Healthy MenPhase 4NCT00317993
LDL Receptor Under Ezetimibe and Simvastatin
A Phase 4 study testing ezetimibe, simvastatin and ezetimibe plus simvastatin in people with Healthy Men, run by University of Cologne at 1 site in Germany.
Trial summary
The purpose of this study is to investigate the effects of the two lipid -lowering drugs, ezetimibe and simvastatin, on lipid metabolism in humans. In specific, the study will investigate in blood cells whether the enzyme that controls cholesterol synthesis, HMG-CoA reductase, and the receptor that takes up… Read more about this study
- Who is it for?
- Ages 18 to 60 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Healthy Men
- What is being tested?
- ezetimibe, simvastatin and ezetimibe plus simvastatin
- How many people
- 60 participants
- Where
- 1 siteGermany
- Study dates
- Apr 2004to Jul 2004
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- healthy male subjects
- age between 18 and 60 years
- body mass index between 18.5 and 30 kg/m2
- LDL cholesterol smaller than 190 mg/dL
- triglicerides smaller than 250 mg/dL
- normal blood pressure
Who cannot join
- intake of lipid-lowering drugs
- excessive alcohol intake
- liver disease
- kidney disease
- coronary heart disease
- eating disorders
- diabetes or other endocrine disorders
- medications that interfere with lipid metabolism
Trial locations and contacts
1 site in 1 country.
Germany1 site
Medizinische Klinik II und Poliklinik für Innere Medizin
Cologne, 50924
About this study
Official title: Effects of Ezetimibe and Simvastatin on LDL Receptor Protein Expression and on LDL Receptor and HMG-CoA Reductase mRNA Expression in Mononuclear Cells: a Randomized Controlled Study in Healthy Men
The purpose of this study is to investigate the effects of the two lipid -lowering drugs, ezetimibe and simvastatin, on lipid metabolism in humans. In specific, the study will investigate in blood cells whether the enzyme that controls cholesterol synthesis, HMG-CoA reductase, and the receptor that takes up cholesterol from the blood, the LDL receptor, are changed during treatment with the aforementioned drugs.
Read the detailed description
Ezetimibe decreases serum total and LDL cholesterol levels by blocking cholesterol absorption in the intestine, causing a compensatory increase in cholesterol synthesis. The exact underlying regulatory mechanisms of the ezetimibe-induced increase in cholesterol synthesis and decrease in serum LDL cholesterol are not known. In addition, it has never been investigated whether changes in LDL receptor expression contribute to the LDL-lowering effect of ezetimibe, as is the case with other agents causing a decrease in cholesterol absorption such as the plant stanols.
In the present study, we plan to examine changes in LDL receptor and HMG-CoA reductase mRNA concentrations during ezetimibe treatment. For comparison, effects of simvastatin and the combined administration of the two will be investigated. Since mRNA expression profiles provide information about effects at the transcriptional but not necessarily at the translational level, we will also analyze changes in the LDL receptor protein at the cell surface of mononuclear blood cells. As a functional marker for HMG-CoA reductase activity the ratio of serum lathosterol to cholesterol concentration will be used since it correlates with HMG-CoA reductase activity and serves also as a marker of total cholesterol synthesis.
In this regard it has been shown that plant sterols, which also act by blocking intestinal cholesterol absorption, increase cholesterol synthesis, decrease LDL synthesis, increase LDL receptor mRNA levels as well as LDL receptor protein concentrations but have no significant effect on HMG-CoA reductase expression or activity in peripheral blood mononuclear cells. Aim of this prospective ran-domized parallel study is to examine changes in HMG-CoA reductase activity/expression and in LDL receptor expression/protein concentration in mononuclear blood cells under treatment with ezetimibe.
For this purpose 3 parallel groups of 20 healthy men will be formed. One group will be treated with ezetimibe (10 mg/day), one with 40 mg/day of simvastatin and another with ezetimibe (10 mg/day) plus simvastatin (40 mg/day). Each treatment period will last for 2 weeks. Blood drawing will be per-formed at baseline (before the initiation of treatment) and at the end of the 2 weeks. (storing of the samples at -80°). The measurements involved in this study include the determination of the lipopro-tein concentrations in serum, isolation of the mononuclear cells, measurement of LDL receptor mRNA from the peripheral blood mononuclear cells, measurement of HMG-CoA reductase mRNA levels in peripheral blood mononuclear cells, measurement of the LDL-receptor protein concentrations on the surface of peripheral blood mononuclear cells. Furthermore, the serum latosterol to cholesterol con-centrations will be measured as a surrogate marker of the HMG-CoA reductase activity.
