Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis MedDRA version: 20.0 Level: PT Classification code 10072579 Term: Granulomatosis with polyangiitis System Organ Class: 10047065 - Vascular disorders MedDRA version: 20.0 Level: PT Classification code 10063344 Term: Microscopic polyangiitis System Organ Class: 10047065 - Vascular disorders MedDRA version: 20.1 Level: PT Classification code 10050894 Term: Anti-neutrophil cytoplasmic antibody positive vasculitis System Organ Class
Conditions
Sponsors
ChemoCentryx, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Clinical diagnosis of granulomatosis with polyangiitis (Wegener's) or microscopic polyangiitis, consistent with Chapel-Hill Consensus Conference definitions 2. Aged at least 18 years, with newly-diagnosed or relapsed AAV where treatment with cyclophosphamide or rituximab is needed; where approved, adolescents (12-17 year old) may be enrolled 3. Positive test for anti-PR3 or anti-MPO (current or historic) antibodies 4. At least one major item, or at least 3 minor items, or at least the 2 renal items of proteinuria and hematuria in the BVAS 5. Estimated glomerular filtration rate =15 mL/minute/1.73 m2 (using the MDRD method for adults and modified Schwartz equation for adolescents) at screening 6. Willing and able to give written Informed Consent and to comply with the requirements of the study protocol; written Informed Consent should be obtained from the legal guardian in accordance with regional laws or regulations for patients 12 to 17 years of age 7. Judged by the Investigator to be fit for the study, based on medical history, physical examination (including electrocardiogram [ECG]), and clinical laboratory assessments. Main OLE phase inclusion criteria: 1. Clinical diagnosis of granulomatosis with polyangiitis (GPA; Wegener's) or microscopic polyangiitis (MPA), consistent with ChapelHill Consensus Conference definitions; 2. Willing and able to give written Informed Consent and to comply with the requirements of the study protocol. For patients 12 to 17 years of age, written assent should be obtained and written Informed Consent must be obtained from the legal guardian in accordance with regional laws or regulations; and 3. Judged by the Investigator to be fit for the open-label extension phase of the study, based on medical history, physical examination (including ECG), and clinical laboratory assessments. Patients with clinical laboratory values that are outside of normal limits (other than those specified in the Exclusion Criteria) and/or with other abnormal clinical findings that are judged by the Investigator not to compromise patient participation in the study, may be entered into the study. Are the trial subjects under 18? yes Number of subjects for this age range: 10 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 240 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 50
Exclusion criteria
Exclusion criteria: 1. Pregnant or breast-feeding 2. Alveolar hemorrhage requiring invasive pulmonary ventilation support anticipated to last beyond the screening period of the study 3. Any other known multi-system autoimmune disease including eosinophilic granulomatosis with polyangiitis (Churg-Strauss), systemic lupus erythematosus, IgA vasculitis (Henoch-Schönlein), rheumatoid vasculitis, Sjögren's syndrome, anti-glomerular basement membrane disease, or cryoglobulinemic vasculitis 4. Required dialysis or plasma exchange within 12 weeks prior to screening 5. Have had a kidney transplant 6. 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 7. Received intravenous glucocorticoids, >3000 mg methylprednisolone equivalent, within 4 weeks prior to screening 8. 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 the screening visit 9. 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 > 0.01x109/L); received anti-TNF treatment, abatacept, alemtuzumab, IVIg, belimumab, tocilizumab, or eculizumab within 12 weeks prior to screening 10. Currently taking a strong inducer of the cytochrome P450 3A4 (CYP3A4) enzyme, such as carbamazepine, phenobarbital, phenytoin, rifampin, or St. John’s wort 11. Any of the following within 12 weeks prior to screening: symptomatic congestive heart failure requiring prescription medication, unstable angina (unless successfully treated with stent or bypass surgery), clinically significant cardiac arrhythmia, myocardial infarction or stroke 12. History or presence of any form of cancer within the 5 years prior to screening, with the exception of excised basal cell or squamous cell carcinoma of the skin, or carcinoma in situ such as cervical or breast carcinoma in situ that has been excised or resected completely and is without evidence of local recurrence or metastasis 13. Evidence of tuberculosis based on interferon ? release assay (IGRA), tuberculin purified protein derivative (PPD) skin test, or chest radiography (X rays or CT scan) done at