A Study Comparing the Mechanisms of Action of Lifibrol and Pravastatin

This study has been completed.
Sponsor:
Information provided by:
University Hospital, Bonn
ClinicalTrials.gov Identifier:
NCT01057654
First received: January 26, 2010
Last updated: NA
Last verified: January 2010
History: No changes posted
  Purpose

Lifibrol is a new lipid-lowering drug which lowers cholesterol to an extent in the order of magnitude of the statins. The mechanism of action of this compound is different from the one of statins but remains unknown. The current study will investigate the mechanism of action using stable-isotope turnover methods. The study will be done in healthy male volunteers.


Condition Intervention Phase
Hypercholesterolemia
Hyperlipoproteinemia
Drug: Pravastatin
Drug: Lifibrol
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: A Stable-isotope Study in Healthy Normolipidemic Volunteers Comparing the Mechanisms of Action of Lifibrol and Pravastatin

Resource links provided by NLM:


Further study details as provided by University Hospital, Bonn:

Primary Outcome Measures:
  • LDL cholesterol lowering [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Changes in other lipoprotein concentrations [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]

Enrollment: 18
Study Start Date: January 1996
Study Completion Date: June 1998
Primary Completion Date: April 1996 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Lifibrol
Lifibrol (K12.148; 4-(4'-tert. butylphenyl)-1-(4'-carboxyphenoxy)-2-butanol) given as a 600 mg film-coated tablet
Drug: Lifibrol
Lifibrol (K12.148; 4-(4'-tert. butylphenyl)-1-(4'-carboxyphenoxy)-2-butanol) given as a 600 mg film-coated tablet
Active Comparator: Pravastatin
Pravastatin 40 mg per day
Drug: Pravastatin
Pravastatin 40 mg

Detailed Description:

Elevated lipoprotein concentrations are a major risk factor for the development of atherosclerotic cardiovascular disease. Effective reduction of low density lipoprotein (LDL)-cholesterol concentrations has been shown to greatly reduce this risk. The most widely used lipid-lowering agents are the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), which have been shown to reduce morbidity and mortality from coronary heart disease (CHD) in large prospective clinical trials. However, despite significant LDL-C reduction approximately 70% of the events are still not avoided and the search for improved or alternative lipid-modifying drug therapies continuous. HDL-C has been addressed as a potential modifiable target for decreasing this residual risk, since a low HDL-C concentration is an acknowledged independent risk factor for CHD. However, recent studies showed that an increase in HDL-C concentrations was surprisingly not associated with a decrease in atherosclerosis, but with a possible increase. Therefore it seems that not the concentrations of HDL-C should be targeted but HDL function in reverse cholesterol transport.

Lifibrol is a lipid-modifying drug which has been shown to improve HDL particle flux via increased apoA-I production, while not having HDL-raising properties. Furthermore, it decreases dose-dependently LDL-C by up to 40%. It is of major interest to clarify the, apparently unique, mechanisms of action of a compound, whose LDL-lowering effects are comparable in magnitude to the ones of statins.

The mechanisms of lifibrol's LDL-lowering effects are not completely clarified. There is evidence suggesting that it increases hepatic LDL receptor expression by a sterol-independent mechanism, i.e. not through a reduction in cholesterol synthesis, the mechanism of action of statins. ApoB turnover studies have indicated that increased catabolism of LDL rather than a decrease in hepatic apoB production may be responsible for its cholesterol-lowering effects. Since apoB metabolism and cholesterol synthesis are closely related, we designed a study to investigate the effects of lifibrol on the metabolism of apoB-100-containing lipoproteins and on endogenous sterol synthesis in parallel, using stable isotope methods. In addition, since lifibrol may inhibit cholesterol synthesis at steps earlier than HMG-CoA reductase, we investigated [13C]acetate catabolism analyzing 13CO2 appearance in breath. The HMG-CoA-reductase inhibitor pravastatin was used as comparator, since its mode of action is well characterized. The principle questions addressed were (i) whether lifibrol exerts its cholesterol-lowering effects through decreased synthesis/enhanced catabolism of apoB-100-containing lipoproteins or through inhibition of sterol de novo synthesis and (ii) whether these effects are interrelated.

  Eligibility

Ages Eligible for Study:   18 Years to 35 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • male volunteers
  • 18 to 35 years old
  • good clinical condition
  • normal eating habits
  • mental abilities to be able to understand the study procedures
  • written informed consent

Exclusion Criteria:

  • relevant pathological findings in the baseline examination
  • known allergic predisposition
  • concomitant drugs
  • alcohol or nicotine abuse
  • participation in other clinical trials in the last 30 days
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01057654

Locations
Germany
Dept. of Clinical Pharmacology, University of Bonn
Bonn, Germany, 53105
Sponsors and Collaborators
University Hospital, Bonn
Investigators
Principal Investigator: Heiner K. Berthold, Professor University of Bonn
  More Information

No publications provided

Responsible Party: Heiner K. Berthold, MD, PhD, Dept. of Clinical Pharmacology, University of Bonn, Germany
ClinicalTrials.gov Identifier: NCT01057654     History of Changes
Other Study ID Numbers: LIF293/95apoB
Study First Received: January 26, 2010
Last Updated: January 26, 2010
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by University Hospital, Bonn:
Cholesterol

Additional relevant MeSH terms:
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Hypercholesterolemia
Hyperlipoproteinemias
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Pravastatin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Lipid Regulating Agents
Therapeutic Uses
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 26, 2014