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| Name | Class |
|---|---|
| CHU de Quebec-Universite Laval | OTHER |
| Centre de recherche du Centre hospitalier universitaire de Sherbrooke | OTHER |
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Metabolic dysfunction-associated steatotic liver disease (MASLD) (aka non-alcoholic fatty liver disease), commonly occurring in individuals with obesity and type 2 diabetes can lead to liver inflammation/ fibrosis. MASLD results from fat being disproportionately deposited in the liver.
The goal of this mechanistic study is to investigate metabolic response in patients aged 20 to 80 years with non-alcoholic fatty liver disease, after niacin (vitamin B3) treatment.
The main questions it aims to answer are:
Researchers will compare Niacin to a placebo (a look-alike substance that contains no drug) to compare the metabolic response.
Duration of study per participant: Up to 28 weeks
It will be a randomized crossover study with two 12-week treatment phases (niacin vs. placebo) with a 4-week washout period between the two treatment phases.
The two 12-week treatment phases will be performed in random order. The treatment will be administered once daily, at the end of the largest meal. There will be a 3-week dose escalation: from 250mg (the first week) to 750mg from week 3 onward.
The outcomes will be assessed at the end of each of these two treatment phases in all participants with metabolic visit A and B (i.e., a total of 4 metabolic visits).
Each metabolic visit will last 9 hours: it will be a test meal with perfusion of stable tracers, blood sampling, PET acquisitions using radiopharmaceuticals (18FTHA and 11C-palmitate) and MRI acquisitions.
The two visits A and B will be performed without and with acute administration of niacin with the test meal, respectively, to determine acute niacin-induced reduction in hepatic fatty acid flux.
The two visits will be performed at four to seven-day interval, in random order during the last week of each of the treatment phase.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo group | Placebo Comparator | It will be a 12-week treatment phase. The placebo treatment will be administered once daily, at the end of the largest meal. |
|
| Niacin group | Active Comparator | It will be a 12-week treatment phase. The treatment will be administered once daily, at the end of the largest meal. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Niacin (250mg) | Drug | Niacin will be orally taken once daily with the largest meal. There will be a 3-week escalation period from 250 mg to 750 mg:
|
| Measure | Description | Time Frame |
|---|---|---|
| Prolonged small-dose niacin treatment does not lead to desensitization of the niacin-induced reduction in hepatic total fatty acids flux. | Total 6 h integrated uptake of circulating NEFAs, DFAs, and all FAs in liver: represents the sum of the rate of NEFA uptake integrated over 360 min for the entire organ and the rate of DFA uptake integrated over 360 min for the entire organ. | Week 12, Week 28 |
| Measure | Description | Time Frame |
|---|---|---|
| Change in White Adipose Tissue (WAT) and lean tissue Dietary Fatty Acid (DFA) uptake | Determined from the same static (whole-body) acquisition image using oral administration of [18F]-Fluoro-6-Thia-Heptadecanoic Acid (FTHA) | Week 12, Week 28 |
| Change in total hepatic fatty acid flux |
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Inclusion Criteria:
Exclusion Criteria:
1) Presence of advanced fibrosis using any of the following criteria 1.1 (i.e., ≥ F3 based on liver stiffness > 10kPa) using vibration-controlled transient elastography (FibroScan), 1.2 (Index for Liver Fibrosis > 2.67) using Fibrosis-4 (FIB-4) which is a calculated score based on age and a combination of lab tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and platelet count), 1.3 serum ALT > 3 times the normal upper limit, 1.4 or signs of portal hypertension. 2) Other hepatic disease. 4) Overt cardiovascular or renal disease, cancer (other than non-melanoma skin cancer), or other uncontrolled medical conditions.
5) Any contraindication to MRI. 6) Previous intolerance or allergy to nicotinic acid. 7) Having participated to a research study with exposure to radiation in the last two years before the start of the study.
8) Being allergic to eggs 9) Smoking (>1 cigarette/day) and/or consumption of >2 alcoholic beverages per day.
10) Women who are pregnant or breastfeeding.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Frédérique Frisch | Contact | 1-819-346-1110 | 12394 | frederique.frisch@usherbrooke.ca |
| Name | Affiliation | Role |
|---|---|---|
| André Carpentier, MD | Université de Sherbrooke | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Centre de recherche du CHUS | Recruiting | Sherbrooke | Quebec | J1H 5N4 | Canada |
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| ID | Term |
|---|---|
| D005234 | Fatty Liver |
| ID | Term |
|---|---|
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
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| ID | Term |
|---|---|
| D009525 | Niacin |
| D009536 | Niacinamide |
| ID | Term |
|---|---|
| D009539 | Nicotinic Acids |
| D000147 | Acids, Heterocyclic |
| D006571 | Heterocyclic Compounds |
| D011725 | Pyridines |
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|
| Placebo Oral Tablet | Drug | Placebo will be orally taken once daily with the largest meal. There will be a 3-week escalation period from 250 mg to 750 mg:
|
|
represents the sum of the rate of NEFA uptake and DFA uptake (PET scan using [18F]-FTHA and [11C]-palmitate |
| Week 12, Week 28 |
| Change in hepatic Non-Esterified-Fatty-Acid (NEFA) uptake oxidation, esterification and secretion into very low-density lipoprotein (VLDL) | [11C]-Palmitate PET. Calculated from the same multicompartmental equation using liver [11C]-palmitate kinetics | Week 12, Week 28 |
| Change in Endogenous Glucose production and meal glucose systemic flux | i.v. and oral stable isotope tracer | Week 12, Week 28 |
| Change in plasma NEFA flux | calculated from i.v. stable isotope tracer (mass spectrometry). | Week 12, Week 28 |
| Change in hepatic Triglyceride (TG) content | magnetic resonance imaging (MRI) | Week 12, Week 28 |
| Change in insulin secretion | Determined by measuring C-peptide kinetics following the liquid meal | Week 12, Week 28 |
| Change in hormonal response | Multiplex assay | Week 12, Week 28 |
| Change in metabolite response | Colorimetric assay | Week 12, Week 28 |
| Change in plasma distribution of DFA metabolites | calculated from i.v. and oral stable isotope tracers (mass spectrometry) incorporated into triglyceride-rich lipoproteins and NEFA. | Week 12, Week 28 |
| Change in glycerol turnover | calculated from [1,1,2,3,3-2H]-glycerol i.v. | Week 12, Week 28 |
| Change in total substrate utilisation | measured by using indirect calorimetry | Week 12, Week 28 |
| Change in insulin resistance /sensitivity | Determined by measuring circulating glucose, NEFA and insulin following the liquid meal. | Week 12, Week 28 |
| Circulating markers of hepatic inflammation | Measurement of Alanine aminotransferase (ALT), Aspartate transaminase (AST) and platelet count for calculation of fibrosis-4 which is an index for liver fibrosis. | Week1, Week 12, Week 16, Week 28 |
| Adverse events | up to 28 weeks |
| D006573 |
| Heterocyclic Compounds, 1-Ring |