The purpose of this study is to compare the effect of AT1001 (migalastat hydrochloride) versus placebo on GL-3 in the kidney.
ID
Source
Brief title
Condition
- Inborn errors of metabolism
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Kidney GL-3 (interstitial capillary histology):
The average number of GL-3 inclusions per kidney interstitial capillary is
assessed by a quantitative histological method used to count GL-3 inclusions in
a sample of interstitial capillaries at baseline and at Month 6
Secondary outcome
* Urine GL-3 levels
* Renal Function (assessed by Iohexol GFR, estimated GFR, and 24-hour urine
protein)
* Safety and tolerability
* Cardiac Function
* Patient Reported Outcomes
* WBC *-Gal A activity
* Exploratory Kidney Histology Assessments
* Pharmacokinetics
Background summary
Patients with Fabry disease have inherited a change of the genetic material
(DNA), which results in lower than normal levels of an enzyme called
alpha-galactosidase A (alpha-Gal A). The alpha-Gal A enzyme is important in
helping the body break down and get rid of certain types of fatty substances.
These fatty substances are called glycolipids and are present in most cells of
healthy human beings. In Fabry disease, because the enzyme is absent or
present in small amounts, there is a buildup of fatty substances in several
tissues such as the kidneys, heart, skin, and blood vessels. The increased
level of these fatty substances, especially the glycolipid
globotriaosylceramide (GL-3), is believed to cause the clinical symptoms common
to Fabry disease.
When enzymes such as alpha-Gal A are produced by the cells, they need to be
folded into a form capable of getting rid of the excess GL-3. Some changes in
the gene that cause Fabry disease affect the correct folding of the alpha-Gal A
enzyme in such a way that the protein is destroyed by the cell. AT1001 is
believed to help the enzyme to fold correctly, and may increase the enzyme
levels in the cells of the human body. As a result, AT1001 may interrupt the
buildup of fatty substances such as GL-3 in the body, which might help improve
disease symptoms.
This study will measure the effect of AT1001 treatment on GL-3 levels in the
kidney. GL-3 in the kidney will be measured in two different ways: by taking
samples (biopsies) of tissue from the kidney to look at GL-3 buildup
(inclusions) in certain cells, and by measuring the levels of GL-3 in the
urine. In addition, the effects of AT1001 treatment on kidney function, heart
function, and health status will be studied.
Study objective
The purpose of this study is to compare the effect of AT1001 (migalastat
hydrochloride) versus placebo on GL-3 in the kidney.
Study design
This double-blind, randomized, placebo-controlled study will be conducted in 60
patients at approximately 30 sites worldwide. The study will consist of two
stages:
Stage 1 includes a screening period of up to 2 months followed by a 6-month
treatment period which will involve 4 visits to the clinic. Patients will be
randomized in equal proportions to receive either AT1001 or placebo.
After completing the 6-month double-blind phase, all patients will enter Stage
2 of the study and receive AT1001 in an open-label manner. Stage 2 treatment
will last for 6 months and will involve 4 visits to the clinic.
Intervention
Subjects will be randomized in equal proportions to receive either 150 mg of
AT1001 once every other day or placebo once every other day during Stage 1.
During the open-label treatment period (Stage 2) subjects will only receive
AT1001
Study burden and risks
Participation in the study will involve a total of nine visits, which will take
place over 15 months. Study assessments will include clinical laboratory tests
(at every visit), 12-lead ECG (at every visit), kidney biopsy (at 3 visits),
kidney function testing (at 3 visits), echocardiography (at 3 visits), and
patient reported outcomes (at 3 visits).
AT1001 has undergone extensive nonclinical and clinical testing, and no
significant safety concerns have emerged to date. The major potential risks to
subjects participating in this study are expected to be the risks associated
with undergoing multiple kidney biopsies, and possible progression of disease.
Use of intravenous iohexol has a low incidence of side effects. Subjects will
be informed of other treatment options that are available for Fabry disease and
alternatives to study participation.
6 Cedar Brook Drive
Cranbury, NJ 08512
US
6 Cedar Brook Drive
Cranbury, NJ 08512
US
Listed location countries
Age
Inclusion criteria
1. Male or female between the ages of 16 and 74 inclusive, diagnosed with Fabry disease. 2. Confirmed GLA mutation that has been shown to be responsive to AT1001 in vitro
3. Subject has never been treated with ERT or has not received ERT for at least 6 months before the screening visit.
4. Urine GL-3 greater than four times the upper limit of normal at Screening
5. Subjects taking angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) must be on a stable dose for a minimum of 4 weeks before the baseline visit
6. Women who can become pregnant and all men agree to be sexually abstinent or use medically accepted methods of birth control during study and for 30 days after study completion
7. Subject is willing and able to provide written informed consent, and assent if applicable
Exclusion criteria
1. Subject has undergone or is scheduled to undergo kidney transplantation, or is currently on dialysis
2. eGFR < 30 mL/min/1.73m2 (Chronic Kidney Disease Stage 4 or 5) based on Modification of Diet in Renal Disease equation at Screening
3. QTc * 450 msec for males or * 470 msec for females at screening
4. Pregnant or breast-feeding
5. History of allergy or sensitivity to study medication (including excipients) or other iminosugars (e.g., miglustat, miglitol)
6. Subject is treated or has been treated with any investigational drug within 30 days of the screening visit
7. Subject is currently treated or has ever been treated with AT1001
8. Any intercurrent condition or concomitant medication use considered to be an absolute contraindication to kidney biopsy or that may preclude accurate interpretation of study data
9. Otherwise unsuitable for the study, in the opinion of the Investigator.
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 | EUCTR2009-013459-31-NL |
| CCMO | NL29907.018.09 |