A Study to Evaluate the Safety and Efficacy of CCX168 in Subjects With ANCA-Associated Vasculitis

Overview

The aim of this trial is to optimize the treatment to induce remission for patients with non-life-threatening anti-neutrophil cytoplasmic antibody vasculitis (AAV). The intent is to reduce the toxicity of induction therapy by reducing the overall exposure to or eliminating entirely the use of systemic corticosteroids during the induction period with an inhibitor of the complement C5a receptor plus cyclophosphamide or rituximab.

Full Title of Study: “Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Evaluate the Safety and Efficacy of CCX168 in Subjects With Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis on Background of Cyclophosphamide or Rituximab Treatment”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Triple (Participant, Care Provider, Investigator)
  • Study Primary Completion Date: October 2015

Detailed Description

The primary safety objective of this study is to evaluate the safety and tolerability of CCX168 in subjects with AAV on background cyclophosphamide or rituximab treatment. The primary efficacy objective is to evaluate the efficacy of CCX168 based on the Birmingham Vasculitis Activity Score (BVAS) version 3. The secondary objectives of this study include assessment of the feasibility of reducing or eliminating the use of corticosteroids in the treatment of subjects with ANCA-associated vasculitis without the need for rescue corticosteroid measures and the effect of CCX168 on several disease parameters.

Interventions

  • Drug: Placebo
    • BID for 84 days
  • Drug: CCX168
    • BID for 84 days

Arms, Groups and Cohorts

  • Placebo Comparator: Placebo
    • Placebo plus a full dose of oral glucocorticoids for steps 1 and 2 of the study
  • Experimental: CCX168
    • 30 mg Active study medication, plus either two-thirds reduced dose of oral glucocorticoids for step 1 of the study, or no oral glucocorticoids for step 2 of the study

Clinical Trial Outcome Measures

Primary Measures

  • Proportion of Subjects Achieving Disease Response at Day 85
    • Time Frame: Baseline to Day 85
    • Disease response is defined as BVAS percentage reduction from baseline of at least 50% plus no worsening in any body system component.

Secondary Measures

  • Proportion of Patients Achieving Renal Response at Day 85
    • Time Frame: Baseline to Day 85
    • Renal response, assessed in patients with hematuria and albuminuria at baseline, and defined as an improvement in renal parameters, i.e., an increase from baseline to Day 85 in eGFR (Estimated glomerular filtration rate), MDRD (Modification of Diet in Renal Disease), serum creatinine equation, a decrease from baseline to Day 85 in haematuria (central laboratory microscopic count of urinary red blood cells) , decrease from baseline to Day 85 in albuminuria count (first morning UACR (urinary albumin:creatinine ratio).
  • Proportion of Subjects Achieving Disease Remission at Day 85
    • Time Frame: Day 85
    • Disease remission is defined as BVAS (Birmingham Vasculitis Activity Score) of 0 or 1 plus no worsening in eGFR (Estimated glomerular filtration rate) and urinary RBC (Red Blood cell) count <10/high power field (hpf)
  • Percent Change From Baseline to Day 85 in BVAS
    • Time Frame: Baseline to Day 85
    • Percent change in Burmingham Vasculitis Index Score (BVAS) at week 12, higher percentage change indicates worse outcome BVAS = Birmingham Vasculitis Activity Score The 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.
  • Change From Baseline to Day 85 in eGFR
    • Time Frame: Baseline to Day 85
    • eGFR (Estimated glomerular filtration rate) based on the MDRD (Modification of Diet in Renal Disease) formula using serum creatinine
  • Percent Change From Baseline to Day 85 in eGFR
    • Time Frame: Baseline to Day 85
    • eGFR (Estimated glomerular filtration rate) based on the MDRD (Modification of Diet in Renal Disease) formula using serum creatinine
  • Proportion of Subjects Achieving Urinary RBC Count <=5/Hpf at Any Time During the 84-day Treatment Period
    • Time Frame: Baseline to Day 85
    • In subjects with baseline hematuria >5 RBCs/hpf (Red Blood Cell/High Power Field)
  • Time to First Achieving Urinary RBC Count <=5/Hpf at Any Point During the 84-day Treatment Period
    • Time Frame: Baseline to Day 85
    • In subjects with baseline hematuria <=5 RBCs/hpf (Red Blood Cell/High Power Field)
  • Proportion of Subjects Achieving Urinary RBC Count <30/Hpf at Any Time During the 84-day Treatment Period
    • Time Frame: Baseline to Day 85
    • In subjects with baseline hematuria >=30 RBCs/hpf,(Red Blood Cell/High Power Field)
  • Time to First Achieving Urinary RBC Count <=30/Hpf at Any Point During the 84-day Treatment Period
    • Time Frame: Baseline to Day 85
    • In subjects with baseline hematuria <=30 RBCs/hpf (Red Blood Cell/High Power Field)
  • Percent Change From Baseline to Day 85 in Urinary RBC Count
    • Time Frame: Baseline to day 85
    • In subjects with hematuria at baseline, RBC (Red Blood Cell)
  • Percent Change From Baseline to Day 85 in UACR
    • Time Frame: Baseline to Day 85
    • In subjects with albuminuria at baseline UACR (urinary albumin:creatinine ratio)
  • Percent Change From Baseline to Day 85 in Urinary MCP-1:Creatinine Ratio
    • Time Frame: Baseline to Day 85
    • Urinary Monocyte Chemoattractant Protein-1 (MCP-1):creatinine ratio
  • Proportion of Subjects Requiring Rescue IV or Oral Glucocorticoid Treatment
    • Time Frame: Baseline to Day 85
  • Change From Baseline to Day 85 in the Vasculitis Damage Index
    • Time Frame: Baseline to Day 85
    • VDI=Vasculitis Damage Index; The 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).
  • Change From Baseline to Day 85 in Health-related Quality of Life as Measured by the SF-36 v2
    • Time Frame: Baseline, Day 29 & Day 85
    • 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).
  • Change From Baseline to Day 85 in Health-related Quality of Life as Measured by the EQ-5D-5L
    • Time Frame: Baseline, Day 29 and Day 85
    • 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).

Participating in This Clinical Trial

Key Inclusion Criteria:

  • Clinical diagnosis of granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis or renal limited vasculitis – Male and postmenopausal or surgically sterile female subjects aged at least 18 years with new or relapsed AAV where treatment with cyclophosphamide or rituximab would be 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 – Estimated glomerular filtration rate (eGFR) ≥ 20mL/min – Have at least one "major" item, or at least 3 non-major items, or at least 2 renal items on the BVAS version 3 Key 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 of 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 high-dose intravenous corticosteroids within 4 weeks of screening – On an oral dose of a corticosteroid of more than 10mg prednisone-equivalent at the time of screening – Received rituximab or other B-cell antibody within 52 weeks of screening or 26 weeks provided B cell reconstitution has occurred; received anti-TNF treatment, abatacept, alemtuzumab, IVIg or plasma exchange within 12 weeks of screening

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • ChemoCentryx
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Pirow Bekker, MD, PhD, Study Director, Clinical Trials Disclosure, ChemoCentryx Inc.

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