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.The secondary objectives of this study include evaluation of:1. The safety of avacopan…
ID
Source
Brief title
Condition
- Renal disorders (excl nephropathies)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is the percent change from baseline to Week 26 in
the C3G Histologic Index for disease activity.
Secondary outcome
Other 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;
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 study 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.
Background summary
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). Genetic mutations leading to defective
complement regulation, including reduced-function mutations of complement
factor H (CFH), have been described in some of these patients. Patients with
C3G often have progressive deterioration in renal function, ultimately leading
to end-stage renal disease.
There is no approved treatment for patients with C3G. Immunosuppressive drugs
such as cyclophosphamide, mycophenolate mofetil, and glucocorticoids, as well
as biologics such as rituximab have been used with limited success. The anti-C5
antibody eculizumab previously
showed evidence of improvement in some patients with C3G. Eculizumab blocks the
formation of C5a and C5b-9 (membrane attack complex) from C5. Evidence from
animal models suggest that inhibition of C5a may be more important than
inhibition of C5b-9 in C3G, because deletion
of C6 (which is part of the C5b-9 complex) in CFH knockout mice failed to
protect the mice from developing symptoms of C3G (Pickering et al, 2006). This
provides support for testing drugs that target C5aR, such as avacopan.
Avacopan is an orally administered, selective inhibitor of the complement 5a
receptor (C5aR) which is in Phase 3 clinical development for treatment of
patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis
(AAV). Phase 2 study data with avacopan in patients with AAV indicate efficacy
with 30 mg avacopan given twice daily based on improvement in disease activity
(Birmingham Vasculitis Activity Score), a significant antiproteinuric effect,
and improvement in quality of life among other improved disease parameters
(Jayne et al, 2017). This treatment effect was observed in subjects receiving
avacopan plus cyclophosphamide or rituximab, but with no oral glucocorticoids.
One patient with treatment refractory C3GN, one of the subtypes of C3G, has
been treated successfully with 30 mg avacopan twice daily since September 2015
under a *Special Needs* program in the UK. This patient had progressive decline
in renal function despite previous
treatment with immunosuppressants, rituximab, and glucocorticoids, as well as a
kidney transplant.
Study 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.
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.
Additionally, changes from baseline in markers of alternative complement
pathway involvement and other markers of inflammation may be assessed in
plasma/serum or urine over the course of the treatment period.
Study design
This is a randomized, double-blind, placebo-controlled, multicenter phase 2
study.
Intervention
The subjects will be randomized 1:1 to receive 30 mg avacopan twice daily or
matching placebo for 26 weeks in a double-blind, placebo-controlled manner. The
primary efficacy analysis will occur when the last enrolled subject has
completed the Week 26 visit. After the 26-week double-blind period, the
avacopan group will continue receiving avacopan for another 26 weeks, and the
placebo group subjects will be switched over in a blinded manner to receive 30
mg avacopan twice daily treatment, instead of placebo, for another 26 weeks.
Study burden and risks
Risks: possible side effects of the study drug and study procedures.
Burden:
Daily taking of the study medication.
There are 22 visits during a period of 62 weeks. The following study procedures
will be conducted:
Blood draws
Urine samples
The patient needs to complete questionnaires
Physical examination
Vital signs measurement
During 7 visits (including the screening visit) an ECG is made
Pregnancy tests if applicable
Maude Ave 850w
Mountain View 94043
US
Maude Ave 850w
Mountain View 94043
US
Listed location countries
Age
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 child-bearing 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.
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 HBV, HCV, or HIV viral screening test indicative of acute or
chronic infection;
8. 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; 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/mL, or neutrophil count less than 1500/mL, or
lymphocyte count less than 500/mL 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 cytochrome P450 3A4 (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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-001821-42-NL |
| CCMO | NL62908.018.17 |