Clinical Trial Results:
A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate the Safety and Efficacy of Avacopan (CCX168) in Patients with C3 Glomerulopathy
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Summary
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EudraCT number |
2017-001821-42 |
Trial protocol |
GB BE DE NL ES DK FR IT IE |
Global end of trial date |
27 Oct 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Jul 2023
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First version publication date |
15 Jul 2023
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CL011_168
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
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Other trial identifiers |
IND Number: 132 321 | ||
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Sponsors
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Sponsor organisation name |
ChemoCentryx, Inc.
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Sponsor organisation address |
850 Maude Avenue, Mountain View, California, United States, 94043
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Public contact |
Clinical trial disclosure, ChemoCentryx, Inc., +1 650 210 2900, clinicaltrials@chemocentryx.com
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Scientific contact |
Clinical trial disclosure, ChemoCentryx, Inc., +1 650 210 2900, clinicaltrials@chemocentryx.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
14 Dec 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
03 Mar 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
27 Oct 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective is to evaluate the efficacy of avacopan compared to placebo based on histologic changes in kidney biopsies taken before and during treatment.
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Protection of trial subjects |
The study was conducted in accordance with the Declaration of Helsinki and with all applicable laws and regulations of the locale and country where the study was conducted, and in compliance with Good Clinical Practice Guidelines. Only subjects that met all the study inclusion and none of the exclusion criteria were entered in the study. The rationale of the study, procedural details, and investigational goals were explained to each subject, along with potential risks and benefits. Each subject was assured of his/her right to withdraw from the study at any time.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
29 Sep 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 6
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Country: Number of subjects enrolled |
Spain: 6
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Country: Number of subjects enrolled |
United Kingdom: 4
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Country: Number of subjects enrolled |
Belgium: 3
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Country: Number of subjects enrolled |
Denmark: 2
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Country: Number of subjects enrolled |
Germany: 3
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Country: Number of subjects enrolled |
Ireland: 6
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Country: Number of subjects enrolled |
Italy: 1
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Country: Number of subjects enrolled |
Canada: 5
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Country: Number of subjects enrolled |
United States: 21
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Worldwide total number of subjects |
57
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EEA total number of subjects |
27
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
2
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Adults (18-64 years) |
51
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From 65 to 84 years |
4
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 104 subjects screened. | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Blinded treatment period (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | ||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo Group | ||||||||||||||||||||||||||||||
Arm description |
Avacopan matching placebo Subjects with Elevated C5b-9 (> 244 ng/mL) and combined C5b-9 (elevated [> 244 ng/mL] and non-elevated C5b-9) in the ITT Population. ITT Population: included all randomized subjects who received at least one dose of study medication; subjects with a histologic activity score of 0 at baseline or who were ongoing and had not completed the Week 26 visit were not included in the ITT population. | ||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Avacopan Matching Placebo
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Investigational medicinal product code |
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Other name |
Placebo
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Matching placebo capsules x 3 administered twice daily during the 26-week blinded treatment period
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Arm title
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Avacopan Group | ||||||||||||||||||||||||||||||
Arm description |
Avacopan (formerly CCX168) Subjects with Elevated C5b-9 (> 244 ng/mL) and combined C5b-9 (elevated [> 244 ng/mL] and non-elevated C5b-9) in the ITT Population. ITT Population: included all randomized subjects who received at least one dose of study medication; subjects with a histologic activity score of 0 at baseline or who were ongoing and had not completed the Week 26 visit were not included in the ITT population | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Avacopan
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Investigational medicinal product code |
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Other name |
CCX168
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Avacopan (formerly CCX168) 10 mg capsules x 3 administered twice daily during the blinded 26-week blinded treatment period
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Baseline characteristics reporting groups
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Reporting group title |
Placebo Group
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Reporting group description |
Avacopan matching placebo Subjects with Elevated C5b-9 (> 244 ng/mL) and combined C5b-9 (elevated [> 244 ng/mL] and non-elevated C5b-9) in the ITT Population. ITT Population: included all randomized subjects who received at least one dose of study medication; subjects with a histologic activity score of 0 at baseline or who were ongoing and had not completed the Week 26 visit were not included in the ITT population. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Avacopan Group
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Reporting group description |
Avacopan (formerly CCX168) Subjects with Elevated C5b-9 (> 244 ng/mL) and combined C5b-9 (elevated [> 244 ng/mL] and non-elevated C5b-9) in the ITT Population. ITT Population: included all randomized subjects who received at least one dose of study medication; subjects with a histologic activity score of 0 at baseline or who were ongoing and had not completed the Week 26 visit were not included in the ITT population | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo Group
