Hepatic Mitochondrial Metabolism in Fatty Liver Disease in Humans

NCT ID: NCT06559878

Last Updated: 2024-08-19

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

ENROLLING_BY_INVITATION

Clinical Phase

NA

Total Enrollment

12 participants

Study Classification

INTERVENTIONAL

Study Start Date

2024-09-01

Study Completion Date

2027-01-31

Brief Summary

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The goal of this clinical trial is to investigate in healthy volunteers the mechanisms by which ethanol and lipids, the two key risk factors of steatotic liver disease (SLD), affect liver mitochondrial metabolism.

The main question it aims to answer is:

• Does acute administration of ethanol and lipids increase hepatic mitochondrial reductive stress as determined by orally ingested stable isotope tracer 13C-alpha-ketoisocaproate and by plasma beta-hydroxybutyrate to acetoacetate ratio (b-OHB/AcAc) in humans?

Detailed Description

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In this study we investigate the effects of ethanol and lipids on hepatic mitochondrial metabolism in healthy volunteers.

At first visit, an informed consent will be obtained, followed by assessment of inclusion/exclusion criteria. Participants fulfilling the criteria will be enrolled in the study. Body composition will be determined with bioelectrical impedance.

At second visit hepatic lipid content will be measured with magnetic resonance spectroscopy.

Participants will be given in random order on three separate visits (3-5):

* Intravenous infusion of ethanol and normal saline (breath alcohol content target and upper limit corresponding to 0.6 per mil in blood)
* Intravenous infusions of lipid emulsion, heparin and normal saline
* Intravenous infusion of normal saline

On study visits participant will drink a tracer dose of 13C-alpha-ketoisocaproate and L-Leucine. Breath samples are collected at different time points for determination of 13C enrichment of CO2. Furthermore "arterialized" blood samples are taken during study visits to obtain beta-hydroxybutyrate to acetoacetate ratios (b-OHB/AcAc) at different timepoints.

Whole-body oxidation of lipids, carbohydrates and protein will be determined using indirect calorimetry.

Conditions

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Non-alcoholic Fatty Liver Disease NAFLD

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

The study protocol includes five clinical visits. At first visit, an informed consent will be obtained, followed by assessment of inclusion/exclusion criteria. Participants fulfilling the criteria will be enrolled in the study. At second visit, magnetic resonance studies will be performed to quantify liver fat content. Visits 3-5 consist of metabolic studies using the 13C-ketoisocaproate breath test and, in a random order, infusions of either a) saline alone, b) saline, a lipid emulsion and heparin or c) saline and ethanol.
Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

NONE

Study Groups

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The order of metabolic visits: 1.Normal saline, 2.Lipid emulsion, 3.Ethanol

Group Type EXPERIMENTAL

13C-α-Ketoisocaproic Acid Breath Test

Intervention Type DIAGNOSTIC_TEST

13C-α-Ketoisocaproic acid with L-Leucine soluted in citric acid drink. The solution is administered orally during metabolic visits (3.-5.).

Ethanol

Intervention Type DIETARY_SUPPLEMENT

6% ethanol soluted in normal saline is given intravenously during one metabolic visit.

Lipid Emulsion

Intervention Type DIETARY_SUPPLEMENT

Lipid emulsion, heparin and normal saline are given intravenously during one metabolic visit.

Normal Saline

Intervention Type OTHER

Normal saline is given intravenously during one metabolic visit.

The order of metabolic visits: 1. Normal saline, 2. Ethanol, 3. Lipid emulsion

Group Type EXPERIMENTAL

13C-α-Ketoisocaproic Acid Breath Test

Intervention Type DIAGNOSTIC_TEST

13C-α-Ketoisocaproic acid with L-Leucine soluted in citric acid drink. The solution is administered orally during metabolic visits (3.-5.).

Ethanol

Intervention Type DIETARY_SUPPLEMENT

6% ethanol soluted in normal saline is given intravenously during one metabolic visit.

Lipid Emulsion

Intervention Type DIETARY_SUPPLEMENT

Lipid emulsion, heparin and normal saline are given intravenously during one metabolic visit.

Normal Saline

Intervention Type OTHER

Normal saline is given intravenously during one metabolic visit.

The order of metabolic visits: 1.Lipid emulsion, 2.Normal saline, 3.Ethanol

Group Type EXPERIMENTAL

13C-α-Ketoisocaproic Acid Breath Test

Intervention Type DIAGNOSTIC_TEST

13C-α-Ketoisocaproic acid with L-Leucine soluted in citric acid drink. The solution is administered orally during metabolic visits (3.-5.).

Ethanol

Intervention Type DIETARY_SUPPLEMENT

6% ethanol soluted in normal saline is given intravenously during one metabolic visit.

Lipid Emulsion

Intervention Type DIETARY_SUPPLEMENT

Lipid emulsion, heparin and normal saline are given intravenously during one metabolic visit.

