New Treatment for Lipoprotein Lipase Deficiency

(AGL12 Trial)

Recruiting in Palo Alto (17 mi)

Overseen by André Carpentier

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: Université de Sherbrooke

Must not be taking: Fibrates, Thiazolidinediones, Beta-blockers, others

Disqualifiers: Cardiovascular disease, Liver disease, Renal disease, others

No Placebo Group

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires participants to stop taking certain medications that affect lipid or carbohydrate metabolism, such as fibrates, thiazolidinediones, and beta-blockers. However, statins, metformin, and some antihypertensive medications can be safely interrupted. If you are on any of these medications, you may need to stop them to participate in the trial.

What data supports the effectiveness of the drug Heparin for treating Lipoprotein Lipase Deficiency?

Research shows that heparin can release lipoprotein lipase, an enzyme important for breaking down fats in the blood, which may help manage conditions related to fat metabolism. However, the effectiveness of heparin specifically for Lipoprotein Lipase Deficiency is not directly addressed in the studies. ^{1 2 3 4 5}

Is unfractionated heparin (UFH) generally safe for humans?

Unfractionated heparin (UFH) is generally safe but can have side effects like bleeding, low platelet count (heparin-induced thrombocytopenia), and bone density loss (osteopenia) with long-term use. It is considered a high-alert drug due to the potential for medication errors, which can lead to harmful effects. ^{6 7 8 9 10}

How does the new drug for lipoprotein lipase deficiency differ from existing treatments?

The new drug for lipoprotein lipase deficiency may involve a unique mechanism related to heparin binding, as research suggests that specific regions in the lipoprotein lipase enzyme are crucial for its interaction with heparin, which is not a focus of standard treatments. This could potentially enhance the drug's effectiveness in managing the condition by targeting these specific binding sites. ^{1 3 4 11 12}

Research Team

André Carpentier

Principal Investigator

Université de Sherbrooke

Eligibility Criteria

This trial is for adults aged 18-75 with Lipoprotein Lipase Deficiency (LPLD), evidenced by high fasting triglyceride levels and specific gene mutations. Healthy individuals with normal blood sugar and triglyceride levels can also join as controls. Participants must not have cardiovascular disease, a history of certain blood disorders or be on medications affecting lipid metabolism.

Inclusion Criteria

Control subjects must have normal glucose and triglyceride levels.

Willing and able to adhere to the specifications of the protocol

Signed an informed consent document indicating understanding of the purpose

Exclusion Criteria

I am under 18 years old.

You have been diagnosed with heparin-induced low platelet count before.

I do not have liver, kidney diseases, or uncontrolled thyroid issues.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

Metabolic Study A0

Participants undergo a postprandial metabolic study without heparin administration, including PET and stable isotopic tracer methods

9 hours

1 visit (in-person)

Metabolic Study A1

Participants undergo a postprandial metabolic study with heparin administration, including PET and stable isotopic tracer methods

9 hours

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after metabolic studies

6 months

Treatment Details

Interventions

• Heparin (Anticoagulant)

Trial Overview The study investigates how LPLD affects the body's handling of dietary fats after eating, specifically looking at fat storage in tissues and its use as fuel for heart function. It involves administering heparin and a liquid meal to understand these metabolic processes in both LPLD patients and healthy controls.

Participant Groups

Group I: LPLD group-A1 Experimental Treatment 2 Interventions

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.

Group II: LPLD group-A0 Experimental Treatment 1 Intervention

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

Group III: Control group-A1 Experimental Treatment 2 Interventions

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.

Group IV: Control group- A0 Experimental Treatment 1 Intervention

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

Who Is Running the Clinical Trial?

Université de Sherbrooke

Lead Sponsor

Trials

317

Recruited

79,300+

Pierre Cossette

Université de Sherbrooke

Chief Executive Officer since 2017

MD from Université de Sherbrooke

Denyse Rémillard

Université de Sherbrooke

Chief Medical Officer since 2023

MD from Université de Sherbrooke

Institut de Recherches Cliniques de Montreal

Collaborator

Trials

72

Recruited

10,300+

Jean-François Côté

Institut de Recherches Cliniques de Montreal

Chief Executive Officer since 2021

PhD in Molecular Biology from Université de Montréal

Dr. André Veillette

Institut de Recherches Cliniques de Montreal

Chief Medical Officer since 2019

MD from Laval University

Findings from Research

In patients with abetalipoproteinemia, the absence of triglyceride-rich lipoproteins is linked to significantly reduced activity of both hepatic lipase and lipoprotein lipase after heparin administration, indicating a potential mechanism for lipid metabolism impairment.

In contrast, patients with heterozygous hypobetalipoproteinemia exhibited normal enzyme activity, suggesting that not all lipid disorders affect lipase activity in the same way.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipoprotein lipase and hepatic lipase activity after heparin administration in abetalipoproteinemia and hypobetalipoproteinemia. Illingworth, DR., Alam, SS., Alam, NA.[2019]

In a study involving rats, low-molecular-weight heparin (LMWH) caused a rapid decline in lipoprotein lipase (LPL) activity within 30 minutes after injection, decreasing by over 80%, while unfractionated heparin (UFH) maintained LPL levels during the same period.

Both heparins released LPL from vascular sites, but LMWH was less effective at delaying its removal by the liver compared to UFH, suggesting that LMWH may lead to faster catabolism of functional LPL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Depletion of lipoprotein lipase after heparin administration. Chevreuil, O., Hultin, M., Ostergaard, P., et al.[2019]

PK 10169, a low molecular weight heparin with a molecular weight of 4000-6000, has a significantly reduced anticoagulant effect in vitro compared to standard heparin.