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Reporting group description |
Avacopan matching placebo Subjects with Elevated C5b-9 (> 244 ng/mL) and combined C5b-9 (elevated [> 244 ng/mL] and non-elevated C5b-9) in the ITT Population. ITT Population: included all randomized subjects who received at least one dose of study medication; subjects with a histologic activity score of 0 at baseline or who were ongoing and had not completed the Week 26 visit were not included in the ITT population. | ||
Reporting group title |
Avacopan Group
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Reporting group description |
Avacopan (formerly CCX168) Subjects with Elevated C5b-9 (> 244 ng/mL) and combined C5b-9 (elevated [> 244 ng/mL] and non-elevated C5b-9) in the ITT Population. ITT Population: included all randomized subjects who received at least one dose of study medication; subjects with a histologic activity score of 0 at baseline or who were ongoing and had not completed the Week 26 visit were not included in the ITT population | ||
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End point title |
Change From Baseline to Week 26 in the C3G Histologic Index for Disease Activity - Subjects With Elevated C5b-9 | ||||||||||||
End point description |
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
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End point type |
Primary
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End point timeframe |
Week 26
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Statistical Analysis 1 for Change From Baseline to Week 26 in the C3G Histologic Index for Disease Activity - Subjects With Elevated C5b-9
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Comparison groups |
Placebo Group v Avacopan Group
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Number of subjects included in analysis |
40
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.967 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.9 | ||||||||||||
upper limit |
1.8 | ||||||||||||
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End point title |
Percent Change From Baseline to Week 26 in the C3G Histologic Index for Disease Activity - Combined C5b-9 Strata | ||||||||||||
End point description |
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.
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End point type |
Primary
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End point timeframe |
Week 26
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Statistical Analysis 1 for Percent Change From Baseline to Week 26 in the C3G Histologic Index for Disease Activity -Combined C5b-9 Strata
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Comparison groups |
Avacopan Group v Placebo Group
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Number of subjects included in analysis |
52
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.3083 [1] | ||||||||||||
Method |
Van Elteren's Test | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.02
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-108.83 | ||||||||||||
upper limit |
67.16 | ||||||||||||
| Notes [1] - Test for normality showed that mean change and mean percent change were not normally distributed. Van Elteren's test was then applied to test mean percent change. |
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End point title |
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 | |||||||||||||||
End point description |
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
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End point type |
Secondary
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End point timeframe |
Week 26
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
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 | |||||||||||||||
End point description |
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
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End point type |
Secondary
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End point timeframe |
Week 26
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Change From Baseline to Week 26 in the C3G Histologic Index for Disease Chronicity - Subjects With Elevated C5b-9 | ||||||||||||
End point description |
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
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End point type |
Secondary
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End point timeframe |
Week 26
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline to Week 26 in the C3G Histologic Index for Disease Chronicity - Combined C5b-9 Strata | ||||||||||||
End point description |
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
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End point type |
Secondary
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End point timeframe |
Week 26
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Renal Function as Assessed by Percent Change From Baseline Over 26 Weeks in eGFR - Subjects With Elevated C5b-9 | ||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Week 26
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Renal Function as Assessed by Percent Change From Baseline Over 26 Weeks in eGFR - Combined C5b-9 Strata | ||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Week 26
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Renal Function as Assessed by Change From Baseline Over 26 Weeks in eGFR - Subjects With Elevated C5b-9 | ||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Week 26
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Renal Function as Assessed by Change From Baseline Over 26 Weeks in eGFR - Combined C5b-9 Strata | ||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Week 26
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percent Change From Baseline Over 26 Weeks in UPCR in Patients With Abnormal UPCR at Baseline - Subjects With Elevated C5b-9 | ||||||||||||
End point description |
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
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End point type |
Secondary
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End point timeframe |
Week 26
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percent Change From Baseline Over 26 Weeks in UPCR in Patients With Abnormal UPCR at Baseline - Combined C5b-9 Strata | ||||||||||||
End point description |
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
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 26
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percent Change From Baseline Over 26 Weeks in Urinary MCP-1 - Subjects With Elevated C5b-9 | ||||||||||||
End point description |
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
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 26
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percent Change From Baseline Over 26 Weeks in Urinary MCP-1 - Combined C5b-9 Strata | ||||||||||||
End point description |
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
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 26
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||
End point title |
Change From Baseline Over 26 Weeks in EQ-5D-5L Health Scale VAS and Index Score - Subjects With Elevated C5b-9 | ||||||||||||||||||
End point description |
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).