Normal Saline

Intervention Type OTHER

Normal saline is given intravenously during one metabolic visit.

The order of metabolic visits: 1.Lipid emulsion, 2.Ethanol, 3.Normal saline

Group Type EXPERIMENTAL

13C-α-Ketoisocaproic Acid Breath Test

Intervention Type DIAGNOSTIC_TEST

13C-α-Ketoisocaproic acid with L-Leucine soluted in citric acid drink. The solution is administered orally during metabolic visits (3.-5.).

Ethanol

Intervention Type DIETARY_SUPPLEMENT

6% ethanol soluted in normal saline is given intravenously during one metabolic visit.

Lipid Emulsion

Intervention Type DIETARY_SUPPLEMENT

Lipid emulsion, heparin and normal saline are given intravenously during one metabolic visit.

Normal Saline

Intervention Type OTHER

Normal saline is given intravenously during one metabolic visit.

The order of metabolic visits: 1. Ethanol, 2. Normal saline, 3. Lipid emulsion

Group Type EXPERIMENTAL

13C-α-Ketoisocaproic Acid Breath Test

Intervention Type DIAGNOSTIC_TEST

13C-α-Ketoisocaproic acid with L-Leucine soluted in citric acid drink. The solution is administered orally during metabolic visits (3.-5.).

Ethanol

Intervention Type DIETARY_SUPPLEMENT

6% ethanol soluted in normal saline is given intravenously during one metabolic visit.

Lipid Emulsion

Intervention Type DIETARY_SUPPLEMENT

Lipid emulsion, heparin and normal saline are given intravenously during one metabolic visit.

Normal Saline

Intervention Type OTHER

Normal saline is given intravenously during one metabolic visit.

The order of metabolic visits: 1. Ethanol, 2. Lipid emulsion, 3. Normal saline

Group Type EXPERIMENTAL

13C-α-Ketoisocaproic Acid Breath Test

Intervention Type DIAGNOSTIC_TEST

13C-α-Ketoisocaproic acid with L-Leucine soluted in citric acid drink. The solution is administered orally during metabolic visits (3.-5.).

Ethanol

Intervention Type DIETARY_SUPPLEMENT

6% ethanol soluted in normal saline is given intravenously during one metabolic visit.

Lipid Emulsion

Intervention Type DIETARY_SUPPLEMENT

Lipid emulsion, heparin and normal saline are given intravenously during one metabolic visit.

Normal Saline

Intervention Type OTHER

Normal saline is given intravenously during one metabolic visit.

Interventions

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13C-α-Ketoisocaproic Acid Breath Test

13C-α-Ketoisocaproic acid with L-Leucine soluted in citric acid drink. The solution is administered orally during metabolic visits (3.-5.).

Intervention Type DIAGNOSTIC_TEST

Ethanol

6% ethanol soluted in normal saline is given intravenously during one metabolic visit.

Intervention Type DIETARY_SUPPLEMENT

Lipid Emulsion

Lipid emulsion, heparin and normal saline are given intravenously during one metabolic visit.

Intervention Type DIETARY_SUPPLEMENT

Normal Saline

Normal saline is given intravenously during one metabolic visit.

Intervention Type OTHER

Other Intervention Names

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Alcohol

Eligibility Criteria

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Inclusion Criteria

1. Participants must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent.
2. Subject must be likely to be available to complete all protocol-required study visits or procedures, to the best of the subject's and investigator's knowledge.
3. Age range from 18-75 years.
4. No known hypersensitivity to egg, soy, or peanut protein, or to any of the substances of Intralipid 20%, or to any other substance to be administered during the study.
5. No severe hyperlipidemia or hemophagocytotic syndrome as judged by history and physical examination and standard laboratory tests.
6. No other liver disease except for SLD.
7. No advanced liver disease as judged by history and physical examination and standard laboratory tests.
8. No claustrophobia or metal implants to allow magnetic resonance studies.
9. No pregnancy or lactation in women.
10. No known or anticipated difficulties in cannulation of peripheral veins.
11. No history or evidence of any other clinically significant disorder, condition or disease other than those outlined above that, in the opinion of the investigator may compromise the ability of the subject to give written informed consent, would pose a risk to subject safety, or interfere with the study evaluation, procedures or completion.
12. No drinking problem based on AUDIT questionnaire.
13. No use of medications interacting with alcohol.
14. No history of heparin induced thrombosytopenia (HIT) or bleeding tendency.
15. No current use of warfarin, direct anticoagulants, or thrombocyte inhibitors.
Minimum Eligible Age

18 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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Helsinki University Central Hospital

OTHER

Sponsor Role lead

Responsible Party

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Panu Luukkonen

MD, PhD

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Panu Luukkonen, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Helsinki University Central Hospital

Locations

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Helsinki Central University Hospital

Helsinki, Uusimaa, Finland

Site Status

Countries

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Finland

Other Identifiers

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HUS/8748/2023

Identifier Type: -

Identifier Source: org_study_id

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