Controlled Trial Evaluating Avacopan in C3 Glomerulopathy

Study Overview
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Brief Summary
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The aim of this trial is to evaluate the effect of avacopan treatment on renal disease activity in patients with complement component 3 glomerulopathy (C3G). Funding Source - FDA OOPD

Detailed Description
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C3 glomerulopathy (C3G) is characterized by evidence of alternative complement activation based on C3 deposition in the glomeruli. There are two forms of the disease: dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). There is no approved treatment for patients with C3G. This is a randomized, double blind, placebo controlled Phase 2 study to evaluate the safety and efficacy of avacopan (CCX168) in patients with C3G. Patients receive avacopan 30mg or matching placebo orally twice-daily. The placebo-controlled treatment period is 26 weeks (182 days). This will be followed by 26 weeks during which time all patients will receive avacopan (results for this second period will be reported in due course in a follow-up publication). Thereafter, all patients will be followed for eight weeks (56 days) without study drug treatment. The primary objective is to evaluate the efficacy of avacopan compared to placebo based on histologic changes in kidney biopsies taken at baseline and after 26 weeks of treatment. The primary endpoint will be based on the percent change from baseline in the C3G Histologic Index for disease activity.

Official Title
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A Randomized, Double Blind, Placebo Controlled Phase 2 Study to Evaluate the Safety and Efficacy of Avacopan (CCX168) in Patients With C3 Glomerulopathy

Conditions
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C3 Glomerulopathy (C3G)

Intervention / Treatment
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* Drug: Avacopan
* Drug: Avacopan Matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy-proven C3G, either DDD or C3GN, with or without a renal transplant, and with the following observations upon renal biopsy taken within 12 weeks prior to screening or during screening: ≥2-levels of magnitude greater staining of C3 than any combination of IgG, IgM, IgA, kappa and lambda light chains, and C1q by immunohistochemistry, and evidence of proliferative glomerulonephritis (mesangial hypercellularity of greater than 3 mesangial cells per mesangial area and/or endocapillary hypercellularity defined as an increased number of cells within glomerular capillary lumina, causing luminal narrowing) based on light microscopy, and confirmation of the presence of electron dense deposits in the glomeruli on electron microscopy corresponding with the C3 immunofluorescence positivity; Male or female subjects, aged at least 18 years; where approved, adolescents (12-17 year old) may be enrolled; female subjects of childbearing potential (i.e., those who have experienced menarche and who is not permanently sterile or postmenopausal, defined as at least 12 consecutive months with no menses without an alternative medical cause) may participate if adequate contraception is used during, and for at least the three months after study completion; Male subjects with partners of childbearing potential may participate in the study if they had a vasectomy at least 6 months prior to randomization or if adequate contraception is used during, and for at least the 3 months after study completion; Adequate contraception is defined as resulting in a failure rate of less than 1% per year (combined estrogen and progestogen [oral, intravaginal, or transdermal], or progestogen-only hormonal contraception (oral, injectable, or implantable), intra-uterine device, intra-uterine hormone releasing system, bilateral tubal occlusion, vasectomized partner, or true sexual abstinence, i.e., in line with the preferred and usual lifestyle of the subject); Willing and able to give written Informed Consent and to comply with the requirements of the study protocol; written Assent and Informed Consent must be obtained from the legal guardian in accordance with regional laws or regulations for subjects 12 to 17 years of age; and Judged to be otherwise fit for the study by the Investigator, based on medical history, physical examination, and clinical laboratory assessments. Subjects 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 be of clinical significance, may be entered into the study. Exclusion Criteria: Pregnant or nursing; Tubulointerstitial fibrosis appears to be more than 50% based on standard assessment using trichrome staining of the renal biopsy; Use of eculizumab or another anti-C5 antibody within 26 weeks prior to dosing; Secondary C3 disease, e.g., infection-associated disease, or associated with another systemic or autoimmune disease; presence of a monoclonal spike on serum or urine protein electrophoresis or immunofixation assay; Currently on dialysis or likely will require dialysis within 7 days after screening; 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; Positive hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) viral screening test indicative of acute or chronic infection; Evidence of tuberculosis based on interferon γ release assay (IGRA), tuberculin purified protein derivative (PPD) skin test, or chest radiography done at screening or within 6 weeks prior to screening; WBC count less than 3500/μL, or neutrophil count less than 1500/μL, or lymphocyte count less than 500/μL before start of dosing; Evidence of hepatic disease; AST, ALT, alkaline phosphatase, or bilirubin >3 x the upper limit of normal before start of dosing; Currently using a strong inducer of the CYP3A4 enzyme, such as carbamazepine, phenobarbital, phenytoin, rifampin, or St. John's wort; Known hypersensitivity to avacopan or inactive ingredients of the avacopan capsules (including gelatin, polyethylene glycol, or Cremophor) or inability to swallow the capsules; 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; and History or presence of any medical condition or disease which, in the opinion of the Investigator, may place the subject at unacceptable risk for study participation.

Ages Eligible for Study
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Minimum Age: 12 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
Interventional Model Description: Placebo crossover to active
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Avacopan<br>Avacopan (formerly CCX168) 10 mg capsules x 3 administered twice daily during the blinded 26 week blinded treatment period | Drug: Avacopan<br>* Orally administered<br>* Other names: CCX168;|
| Placebo Comparator: Avacopan Matching Placebo<br>Matching placebo capsules x 3 administered twice daily during the 26 week blinded treatment period period | Drug: Avacopan Matching Placebo<br>* avacopan matching placebo<br>* Other names: placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 26 in the C3G Histologic Index for Disease Activity - Subjects With Elevated C5b-9 | Change from baseline to Week 26 in the biopsy-based C3G Histologic Index for disease activity - Subjects with Elevated C5b-9 (> 244 ng/mL) in the Intent-to-Treat Population. C3G Histological Index for Disease Activity Scores can range from 0 to 21. A decrease indicates improvement. C3G=C3 glomerulopathy | Week 26 | 
| Percent Change From Baseline to Week 26 in the C3G Histologic Index for Disease Activity - Combined C5b-9 Strata | Percent change from baseline to Week 26 in the biopsy-based C3G Histologic Index for disease activity - Combined C5b-9 Strata (elevated [> 244 ng/mL] and non-elevated C5b-9) in the Intent-to-Treat Population. C3G Histological Index for Disease Activity Scores can range from 0 to 21. A decrease indicates improvement. C3G=C3 glomerulopathy * Multiple Imputation: Missing Week 26 values are imputed using the regression method to create 100 complete datasets. | Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects Who Have a Histologic Response Defined as a Decrease (Improvement) in the Biopsy-based C3G Histologic Index for Activity of at Least 35% From Baseline to 26 Weeks - Subjects With Elevated C5b-9 | Proportion of subjects who have a histologic response defined as a decrease (improvement) in the biopsy-based C3G Histologic Index for activity of at least 35% from baseline to 26 weeks - Subjects with Elevated C5b-9 (> 244 ng/mL) in the Intent-to-Treat Population. C3G Histological Index for Disease Activity Scores can range from 0 to 21. A decrease indicates improvement. C3G=C3 glomerulopathy | Week 26 | 
| Proportion of Subjects Who Have a Histologic Response Defined as a Decrease (Improvement) in the Biopsy-based C3G Histologic Index for Activity of at Least 35% From Baseline to 26 Weeks - Combined C5b-9 Strata | Proportion of subjects who have a histologic response defined as a decrease (improvement) in the biopsy-based C3G Histologic Index for activity of at least 35% from baseline to 26 weeks - Combined C5b-9 Strata (elevated [> 244 ng/mL] and non-elevated C5b-9) in the Intent-to-Treat Population. C3G Histological Index for Disease Activity Scores can range from 0 to 21. A decrease indicates improvement. C3G=C3 glomerulopathy | Week 26 | 
| Change From Baseline to Week 26 in the C3G Histologic Index for Disease Chronicity - Subjects With Elevated C5b-9 | Change from baseline to Week 26 in the biopsy-based C3G Histologic Index for disease chronicity over the placebo-controlled treatment period - Subjects with Elevated C5b-9 (> 244 ng/mL) in the Intent-to-Treat Population. C3G Histological Index for Disease Chronicity Scores can range from 0 to 10. A decrease indicates improvement. C3G=C3 glomerulopathy | Week 26 | 
| Change From Baseline to Week 26 in the C3G Histologic Index for Disease Chronicity - Combined C5b-9 Strata | Change from baseline to Week 26 in the biopsy-based C3G Histologic Index for disease chronicity over the placebo-controlled treatment period - Combined C5b-9 Strata (elevated [> 244 ng/mL] and non-elevated C5b-9) in the Intent-to-Treat Population. C3G Histological Index for Disease Chronicity Scores can range from 0 to 10. A decrease indicates improvement. C3G=C3 glomerulopathy | Week 26 | 
| Renal Function as Assessed by Percent Change From Baseline Over 26 Weeks in eGFR - Subjects With Elevated C5b-9 | The percent change from baseline over 26 weeks in estimated Glomerular Filtration Rate (eGFR) - Subjects with Elevated C5b-9 (> 244 ng/mL) in the Intent-to-Treat Population. | Week 26 | 
| Renal Function as Assessed by Percent Change From Baseline Over 26 Weeks in eGFR - Combined C5b-9 Strata | The percent change from baseline over 26 weeks in estimated Glomerular Filtration Rate (eGFR) - Combined C5b-9 Strata (elevated [> 244 ng/mL] and non-elevated C5b-9) in the Intent-to-Treat Population. | Week 26 | 
