Duration of Effect of Alipogene Tiparvovec Treatment, Which Was Administered in Other Studies

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Hyperlipoproteinemia Type I

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has provided signed informed consent. Male or female aged 18 to 70 years, inclusive at the time of consent. Females of childbearing potential must have a negative serum pregnancy test and agree to use a medically acceptable effective form of birth control from screening through Day 21 visit. Subjects in Cohort 1 (previously treated LPLD Cohort) must have received AMT-011 during Studies CT-AMT-011-01 or -02 as verified by site personnel. Subjects in Cohort 2 (untreated LPLD control Cohort)) may have completed study PREPARATION-02 as verified by site personnel or known patients with genetically confirmed LPLD. Volunteers in Cohort 3 (normal healthy control Cohort) must not have LPLD. Subjects must be in good general physical health with, in the opinion of the investigator, no other clinically significant and relevant abnormalities of medical history, and no abnormalities at the physical examination and routine laboratory evaluation performed prior to the study. Must be able to communicate fully and effectively with the study personnel. Exclusion Criteria: Female subjects who have a positive serum pregnancy test or who are nursing. Known allergy to any of the constituents of the radiolabeled meal/radio labeled agent, or a history of severe allergic or anaphylactic reactions. Investigator-determined clinically significant disease (other than LPLD for those subjects with LPLD), that would affect the subject's participation in the study. Healthy Volunteers with a history or presence of neurological, haematological, psychiatric, gastrointestinal, pulmonary, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs, including plasma lipids out side normal range for age and gender and a body mass index (BMI) >30. Any current or relevant previous history of serious, severe, or unstable physical or psychiatric illness, any medical disorder that may make the participant unlikely to fully complete the study, or any condition that presents undue risk from the study medication or procedures. A laboratory value at screening outside the normal range unless it is judged by the investigator as not clinically significant after appropriate evaluation. Clinically significant ECG at screening as determined by the investigator. Blood donations (≥1 unit) during the 2 months preceding and following the study or other significant blood loss. Other unspecified reasons that, in the opinion of the investigator or sponsor, make the subject unsuitable for enrolment. Any individual involved in the planning or conduct of this study. -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| previously treated LPLD Cohort<br>Subjects in Cohort 1 (previously treated LPLD Cohort) must have received AMT-011 during Studies CT-AMT-011-01 or -02 | |
| untreated LPLD control Cohort<br>Subjects in Cohort 2 (untreated LPLD control Cohort)) may have completed study PREPARATION-02 or known patients with genetically confirmed LPLD | |
| normal healthy control Cohort<br>Volunteers in Cohort 3 (normal healthy control Cohort) must not have LPLD | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of Pharmacodynamics | Peak level, time-to-peak, and area under the curve (AUC) for tracer in plasma and chylomicron (CM) fraction to assess metabolism of newly-formed CMs in LPLD subjects previously treated with alipogene tiparvovec and to compare with untreated LPLD subjects and healthy controls. | pre dose, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 24 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Triglyceride (TG)-rich lipoproteins | Surface and core components of TG-rich lipoproteins (TG, TChol, apoB100, and apoB48)in plasma and in the CM fraction will be measured. | pre dose, 0, 1, 2, 3, 4, 4, 6, 7, 8, 9, 12, 24 hours post dose | 
| Glucose | The levels of glucose in plasma. | pre dose, 0, 2, 3, 4, 5, 6, 7, 8, 9, 12, 24 hours post dose | 
| Adverse Events (AE) | Monitoring general state of health of subjects and to assess the safety of ingestion of a radiolabeled meal, containing the radiolabel 3H palmitate through review of the incidence and severity of adverse events (AEs). | Up to 21 days. Serious AEs will be followed to their resolution. | 
| Laboratory tests | Monitoring general state of health in LPLD subjects previously treated with alipogene tiparvovec compared to untreated LPLD subjects and healthy volunteers through review of laboratory findings (haematology, clinical chemistry, and urinalysis). | Up to 21 days | 
| Vital signs | To monitor the general state of health in LPLD subjects previously treated with alipogene tiparvovec compared to untreated LPLD subjects and healthy volunteers through review of the vital signs. | Up to 21 days | 
| Physical examination | To monitor the general state of health in LPLD subjects previously treated with alipogene tiparvovec compared to untreated LPLD subjects and healthy volunteers through review of physical examination findings. | Up to 21 days | 
| ECG | To monitor the general state of health in LPLD subjects previously treated with alipogene tiparvovec compared to untreated LPLD subjects and healthy volunteers through review of 12-lead electrocardiograms (ECGs). | Up to 21 days | 
| C-peptide | Levels of C-peptide in plasma | pre dose, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 24 post dose | 
| Non Esterified Fatty Acids (NEFA) | Levels of NEFA in plasma will be measured | pre dose, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 24 post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyperlipoproteinemia Type I