A Study Comparing the Mechanisms of Action of Lifibrol and Pravastatin

NCT ID: NCT01057654

Last Updated: 2010-01-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 1996-01-31
• Study Completion Date: 1998-06-30

Brief Summary

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.

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.

Conditions

Hypercholesterolemia; Hyperlipoproteinemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: QUADRUPLE

Study Groups

Lifibrol

Lifibrol (K12.148; 4-(4'-tert. butylphenyl)-1-(4'-carboxyphenoxy)-2-butanol) given as a 600 mg film-coated tablet

Group Type: EXPERIMENTAL

Lifibrol

Intervention Type: DRUG

Lifibrol (K12.148; 4-(4'-tert. butylphenyl)-1-(4'-carboxyphenoxy)-2-butanol) given as a 600 mg film-coated tablet

Pravastatin

Pravastatin 40 mg per day

Group Type: ACTIVE_COMPARATOR

Pravastatin

Intervention Type: DRUG

Pravastatin 40 mg

Interventions

Pravastatin

Pravastatin 40 mg

Intervention Type: DRUG

Lifibrol

Lifibrol (K12.148; 4-(4'-tert. butylphenyl)-1-(4'-carboxyphenoxy)-2-butanol) given as a 600 mg film-coated tablet

Intervention Type: DRUG

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

University Hospital, Bonn

OTHER

Sponsor Role: lead

Responsible Party

Dept. of Clinical Pharmacology, University of Bonn, Germany

Principal Investigators

Heiner K. Berthold, Professor

Role: PRINCIPAL_INVESTIGATOR

University of Bonn

Locations

Dept. of Clinical Pharmacology, University of Bonn

Bonn, , Germany

Countries

Germany

Other Identifiers

LIF293/95apoB

Identifier Type: -

Identifier Source: org_study_id