Clinical Trial to Evaluate Safety and Efficacy of CCX168 in ANCA-Associated Vasculitis

Study Overview
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Brief Summary
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The aim of this trial is to test the safety and efficacy of two dose regimens of the complement C5a receptor CCX168 in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Funding Source - FDA OOPD

Detailed Description
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Complement 5a and its receptor C5aR (CD88) is involved in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. This is a randomized, double-blind, placebo-controlled Phase 2 study to evaluate the safety and efficacy of the C5aR inhibitor CCX168 in subjects with ANCA-associated vasculitis. The aim of this trial is to test the safety and efficacy of two dose regimens of the complement C5a receptor CCX168 in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Dose Assessment Phase 2 Study to Evaluate the Safety and Efficacy of CCX168 in Subjects With Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis

Conditions
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ANCA-associated Vasculitis

Intervention / Treatment
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* Drug: CCX168 10 mg, twice daily, plus cyclophosphamide/rituximab plus glucocorticoids
* Drug: CCX168 30 mg, twice daily, cyclophosphamide/rituximab plus glucocorticoids
* Other: Placebo, twice daily, plus cyclophosphamide/rituximab plus glucocorticoids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis or renal limited vasculitis Male and female subjects, aged at least 18 years, with new or relapsed AAV where treatment with cyclophosphamide or rituximab would be required Use of adequate contraception during, and for at least the three months after, any administration of study medication is required Positive indirect immunofluorescence (IIF) test for P-ANCA or C-ANCA, or positive ELISA test for anti-proteinase-3 (PR3) or anti-myeloperoxidase (MPO) at screening Have at least one major item, or at least 3 other items, or at least 2 renal items on the Birmingham Vasculitis Activity Score (BVAS) version 3 Estimated glomerular filtration rate (eGFR) ≥ 20 mL per minute Exclusion Criteria: Severe disease as determined by rapidly progressive glomerulonephritis, alveolar hemorrhage, hemoptysis, rapid-onset mononeuritis multiplex or central nervous system involvement Any other multi-system autoimmune disease Medical history of coagulopathy or bleeding disorder 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 corticosteroids, >3000 mg methylprednisolone equivalent, within 12 weeks prior to screening Received an oral daily dose of a corticosteroid of more than 10 mg prednisone-equivalent for more than 6 weeks continuously prior to the screening visit Received rituximab or other B-cell antibody within 52 weeks of screening or 26 weeks provided B cell reconstitution has occurred; received anti-tumor necrosis factor (TNF) treatment, abatacept, alemtuzumab, intravenous immunoglobulin (IVIg), belimumab, tocilizumab, or plasma exchange within 12 weeks prior to screening

