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Quantifying Hepatic Mitochondrial Fluxes in Humans

Primary Purpose

Non-Alcoholic Fatty Liver Disease, Type 2 Diabetes, Mitochondrial Metabolism Disorders

Status

Recruiting

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Pioglitazone

Placebo

About this trial

This is an interventional basic science trial for Non-Alcoholic Fatty Liver Disease focused on measuring NAFLD, Diet, Exercise

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

T2D with NAFL

Inclusion Criteria:

Confirmed T2D based on OGTT (2 h glucose ≥200 mg/dl).
Treated with diet, metformin, and/or sulfonylurea and in good general health determined by medical history, physical exam, and routine blood chemistries;
age = 18-75 years;
BMI = 25-40 kg/m2;
HbA1c = 7-10%; stable body weight (±4 pounds) over the preceding 3-months;
not taking any medication known to affect glucose metabolism other than antidiabetic medications.
Evidence of moderate/severe fatty liver (steatosis; grade S2/S3 on FibroScan corresponding to ≥10% fat on MRI-PDFF) and no/minimal hepatic fibrosis (grade F0/F1 on FibroScan).

Exclusion Criteria:

Alcohol consumption >14 units/week for women and >21 units/week for men.
Cirrhosis (fibrosis stage 4).
Type 1 diabetes and/or GAD positive subjects.
Subjects not drug naive or have been on metformin more than 3 months.
Presence of proliferative retinopathy.
Urine albumin excretion > 300 mg/day.
Evidence of other forms of chronic liver disease, including alcoholic liver disease, hepatitis B and C, primary biliary cholangitis, suspected/proven liver cancer and any other liver disease other than NAFLD.
History of NY Class III-IV heart failure

T2D with NASH

Inclusion Criteria:

Confirmed T2D based on OGTT (2 h glucose ≥200 mg/dl).
Treated with diet, metformin, and/or sulfonylurea and in good general health determined by medical history, physical exam, and routine blood chemistries;
age = 18-75 years;
BMI = 25-40 kg/m2;
HbA1c = 7-10%;
stable body weight (±4 pounds) over the preceding 3-months;
not taking any medication known to affect glucose metabolism other than antidiabetic medications.
Evidence of moderate/severe fatty liver (steatosis; grade S2/S3 on FibroScan corresponding to ≥10% liver fat on MRI-PDFF) and moderate/severe hepatic fibrosis (grade F2/F3 on FibroScan).

Exclusion Criteria:

Alcohol consumption >14 units/week for women and >21 units/week for men.
Cirrhosis (fibrosis stage 4).
Type 1 diabetes and/or GAD positive subjects.
Subjects not drug naive or have been on metformin more than 3 months.
Presence of proliferative retinopathy.
Urine albumin excretion > 300 mg/day.
Evidence of other forms of chronic liver disease, including alcoholic liver disease, hepatitis B and C, primary biliary cholangitis, suspected/proven liver cancer and any other liver disease other than NAFLD.
History of NY Class III-IV heart failure

Sites / Locations

Texas Diabetes Institute - University Health SystemRecruiting
University of Texas Health Science Center at San AntonioRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Arm Label

NAFL TZD

NAFL Placebo

NASH TZD

NASH Placebo

Arm Description

T2D with non-alcoholic fatty liver (NAFL), treated with pioglitazone

T2D with non-alcoholic fatty liver (NAFL), treated with placebo

T2D with non-alcoholic steatohepatitis (NASH), treated with pioglitazone

T2D with non-alcoholic steatohepatitis (NASH), treated with placebo

Outcomes

Primary Outcome Measures

Effect of pioglitazone on hepatic mitochondrial TCA cycle fluxes

Quantitated using a combine stable isotope approach before and after treatment with pioglitazone

Secondary Outcome Measures

Mean absolute change from baseline in liver fat content by magnetic resonance Imaging - Proton Density Fat Fraction (MRI-PDFF)

Mean absolute change from baseline in liver fat content by MRI-PDFF

Mean change from baseline in body weight

Mean change from baseline in body composition

Mean change from baseline in lean and fat mass measured by DEXA

Quantitate the effect of pioglitazone on liver histology by improvement of fibrosis

Percentage of Participants with ≥1 Point Decrease in Fibrosis Stage with No Worsening of NASH on Liver Histology

Quantitate the effect of pioglitazone on NAFLD Activity Score (NAS)

Percentage of Participants that Achieve a ≥2 Point Decrease in NAS on Liver Histology, with ≥1 Point Reduction in at Least 2 NAS Components

