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Effects of FXR Activation on Hepatic Lipid and Glucose Metabolism

Primary Purpose

Metabolic Syndrome, Familial Hypertriglyceridemia, Familial Combined Hyperlipidemia

Status
Completed
Phase
Early Phase 1
Locations
Switzerland
Study Type
Interventional
Intervention
chenodeoxycholic acid
placebo capsules
Sponsored by
University Hospital, Basel, Switzerland
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metabolic Syndrome

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  1. Age between 18 and 65 years.
  2. Patients with a metabolic syndrome defined by the presence of >= 3 of the following criteria:

    • Abdominal obesity (waist circumference > 102 cm in men, > 88 cm in women)
    • Fasting plasma triglycerides > 1.7 mmol/l
    • HDL cholesterol < 1.0 mmol/l in men and < 1.3 mmol/l in women
    • Blood pressure > 130/85 mmHg or antihypertensive medication
    • Fasting plasma glucose > 6.1 mmol/l
  3. Patients with Familial Combined Hyperlipidemia characterized by the following criteria:

    • Fasting plasma triglycerides > 1.7 mmol/l
    • Fasting plasma apolipoprotein B concentrations > 1.2 g/l
    • Family history with hypertriglyceridemia and/or hypercholesterolemia present in at least 1 additional first degree family members
  4. Patients with Familial Hypertriglyceridemia characterized by the following criteria:

    • Fasting plasma triglycerides > 2.3 mmol/l
    • Family history of hypertriglyceridemia in at least 1 additional first degree family member
    • Absence of the metabolic syndrome as defined above
  5. Controls fulfilling the following criteria:

    • Non smoking.
    • No current or previous organ or systemic disease (including diabetes and lipid disorders).
    • Plasma triglycerides and cholesterol within the normal range (see exclusion criteria).
    • Plasma glucose concentrations <6.1 mmol/l Subjects meeting criterium 1 and any of the criteria 2. - 5. are eligible for the study.

Exclusion Criteria:

  1. Any significant hepatic, cardiac, pulmonary, renal, neurological, musculoskeletal, hematological or endocrine disease.
  2. Any form of primary or secondary hyperlipidemia other than the metabolic syndrome, FHTG or FCHL. [These may include: Familial hypercholesterolemia and Familial defective apolipoprotein B (to be assessed by family history and lipid profiles), and Familial Dysbetalipoproteinemia (to be assessed by apo E genotyping), hypothyroidism, nephrotic syndrome, diabetes mellitus, cholestatic liver disease, drug induced hyperlipidemia (thiazides > 25 mg/d, non cardioselective betablockers, isotretinoin, systemic glucocorticoids, cyclosporin A, tacrolimus, non nucleoside HIV protease inhibitors)].
  3. Plasma TG levels > 12 mmol/l in the past or at any time point during the study.
  4. History of acute pancreatitis
  5. History of cardiovascular disease, i.e. coronary artery disease, cerebrovascular disease, peripheral vascular disease, when assessed by medical history, physical exam. Additionally, a stress test will be performed in subjects with MS and FCHL at risk for CHD (see below).
  6. Pregnant or Breast Feeding women
  7. Woman of childbearing potential not using a reliable method of birth control such as oral contraceptives or IUD.
  8. Alcohol intake of greater than 1 drink daily.
  9. Cigarette smokers
  10. History of claustrophobia
  11. Ferromagnetic implants including pacemakers.
  12. Subjects refusing or unable to give written informed consent.

Sites / Locations

  • University Hospital Basel

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

A

B

Arm Description

chenodeoxycholic acid treatment

placebo treatment

Outcomes

Primary Outcome Measures

plasma triglyceride concentrations

Secondary Outcome Measures

hepatic insulin sensitivity
heptic triglyceride content

Full Information

First Posted
April 24, 2007
Last Updated
March 8, 2012
Sponsor
University Hospital, Basel, Switzerland
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1. Study Identification

Unique Protocol Identification Number
NCT00465751
Brief Title
Effects of FXR Activation on Hepatic Lipid and Glucose Metabolism
Official Title
Effects of Activation of the Farnesoid X Receptor (FXR) on Hepatic Lipid and Glucose Metabolism in Patients With the Metabolic Syndrome and Familial Forms of Hypertriglyceridemia
Study Type
Interventional

2. Study Status

Record Verification Date
March 2012
Overall Recruitment Status
Completed
Study Start Date
October 2004 (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Basel, Switzerland

