The objectives of this study are (1) to document renal function and other Fabry disease manifestations across age in treatment-naïve, young male patients with Fabry disease; and (2) to provide a reference group for comparison with interventional…
Source
Brief title
Condition
- Chromosomal abnormalities, gene alterations and gene variants
- Inborn errors of metabolism
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety endpoints:
The safety of study procedures will be assessed by evaluation of the incidence
of adverse events (AEs).
Fabry Disease Parameters:
* Renal Function (all assessments by central laboratories):
• GFR estimated from serum creatinine using age-appropriate formulas (eGFR).
• GFR measurement by plasma iohexol clearance (iGFR). NOTE: iGFR will not be
measured for patients with a screening eGFR <30 mL/min/1.73m2.
• Albumin/creatinine ratio (ACR)
• Total protein/creatinine ratio (PCR)
• Retinol binding protein (RBP)
• β2-microglobulin, as measured in three first morning void urine samples, each
obtained at least 1 week apart and not more than 2 weeks apart.
* Cardiovascular Function (all tests read by central laboratories):
• ECG
• Echo
* Gastrointestinal (GI) Symptoms:
• Information on GI symptoms, obtained by asking patients a series of specific
questions.
* Quality of Life (QoL)
* Other Disease Characteristics (all assessments by central laboratories):
• Plasma and urine globotriaosylceramide (total GL-3 and lyso-GL-3)
• Genotyping for αGAL gene mutations
Secondary outcome
Exploratory Biomarkers (all assessments by central laboratories):
•Blood and urine samples will also be collected for exploratory analyses of
potential biomarkers of Fabry disease, which will be identified on the basis of
emerging scientific data and will be analyzed individually or in multi-analyte
biomarker panels. Blood and urine samples collected for exploratory biomarker
analyses in this study will not be used for genetic testing.
Background summary
Fabry disease is a rare, X-linked lysosomal storage disorder caused by a
deficiency of the enzyme α-galactosidase A (αGAL) and the accumulation of
globotriaosylceramide (GL-3), the enzyme*s major glycosphingolipid substrate.
Fabry disease results in widespread deposition of GL-3, and to a lesser extent,
other α-galactoside-containing glycolipids, in various cell and tissue types.
This process causes damage to endothelial, perithelial, and smooth-muscle cells
of the vascular system; glomerular and tubular cells of the kidney; myocardial
cells and valvular fibrocytes; epithelial cells of the cornea; and ganglion
cells of the dorsal root and autonomic nervous system, as well as cortical and
brain-stem structures. The clinical manifestations of Fabry disease include
progressive renal disease, cardiac disease, cerebrovascular disease and reduced
lifespan, with a wide spectrum of disease severity.
Tissue GL-3 accumulation has been documented in children early in life.
Previous case reports describing GL-3 in fetal corneal and renal tissue support
the fact that extensive accumulation is already significant at the second
trimester of gestation. Extensive storage and very low αGAL activities have
been observed in the placental tissue of a mother heterozygous for Fabry
disease who gave birth to a hemizygous son.
Childhood manifestations of Fabry disease often include, but are not limited
to, angiokeratoma, excruciating acral pain, paraesthesia, hypohidrosis, corneal
and lenticular opacities, gastrointestinal (GI) symptoms, and elevated urinary
protein excretion rate. Although exceptional, strokes have been reported in
children with Fabry disease. Pediatric patients with Fabry disease experience
pain and have a significantly decreased quality of life (QoL) compared with
their healthy peers. The frequently unrecognized symptom complex in pediatric
Fabry patients often delays the diagnosis until later in life when cardiac,
cerebrovascular, and renal complications of GL-3 accumulation have occurred.
The burden of disease, as assessed by the number of organ systems affected,
increases with age. Left untreated, progressive glycolipid deposition leads to
failure of target organs, commonly resulting in premature death.
Progressive decline in renal function, ultimately leading to renal failure, is
a hallmark of Fabry disease. Patients very often initiate enzyme replacement
therapy (ERT) only after significant decline of glomerular filtration rate
(GFR) or onset of proteinuria. Recent publications indicate
that histological glomerular and vascular changes are present before
progression to overt proteinuria and decreased GFR; in addition, the presence
of podocyte injury in normoalbuminuric young patients suggests that
albuminuria/proteinuria is not sensitive enough to detect early kidney injury
in Fabry nephropathy. However, until now the onset of renal function decline in
young Fabry patients has not been studied systematically in a large patient
cohort and with a robust methodology, and the rate of progression remains
poorly documented.