Examine the effect of pioglitazone on non-invasive markers of NAFLD

Mean change from baseline in Fibrosis-4 (FIB-4), transient elastography (Fibroscan®), NAFLD fibrosis score (NFS), alanine transaminase (ALT) and aspartate transaminase (AST)

Effect of pioglitazone on the hepatic lipidome

Lipidomics will be carried out using mass-spectrometry methods

Effect of pioglitazone on hepatic gene regulatory networks

Multimodal RNA-Seq and ATAC-Seq will be used to examine gene regulatory networks in liver samples

Full Information

NCT ID

NCT05305287

First Posted

March 22, 2022

Last Updated

August 21, 2023

Sponsor

The University of Texas Health Science Center at San Antonio

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

1. Study Identification

Unique Protocol Identification Number

NCT05305287

Brief Title

Quantifying Hepatic Mitochondrial Fluxes in Humans

Official Title

Quantitation of Hepatic Mitochondrial Fluxes in Humans With Nonalcoholic Fatty Liver Disease (NAFLD)

Study Type

Interventional

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Recruiting

Study Start Date

November 1, 2022 (Actual)

Primary Completion Date

March 31, 2027 (Anticipated)

Study Completion Date

March 31, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

The University of Texas Health Science Center at San Antonio

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

In this study the investigators will quantitate hepatic mitochondrial fluxes in T2D patients with NAFL and NASH before and after 16-weeks treatment with the insulin sensitizer pioglitazone

Detailed Description

The study team will examine hepatic mitochondrial TCA flux and pyruvate cycling (oral [U-13C]-propionate), hepatic gluconeogenesis (oral 2H2O), and hepatic insulin sensitivity (intravenous [3,4-13C2]-glucose with euglycemic insulin clamp) before and after 16 weeks treatment with the FDA approved insulin sensitizer pioglitazone. These studies will be performed in (i) type 2 diabetic subjects with NAFL but without evidence of fibrosis, and (ii) type 2 diabetic patients with NASH. Liver biopsies will be obtained before and after treatment for the diagnosis of NAFL/NASH and for molecular analyses.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Non-Alcoholic Fatty Liver Disease, Type 2 Diabetes, Mitochondrial Metabolism Disorders

Keywords

NAFLD, Diet, Exercise

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Model Description

Patients with T2D and NAFL or NASH will be randomly assigned to receive placebo or pioglitazone treatment groups.

Masking

Participant

Allocation

Randomized

Enrollment

60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

NAFL TZD

Arm Type

Experimental

Arm Description

T2D with non-alcoholic fatty liver (NAFL), treated with pioglitazone

Arm Title

NAFL Placebo

Arm Type

Placebo Comparator

Arm Description

T2D with non-alcoholic fatty liver (NAFL), treated with placebo

Arm Title

NASH TZD

Arm Type

Experimental

Arm Description

T2D with non-alcoholic steatohepatitis (NASH), treated with pioglitazone

Arm Title

NASH Placebo

Arm Type

Placebo Comparator

Arm Description

T2D with non-alcoholic steatohepatitis (NASH), treated with placebo

Intervention Type

Drug

Intervention Name(s)

Pioglitazone

Other Intervention Name(s)

Actos

Intervention Description

An insulin sensitizer and anti-diabetic agent. Participants will be started on 15 mg/day, increased to 30 mg/day at week 2 and then to 45 mg/day at week 4.

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

Placebo for pioglitazone

Primary Outcome Measure Information:

Title

Effect of pioglitazone on hepatic mitochondrial TCA cycle fluxes

Description

Quantitated using a combine stable isotope approach before and after treatment with pioglitazone

Time Frame

Baseline, week 16

Secondary Outcome Measure Information:

Title

Mean absolute change from baseline in liver fat content by magnetic resonance Imaging - Proton Density Fat Fraction (MRI-PDFF)

Description

Mean absolute change from baseline in liver fat content by MRI-PDFF

Time Frame

Baseline, Week 16

Title

Mean change from baseline in body weight

Description

Mean change from baseline in body weight

Time Frame

Baseline, Week 16

Title

Mean change from baseline in body composition

Description

Mean change from baseline in lean and fat mass measured by DEXA

Time Frame

Baseline, Week 16

Title

Quantitate the effect of pioglitazone on liver histology by improvement of fibrosis

Description

Percentage of Participants with ≥1 Point Decrease in Fibrosis Stage with No Worsening of NASH on Liver Histology

