| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis |
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| E.1.1.1 | Medical condition in easily understood language |
| Vasculitis (a disorder that destroys blood vessels by inflammation) of a certain kind, called ANCA-associated vasculitis |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10072579 |
| E.1.2 | Term | Granulomatosis with polyangiitis |
| E.1.2 | System Organ Class | 10047065 - Vascular disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063344 |
| E.1.2 | Term | Microscopic polyangiitis |
| E.1.2 | System Organ Class | 10047065 - Vascular disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10050894 |
| E.1.2 | Term | Anti-neutrophil cytoplasmic antibody positive vasculitis |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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 |
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| E.2.2 | Secondary objectives of the trial |
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.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. |
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| E.4 | Principal 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 γ 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, cyclophophasmide, mycophenolate, or prednisone, or excipients, where applicable, as per the local prescribing information; for patients who will receive azathioprine, concomitant use with allopurinol is contraindicated;
20. For patients scheduled to receive cyclophosphamide treatment, urinary outflow obstruction, active infection (especially varicella zoster infection), or platelet count < 50,000/L before start of dosing
21. Participated in any clinical study of an investigational product within 30 days prior to screening or within 5 half-lives after taking the last dose;
22. Participated previously in a CCX168 study
23. History or presence of any medical condition or disease which, in the opinion of the Investigator, may place the patient at unacceptable risk for study participation |
|
| E.5 End points |
| E.5.1 | 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 as remission at Week 26 without relapse to Week 52 (BVAS of 0 and not taking glucocorticoids for the treatment of AAV within 4 weeks prior to Week 52).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Both endpoints will be assessed after 52 weeks of treatment |
|
| E.5.2 | 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 no glucocorticoids for treament of vasculitis for 4 weeks) in the study;
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:
1. Change and percent change from baseline in plasma biomarkers such as cystatin C, complement fragments, inflammatory chemokine and cytokine levels.
2. Change and percent change from baseline in urine biomarkers such as renal injury and inflammation markers (e.g., KIM-1 and NGAL), soluble CD163, complement fragments, inflammatory chemokine and cytokine levels;
3. Change from baseline in CBC count (especially WBCs, neutrophils, and lymphocytes) and lymphocyte subset counts including B cells, T cells, and natural killer cells;
4. Change from baseline in blood cell gene expressions such as neutrophil functional status markers.
The effect of polymorphism in genetic markers, as well as C5aR polymorphism may also be investigated.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| various, refer to information in E.5.2 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 106 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Belgium |
| Canada |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Netherlands |
| New Zealand |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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