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Postprandial Fatty Acid Metabolism in Subjects With Lipoprotein Lipase Deficiency (AGL12)

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ClinicalTrials.gov Identifier: NCT04227678
Recruitment Status : Recruiting
First Posted : January 14, 2020
Last Update Posted : January 18, 2020
Sponsor:
Collaborator:
Institut de Recherches Cliniques de Montreal
Information provided by (Responsible Party):
André Carpentier, Université de Sherbrooke

Brief Summary:
Lipoprotein lipase (LPL) is an enzyme that plays an important role in removing triglycerides (TG) (molecules that transport dietary fat) from the blood. Patients with LPL deficiency (LPLD) display during their whole life very high plasma TG levels often associated with episodes of postprandial abdominal pain, malaise, blurred vision, dizziness (hyperchylomicronemia syndrome) that may lead to recurrent pancreatitis episodes. Because of their very slow clearance in blood of their chylomicron-TG, these patients need to severely restrict their dietary fat intake to avoid these complications. Fortunately, novel treatments are being developed to circumvent LPL deficiency (LPLD) metabolic effect on chylomicron-TG clearance. However, there is no data on how LPLD affect organ-specific dietary fatty acid metabolism nor how the novel therapeutic agents may change this metabolism. For example, it is currently not understood how subjects with LPLD store their DFA into adipose tissues and whether they are able to use DFA as a fuel to sustain their cardiac metabolism, as healthy individuals do. This study aims to better understand theses two questions.

Condition or disease Intervention/treatment Phase
Lipoprotein Lipase Deficiency Drug: Heparin Dietary Supplement: liquid meal Not Applicable

Detailed Description:
The study protocol includes 3 visits: the screening visit and 2 postprandial metabolic studies performed in random order at an interval of 7 to 14 days, and performed with (A1) and without (A0) an intravenous (i.v.) heparin bolus followed by 250 IU/h i.v during 6 hours. Each metabolic study will last 9 hours (with 6 hours postprandial) and will include PET and stable isotopic tracer methods. At time 0, a low fat liquid meal will be ingested over 20 minutes.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 16 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Postprandial Fatty Acid Metabolism in Subjects With Lipoprotein Lipase Deficiency
Actual Study Start Date : December 9, 2019
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : June 2021


Arm Intervention/treatment
Control group- A0

Control group: Healthy subjects with fasting glucose < 5.6, 2-hour post 75g Oral Glucose Tolerance Test (OGTT) glucose < 7.8 mmol/l and HbA1c < 5.8%; fasting TG < 1.5 mmol/l);

A0: without heparin administered

Dietary Supplement: liquid meal
low fat meal: (500 mL, 898 Kcal, 13% fat, 20.3% protein and 62.3% carbohydrates) will be ingested over 20 minutes

LPLD group-A0

LPLD group: LPL deficient subjects with history of fasting TG > 5 mmol/l and homozygote or compound heterozygote for a LPL-gene mutation;

A0: without heparin administered

Dietary Supplement: liquid meal
low fat meal: (500 mL, 898 Kcal, 13% fat, 20.3% protein and 62.3% carbohydrates) will be ingested over 20 minutes

Control group-A1

Control group: Healthy subjects with fasting glucose < 5.6, 2-hour post 75g OGTT glucose < 7.8 mmol/l and HbA1c < 5.8%; fasting TG < 1.5 mmol/l);

A1: with an intravenous (i.v.) heparin bolus (50 IU/kg i.v.) followed by 250 IU/h i.v. during 6 hours starting 15 minutes before ingestion of liquid meal.

Drug: Heparin
an intravenous (i.v.) heparin bolus (50 IU/kg i.v.) followed by 250 IU/h i.v. during 6 hours, starting 15 minutes before ingestion of liquid meal

Dietary Supplement: liquid meal
low fat meal: (500 mL, 898 Kcal, 13% fat, 20.3% protein and 62.3% carbohydrates) will be ingested over 20 minutes

LPLD group-A1

LPLD group: LPL deficient subjects with history of fasting TG > 5 mmol/l and homozygote or compound heterozygote for a LPL-gene mutation;

A1: with an intravenous (i.v.) heparin bolus (50 IU/kg i.v.) followed by 250 IU/h i.v. during 6 hours starting 15 minutes before ingestion of liquid meal.