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Week 26
|
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|
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| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
Change From Baseline Over 26 Weeks in EQ-5D-5L Health Scale VAS and Index Score - Combined C5b-9 Strata | ||||||||||||||||||
End point description |
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).
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Week 26
|
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|
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| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
End point title |
Change From Baseline Over 26 Weeks in SF-36 v2 - Subjects With Elevated C5b-9 | ||||||||||||||||||||||||||||||||||||||||||
End point description |
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)
|
||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Week 26
|
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|
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| Notes [2] - All categories have 20 participants except SF-36v2: General Health Perceptions with 19. [3] - All categories have 18 participants except SF-36v2: Bodily Pain and Social Functioning with 17. |
|||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
End point title |
Change From Baseline Over 26 Weeks in SF-36 v2 - Combined C5b-9 Strata | ||||||||||||||||||||||||||||||||||||||||||
End point description |
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).
|
||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Week 26
|
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|
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| Notes [4] - All categories have 25 participants except SF-36v2: General Health Perceptions with 24 participants [5] - All categories have 25 participants except SF-36v2: Bodily Pain and Social Functioning with 24. |
|||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||
End point title |
Number of Subjects With Treatment-emergent SAEs, AEs, Relatedness to Study Medication and Withdrawals Due to AEs | |||||||||||||||||||||
End point description |
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
Safety Population: The safety population included all subjects who were randomized and had received at least one dose of study drug.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
From day 1 throughout the study period (day 182/week 26)
|
|||||||||||||||||||||
|
||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||
|
||||||||||||||||||||||
End point title |
Number of Treatment-emergent SAEs, AEs, Relatedness to Study Medication and Withdrawals Due to AEs | |||||||||||||||||||||
End point description |
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
Safety Population: The safety population included all subjects who were randomized and had received at least one dose of study drug.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
From day 1 throughout the study period (day 182/week 26)
|
|||||||||||||||||||||
|
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| No statistical analyses for this end point | ||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Adverse events information
|
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Timeframe for reporting adverse events |
From day 1 throughout the study period (day 182/week 26)
|
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Adverse event reporting additional description |
An adverse event is considered treatment-emergent if the start date/time of the event is on or after the date/ time of first study drug treatment up to the final observation in the double-blind treatment period (week 26).
|
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.1
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Reporting groups
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Reporting group title |
Placebo Group
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Reporting group description |
Avacopan-matching placebo capsules x 3 administered twice daily during the 26 week blinded treatment period Avacopan-matching placebo: Orally administered The safety population included all subjects who were randomized and had received at least one dose of study drug. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Avacopan Group
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Reporting group description |
Avacopan (formerly CCX168) 10 mg capsules x 3 administered twice daily during the blinded 26 week blinded treatment period Avacopan: Orally administered The safety population included all subjects who were randomized and had received at least one dose of study drug. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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||||||||||
Substantial protocol amendments (globally) |
||||||||||
| Were there any global substantial amendments to the protocol? Yes | ||||||||||
Date |
Amendment |
|||||||||
13 Sep 2017 |
Protocol amendment 1
• added 12-lead ECG to screening and safety assessments
• added urinary albumin:creatinine ratio (UACR) and protein: creatinine ratio (UPCR) to screening evaluations
• clarified that the week 52 biopsy in adolescent subjects was optional and was not a protocol deviation if not collected
• added active uncontrolled infection to the exclusion criteria
• clarified that pharmacodynamic markers were exploratory endpoints
• clarified albuminuria measurement
• clarified that it was not necessary to use CTCAE grading for clinical events. CTCAE criteria could be used for severity assessment of lab values. If there was a clinical adverse event related to a lab abnormality, the adverse event was to be reported as the clinical event, where possible.