screening or within 6 weeks prior to screening 14. HBV, HCV, or HIV viral screening test showing evidence of active or chronic prior viral infection done at screening or within 6 weeks prior to screening 15. Received a live vaccine within 4 weeks prior to screening 16. WBC count less than 3500/µL, or neutrophil count less than 1500/µL, or lymphocyte count less than 500/µL before start of dosing 17. Evidence of hepatic disease: AST, ALT, alkaline phosphatase, or bilirubin > 3 times the upper limit of normal before start of dosing 18. Clinically significant abnormal ECG during screening, e.g., QTcF greater than 450 msec 19. Known hypersensitivity to CCX168 or inactive ingredients of the CCX168 capsules (including gelatin, polyethylene glycol, or Cremophor), cyclophosphamide or its metabolites (for patients scheduled to receive cyclophosphamide), or known Type I hypersensitivity or anaphylactic reactions to murine proteins, Chinese Hamster Ovary cell proteins, or to any component of rituximab (for patients scheduled to receive rituximab), or any contraindications or hypersensitivity to the use of azathioprine,
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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 The primary objective of the open-label extension (OLE) phase of the study is to evaluate the long-term safety of CCX168 in patients with AAV who have completed 52 weeks of treatment with CCX168 (avacopan) or placebo in the double-blind phase. Safety will be assessed based on the incidence of adverse events and changes in vital signs, physical examinations, clinical laboratory tests, and ECGs. ;Secondary Objective: 1. Evaluation of the glucocorticoid-induced toxicity compared between test and control group 2. Evaluation of rapidity of response compared between test and control group 3. Evaluation of the safety compared between test and control group 4. Assessment of health-related quality-of-life changes compared between test and control group 5. Assessment of changes in parameters of renal disease compared between test and control group 6. Assessment of changes in cumulative organ damage compared between test and control group 7. Assessment of changes in markers of pharmacodynamics in plasma and urine compared between test and control group 8. Evaluation of the pharmacokinetic profile of CCX168 in patients with AAV. OLE exploratory efficacy objectives: 1. durability of the effectiveness of continued CCX168. 3. changes in cumulative organ damage during the OLE 4. health-related quality-of-life changes during the OLE 5. changes in parameters of renal disease during the OLE.;Primary end point(s): 1. The proportion of patients achieving disease remission at Week 26, defined as a BVAS of 0 and not taking glucocorticoids for the treatment of AAV within 4 weeks prior to Week 26. 2. The proportion of patients achieving sustained disease remission, defined | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary efficacy endpoints include: 1. Glucocorticoid-induced toxicity as measured by change from baseline over the first 26 weeks in the glucocorticoid toxicity index; 2. Early remission, defined as BVAS of 0 at Week 4; 3. Change from baseline over 52 weeks in health-related quality-of-life as measured by the domains and component scores of the SF-36 v2 and EQ-5D-5L VAS and index; 4. Proportion of patients and time to experiencing a relapse after previously achieving remission in the study; relapse is 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 having received glucocorticoids for treatment of vasculitis for 4 weeks) 5. In patients with renal disease at baseline (based in the BVAS renal component), the change in eGFR from baseline over 52 weeks; 6. In patients with renal disease at baseline (based in the BVAS renal component), the percent change in UACR from baseline over 52 weeks; 7. In patients 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; 8. Change in the VDI from baseline over 52 weeks. Safety endpoints, other than glucocorticoid-induced toxicity listed under the efficacy endpoints, include: 1. Patient incidence of treatment-emergent serious adverse events, adverse events, and withdrawals due to adverse events; 2. Change from baseline and shifts from baseline in all safety laboratory parameters; 3. Change from baseline in vital signs, and 4. Incidence of clinically significant ECG changes from baseline. PK endpoint: CCX168 (and metabolite) plasma concentration results will be used to calculate trough plasma concentrations (Cmin) over the course of the clinical trial. PD endpoints: The following PD endpoints may be assessed: | — |
Countries
Australia, Austria, Belgium, Canada, Czech Republic, Denmark, France, Germany, Hungary, Ireland, Italy, Netherlands, New Zealand, Norway, Spain, Sweden, Switzerland, United Kingdom, United States
Contacts
Public ContactAntonia Potarca
ChemoCentryx, Inc.
Outcome results
None listed