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to determine whether chenodeoxycholic acid decreases de novo hepatic lipogenesis, hepatic fat content, hepatic triglyceride production and plasma triglyceride concentrations and improves hepatic glucose metabolism in patients with the metabolic syndrome, Familial Hypertriglyceridemia and Familial Combined Hyperlipidemia.
Detailed Description
Insulin resistance has been found to be the key pathophysiological factor of the metabolic syndrome and may precede the onset of impaired glucose tolerance, diabetes and dyslipidemia. Recently, nonalcoholic fatty liver disease (NAFLD), has been identified as another feature of this syndrome. Importantly, a close relation between liver fat content and hepatic insulin sensitivity has been described. We hypothesize that activation of FXR with chenodeoxycholic acid decreases hepatic de novo lipogenesis and subsequently hepatic fat content and triglyceride production. The decrease in liver fat content will be associated with improved hepatic insulin sensitivity and a decrease in hepatic glucose production. Patients diagnosed with metabolic syndrome, familial hypertriglyceridemia or familial combined hyperlipidemia will be recruited from the the outpatients department of the Division of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Basel. Eligible patients will be admitted to the CRC for metabolic studies, including baseline blood samples for the measurement of hormones, cytokines and adipokines, euglycemic-hyperinsulinemic clamp studies for the assessment of glucose turnover and insulin sensitivity and in vivo NMR studies to determine intrahepatic and intramyocellular lipid content. Patients will alternatively receive chenodeoxycholic acid and placebo. The study population will be compared to a group of age, gender and weight matched normolipidemic controls.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metabolic Syndrome, Familial Hypertriglyceridemia, Familial Combined Hyperlipidemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Non-Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
A
Arm Type
Active Comparator
Arm Description
chenodeoxycholic acid treatment
Arm Title
B
Arm Type
Placebo Comparator
Arm Description
placebo treatment
Intervention Type
Drug
Intervention Name(s)
chenodeoxycholic acid
Intervention Description
chenodeoxycholic acid 500 mg capsules tid po
Intervention Type
Drug
Intervention Name(s)
placebo capsules
Intervention Description
placebo capsules containing mannitol tid po
Primary Outcome Measure Information:
Title
plasma triglyceride concentrations
Time Frame
3 months
Secondary Outcome Measure Information:
Title
hepatic insulin sensitivity
Time Frame
3 months
Title
heptic triglyceride content
Time Frame
3 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Age between 18 and 65 years. Patients with a metabolic syndrome defined by the presence of >= 3 of the following criteria: Abdominal obesity (waist circumference > 102 cm in men, > 88 cm in women) Fasting plasma triglycerides > 1.7 mmol/l HDL cholesterol < 1.0 mmol/l in men and < 1.3 mmol/l in women Blood pressure > 130/85 mmHg or antihypertensive medication Fasting plasma glucose > 6.1 mmol/l Patients with Familial Combined Hyperlipidemia characterized by the following criteria: Fasting plasma triglycerides > 1.7 mmol/l Fasting plasma apolipoprotein B concentrations > 1.2 g/l Family history with hypertriglyceridemia and/or hypercholesterolemia present in at least 1 additional first degree family members Patients with Familial Hypertriglyceridemia characterized by the following criteria: Fasting plasma triglycerides > 2.3 mmol/l Family history of hypertriglyceridemia in at least 1 additional first degree family member Absence of the metabolic syndrome as defined above Controls fulfilling the following criteria: Non smoking. No current or previous organ or systemic disease (including diabetes and lipid disorders). Plasma triglycerides and cholesterol within the normal range (see exclusion criteria). Plasma glucose concentrations <6.1 mmol/l Subjects meeting criterium 1 and any of the criteria 2. - 5. are eligible for the study. Exclusion Criteria: Any significant hepatic, cardiac, pulmonary, renal, neurological, musculoskeletal, hematological or endocrine disease. Any form of primary or secondary hyperlipidemia other than the metabolic syndrome, FHTG or FCHL. [These may include: Familial hypercholesterolemia and Familial defective apolipoprotein B (to be assessed by family history and lipid profiles), and Familial Dysbetalipoproteinemia (to be assessed by apo E genotyping), hypothyroidism, nephrotic syndrome, diabetes mellitus, cholestatic liver disease, drug induced hyperlipidemia (thiazides > 25 mg/d, non cardioselective betablockers, isotretinoin, systemic glucocorticoids, cyclosporin A, tacrolimus, non nucleoside HIV protease inhibitors)]. Plasma TG levels > 12 mmol/l in the past or at any time point during the study. History of acute pancreatitis History of cardiovascular disease, i.e. coronary artery disease, cerebrovascular disease, peripheral vascular disease, when assessed by medical history, physical exam. Additionally, a stress test will be performed in subjects with MS and FCHL at risk for CHD (see below). Pregnant or Breast Feeding women Woman of childbearing potential not using a reliable method of birth control such as oral contraceptives or IUD. Alcohol intake of greater than 1 drink daily. Cigarette smokers History of claustrophobia Ferromagnetic implants including pacemakers. Subjects refusing or unable to give written informed consent.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stefan Bilz, MD
Organizational Affiliation
Cantonal Hospital of St. Gallen
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Basel
City
Basel
ZIP/Postal Code
4031
Country
Switzerland

12. IPD Sharing Statement

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Effects of FXR Activation on Hepatic Lipid and Glucose Metabolism

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