Tauroursodeoxycholic Acid for Protease-inhibitor Associated Insulin Resistance

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT01877551
• Collaborator: National Institutes of Health (NIH) (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 27
• Location: 1
• Arms: 2
• Actual Duration (Months): 56
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Rates of cardiovascular disease and diabetes are more than 2-fold greater in HIV infected people than the general population. Protease inhibitor booster antiretroviral therapy (PI-ART) which is used by ~50% of HIV infected people in the USA is an established risk factor for diabetes. Tauroursodeoxycholic acid (TUDCA), a naturally occurring bile salt, improves insulin sensitivity in HIV uninfected subjects, although the mechanisms for these benefits are unclear. This study will explore the hypothesis that TUDCA will improve insulin action in people with HIV who are receiving PI-ART. Further, this project will clarify the molecular mechanisms responsible for these improvements potentially benefiting society, irrespective of HIV status.

Condition or Disease	Intervention/Treatment	Phase
HIV Related Insulin Resistance; Protease Inhibitor Related Insulin Resistance; Endoplasmic Reticulum Stress	Drug: Tauroursodeoxycholic acid; Other: Placebo tablet	N/A

Detailed Description

The purpose of this study is to determine if, and through which mechanisms, tauroursodeoxycholic acid improves insulin sensitivity in subjects with protease-inhibitor associated insulin resistance.

The investigators will perform body composition analysis by using a DEXA machine, liver fat measurement by using an MRI, and hyperinsulinemic euglycemic clamp procedures in 48 HIV infected, insulin-resistant/prediabetic subjects before and after 30 days of treatment with tauroursodeoxycholic acid or matching placebo. Biopsies of adipose tissue and skeletal muscle will be taken during fasting conditions and during insulin infusion, before and after treatment to measure markers of endoplasmic reticulum stress and thyroid hormone deiodinase.

Outcome measures:

The primary outcome measures will be change in glucose clearance during insulin infusion, change in markers of endoplasmic reticulum stress and change in content of D2 in muscle.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Tauroursodeoxycholic Acid for Protease-inhibitor Associated Insulin Resistance
• Actual Study Start Date: Sep 1, 2013
• Actual Primary Completion Date: May 1, 2018
• Actual Study Completion Date: May 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: tauroursodeoxycholic acid This group will receive 1.75 grams per day of tauroursodeoxycholic acid given once daily for 30 days.	Drug: Tauroursodeoxycholic acid; The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days.; Other Names: taurolite tudcabil
Placebo Comparator: placebo This group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days.	Other: Placebo tablet; The placebo group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days.

Outcome Measures

Primary Outcome Measures

1. Glucose Uptake [Glucose uptake is measured at baseline and 30 days after study intervention]

   We will examine the ability of insulin to cause muscle to take up insulin. Each subject will receive intravenous insulin for 6 hours to see how much sugar needs to be given intravenously to keep the blood sugar normal, a measure called glucose uptake. We will compare glucose uptake measured as the amount of 20% dextrose that is needed to keep the blood sugar at ~100mg/dl during insulin infusion before and after 30 days of treatment with drug or placebo.

Secondary Outcome Measures

1. Body Composition [Pre-Treatment and Post 30 day-Treatment]

   We will measure how much fat is present in each subject before and after treatment with TUDCA or placebo.

2. Liver Fat [Pre-Treatment and Post 30 day-Treatment]

   We will use MRI to measure the relative (%) amount of fat in each subject's liver before and after 30 days of treatment. This will allow us to determine if the drug reduces liver fat. This is calculated by subtracting the amount of fat in the liver at the beginning of the study from the amount of fat in the liver after 30 days of treatment. Subjects who have claustrophobia or are unable to undergo MRI will not have this measure performed. Due to these reasons liver MRS was only performed in 10 patients in the tauroursodeoxycholic acid group and 9 subjects in the placebo group

3. Liver Function Tests [Pre-Treatment and Post 30 day-Treatment]

   We will measure liver function tests before and after the study drug to ensure that no abnormalities in liver function occurs with the drug.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• HIV+

• receiving protease inhibitor containing antiretroviral therapy for >6 months

• Undetectable viral load

• insulin resistant

1. impaired fasting glucose (fasting blood glucose>100mg/dl)

2. impaired glucose tolerance (blood glucose >140mg/dl at 2 hours during oral glucose tolerance testing).