Time Frame

Week 16

Title

Quantitate the effect of pioglitazone on NAFLD Activity Score (NAS)

Description

Percentage of Participants that Achieve a ≥2 Point Decrease in NAS on Liver Histology, with ≥1 Point Reduction in at Least 2 NAS Components

Time Frame

Week 16

Title

Examine the effect of pioglitazone on non-invasive markers of NAFLD

Description

Mean change from baseline in Fibrosis-4 (FIB-4), transient elastography (Fibroscan®), NAFLD fibrosis score (NFS), alanine transaminase (ALT) and aspartate transaminase (AST)

Time Frame

Baseline, Week 16

Title

Effect of pioglitazone on the hepatic lipidome

Description

Lipidomics will be carried out using mass-spectrometry methods

Time Frame

Baseline, Week 16

Title

Effect of pioglitazone on hepatic gene regulatory networks

Description

Multimodal RNA-Seq and ATAC-Seq will be used to examine gene regulatory networks in liver samples

Time Frame

Baseline, Week 16

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

T2D with NAFL Inclusion Criteria: Confirmed T2D based on OGTT (2 h glucose ≥200 mg/dl). Treated with diet, metformin, and/or sulfonylurea and in good general health determined by medical history, physical exam, and routine blood chemistries; age = 18-80 years; BMI = 25-40 kg/m2; HbA1c = 7-10%; stable body weight (±4 pounds) over the preceding 3-months; not taking any medication known to affect glucose metabolism other than antidiabetic medications. Evidence of moderate/severe fatty liver (steatosis; grade S2/S3 on FibroScan corresponding to ≥10% fat on MRI-PDFF) and no/minimal hepatic fibrosis (grade F0/F1 on FibroScan). Exclusion Criteria: Alcohol consumption >14 units/week for women and >21 units/week for men. Cirrhosis (fibrosis stage 4). Type 1 diabetes and/or GAD positive subjects. Subjects not drug naive or have been on metformin more than 3 months. Presence of proliferative retinopathy. Urine albumin excretion > 300 mg/day. Evidence of other forms of chronic liver disease, including alcoholic liver disease, hepatitis B and C, primary biliary cholangitis, suspected/proven liver cancer and any other liver disease other than NAFLD. History of NY Class III-IV heart failure T2D with NASH Inclusion Criteria: Confirmed T2D based on OGTT (2 h glucose ≥200 mg/dl). Treated with diet, metformin, and/or sulfonylurea and in good general health determined by medical history, physical exam, and routine blood chemistries; age = 18-80 years; BMI = 25-40 kg/m2; HbA1c = 7-10%; stable body weight (±4 pounds) over the preceding 3-months; not taking any medication known to affect glucose metabolism other than antidiabetic medications. Evidence of moderate/severe fatty liver (steatosis; grade S2/S3 on FibroScan corresponding to ≥10% liver fat on MRI-PDFF) and moderate/severe hepatic fibrosis (grade F2/F3 on FibroScan). Exclusion Criteria: Alcohol consumption >14 units/week for women and >21 units/week for men. Cirrhosis (fibrosis stage 4). Type 1 diabetes and/or GAD positive subjects. Subjects not drug naive or have been on metformin more than 3 months. Presence of proliferative retinopathy. Urine albumin excretion > 300 mg/day. Evidence of other forms of chronic liver disease, including alcoholic liver disease, hepatitis B and C, primary biliary cholangitis, suspected/proven liver cancer and any other liver disease other than NAFLD. History of NY Class III-IV heart failure

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Luke Norton, PhD

Phone

210-567-0739

nortonl@uthscsa.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Andrea Hansis-Diarte, MPH

Phone

210-567-3208

hansisdiarte@uthscs.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Luke Norton, PhD

Organizational Affiliation

University of Texas Health Science Center San Antonio

Official's Role

Principal Investigator

Facility Information:

Facility Name

Texas Diabetes Institute - University Health System

City

San Antonio

State/Province

Texas

ZIP/Postal Code

78207

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Andrea Hansis-Diarte, MPh

Phone

210-567-6691

hansisdiarte@uthscsa.edu

First Name & Middle Initial & Last Name & Degree

Luke Norton, PhD

Phone

210-567-0739

hansisdiarte@uthscsa.edu

Facility Name

University of Texas Health Science Center at San Antonio

City

San Antonio

State/Province

Texas

ZIP/Postal Code

78229

Country

United States

Individual Site Status

Recruiting

12. IPD Sharing Statement

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Quantifying Hepatic Mitochondrial Fluxes in Humans

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