Despite its lower anticoagulant capacity, PK 10169 effectively retains the ability to enhance lipoprotein lipase and hepatic lipase activity after intravenous injection, suggesting potential therapeutic benefits in lipid metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Release of LPL activity after intravenous injection of a low molecular weight heparin. Etienne, J., Millot, F., Pieron, R., et al.[2019]

In a study involving seven chronic haemodialysis patients, switching from unfractionated heparin (UH) to low molecular weight heparin (LMWH) resulted in a significant increase in tissue releasable lipoprotein lipase activity after 6 months, suggesting improved lipid metabolism over time.

Hepatic lipase activity remained unchanged regardless of the type of heparin used, indicating that LMWH specifically benefits lipoprotein lipase stores without affecting hepatic lipase levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Different types of heparin in haemodialysis: long-term effects on post-heparin lipases. Arnadottir, M., Kurkus, J., Nilsson-Ehle, P.[2019]

In a study of 720 patients with acute venous thromboembolism (VTE), subcutaneous unfractionated heparin (UFH) was found to be as effective as fixed-dose nadroparin for preventing recurrent thromboembolic events, with similar rates of recurrence (4.2% for UFH vs. 3.9% for nadroparin).

The safety profiles were comparable, with only 1.1% of patients on UFH and 0.8% on nadroparin experiencing major bleeding, indicating that both treatments are safe options for initial VTE management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous adjusted-dose unfractionated heparin vs fixed-dose low-molecular-weight heparin in the initial treatment of venous thromboembolism. Prandoni, P., Carnovali, M., Marchiori, A.[2006]

In a study involving 52 horses with colic, low molecular weight heparin (LMWH) was found to have significantly fewer side effects compared to unfractionated heparin (UFH), particularly regarding changes in jugular veins and blood parameters.

Horses treated with UFH experienced a decrease in packed cell volume and prolonged coagulation times, while those treated with LMWH showed stable blood parameters, suggesting that LMWH is a safer option for preventing coagulation disorders in colic-affected horses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of unfractioned and low molecular weight heparin for prophylaxis of coagulopathies in 52 horses with colic: a randomised double-blind clinical trial. Feige, K., Schwarzwald, CC., Bombeli, T.[2019]

A Phase I pharmacokinetic study showed that oral heparin/SNAC reaches peak anti-factor Xa activity within 45-60 minutes and returns to baseline after 4 hours, indicating effective absorption and action.

In a randomized trial with 123 patients undergoing total hip arthroplasty, oral heparin/SNAC demonstrated a safety profile similar to subcutaneous unfractionated heparin, with no significant differences in venous thromboembolic events or major bleeding, supporting its potential for thromboprophylaxis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral heparin administration with a novel drug delivery agent (SNAC) in healthy volunteers and patients undergoing elective total hip arthroplasty. Berkowitz, SD., Marder, VJ., Kosutic, G., et al.[2023]

Enoxaparin was found to be more effective than unfractionated heparin (UFH) in reducing the combined risk of death, myocardial infarction, and urgent revascularization in both obese and non-obese patients, as well as those without severe renal impairment.

Patients with severe renal impairment showed a higher risk of adverse clinical events and major hemorrhages, indicating that while enoxaparin is effective, this population may require closer monitoring due to increased risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of unfractionated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: analysis from the ESSENCE and TIMI 11B studies. Spinler, SA., Inverso, SM., Cohen, M., et al.[2014]

Heparin injection leads to a quick rise in serum lipoprotein lipase levels, which are believed to circulate as a complex with heparin, indicating a potential mechanism for enhancing lipolysis.

The study in unanesthetized dogs shows that the liver plays a crucial role in removing lipoprotein lipase activity from circulation, and high doses of heparin can inhibit this removal process, suggesting a two-step inactivation mechanism involving heparin breakdown.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of heparin on the inactivation of serum lipoprotein lipase by the liver in unanesthetized dogs. Whayne, TF., Felts, JM., Harris, PA.[2018]

References

1. United States pubmed.ncbi.nlm.nih.gov

Long-term use of low molecular weight heparin ameliorates hyperlipidemia in patients on hemodialysis. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Lipoprotein lipase and hepatic lipase activity after heparin administration in abetalipoproteinemia and hypobetalipoproteinemia. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Depletion of lipoprotein lipase after heparin administration. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Release of LPL activity after intravenous injection of a low molecular weight heparin. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Different types of heparin in haemodialysis: long-term effects on post-heparin lipases. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Unfractionated heparin: focus on a high-alert drug. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Subcutaneous adjusted-dose unfractionated heparin vs fixed-dose low-molecular-weight heparin in the initial treatment of venous thromboembolism. [2006]

8. United States pubmed.ncbi.nlm.nih.gov

Comparison of unfractioned and low molecular weight heparin for prophylaxis of coagulopathies in 52 horses with colic: a randomised double-blind clinical trial. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Oral heparin administration with a novel drug delivery agent (SNAC) in healthy volunteers and patients undergoing elective total hip arthroplasty. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Safety and efficacy of unfractionated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: analysis from the ESSENCE and TIMI 11B studies. [2014]

11. United States pubmed.ncbi.nlm.nih.gov

Effect of heparin on the inactivation of serum lipoprotein lipase by the liver in unanesthetized dogs. [2018]

12. United States pubmed.ncbi.nlm.nih.gov

Mutagenesis in four candidate heparin binding regions (residues 279-282, 291-304, 390-393, and 439-448) and identification of residues affecting heparin binding of human lipoprotein lipase. [2021]