathioprine at a rate that was non-inferior to the active comparator prednisone at week 26 and superior to prednisone in sustained remission at Week 52. A significant reduction in glucocorticoid-related toxicity was observed in the avacopan vs. prednisone arms. Significant increase in eGFR in subjects with renal disease was also observed in avacopan vs. prednisone. The safety profile of avacopan appears acceptable for development in AAV. Avacopan treatment for AAV is efficacious and exhibits benefits not seen with chronic prednisone therapy.References:None.Disclosure of Interests:Peter A Merkel Grant/research support from: AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, Celgene, ChemoCentryx, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Kypha, TerumoBCT, Consultant of: Abbvie, AstraZeneca, Biogen, Boeringher-Ingelheim, Bristol-Myers Squibb, Celgene, ChemoCentryx, CSL Behring, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Insmed, Jannsen, Kiniksa, Pfizer, Sparrow, Talaris, David Jayne Grant/research support from: ChemoCentryx, GSK, Roche/Genentech, Sanofi-Genzyme, Consultant of: Astra-Zeneca, ChemoCentryx, GSK, InflaRx, Takeda, Insmed, Chugai, Boehringer-Ingelheim, Huibin Yue Shareholder of: ChemoCentryx, Employee of: ChemoCentryx, Thomas Schall Shareholder of: ChemoCentryx, Employee of: ChemoCentryx, Catherine Kelleher Shareholder of: Amgen, ChemoCentryx, Inc., Grant/research support from: Not active, Consultant of: Independent Consultant in the past, Employee of: ChemoCentryx, Inc., Pirow Bekker Shareholder of: Stock options ChemoCentryx, Consultant of: ChemoCentryx, Employee of: ChemoCentryx

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