Liver Fibrosis/NASH, Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD), Non-Alcoholic Steato-Hepatitis (NASH)
Conditions
Keywords
Fatty liver, Niacin, vitamin B3, nicotinic acid
Brief summary
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: * Does Niacin lower the fat deposition in the liver? * Does Niacin raise White Adipose Tissue storage of dietary fatty acids? 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
Detailed description
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.
Interventions
DRUGNiacin (250mg)
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: * Week 1: 250mg * Week 2: 500mg * Week 3 to Week 12: 750mg (3 x 250mg caplets)
DRUGPlacebo Oral Tablet
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: * Week 1: 250mg * Week 2: 500mg * Week 3 to Week 12: 750mg (3 x 250mg caplets)
Sponsors
Université de Sherbrooke
CHU de Quebec-Universite Laval
Centre de recherche du Centre hospitalier universitaire de Sherbrooke
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* aged 20 to 80 years; * diagnosed with MASLD, defined as the presence of liver steatosis + abdominal obesity (as defined by the International Diabetes Federation country/ethnic group-specific 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Prolonged small-dose niacin treatment does not lead to desensitization of the niacin-induced reduction in hepatic total fatty acids flux. | Week 12, Week 28 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in total hepatic fatty acid flux | Week 12, Week 28 | represents the sum of the rate of NEFA uptake and DFA uptake (PET scan using \[18F\]-FTHA and \[11C\]-palmitate |
| Change in hepatic Non-Esterified-Fatty-Acid (NEFA) uptake oxidation, esterification and secretion into very low-density lipoprotein (VLDL) | Week 12, Week 28 | \[11C\]-Palmitate PET. Calculated from the same multicompartmental equation using liver \[11C\]-palmitate kinetics |
| Change in Endogenous Glucose production and meal glucose systemic flux | Week 12, Week 28 | i.v. and oral stable isotope tracer |
| Change in plasma NEFA flux | Week 12, Week 28 | calculated from i.v. stable isotope tracer (mass spectrometry). |
| Change in hepatic Triglyceride (TG) content | Week 12, Week 28 | magnetic resonance imaging (MRI) |
| Change in insulin secretion | Week 12, Week 28 | Determined by measuring C-peptide kinetics following the liquid meal |
| Change in hormonal response | Week 12, Week 28 | Multiplex assay |
| Change in White Adipose Tissue (WAT) and lean tissue Dietary Fatty Acid (DFA) uptake | Week 12, Week 28 | Determined from the same static (whole-body) acquisition image using oral administration of \[18F\]-Fluoro-6-Thia-Heptadecanoic Acid (FTHA) |
| Change in plasma distribution of DFA metabolites | Week 12, Week 28 | calculated from i.v. and oral stable isotope tracers (mass spectrometry) incorporated into triglyceride-rich lipoproteins and NEFA. |
| Change in glycerol turnover | Week 12, Week 28 | calculated from \[1,1,2,3,3-2H\]-glycerol i.v. |
| Change in total substrate utilisation | Week 12, Week 28 | measured by using indirect calorimetry |
| Change in insulin resistance /sensitivity | Week 12, Week 28 | Determined by measuring circulating glucose, NEFA and insulin following the liquid meal. |
| Circulating markers of hepatic inflammation | Week1, Week 12, Week 16, Week 28 | Measurement of Alanine aminotransferase (ALT), Aspartate transaminase (AST) and platelet count for calculation of fibrosis-4 which is an index for liver fibrosis. |
| Adverse events | up to 28 weeks | — |
| Change in metabolite response | Week 12, Week 28 | Colorimetric assay |
Countries
Canada
Contacts
CONTACTFrédérique Frisch
PRINCIPAL_INVESTIGATORAndré Carpentier, MD
Université de Sherbrooke
Outcome results
None listed