- Conditions
- Healthy Men
- Being tested
- ezetimibe, simvastatin, ezetimibe plus simvastatin
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ezetimibeDrug
simvastatinDrug
ezetimibe plus simvastatinDrug
What is being measured
The primary outcome is the main question the study is designed to answer.
HMG-CoA reductase activity
HMG-CoA reductase mRNA expression
LDL receptor mRNA expression
LDL receptor protein
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Apr 2006 (estimated)
- Study startApr 2004
- Primary completionJul 2004
- Study completionJul 2004
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Healthy MenStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Enrolment
- 60 participants
Sponsor and investigators
- Lead sponsor
- University of Cologne
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Investigators
- Ioanna Gouni-Berthold, MD, Principal investigator, Medizinische Klinik II und Poliklinik für Innere Medizin
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00317993
- Sponsor's protocol ID
- EZE04-003
- Status last verified
- Dec 2014
- First submitted
- 24 Apr 2006
- Last updated
- 3 Dec 2014
- Results posted
- No
Publications
Berthold HK, Rizzo M, Spenrath N, Montalto G, Krone W, Gouni-Berthold I. Effects of lipid-lowering drugs on high-density lipoprotein subclasses in healthy men-a randomized trial. PLoS One. 2014 Mar 24;9(3):e91565. doi: 10.1371/journal.pone.0091565. eCollection 2014.
PubMed 24662777Gouni-Berthold I, Berthold HK, Huh JY, Berman R, Spenrath N, Krone W, Mantzoros CS. Effects of lipid-lowering drugs on irisin in human subjects in vivo and in human skeletal muscle cells ex vivo. PLoS One. 2013 Sep 2;8(9):e72858. doi: 10.1371/journal.pone.0072858. eCollection 2013.
PubMed 24023786Berthold HK, Seidah NG, Benjannet S, Gouni-Berthold I. Evidence from a randomized trial that simvastatin, but not ezetimibe, upregulates circulating PCSK9 levels. PLoS One. 2013;8(3):e60095. doi: 10.1371/journal.pone.0060095. Epub 2013 Mar 27.
PubMed 23544125Berthold HK, Berneis K, Mantzoros CS, Krone W, Gouni-Berthold I. Effects of simvastatin and ezetimibe on interleukin-6 and high-sensitivity C-reactive protein. Scand Cardiovasc J Suppl. 2013 Feb;47(1):20-7. doi: 10.3109/14017431.2012.734635. Epub 2012 Oct 18.
PubMed 23013513Berneis K, Rizzo M, Berthold HK, Spinas GA, Krone W, Gouni-Berthold I. Ezetimibe alone or in combination with simvastatin increases small dense low-density lipoproteins in healthy men: a randomized trial. Eur Heart J. 2010 Jul;31(13):1633-9. doi: 10.1093/eurheartj/ehq181. Epub 2010 Jun 6.
PubMed 20525999
Study at a glance
From the registry record, last updated by the sponsor on 3 Dec 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects of Ezetimibe and Simvastatin on LDL Receptor Protein Expression and on LDL Receptor and HMG-CoA Reductase mRNA Expression in Mononuclear Cells: a Randomized Controlled Study in Healthy Men
- ClinicalTrials.gov ID
- NCT00317993
- Acronym / sponsor ID
- EZE04-003
- Conditions
- Healthy Men
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 60 participants
- Lead sponsor
- University of CologneUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- Apr 2004
- Primary completion
- Jul 2004 (actual)
- Study completion
- Jul 2004 (actual)
- First posted
- 25 Apr 2006 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to investigate the effects of the two lipid -lowering drugs, ezetimibe and simvastatin, on lipid metabolism in humans. In specific, the study will investigate in blood cells whether the enzyme that controls cholesterol synthesis, HMG-CoA reductase, and the receptor that takes up cholesterol from the blood, the LDL receptor, are changed during treatment with the aforementioned drugs.
Detailed description
Ezetimibe decreases serum total and LDL cholesterol levels by blocking cholesterol absorption in the intestine, causing a compensatory increase in cholesterol synthesis. The exact underlying regulatory mechanisms of the ezetimibe-induced increase in cholesterol synthesis and decrease in serum LDL cholesterol are not known. In addition, it has never been investigated whether changes in LDL receptor expression contribute to the LDL-lowering effect of ezetimibe, as is the case with other agents causing a decrease in cholesterol absorption such as the plant stanols.
In the present study, we plan to examine changes in LDL receptor and HMG-CoA reductase mRNA concentrations during ezetimibe treatment. For comparison, effects of simvastatin and the combined administration of the two will be investigated. Since mRNA expression profiles provide information about effects at the transcriptional but not necessarily at the translational level, we will also analyze changes in the LDL receptor protein at the cell surface of mononuclear blood cells. As a functional marker for HMG-CoA reductase activity the ratio of serum lathosterol to cholesterol concentration will be used since it correlates with HMG-CoA reductase activity and serves also as a marker of total cholesterol synthesis.