• abstained from medications that affect glucose (e.g. prednisone, growth hormone)

• stable medications for >3 months

Exclusion Criteria:

• weight loss of >5% of body weight in prior 6 months

• active gastrointestinal disease (gallstones, pancreatitis, hepatitis, diarrhea)

• use of anti-diabetic medications

• cardiovascular disease (uncontrolled hypertension, heart attack, heart failure, prior endocarditis)

• history of or active substance abuse

• blood clotting disorder or taking medications that affect blood clotting (e.g. coumadin, warfarin)

• pregnant, planning to become pregnant or lactating

• unable to give informed consent

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
• National Institutes of Health (NIH)
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Dominic N. Reeds, M.D., Washington University School of Medicine

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 6, 2019

More Information

Additional Information:

• Washington University AIDS Clinical Trials Unit

Publications

• Kars M, Yang L, Gregor MF, Mohammed BS, Pietka TA, Finck BN, Patterson BW, Horton JD, Mittendorfer B, Hotamisligil GS, Klein S. Tauroursodeoxycholic Acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes. 2010 Aug;59(8):1899-905. doi: 10.2337/db10-0308. Epub 2010 Jun 3.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT01877551
• Other Study ID Numbers: 201306105; R01DK096982
• First Posted: Jun 13, 2013
• Last Update Posted: Jan 27, 2020
• Last Verified: Jan 1, 2020

• Keywords provided by Washington University School of Medicine: HIV; Protease inhibitor; insulin resistance; Tauroursodeoxycholic acid
• Additional relevant MeSH terms: Insulin Resistance; Ursodoxicoltaurine

Study Results

Participant Flow

Arm/Group Title	Tauroursodeoxycholic Acid	Placebo
Arm/Group Description	This group will receive 1.75 grams per day of tauroursodeoxycholic acid given once daily for 30 days. Tauroursodeoxycholic acid: The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days.	This group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days. Placebo tablet: The placebo group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days.
Period Title: Overall Study
STARTED	13	14
COMPLETED	13	13
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Tauroursodeoxycholic Acid	Placebo	Total
Arm/Group Description	This group will receive 1.75 grams per day of tauroursodeoxycholic acid given once daily for 30 days. Tauroursodeoxycholic acid: The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days.	This group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days. Placebo tablet: The placebo group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days.	Total of all reporting groups
Overall Participants	13	14	27
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	13 100%	14 100%	27 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43 (11)	51 (10)	48 (11)
Sex: Female, Male (Count of Participants)
Female	4 30.8%	2 14.3%	6 22.2%
Male	9 69.2%	12 85.7%	21 77.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	2 14.3%	2 7.4%
Not Hispanic or Latino	13 100%	12 85.7%	25 92.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	7 53.8%	10 71.4%	17 63%
White	6 46.2%	4 28.6%	10 37%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	13 100%	14 100%	27 100%

Outcome Measures

1. Primary Outcome

Title	Glucose Uptake
Description	We will examine the ability of insulin to cause muscle to take up insulin. Each subject will receive intravenous insulin for 6 hours to see how much sugar needs to be given intravenously to keep the blood sugar normal, a measure called glucose uptake. We will compare glucose uptake measured as the amount of 20% dextrose that is needed to keep the blood sugar at ~100mg/dl during insulin infusion before and after 30 days of treatment with drug or placebo.
Time Frame	Glucose uptake is measured at baseline and 30 days after study intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tauroursodeoxycholic Acid	Placebo
Arm/Group Description	This group will receive 1.75 grams per day of tauroursodeoxycholic acid given once daily for 30 days. Tauroursodeoxycholic acid: The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days.	This group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days. Placebo tablet: The placebo group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days.
Measure Participants	13	13
Mean (Standard Error) [change in glucose infusion rate (ml/hr)]	0 (11)	8 (7)