Drug: Heparin
an intravenous (i.v.) heparin bolus (50 IU/kg i.v.) followed by 250 IU/h i.v. during 6 hours, starting 15 minutes before ingestion of liquid meal

Dietary Supplement: liquid meal
low fat meal: (500 mL, 898 Kcal, 13% fat, 20.3% protein and 62.3% carbohydrates) will be ingested over 20 minutes




Primary Outcome Measures :
  1. Organ-specific Dietary Fatty Acid (DFA) partitioning [ Time Frame: 2 months ]
    will be determined using oral administration of [18F ]-Fluoro-6-Thia- Heptadecanoic Acid (FTHA ) during whole-body acquisition.

  2. Myocardial DFA uptake [ Time Frame: 2 months ]
    will be assessed using oral administration of [18F]-FTHA during dynamic PET acquisition.


Secondary Outcome Measures :
  1. Myocardial nonesterified fatty acids (NEFA) metabolism [ Time Frame: 2 months ]
    will be determined using [11C]-palmitate during dynamic PET acquisition.

  2. Dietary fatty acid oxidation rate [ Time Frame: 6 months ]
    will be measured using breath [13C]-carbon dioxide enrichment

  3. Total oxidation rate [ Time Frame: 2 months ]
    will be determined by indirect calorimetry

  4. postprandial plasma NEFA turnover [ Time Frame: 6 months ]
    will be determined using stable isotope tracers of fatty acids

  5. postprandial plasma glucose turnover [ Time Frame: 6 months ]
    will be determined using stable isotope tracers of glucose

  6. Left ventricular function by Positron Emitting Positron (PET) ventriculography [ Time Frame: 2 months ]
    will be determined using [11C]-acetate PET/CT. 180 megabecquerel (MBq) will be administered by bolus injection

  7. Myocardial oxidative metabolism [ Time Frame: 2 months ]
    will be determined using i.v. [11C]-acetate during dynamic PET/CT scanning.

  8. Insulin sensitivity [ Time Frame: 6 months ]
    will be determined using a multiplex ELISA which will measure multiple analytes in a single experiment.

  9. Liver nonesterified fatty acids (NEFA) metabolism [ Time Frame: 2 months ]
    will be determined using [11C]-palmitate during dynamic PET acquisition.

  10. Metabolites distribution in plasma [ Time Frame: 2 months ]
    will be determined using oral administration of [18F]-FTHA



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • 8 healthy LPL-deficient individuals (LPLD subjects) with history of fasting TG > 5 mmol/l and homozygote or compound heterozygote for a LPL-gene mutation;
  • 8 control subjects (fasting glucose < 5.6, 2-hour post 75g OGTT glucose < 7.8 mmol/l and HbA1c < 5.8%; fasting TG < 1.5 mmol/l);
  • age 18 to 75 yo;
  • To be willing and able to adhere to the specifications of the protocol;
  • To have signed an informed consent document indicating that they understood the purpose

Exclusion Criteria:

  • age < 18 yo;
  • overt cardiovascular disease as assessed by medical history, physical exam, and abnormal ECG
  • Treatment with a fibrate, thiazolidinedione, beta-blocker or other drug known to affect lipid or carbohydrate metabolism (except statins, metformin, and other antihypertensive agents that can be safely interrupted);
  • Treatment with anti-hypertensive medication (only for LPL-deficient individuals);
  • presence of liver or renal disease; uncontrolled thyroid disorder;
  • previous diagnosis of heparin-induced thrombocytopenia;
  • Treatment with oral anticoagulation medication or platelet aggregation inhibiting drugs;
  • A history of major hemorrhagic event;
  • smoking (>1 cigarette/day) and/or consumption of >2 alcoholic beverages per day;;
  • Female of child-bearing potential who is pregnant, breast feeding or intends to become pregnant or pre-menopausal female with a positive serum pregnancy test at the time of enrollment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04227678


Contacts
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Contact: Frédérique Frisch 819-346-1110- ext12394 frederique.frisch@usherbrooke.ca

Locations
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Canada, Quebec
Centre de recherche du CHUS Recruiting
Sherbrooke, Quebec, Canada, J1H 5N4
Contact: Frédérique Frisch    819-346-1110- ext12394    frederique.frisch@usherbrooke.ca   
Sponsors and Collaborators
Université de Sherbrooke
Institut de Recherches Cliniques de Montreal
Investigators
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Principal Investigator: André Carpentier Université de Sherbrooke
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Responsible Party: André Carpentier, tenured professor, Université de Sherbrooke
ClinicalTrials.gov Identifier: NCT04227678    
Other Study ID Numbers: 2019-2764
First Posted: January 14, 2020    Key Record Dates
Last Update Posted: January 18, 2020
Last Verified: January 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hyperlipoproteinemia Type I
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Hyperlipoproteinemias
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Heparin
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action