In this regard it has been shown that plant sterols, which also act by blocking intestinal cholesterol absorption, increase cholesterol synthesis, decrease LDL synthesis, increase LDL receptor mRNA levels as well as LDL receptor protein concentrations but have no significant effect on HMG-CoA reductase expression or activity in peripheral blood mononuclear cells. Aim of this prospective ran-domized parallel study is to examine changes in HMG-CoA reductase activity/expression and in LDL receptor expression/protein concentration in mononuclear blood cells under treatment with ezetimibe.
For this purpose 3 parallel groups of 20 healthy men will be formed. One group will be treated with ezetimibe (10 mg/day), one with 40 mg/day of simvastatin and another with ezetimibe (10 mg/day) plus simvastatin (40 mg/day). Each treatment period will last for 2 weeks. Blood drawing will be per-formed at baseline (before the initiation of treatment) and at the end of the 2 weeks. (storing of the samples at -80°). The measurements involved in this study include the determination of the lipopro-tein concentrations in serum, isolation of the mononuclear cells, measurement of LDL receptor mRNA from the peripheral blood mononuclear cells, measurement of HMG-CoA reductase mRNA levels in peripheral blood mononuclear cells, measurement of the LDL-receptor protein concentrations on the surface of peripheral blood mononuclear cells. Furthermore, the serum latosterol to cholesterol con-centrations will be measured as a surrogate marker of the HMG-CoA reductase activity.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
Who may qualify
- Ages
- 18 to 60 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- healthy male subjects
- age between 18 and 60 years
- body mass index between 18.5 and 30 kg/m2
- LDL cholesterol smaller than 190 mg/dL
- triglicerides smaller than 250 mg/dL
Key exclusion criteria (8 listed)
- intake of lipid-lowering drugs
- excessive alcohol intake
- liver disease
- kidney disease
- coronary heart disease
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ezetimibe | Drug | – |
| simvastatin | Drug | – |
| ezetimibe plus simvastatin | Drug | – |
Primary outcome
HMG-CoA reductase activity
HMG-CoA reductase mRNA expression
LDL receptor mRNA expression
LDL receptor protein
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Dec 2014.
- Derived from this study: PubMed 24662777Berthold HK, Rizzo M, Spenrath N, Montalto G, Krone W, Gouni-Berthold I. Effects of lipid-lowering drugs on high-density lipoprotein subclasses in healthy men-a randomized trial. PLoS One. 2014 Mar 24;9(3):e91565. doi: 10.1371/journal.pone.0091565. eCollection 2014.
- Derived from this study: PubMed 24023786Gouni-Berthold I, Berthold HK, Huh JY, Berman R, Spenrath N, Krone W, Mantzoros CS. Effects of lipid-lowering drugs on irisin in human subjects in vivo and in human skeletal muscle cells ex vivo. PLoS One. 2013 Sep 2;8(9):e72858. doi: 10.1371/journal.pone.0072858. eCollection 2013.
- Derived from this study: PubMed 23544125Berthold HK, Seidah NG, Benjannet S, Gouni-Berthold I. Evidence from a randomized trial that simvastatin, but not ezetimibe, upregulates circulating PCSK9 levels. PLoS One. 2013;8(3):e60095. doi: 10.1371/journal.pone.0060095. Epub 2013 Mar 27.
- Derived from this study: PubMed 23013513Berthold HK, Berneis K, Mantzoros CS, Krone W, Gouni-Berthold I. Effects of simvastatin and ezetimibe on interleukin-6 and high-sensitivity C-reactive protein. Scand Cardiovasc J Suppl. 2013 Feb;47(1):20-7. doi: 10.3109/14017431.2012.734635. Epub 2012 Oct 18.
- Derived from this study: PubMed 20525999Berneis K, Rizzo M, Berthold HK, Spinas GA, Krone W, Gouni-Berthold I. Ezetimibe alone or in combination with simvastatin increases small dense low-density lipoproteins in healthy men: a randomized trial. Eur Heart J. 2010 Jul;31(13):1633-9. doi: 10.1093/eurheartj/ehq181. Epub 2010 Jun 6.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ioanna Gouni-Berthold, MD principal investigator
Medizinische Klinik II und Poliklinik für Innere Medizin
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing ezetimibe, simvastatin and ezetimibe plus simvastatin in people with Healthy Men, run by University of Cologne at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Dec 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
HMG-CoA reductase activity. The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00317993, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Dec 2014.