| Renal Function as Assessed by Change From Baseline Over 26 Weeks in eGFR - Subjects With Elevated C5b-9 | The change from baseline over 26 weeks in estimated Glomerular Filtration Rate (eGFR) - Subjects with Elevated C5b-9 (> 244 ng/mL) in the Intent-to-Treat Population. | Week 26 | 
| Renal Function as Assessed by Change From Baseline Over 26 Weeks in eGFR - Combined C5b-9 Strata | The change from baseline over 26 weeks in estimated Glomerular Filtration Rate (eGFR) - Combined C5b-9 Strata (elevated [> 244 ng/mL] and non-elevated C5b-9) in the Intent-to-Treat Population. | Week 26 | 
| Percent Change From Baseline Over 26 Weeks in UPCR in Patients With Abnormal UPCR at Baseline - Subjects With Elevated C5b-9 | Percent change from baseline Over 26 Weeks in UPCR in patients with Abnormal UPCR at Baseline (>= 0.15 g/g) - Subjects with Elevated C5b-9 (> 244 ng/mL) in the Intent-to-Treat Population. LSM=Least Squares Mean; UPCR = Urine Protein : Creatinine Ratio | Week 26 | 
| Percent Change From Baseline Over 26 Weeks in UPCR in Patients With Abnormal UPCR at Baseline - Combined C5b-9 Strata | Percent change from baseline Over 26 Weeks in UPCR in patients with Abnormal UPCR at Baseline (>= 0.15 g/g) - Combined C5b-9 Strata (elevated [> 244 ng/mL] and non-elevated C5b-9) in the Intent-to-Treat Population. LSM=Least Squares Mean; UPCR = Urine Protein : Creatinine Ratio | Week 26 | 
| Percent Change From Baseline Over 26 Weeks in Urinary MCP-1 - Subjects With Elevated C5b-9 | Percent change from baseline over 26 weeks in urinary MCP-1: creatinine ratio - Subjects with Elevated C5b-9 (> 244 ng/mL) in the Intent-to-Treat Population. LSM=Least Squares Mean; MCP-1=Monocyte Chemoattractant Protein-1 | Week 26 | 
| Percent Change From Baseline Over 26 Weeks in Urinary MCP-1 - Combined C5b-9 Strata | Percent change from baseline over 26 weeks in urinary MCP-1: creatinine ratio - Combined C5b-9 Strata (elevated [> 244 ng/mL] and non-elevated C5b-9) in the Intent-to-Treat Population. LSM=Least Squares Mean; MCP-1=Monocyte Chemoattractant Protein-1 | Week 26 | 
| Change From Baseline Over 26 Weeks in EQ-5D-5L Health Scale VAS and Index Score - Subjects With Elevated C5b-9 | Change from baseline over 26 weeks in EQ-5D-5L Health Scale VAS and Index Score - Subjects with Elevated C5b-9 (> 244 ng/mL) in the Intent-to-Treat Population. 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). | Week 26 | 
| Change From Baseline Over 26 Weeks in EQ-5D-5L Health Scale VAS and Index Score - Combined C5b-9 Strata | Change from baseline over 26 weeks in EQ-5D-5L Health Scale VAS and Index Score - Combined C5b-9 Strata (elevated [> 244 ng/mL] and non-elevated C5b-9) in the Intent-to-Treat Population. 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). | Week 26 | 
| Change From Baseline Over 26 Weeks in SF-36 v2 - Subjects With Elevated C5b-9 | Change from baseline over 26 weeks in SF-36 v2 - Subjects with Elevated C5b-9 (> 244 ng/mL) in the Intent-to-Treat Population. 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). | Week 26 | 
| Change From Baseline Over 26 Weeks in SF-36 v2 - Combined C5b-9 Strata | Change from baseline over 26 weeks in SF-36 v2 - Combined C5b-9 Strata (elevated [> 244 ng/mL] and non-elevated C5b-9) in the Intent-to-Treat Population. 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). | Week 26 | 
| Number of Subjects With Treatment-emergent SAEs, AEs, Relatedness to Study Medication and Withdrawals Due to AEs | Number of Subjects with Treatment-emergent SAEs, AEs, relatedness to study medication and Withdrawals Due to AEs AEs=Adverse events SAEs=Serious adverse events TEAE=Treatment-emergent adverse events 'Possibly related' refers to the Investigators' causality assessment | From day 1 throughout the study period (day 182/week 26) | 
| Number of Treatment-emergent SAEs, AEs, Relatedness to Study Medication and Withdrawals Due to AEs | Number of Treatment-emergent SAEs, AEs, relatedness to study medication and Withdrawals Due to AEs AEs=Adverse events SAEs=Serious adverse events TEAE=Treatment-emergent adverse events 'Possibly related' refers to the Investigators' causality assessment | From day 1 throughout the study period (day 182/week 26) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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C3 Glomerulonephritis, C3 glomerulopathy, C3G, DDD, dense deposit disease, membranoproliferative glomerulonephritis, MPGN, C3GN, idiopathic MPGN