TUDCA/PBA: Effect of Endoplasmic Reticulum Stress on Metabolic Function

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT00771901
• Collaborator: (none)
• Enrollment: 101
• Location: 1
• Arms: 3
• Actual Duration (Months): 82
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

Normally, the hormone insulin works to help keep blood sugar normal. However, as a person gains weight, insulin does not work as well and blood sugar tends to be a little higher than normal. This is called "insulin resistance".

Two investigational drugs (not approved by the Food and Drug Administration) for the treatment of high lipid levels or insulin resistance are being examined in this study: one drug is called tauroursodeoxycholic acid (TUDCA), the other is called sodium phenylbutyrate (PBA). This study is designed to test if TUDCA and/or PBA is effective in people who are obese with insulin resistance and high lipids. We hypothesize that pharmacologically-induced decreases in ER stress will improve insulin action and hepatic lipid metabolism in obese subjects.

Condition or Disease	Intervention/Treatment	Phase
Insulin Resistance; Diabetes; Obesity	Drug: tauroursodeoxycholic acid; Other: placebo; Drug: sodium phenylbutyrate	N/A

Detailed Description

A 4-week randomized, controlled trial will be conducted to evaluate the following specific aims in obese subjects:

Determine the effect of treatment with TUDCA or PBA on:

1. Body fat distribution: a) intrahepatic triglyceride (IHTG) content, b) intramyocellular triglyceride (IMTG) content, and c) intra-abdominal fat content, assessed by using magnetic resonance spectroscopy and magnetic resonance imaging.

2. In vivo insulin sensitivity in adipose tissue (suppression of lipolysis), liver (suppression of glucose production), and skeletal muscle (stimulation of glucose uptake), assessed by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotope tracer infusion.

3. VLDL-triglyceride (TG) and VLDL-apolipoprotein-B100 (apoB-100) secretion rates, assessed by stable isotopically labeled tracer infusion methods.

4. Skeletal muscle intracellular insulin signaling, fatty acid oxidation, and markers of inflammation, assessed by evaluating skeletal muscle biopsies ex vivo.

5. Adipose tissue insulin signaling, ER stress, and inflammation, assessed by evaluating adipose tissue biopsies ex vivo.

Study Design

• Study Type: Interventional
• Actual Enrollment: 101 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Basic Science
• Official Title: Effect of Endoplasmic Reticulum Stress on Metabolic Function
• Actual Study Start Date: Feb 1, 2008
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Subjects will be given a placebo rather than tauroursodeoxycholic acid.	Other: placebo; 7 pills daily for 4 weeks
Experimental: tauroursodeoxycholic acid Subjects will receive tauroursodeoxycholic acid for four weeks.	Drug: tauroursodeoxycholic acid; 1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner.; Other Names: TUDCA
Experimental: PBA Subjects will receive sodium phenylbutyrate for four weeks.	Drug: sodium phenylbutyrate; 20g/day for four weeks.; Other Names: PBA

Outcome Measures

Primary Outcome Measures

1. Body Composition [Baseline and four weeks]

   Fat mass (%)

Secondary Outcome Measures

1. Insulin Sensitivity in the Liver [Baseline and four weeks]

   HISI (hepatic insulin sensitivity index). HISI is the inverse of the product of endogenous glucose production and plasma insulin concentration and provides an index of how well circulating insulin controls the amount of glucose supplied by the liver. A higher number is indicative of greater insulin sensitivity.

2. VLDL-triglyceride (TG) Concentration [Baseline and four weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• BMI range 30 to 45

• sedentary (defined as regular exercise < 1 h per week or < 2 x/week for the last 6 months)

Exclusion Criteria:

• active or previous infection with hepatitis B or C

• liver diseases

• history of alcohol abuse

• current alcohol consumption > 20 g/day

• severe hypertriglyceridemia ( > 400 mg/dL)

• active peptic ulcer disease

• taking cholestyramine or oral contraceptives

• women who are pregnant or lactating

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine

Investigators

• Principal Investigator: Samuel Klein, MD, Washington University School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT00771901
• Other Study ID Numbers: 07-1114
• First Posted: Oct 15, 2008
• Last Update Posted: May 29, 2018
• Last Verified: Apr 1, 2018

• Keywords provided by Washington University School of Medicine: obesity; insulin resistance; type II diabetes
• Additional relevant MeSH terms: Insulin Resistance; Ursodoxicoltaurine; 4-phenylbutyric acid

Study Results

Participant Flow

Recruitment Details	Participants will be recruited by reviewing the VFH database pf research subjects and by local postings. Potential subjects will be contacted by telephone for an initial pre-screen, at which time the study is discussed and a brief medical history and concomitant medication list is obtained. ICF will be sent to interested subjects.
Pre-assignment Detail	Screening tests to determine eligibility included: medical hx & PE, blood tests, resting ECG, OGTT, MRI/MRS/MRE of abdomen/liver, and DEXA scan. Two baseline metabolism studies prior to study drug intervention. There were 67 screen fails, 4 subjects withdrew consent before beginning study intervention.