Study objective
The objectives of this study are (1) to document renal function and other Fabry
disease manifestations across age in treatment-naïve, young male patients with
Fabry disease; and (2) to provide a reference group for comparison with
interventional clinical trials of Fabry disease.
Study design
This will be a multicenter, multinational, non-treatment, cross-sectional study
of young male patients with Fabry disease who have not yet initiated
interventional treatment for this disease. The study will consist of a
screening visit(s), a clinical investigation visit(s), and a follow-up phone
contact.
Patients who meet all eligibility criteria based on screening assessments will
be scheduled to return to the clinic for assessments of renal function and
other disease-related parameters, which may be scheduled over one or more
clinical investigation visits. The clinical investigation visit(s) will be
scheduled such that renal and cardiac assessments occur after the required
medication washout (see exclusion criterion #3 below); other procedures may be
performed either before or after the medication washout, at the discretion of
the investigator. A safety follow-up phone contact will occur approximately 4
weeks (28 days) after administration of iohexol.
The duration of each patient*s participation in the study, inclusive of the
screening visit and follow-up phone contact, will be approximately 12 weeks.
All patients will be encouraged to enroll in the Fabry Registry for continued
follow-up after completion of the study.
Study burden and risks
The burden and risk for the patient is:
- Glomerular filtration rate will be calculated by plasma iohexol clearance
after the required medication washout. This is an invasieve method. Blood
samples will be taken prior to and at 120, 150, 180, 210, and 240 minutes (2,
2.5, 3, 3.5, and 4 hours) after injection of iohexol, and must not be taken
from the same arm as iohexol injections. People sensitive for iodine can
develop an allergic reaction after an Omnipaque injection. There is also a
chance of kidney failure.
- The patients will be asked to complete a Quality of Life questionnaire. A
physical examination will be done twice and an ECG and ECHO of the heart will
be performed.
- The total time spent for the study is about 10 to 12 hours.
The benefit of the study is that participation in this study may indirectly
benefit the patient with respect to disease management (e.g. early detection of
complications and organ manifestations).
Kampenringweg 45
GOUDA 2803 PE
NL
Kampenringweg 45
GOUDA 2803 PE
NL
Listed location countries
Age
Inclusion criteria
A patient must meet all of the following criteria to be eligible for this study.
1. The patient and/or their parent/legal guardian is willing and able to provide signed informed consent. If the patient is below the age of consent per local guidelines, he is willing to provide assent, if deemed able to do so.
2. The patient must have a confirmed diagnosis of Fabry disease as documented by leukocyte α-galactosidase A (αGAL) of <4 nmol/hr/mg leukocyte (preferred assay; results from a central laboratory). If the leukocyte αGAL activity assay is difficult to obtain, the patient may be enrolled based on documented plasma αGAL <1.5 nmol/hr/mL (results from a central laboratory), with the agreement of the Genzyme Medical Monitor.
3. The patient must be male and >=5 and <=25 years of age at screening.
Exclusion criteria
A patient who meets any of the following criteria will be excluded from this study.
1. Patient has received prior treatment with enzyme replacement therapy (ERT) or oral pharmacological chaperone therapy for Fabry disease.
2. Patient has received an investigational drug within 30 days of the screening visit.
3. Patient is receiving any of the following medications and is clinically unable or unwilling to temporarily discontinue treatment with these medications for the indicated washout period prior to the renal function assessments until completion of these assessments:
•Angiotensin converting enzyme inhibitors or angiotensin receptor blockers (6 week washout);
• Non-steroidal anti-inflammatory drugs (3 day washout).
NOTE: Patients who are on chronic dialysis or have had a kidney transplant will not be required to discontinue the above medications because renal function assessments will not be performed in these patients.
4. Patient has any contraindication mentioned in the labeling of iohexol. NOTE: patients with an eGFR <30 mL/min/1.73m2 and patients who are on chronic dialysis or have had a kidney transplant may be enrolled irrespective of any contraindication to iohexol because iGFR will not be measured in these patients.
5. Patient has any medical condition or extenuating circumstance which, in the opinion of the Investigator, could interfere with the patient*s ability to complete all study procedures, or with the interpretation of study results.
6. The patient and/or their parent or legal guardian, in the opinion of the Investigator, is unable to adhere to the requirements of the study.
Design
Recruitment
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 |
---|---|
Other | clinicaltrials.gov NCT number |
CCMO | NL40702.018.13 |