Hyperlipoproteinemia Type I Clinical Trial
Official title:
Prospective, Non-interventional, Non-randomised, Open-label, Adult Study to Assess the Long Term Biological Therapeutic Response to Alipogene Tiparvovec in Lipoprotein Lipase Deficiency (LPLD) and Comparing Postprandial Chylomicron Metabolism Following a Radiolabeled Meal in LPLD Subjects Previously Treated With Alipogene Tiparvovec (Studies CT-AMT-011-01 or -02) to Untreated LPLD Subjects (Study PREPARATION-02) and to Healthy Volunteers
LPL (Lipoprotein Lipase) is an enzyme which plays an important role in the elimination of
triglycerides (fat) and the clearance of dietary fat particles known as chylomicrons (CM) in
the blood. In patients who have an abnormal LPL gene, the enzyme does not work (total,
hereditary LPL deficiency), which results in a large increase in the amount of triglycerides
(fats) and chylomicrons in the blood. This increases the risk of inflammation in the
pancreas and leads to long term negative effects for bloods vessels (atherosclerosis).
Current medications and / or a strict and low fat diet do not sufficiently reduce the level
of triglycerides in order to prevent these conditions. To solve this problem, the company,
AMT is developing a gene therapy (AMT-011).
In normal healthy individuals, fat particles are rapidly cleared from the circulation
following a standard meal. Within approximately 3 hours the highest levels of fat is reached
and clearance is achieved within the subsequent 9 hours. In LPLD subjects, the clearance of
fat is greatly reduced as a direct consequence of the lack of LPL. During this study, a
standard meal with a tracer (3H-palmitate) is given. Since palmitate is incorporated in the
dietary fat, this study enabled monitoring of appearance of newly formed dietary fat into-
and clearance of these newly formed dietary fats from the circulation, over time.
The principal aim of the study is to verify if the gene therapy (AMT 011) is still effective
in the treatment of this condition. Systemic appearance and clearance of new formed dietary
fat particles after ingestion of the meal will be determined by measuring the level of
tracer at different time points.
Lipoprotein lipase deficiency (LPLD) is a rare autosomal recessive inherited disorder caused
by loss-of-function mutations in the lipoprotein lipase (LPL) gene. It is the most common
genetic cause of hyperchylomicronaemia, a condition which results in continuous and
excessively high levels of plasma chylomicrons (CM) and severe hypertriglyceridaemia.
Lipoprotein lipase normally mediates the hydrolysis of triglycerides (TG) in CMs and very
low-density lipoproteins (VLDL) and thereby aids in the clearance of TG-rich lipoproteins
and reduction of TGs in the circulation.
Alipogene tiparvovec (Glybera®) is in development for the therapy of LPLD. In summary,
alipogene tiparvovec contains the human lipoprotein (LPL) gene variant LPLS447X in a
non-replicating vector in solution administered in a one-time series of intramuscular
injections in the arms/legs.The aim of alipogene tiparvovec (Glybera®) administration is to
provide LPL activity and to stimulate CM metabolism in LPLD patients.
To test the activity of LPL in subjects previously treated with alipogene tiparvovec in this
study LPLD subjects will be given a radiolabeled meal supplemented with a labeled tracer,
3H-palmitate. Since dietary palmitate is incorporated into CMs as they are formed in the
enterocytes of the gut, this enables monitoring of the appearance and subsequent clearance
of newly formed CMs from the circulation over time, the so-called "postprandial test". The
radiolabeled meal will be provided in a liquid form similar to a milkshake. After ingestion
of the radiolabeled meal, level of radiolabel in the CM fraction at different time points
prior to and during the postprandial phase will be measured and thus determine the
appearance and clearance of CMs within the circulation.
The principal aim of the study is to increase the understanding of how long alipogene
tiparvovec may be effective in the treatment of LPLD. To understand this, 3 cohorts of
subjects will be studied: 1) Subjects with LPLD who have previously been treated with
alipogene tiparvovec; 2) Subjects with LPLD who have not been treated with alipogene
tiparvovec; and 3) Subjects who do not have LPLD (healthy volunteers). The subject's general
state of health will also be monitored during the clinical study, and the possible
disadvantages associated with the postprandial test will be assessed.
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Observational Model: Case Control, Time Perspective: Prospective
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