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CCX168 low dose plus standard of care<br>Capsule, 10 mg, twice daily + standard of care for 12 weeks | Drug: CCX168 10 mg, twice daily, plus cyclophosphamide/rituximab plus glucocorticoids<br> <br> |
| Active Comparator: CCX168 high dose plus standard of care<br>Capsule, 30 mg, twice daily + standard of care for 12 weeks | Drug: CCX168 30 mg, twice daily, cyclophosphamide/rituximab plus glucocorticoids<br> <br> |
| Placebo Comparator: Placebo, twice daily + standard of care<br>Capsule, placebo, twice daily + standard of care for 12 weeks | Other: Placebo, twice daily, plus cyclophosphamide/rituximab plus glucocorticoids<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events | This is a safety study to assess the overall rates of treatment-emergent adverse events (TEAEs) across all study arms. | Baseline to Day 85 | 
| Proportion of Patients Achieving Disease Response Based on BVAS at Day 85 | Proportion of Patients achieving 50% reduction in the Birmingham Vasculitis Activity Score [BVAS] at Day 85 and no worsening in any body system component at day 85 | Day 85 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects Achieving Disease Remission Based on BVAS at Day 85. | Proportion of subjects achieving disease remission based on Birmingham Vasculitis Activity Score (BVAS) defined as 0 at Day 85. | Day 85 | 
| Proportion of Subjects Achieving Early Disease Remission Based on BVAS of 0 at Days 29 and 85. | Proportion of subjects achieving early disease remission based on Birmingham Vasculitis Activity Score (BVAS) score of 0 at Days 29 and 85. | Day 29 and 85 | 
| Percent Change From Baseline to Day 85 in BVAS. | The Birmingham Vasculitis Activity (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). A negative percentage change indicated improvement in health. | Baseline to Day 85 | 
| Proportion of Subjects With Hematuria and Albuminuria at Baseline Who Showed a Renal Response at Day 85 | Renal responses among patients (who had hematuria or albuminuria at baseline determined secondary to ANCA-associated vasculitis) were defined as improvement in the following parameters of renal vasculitis: (1) increase from baseline to day 85 in eGFR [Modification of Diet in Renal Disease (MDRD equation)], (2) decrease from baseline to day 85 in hematuria (microscopic count of urinary red blood cells [RBC]), and (3) decrease from baseline to day 85 in albuminuria (first morning urinary albumin:creatinine ratio). | Day 85 | 
| Change in Estimated Glomerular Filtration Rate at Day 85 | Mean Change in Estimated Glomerular Filtration Rate based on modification of diet in renal disease formula, for patients with renal disease at baseline. | Baseline to Day 85 | 
| Percentage Change in Estimated Glomerular Filtration Rate at Day 85 | Mean Percentage Change in Estimated Glomerular Filtration Rate based on modification of diet in renal disease formula. | Baseline to Day 85 | 
| Percent Change of Urinary Red Blood Cells in Patient With Hematuria From Baseline to Day 85 | Mean Percent Change of Urinary Red Blood Cells (UBC) in Patients in Hematuria at Baseline. | Baseline to Day 85 | 
| Percent Change of Urinary Albumin:Creatinine Ratio in Patients With Albuminuria From Baseline to Day 85 | Mean Percent Change of Urinary Albumin:Creatinine Ratio in Patients with Albuminuria at Baseline | Baseline to Day 85 | 
| Percent Change of Urinary MCP-1:Creatinine Ratio From Baseline to Day 85 | Mean Percent Change of Urinary monocyte chemoattractant protein (MCP-1:creatinine) ratio from Baseline | Baseline to Day 85 | 
| Change From Baseline to Day 85 in the VDI | The Vasculitis Damage Index (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) | Baseline to Day 85 | 
| Change From Baseline to Day 85 in Health-Related Quality-Of-Life as Measured by the SF-36v2 | Change from Baseline to Day 85 in Health-Related Quality-Of-Life as Measured by the Short Form-36 (SF-36v2) SF-36v2: Medical Outcomes Survey Short Form-36 version 2. SF-36v2 measures each of the following eight health domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Scores on each item are summed and averaged. The SF-36v2 component domain scores range from 0 (worst health) to 100 (best health). | Baseline to Day 85 | 
| Mean Change From Baseline to Day 85 in Health-related Quality-of-life as Measured by the EQ-5D-5L | Mean Change from baseline to Day 85 in health-related quality-of-life as measured by the Euro Quality-of-Life-5 Domains-5 Levels (EQ-5D-5L). EQ-5D-5L: EuroQuality of Life-5 Domains-5 Levels. The EQ-5D-5L consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The answers given can be converted into an Index Score ranging from 0 for death to 1 for perfect health. The EQ-5D questionnaire also includes a Visual Analog Scale (VAS), by which respondents can report their perceived health status with a grade ranging from 0 (the worst imaginable health) to 100 (the best imaginable health). | Baseline to Day 85 | 
| Proportion of Subjects Requiring Rescue Glucocorticoid Treatment From Baseline to Day 85 | Proportion of subjects requiring rescue glucocorticoid treatment from Baseline to Day 85 | Baseline to Day 85 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ANCA-associated vasculitis, complement, vasculitis, C5aR