Arm/Group Title	Placebo	Tauroursodeoxycholic Acid	Sodium Phenylbutyrate
Arm/Group Description	Subjects will be given a placebo rather than tauroursodeoxycholic acid. placebo: 7 pills daily for 4 weeks	Subjects will receive tauroursodeoxycholic acid for four weeks. tauroursodeoxycholic acid: 1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner.	Subjects will receive sodium phenylbutyrate for four weeks. sodium phenylbutyrate: 20g/day for four weeks.
Period Title: Overall Study
STARTED	10	10	10
COMPLETED	10	10	6
NOT COMPLETED	0	0	4

Baseline Characteristics

Arm/Group Title	Placebo	Tauroursodeoxycholic Acid	Sodium Phenylbutyrate	Total
Arm/Group Description	Subjects will be given a placebo rather than tauroursodeoxycholic acid. placebo: 7 pills daily for 4 weeks	Subjects will receive tauroursodeoxycholic acid for four weeks. tauroursodeoxycholic acid: 1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner.	Subjects will receive sodium phenylbutyrate for four weeks. sodium phenylbutyrate: 20g/day for four weeks.	Total of all reporting groups
Overall Participants	10	10	6	26
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	10 100%	10 100%	6 100%	26 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49 (14)	47 (9)	49 (8)	47 (10.6)
Sex: Female, Male (Count of Participants)
Female	6 60%	6 60%	2 33.3%	14 53.8%
Male	4 40%	4 40%	4 66.7%	12 46.2%
Region of Enrollment (participants) [Number]
United States	10 100%	10 100%	6 100%	26 100%

Outcome Measures

1. Primary Outcome

Title	Body Composition
Description	Fat mass (%)
Time Frame	Baseline and four weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Tauroursodeoxycholic Acid	Sodium Phenylbutyrate
Arm/Group Description	Subjects will be given a placebo rather than tauroursodeoxycholic acid. placebo: 7 pills daily for 4 weeks	Subjects will receive tauroursodeoxycholic acid for four weeks. tauroursodeoxycholic acid: 1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner.	Subjects will receive sodium phenylbutyrate for four weeks. sodium phenylbutyrate: 20g/day for four weeks.
Measure Participants	10	10	6
Before Intervention	39 (7)	39 (8)	37 (6)
After Intervention	39 (7)	39 (8)	39 (7)

2. Secondary Outcome

Title	Insulin Sensitivity in the Liver
Description	HISI (hepatic insulin sensitivity index). HISI is the inverse of the product of endogenous glucose production and plasma insulin concentration and provides an index of how well circulating insulin controls the amount of glucose supplied by the liver. A higher number is indicative of greater insulin sensitivity.
Time Frame	Baseline and four weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Tauroursodeoxycholic Acid	Sodium Phenylbutyrate
Arm/Group Description	Subjects will be given a placebo rather than tauroursodeoxycholic acid. placebo: 7 pills daily for 4 weeks	Subjects will receive tauroursodeoxycholic acid for four weeks. tauroursodeoxycholic acid: 1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner.	Subjects will receive sodium phenylbutyrate for four weeks. sodium phenylbutyrate: 20g/day for four weeks.
Measure Participants	10	10	7
Before Intervention	0.010 (0.007)	0.009 (0.004)	0.008 (0.003)
After Intervention	0.008 (0.004)	0.012 (0.006)	0.009 (0.003)

3. Secondary Outcome

Title	VLDL-triglyceride (TG) Concentration
Time Frame	Baseline and four weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Tauroursodeoxycholic Acid	Sodium Phenylbutyrate
Arm/Group Description	Subjects will be given a placebo rather than tauroursodeoxycholic acid. placebo: 7 pills daily for 4 weeks	Subjects will receive tauroursodeoxycholic acid for four weeks. tauroursodeoxycholic acid: 1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner.	Subjects will receive sodium phenylbutyrate for four weeks. sodium phenylbutyrate: 20g/day for four weeks.
Measure Participants	7	8	5
Before Intervention	0.57 (0.33)	0.74 (0.50)	0.89 (0.25)
After Intervention	0.58 (0.33)	0.75 (0.56)	0.97 (0.18)

Adverse Events

Time Frame	Adverse event data was collected from the time participants signed the informed consent until 30 days after study completion.
Arm/Group Title	Placebo		Tauroursodeoxycholic Acid		Sodium Phenylbutyrate
Arm/Group Description	Subjects will be given a placebo rather than tauroursodeoxycholic acid. placebo: 7 pills daily for 4 weeks		Subjects will receive tauroursodeoxycholic acid for four weeks. tauroursodeoxycholic acid: 1750 mg/day for four weeks. Seven pills daily, 2 with breakfast, 2 with lunch, and 3 with dinner.		Subjects will receive sodium phenylbutyrate for four weeks. sodium phenylbutyrate: 20g/day for four weeks.
All Cause Mortality
	Placebo		Tauroursodeoxycholic Acid		Sodium Phenylbutyrate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/6 (0%)
Serious Adverse Events
	Placebo		Tauroursodeoxycholic Acid		Sodium Phenylbutyrate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Tauroursodeoxycholic Acid		Sodium Phenylbutyrate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.