2. Secondary Outcome

Title	Body Composition
Description	We will measure how much fat is present in each subject before and after treatment with TUDCA or placebo.
Time Frame	Pre-Treatment and Post 30 day-Treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tauroursodeoxycholic Acid	Placebo
Arm/Group Description	This group will receive 1.75 grams per day of tauroursodeoxycholic acid given once daily for 30 days. Tauroursodeoxycholic acid: The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days.	This group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days. Placebo tablet: The placebo group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days.
Measure Participants	9	7
Pre	35.7 (2.3)	32.6 (2.8)
Post	35.7 (2.3)	31.7 (2.8)

3. Secondary Outcome

Title	Liver Fat
Description	We will use MRI to measure the relative (%) amount of fat in each subject's liver before and after 30 days of treatment. This will allow us to determine if the drug reduces liver fat. This is calculated by subtracting the amount of fat in the liver at the beginning of the study from the amount of fat in the liver after 30 days of treatment. Subjects who have claustrophobia or are unable to undergo MRI will not have this measure performed. Due to these reasons liver MRS was only performed in 10 patients in the tauroursodeoxycholic acid group and 9 subjects in the placebo group
Time Frame	Pre-Treatment and Post 30 day-Treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tauroursodeoxycholic Acid	Placebo
Arm/Group Description	This group will receive 1.75 grams per day of tauroursodeoxycholic acid given once daily for 30 days. Tauroursodeoxycholic acid: The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days.	This group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days. Placebo tablet: The placebo group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days.
Measure Participants	10	9
Mean (Standard Error) [Change in Percent liver fat]	-0.3 (0.2)	1.2 (0.6)

4. Secondary Outcome

Title	Liver Function Tests
Description	We will measure liver function tests before and after the study drug to ensure that no abnormalities in liver function occurs with the drug.
Time Frame	Pre-Treatment and Post 30 day-Treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tauroursodeoxycholic Acid	Placebo
Arm/Group Description	This group will receive 1.75 grams per day of tauroursodeoxycholic acid given once daily for 30 days. Tauroursodeoxycholic acid: The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days.	This group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days. Placebo tablet: The placebo group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days.
Measure Participants	13	13
ALT-PRE	25 (4)	21 (2)
ALT-Post	19 (3)	23 (4)

Adverse Events

Time Frame	Adverse event data were taken over a 6 week period after initiation of drug or placebo
Adverse Event Reporting Description	Subjects were followed for 6 weeks
Arm/Group Title	Tauroursodeoxycholic Acid		Placebo
Arm/Group Description	This group will receive 1.75 grams per day of tauroursodeoxycholic acid given once daily for 30 days. Tauroursodeoxycholic acid: The intervention group will receive 1.75 grams of tauroursodeoxycholic acid daily for 30 days.		This group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days. Placebo tablet: The placebo group will receive a placebo tablet that is identical to the treatment group except that it does not contain tauroursodeoxycholic acid. The pills will be taken once daily for 30 days.
All Cause Mortality
	Tauroursodeoxycholic Acid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/14 (0%)
Serious Adverse Events
	Tauroursodeoxycholic Acid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Tauroursodeoxycholic Acid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/13 (7.7%)		0/14 (0%)
Infections and infestations
influenza	1/13 (7.7%)	1	0/14 (0%)	0

Limitations/Caveats

We were unable to recruit our targeted enrollment reducing the power of the study

More Information

Certain Agreements

Principal Investigators are NOT 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.