• added a new section to accommodate reports of overdose, misuse and abuse of the investigational medicinal product. All associated adverse events were to be reported as adverse events or serious adverse events using the adverse events electronic case report form (eCRF) and/or the serious adverse event report form.
• added instruction that subjects who terminated early from the trial would have serious adverse events recorded at follow-up visits or at least 30 days after last investigational product administration.
• added instruction that serious adverse event information should be entered as soon as possible when EDC access is returned.
|
|||||||||
16 Apr 2018 |
Protocol Amendment 2
• added a secondary population with diagnosed C3G and lower levels of circulating C5b-9 levels which was previously excluded
• expanded screening from 4 weeks to 6 weeks
• clarified that adolescent subjects were enrolled only in regulatory territories where approval was received, and that the dose in adolescents depended on body weight and avacopan plasma exposure (AUC0-6hr) or avacopan trough concentrations
• expanded the number of subjects enrolled in the study from 44 to 88
• added to inclusion criteria that the Investigator would provide assurance that adolescent subjects were willing and able to ingest the size “0” tablet
• clarified that CT-scan or chest X-ray was not mandatory, if evidence of tuberculosis was excluded by other methods described
• increase the number of lesions to be included in the C3G Histologic Index for disease activity from 4 to 7
• expanded description of the C3G Histologic Index for Activity scoring system using the glomerulopathy histologic score as described by Bomback et al (Bomback et al, 2018)
• added text to the statistics methods to accommodate the new C5b-9 strata
• added that missing data would be imputed with the last observation carried forward (LOCF). Multiple imputation using other statistical methods could also be performed.
• added that the day 183 morning dose for adolescent subjects was to be taken in the clinic rather than at home
• added that subjects were to be reminded through a telephone call that the week 52 dose should not be taken.
• added that the final 4 PK samples (Weeks 52, 54, 57, 60) were for terminal PK evaluation
• added exploratory endpoints around PK parameters and PK/PD relationship
• added criteria for potential for early termination of the stratum with C5b 9 levels 244 ng/m
• added that PK parameters would be calculated based on plasma concentration for samples collected on both day 1 and day 183 (week 26)
|
|||||||||
02 Aug 2018 |
Protocol Amendment 3
• added visits at week 23, 35, 41, and 48 per DMC recommendation to increase the frequency of liver testing; data on concomitant medications and Adverse events were to be collected for the added visits
• added serum chemistries at week 2, 23, 35, 41, and 48 per DMC recommendation to increase the frequency of liver testing
• added that any changes in concomitant medication use were to be recorded per DMC recommendation
• added new safety information from an ongoing clinical trial in a different indication to coincide with updated Reference Safety Information in the Investigator’s Brochure
• clarified that a follow-up renal biopsy was to be performed within 2 weeks before the week 26 visit and was to be completed before open-label medication was started
• added scale to be used for crescent formation and fibrinoid necrosis involvement
• clarified hepatic enzyme criteria under which dosing with investigational product would be suspended for that subject during investigation into the causality of abnormal liver tests and criteria for resumption of investigational product.
|
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20 Mar 2019 |
Protocol Amendment 4
• clarified throughout that the investigational product was blinded
• increased the duration of the study from 26 to 32 months to accommodate previous increase in sample size and slower than expected enrollment
• updated the earliest time point for primary efficacy analysis
• increase the frequency of hematology testing per DMC recommendation
• clarified time allowed to differentiate between common fluctuations of renal function and true deterioration of renal function to prevent unnecessary discontinuation
• clarified that investigational product dosing was paused during investigation of causality of abnormal liver tests, abnormal hematology, and serum chemistry tests and investigational product was to be discontinued, if applicable
• updated clinical evaluation to include current clinical status, clarify patient safety information and to include the clinical safety information
|
|||||||||
Interruptions (globally) |
||||||||||
| Were there any global interruptions to the trial? Yes | ||||||||||
|
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Limitations and caveats |
||||||||||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | ||||||||||
| None reported | ||||||||||
