A Clinical Trial to Evaluate the Safety and Efficacy of CCX168 (Avacopan), a new drug for the treatment of a group of related conditions that cause the kidneys to malfunction, called C3 Glomerulopathy.

• Register: EUCTR
• Last refreshed on: 15 November 2021
• Main ID: EUCTR2017-001821-42-BE
• Date of registration: 06/10/2017
• Prospective Registration: Yes
• Primary sponsor: ChemoCentryx, Inc.
• Public title: A Clinical Trial to Evaluate the Safety and Efficacy of CCX168 (Avacopan), a new drug for the treatment of a group of related conditions that cause the kidneys to malfunction, called C3 Glomerulopathy.
• Scientific title: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate the Safety and Efficacy of Avacopan (CCX168) in Patients with C3 Glomerulopathy
• Date of first enrolment: 15/01/2018
• Target sample size: 88
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-001821-42
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Canada, Denmark, France, Germany, Ireland, Italy, Netherlands, Spain, United Kingdom, United States

Contacts

• Name: Vasiliki Iassonidou
• Affiliation: Medpace Germany GmbH

• Name: Vasiliki Iassonidou
• Affiliation: Medpace Germany GmbH

Key inclusion & exclusion criteria

Inclusion criteria:
1.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:
a.=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
b.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
c.confirmation of the presence of electron dense deposits in the glomeruli on electron microscopy corresponding with the C3 immunofluorescence positivity;
2.Male or female patients, aged at least 18 years; where approved, adolescents (12-17 year old) may be enrolled; female patients 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 patients with partners of childbearing potential may be excluded if they plan to father a child during the study. 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 patient). In addition, a barrier method (i.e., cervical cap, diaphragm or condom) must be used during intercourse between a male patient and a female of childbearing potential;
3.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 patients 12 to 17 years of age; and
4.Judged to be otherwise fit for the study by the Investigator, based on medical history, physical examination, and clinical laboratory assessments. Patients 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. At sites in which adolescents are allowed to be enrolled, the Investigator assures that the adolescent patient is willing and able to ingest the size "0" study drug.

Are the trial subjects under 18? yes
Number of subjects for this age range: 8
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 50
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 30

Exclusion criteria:
1.Pregnant or nursing;
2.Tubulointerstitial fibrosis appears to be more than 50% based on standard assessment using trichrome staining of the renal biopsy;
3.Use of eculizumab or another anti-C5 antibody within 26 weeks prior to dosing;
4.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;
5.Currently on dialysis or likely will require dialysis within 7 days after screening;
6.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;
7.Positive hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) viral screening test indicative of acute or chronic infection;
8.Evidence of tuberculosis based on interferon ? release assay (IGRA), tuberculin purified protein derivative (PPD) skin test, or chest radiography done at screening or within 6 weeks prior to screening; a CT scan or chest X-ray are not mandatory if evidence of tuberculosis was excluded by any of the other methods specified above;
9. Active uncontrolled infection;
10. WBC count less than 3500/µL, or neutrophil count less than 1500/µL, or lymphocyte count less than 500/µL before start of dosing;
11.Evidence of hepatic disease; AST, ALT, alkaline phosphatase, or bilirubin >3 x the upper limit of normal before start of dosing;
12.Currently using a strong inducer of the CYP3A4 enzyme, such as carbamazepine, phenobarbital, phenytoin, rifampin, or St. John's wort;
13.Known hypersensitivity to avacopan or inactive ingredients of the avacopan capsules (including gelatin, polyethylene glycol, or Cremophor) or inability to swallow the capsules;
14.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
15.History or presence of any medical condition (for example: contraindication to local anesthesia required for renal biopsy, or recurring serious infections) or disease which, in the opinion of the Investigator, may place the patient at unacceptable risk for study participation.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

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, formerly called membranoproliferative glomerulonephritis [MPGN] Type II) and C3 glomerulonephritis (C3GN, formerly called idiopathic MPGN).
MedDRA version: 20.0 Level: PT Classification code 10077827 Term: C3 glomerulopathy System Organ Class: 10038359 - Renal and urinary disorders

Intervention(s)

Product Name: Avacopan
Product Code: CCX168
Pharmaceutical Form: Capsule
INN or Proposed INN: AVACOPAN
CAS Number: 1346623-17-3
Current Sponsor code: CCX168
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Week 26

Main Objective: 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.

Secondary Objective: The secondary objectives of this study include evaluation of:
1.The safety of avacopan compared to placebo based on the incidence of adverse events, changes in clinical laboratory measurements, and vital signs;
2.Changes in laboratory parameters of renal disease including estimated glomerular filtration rate (eGFR), proteinuria, and urinary excretion of monocyte chemoattractant protein-1 (MCP-1) with avacopan compared to placebo;
3.Health-related quality-of-life changes based on Short Form-36 version 2 (SF-36 v2) and EuroQOL-5D-5L (EQ-5D-5L) with avacopan compared to placebo;
4.The pharmacokinetic profile of avacopan in patients with C3G.

Primary end point(s): The percent change from baseline to Week 26 in the C3G Histologic Index for disease activity

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: week 26 of the double-blind, placebo controlled treatment period and week 26 of the open-label treatment period.
Liver function will be monitored at least every 4 weeks throughout the study.

Secondary end point(s): Secondary efficacy endpoints include:
1.The proportion of patients who have a histologic response, defined as a decrease (improvement) in the C3G Histologic Index for activity of at least 35% from baseline to Week 26 (see Section 8.7 for basis of selection of 35% threshold);
2.The percent change from baseline in the C3G Histologic Index for disease chronicity over the placebo-controlled 26-week treatment period;
3.The change and percent change from baseline in eGFR over the placebo-controlled 26-week treatment period;
4.The percent change from baseline in UPCR over the placebo-controlled 26-week treatment period;
5.The percent change from baseline in urinary MCP-1:creatinine ratio over the placebo-controlled 26-week treatment period;
6.Change from baseline in EQ-5D-5L (visual analogue scale and index) and SF-36 v2 (domains and component scores) over the placebo-controlled 26-week treatment period.

Safety 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.

PK endpoints
Avacopan (and its metabolite CCX168-M1) plasma concentration results for both C5b-9 level strata combined will be used to calculate trough plasma concentrations (Cmin) over the course of the clinical trial. When possible, the terminal elimination half-life will also be calculated.
The Cmax, Tmax, and AUC0-6hr will be determined for patients 12 to 17 years old based on avacopan and metabolite plasma concentration data on Day 1 and on Day 183 (Week 26).

PD endpoints
The following PD endpoints may be assessed:
1.Change and percent change from baseline in plasma biomarkers such as inflammatory cytokine and chemokine levels.
2.Change and percent change from baseline in urine biomarkers such as urinary sCD163:creatinine ratio, inflammatory cytokine and chemokine 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. The relationship between PK parameters and renal function based on eGFR will be evaluated. The data may also be used to evaluate the PK/PD relationship of avacopan treatment for both C5b-9 level strata separately as well as combined. To this end, the change and/or percent change from baseline in the C3G Histologic Index, UPCR, eGFR, urinary MCP-1:creatinine ratio, and other biomarkers may be used as PD markers.

Secondary ID(s)

2017-001821-42-GB

132321

CL011_168

Source(s) of Monetary Support

ChemoCentryx, Inc.

Ethics review

Status: Approved
Approval date: 12/06/2018
Contact: