The aim of the research is to determine the effect of GZ/SAR402671 on the total growth in kidney volume (total kidney volume, TKV) in patients with ADPKD. This research also looks at the effectiveness of GZ / SAR402671 in slowing down the decrease…
ID
Source
Brief title
Condition
- Renal disorders (excl nephropathies)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Stage 1
Primary endpoint:
*Annualized rate of change in TKV based on MRI from baseline to 18 months.
Stage 2
Primary endpoint:
*Annualized rate of change in eGFR (CKD-EPI equation) from baseline to 24
months.
Secondary outcome
Stage 1
Secondary endpoints:
* Annualized rate of change in eGFR (CKD-EPI equation) from baseline to 18
months.
* Change in Pain (BPI - Item 3) from baseline to 18 months, from the daily
symptom diary.
* Change in fatigue (BFI - Item 3) from baseline to 18 months, from the daily
symptom diary.
* Plasma venglustat concentrations.
Exporatory endpoint:
* Annualized rate of change in total liver volume based on MRI (in patients
with htTLV >2 L/m) from baseline to 18 months
Stage 2
Secondary endpoints:
* Annualized rate of change in TKV based on MRI from baseline to 18 months.
* Change in pain (BPI - Item 3) from baseline to 24 months, from the daily
symptom diary.
* Change in fatigue (BFI - Item 3) from baseline to 24 months, from the daily
symptom diary.
* Plasma venglustat concentrations.
Exploratory endpoints:
* Annualized rate of change in mGFR from baseline to 24 months (substudy).
* Annualized rate of change in eGFR (CKD-EPI equation) from baseline to 24
months in patients with a screening eGFR between 30 and 44.9 mL/min/1.73 m2.
* Annualized rate of change in total liver volume based on MRI (in patients
with htTLV >2 L/m) from baseline to 18 months
Stage 1 and Stage 2:
Safety/tolerability endpoints:
Safety in terms of TEAEs/AEs/SAEs, laboratory parameters, vital signs,
electrocardiogram and findings from physical examination will be assessed
through the study and will be reported in the eCRF. Adverse event data will be
collected throughout the study. Treatment-emergent AEs are defined as AEs that
develop, worsen (according to the Investigator opinion), or become serious
during the treatment period. The treatment
period is defined as the time from first dose of study treatment up to 30 days
after last dose of study treatment.
* Change in score of BDI-II during the treatment-emergent period.
* Change in the lens clarity by ophthalmological examination during the
treatment-emergent period.
Background summary
ADPKD is a genetic disease with an autosomal dominant pattern of heredity. This
means that a patient with ADPKD has a gene that works incorrectly. A child of
such a patient has a 50% chance of inheriting this gene and also developing the
disease. The wrong working gene causes in patients with ADPKD a problem in the
wall (membrane) of cells in certain parts of the body, especially in the
kidneys. The error in the cells leads to the development of cysts. When the
disease progresses, kidney cysts increase and these can take up more and more
space from the kidneys. This makes the kidneys work less well and this
eventually leads to kidney failure.
Approximately half of the people with ADPKD develop kidney failure, requiring
dialysis or a kidney transplant before their 60th birthday.
Having ADPKD increases the chance of getting high blood pressure. About 1 in 10
people with ADPKD develop an aneurysm in a vein in the brain.
The wrong gene can lead to the development of kidney cysts in ADPKD in
different ways. One of the ways is the accumulation of glucosylceramide: a
natural substance in the body made up of sugar and fat. Glucosylceramide is a
type of glycosphingolipid (GSL), a fatty substance. Glucosylceramide is part of
cell membranes and is important for regulating many cellular processes. The
accumulation of glucosylceramide leads to changes in the behavior of kidney
cells, which form cysts that are becoming larger and larger.
There is currently no cure for ADPKD. The medicine Tolvaptan is approved for
use in Japan, the EU, USA and Canada, for delaying the progress of developing
cysts and reduced kidney function. Unfortunately, not all patients can tolerate
this drug due to increased thirst, large amounts of urination, frequent
urination at night, and regular liver tests.
Study objective
The aim of the research is to determine the effect of GZ/SAR402671 on the total
growth in kidney volume (total kidney volume, TKV) in patients with ADPKD. This
research also looks at the effectiveness of GZ / SAR402671 in slowing down the
decrease of the renal function, and assesses the effect of GZ/SAR402671 on
kidney concentration, by looking at urinary osmolality, as well as the change
in urinary frequency and the impact on nocturia.
Study design
This is an international, multicenter, randomized, double-blind,
placebo-controlled two stage study in adult patients at risk of rapidly
progressive ADPKD.
The study is divided into 2 stages:
Stage 1: patients aged 18-50 years (both inclusive) with an estimated
glomerular filtration rate between 45-89,9 ml / min / 1,73 m2
An up to 30-day screening period including a 2-week placebo run-in (to identify
participants who are unlikely to follow the assigned treatment regimen),
followed by a randomized double-blind comparative placebocontrolled core
treatment period of 24 months duration.
After run-in, eligible patients will be randomized with a 1:1:1 ratio to
placebo, 8 mg GZ/SAR402671, or 15 mg GZ/SAR402671. Patients will be stratified
based on their predicted ADPKD progression rate (1C versus 1D versus 1E)
according to Mayo Imaging Classification.
Stage 2: After the first 150 randomized patients from Stage 1 have completed 1
month of treatment (or have prematurely discontinued), the
Data Monitoring Committee (DMC) will review in an unblinded fashion the
aggregate safety data from Stage 1 and will select the GZ/SAR402671
dose for Stage 2 (8 mg or 15 mg). The selected dose will be the highest dose
determined to be safe and well tolerated in Stage 1.
Stage 2: 360 patients aged 18-50 years (both inclusive) with an estimated
glomerular filtration rate between 45-89,9 ml / min / 1,73 m2 during screening
and 80 patients aged 18-55 years (both inclusive) with an estimated glomerular
filtration rate between 30-44,9 ml / min / 1,73 m2 during screening.
This stage will also start with an up to 30-day screening period including a
2-week placebo run-in (to identify participants who are unlikely to follow the
assigned treatment regimen), followed by a randomized double-blind comparative
placebocontrolled core treatment period of 24 months duration. After run-in,
patients will be randomized with a 1:1 ratio to placebo and GZ/SAR402671 (dose
to be determined in Stage 1). Patients will be stratified based on their
predicted progression rate (1C versus 1D versus 1E) according to Mayo Imaging
Classification.
Patients, selected for stage 2, will be informed about a mGFR substudy, and
requested if they would consider to additionally participate in this substudy
(expectation 15% of the study population).
Intervention
In Stage 1, during the run-in period the patient will receive placebo matching
GZ/SAR402671 (2 capsules) once daily for 2 weeks.
During the double-blind core treatment period, the patient will receive once
daily doses of GZ/SAR402671 or matching placebo for 24 months:
*GZ/SAR402671 8 mg (2 capsules of GZ/SAR402671 4 mg).
*GZ/SAR402671 15 mg (1 capsule of GZ/SAR402671 15 mg, 1 capsule of placebo).
*Placebo matching GZ/SAR402671 (2 capsules of placebo).
In Stage 2, during the run-in period the patient will receive placebo matching
GZ/SAR402671 (1 capsule) once daily for 2 weeks.
The dose of GZ/SAR402671 or placebo will be administered once per day for 24
months:
*GZ/SAR402671 15 mg.
*Placebo matching GZ/SAR402671.
Study burden and risks
The burden for the patient are the visits to the research center and the
research procedures to be undergone.
The risks are related to the blood tests, some research procedures (ECG, MRI,
ophthalmological) and the possible side effects of the study medication.
Paasheuvelweg 25
Amsterdam 1105 BP
NL
Paasheuvelweg 25
Amsterdam 1105 BP
NL
Listed location countries
Age
Inclusion criteria
- Male or female adult with ADPKD:
a) between ages of 18 and 50 years (inclusive) for patients in Stage 1
b) between 18 and 50 years (inclusive) for patients in Stage 2 with an eGFR
between 45 and 89.9 mL/min/1.73 m2 during the screening period
c) between 18 and 55 years (inclusive) for patients in Stage 2 with an eGFR
between 30 and 44.9 mL/min/1.73 m2 during the screening period
Diagnosis of ADPKD in patients with a family history, will be based on unified
Pei criteria. In the absence of a family history, the diagnosis will be based
on the presence of renal cysts bilaterally, totaling at least 20, in the
absence of findings suggestive of other cystic renal diseases.
- Mayo Imaging Classification of ADPKD Class 1C, 1D or 1E.
- Estimated glomerular filtration rate between 45 to 89,9 mL/min/1.73 m2 during
the screening period (Chronic Kidney Disease Epidemiology Collaboration
[CKD-EPI]) for stage 1.
- Estimated glomerular filtration rate between 30 and 89.9 mL/min/1.73 m2
during the
screening period (CKD-EPI equation) for Stage 2.
- Stable treatment regimen of antihypertensive therapy for at least 30 days
prior to the screening visit for hypertensive patient.
- Able to read, comprehend, and respond to the study questionnaires.
- Patient has given voluntary written informed consent before performance of
any study related procedures not part of standard medical care.
- Patient does not have access to tolvaptan at the time of study start or
tolvaptan is not indicated for treatment of patient according to treating
physician (patient does not meet recommended criteria for treatment or does not
tolerate treatment with tolvaptan).
- The patient, if female of childbearing potential, must have a negative blood
pregnancy test (*-human chorionic gonadotropin [*-hCG]) at the screening visit
and a negative urine pregnancy test at the baseline visit.
- Female patients of childbearing potential and male patients must agree to
practice true abstinence in line with their preferred and usual lifestyle or to
use double-contraceptive methods (including a highly effective method of
contraception for female participants of childbearing potential) for the entire
duration of the study and for at least 6 weeks for females and 90 days for
males following their last dose of study drug
Exclusion criteria
- Systolic BP >160 mmHg at run-in and baseline visits.
- History of administration of tolvaptan or other Polycystic Kidney
Disease-modifying agents (somatostatin analogues) within 3 months prior to the
screening visit.
- The patient, in the opinion of the Investigator, is unable to adhere to the
requirements of the study or unable to undergo study assessments (eg, has
contraindications to pupillary dilation or unable to undergo magnetic resonance
imaging [MRI] [For example: patient*s weight exceeds weight capacity of the
MRI, ferromagnetic metal prostheses, aneurysm clips, severe claustrophobia,
large abdominal/back tattoos, etc]).
- Current participation in another investigational interventional study or use
of investigational medicinal product (IMP), within 3 months or 5 half-lives,
whichever is longer, before randomization.
- The patient has a positive result of any of the following tests: hepatitis B
surface antigen [HBsAg], anti-hepatitis C virus [anti-HCV] antibodies,
anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2
Ab). Patients with a positive hepatitis B surface antibody (HBsAb) test are
eligible if other criteria are met (ie, negative tests for: HBsAg, hepatitis B
core antibody [HBcAb], and hepatitis C virus antibody [HCVAb]). Patients immune
due to natural infection (positive HBsAb, negative HBsAg, positive HBcAb) are
eligible if they have a negative HBV DNA test.
- A history of drug and/or alcohol abuse within the past year prior to the
screening visit.
- A history of alcohol dependence within the 5 years prior to the screening
visit.
- Any patient who is the Investigator or any Subinvestigator, research
assistant, pharmacist, study coordinator, other staff, or relative thereof
directly involved in the conduct of the study.
- The patient is scheduled for in-patient hospitalization including elective
surgery, during the
study.
- The patient has a clinically significant, uncontrolled medical condition
that, in the opinion of the investigator, would put the safety of the subject
at risk through participation, or which would affect the efficacy or safety
analysis if the condition exacerbated during the study, or that may
significantly interfere with study compliance, including all prescribed
evaluations and follow-up activities.
The list of medical conditions that should be taken into account includes, but
is not limited
to the following:
Congestive heart failure New York Heart Association (NYHA) Grade III/IV),
clinically significant cardiac arrhythmia, severe unstable angina pectoris
within 6 months of Visit 1, hypertensive
emergency within 6 months of Visit 1, stroke or transient ischemic attack
within 3 months of Visit 1, myocardial infarction within 3 months of Visit 1,
current malignancy, tuberculosis (current or untreated), Cushing's disease,
Addison's disease, uncontrolled diabetes mellitus, uncontrolled thyroid disorder
- Any country-related specific regulation that would prevent the patient from
entering the
study.
- The patients did not adhere to treatment (<70% compliance rate) in the run-in.
- The patient has, according to World Health Organization (WHO) Grading (13), a
cortical cataract *1-quarter of the lens circumference (Grade cortical
cataract-2 [COR-2]) or a posterior subcapsular cataract *2 mm (Grade posterior
subcapsular cataract-2 [PSC-2]). Patients with nuclear cataracts will not be
excluded.
- The patient is currently receiving potentially cataractogenic medications,
including a chronic regimen (more frequently than every 2 weeks) of any route
of corticosteroids (including medium and high potency topical steroids), or any
medication that may cause cataract, according to the Prescribing Information.
- The patient has received strong or moderate inducers or inhibitors of CYP3A4
within 14 days or 5 half-lives, whichever is longer, prior to randomization.
This also includes the consumption of grapefruit, grapefruit juice, or
grapefruit containing products within 72 hours of starting GZ/SAR402671
administration.
- The patient is pregnant, or lactating.
- Liver enzymes (alanine aminotransferase [ALT]/aspartate aminotransferase
[AST]) or total
bilirubin >2 times the upper limit of normal (ULN) unless the patient has the
diagnosis of Gilbert syndrome. Patients with the Gilbert syndrome should have
no additional symptoms or signs which suggest hepatobiliary disease and serum
total bilirubin level no more than 3 mg/dl (51 *mol/L) with conjugated
bilirubin less than 20% of the total bilirubin fraction.
- Presence of severe depression as measured by BDI-II >28 and/or a history of a
major affective disorder within 1 year of the screening visit.
- Known hypersensitivity to GZ/SAR402671 or any component of the excipients.
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 | EUCTR2017-004084-12-NL |
| CCMO | NL65828.042.18 |
| Other | U1111-1202-0775 |