- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00465751
Effects of FXR Activation on Hepatic Lipid and Glucose Metabolism
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 Overview
Status
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Early Phase 1
Contacts and Locations
Study Locations
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Basel, Switzerland, 4031
- University Hospital Basel
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Crossover Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: A
chenodeoxycholic acid treatment
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chenodeoxycholic acid 500 mg capsules tid po
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Placebo Comparator: B
placebo treatment
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placebo capsules containing mannitol tid po
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
plasma triglyceride concentrations
Time Frame: 3 months
|
3 months
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
hepatic insulin sensitivity
Time Frame: 3 months
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3 months
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heptic triglyceride content
Time Frame: 3 months
|
3 months
|
Collaborators and Investigators
Investigators
- Principal Investigator: Stefan Bilz, MD, Cantonal Hospital of St. Gallen
Study record dates
Study Major Dates
Study Start
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Glucose Metabolism Disorders
- Metabolic Diseases
- Disease
- Genetic Diseases, Inborn
- Insulin Resistance
- Hyperinsulinism
- Metabolism, Inborn Errors
- Lipid Metabolism Disorders
- Dyslipidemias
- Lipid Metabolism, Inborn Errors
- Hyperlipoproteinemias
- Syndrome
- Metabolic Syndrome
- Hyperlipidemias
- Hypertriglyceridemia
- Hyperlipidemia, Familial Combined
- Hyperlipoproteinemia Type IV
- Gastrointestinal Agents
- Cathartics
- Chenodeoxycholic Acid
Other Study ID Numbers
- EKBB 211/04 SB
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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