- ICH GCP
- US Clinical Trials Registry
- Klinisk forsøg NCT01057654
A Study Comparing the Mechanisms of Action of Lifibrol and Pravastatin
A Stable-isotope Study in Healthy Normolipidemic Volunteers Comparing the Mechanisms of Action of Lifibrol and Pravastatin
Studieoversigt
Status
Betingelser
Intervention / Behandling
Detaljeret beskrivelse
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.
Undersøgelsestype
Tilmelding (Faktiske)
Fase
- Fase 3
Kontakter og lokationer
Studiesteder
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Bonn, Tyskland, 53105
- Dept. of Clinical Pharmacology, University of Bonn
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Deltagelseskriterier
Berettigelseskriterier
Aldre berettiget til at studere
Tager imod sunde frivillige
Køn, der er berettiget til at studere
Beskrivelse
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
Studieplan
Hvordan er undersøgelsen tilrettelagt?
Design detaljer
- Primært formål: Grundvidenskab
- Tildeling: Randomiseret
- Interventionel model: Parallel tildeling
- Maskning: Firedobbelt
Våben og indgreb
Deltagergruppe / Arm |
Intervention / Behandling |
---|---|
Eksperimentel: Lifibrol
Lifibrol (K12.148;
4-(4'-tert.
butylphenyl)-1-(4'-carboxyphenoxy)-2-butanol) given as a 600 mg film-coated tablet
|
Lifibrol (K12.148;
4-(4'-tert.
butylphenyl)-1-(4'-carboxyphenoxy)-2-butanol) given as a 600 mg film-coated tablet
|
Aktiv komparator: Pravastatin
Pravastatin 40 mg per day
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Pravastatin 40 mg
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Hvad måler undersøgelsen?
Primære resultatmål
Resultatmål |
Tidsramme |
---|---|
LDL cholesterol lowering
Tidsramme: 4 weeks
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4 weeks
|
Sekundære resultatmål
Resultatmål |
Tidsramme |
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Changes in other lipoprotein concentrations
Tidsramme: 4 weeks
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4 weeks
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Samarbejdspartnere og efterforskere
Sponsor
Efterforskere
- Ledende efterforsker: Heiner K. Berthold, Professor, University of Bonn
Datoer for undersøgelser
Studer store datoer
Studiestart
Primær færdiggørelse (Faktiske)
Studieafslutning (Faktiske)
Datoer for studieregistrering
Først indsendt
Først indsendt, der opfyldte QC-kriterier
Først opslået (Skøn)
Opdateringer af undersøgelsesjournaler
Sidste opdatering sendt (Skøn)
Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier
Sidst verificeret
Mere information
Begreber relateret til denne undersøgelse
Nøgleord
Yderligere relevante MeSH-vilkår
- Metaboliske sygdomme
- Lipidmetabolismeforstyrrelser
- Dyslipidæmi
- Hyperkolesterolæmi
- Hyperlipidæmi
- Hyperlipoproteinæmier
- Molekylære mekanismer for farmakologisk virkning
- Enzymhæmmere
- Antimetabolitter
- Antikolesteræmiske midler
- Hypolipidæmiske midler
- Lipidregulerende midler
- Hydroxymethylglutaryl-CoA-reduktasehæmmere
- Pravastatin
Andre undersøgelses-id-numre
- LIF293/95apoB
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