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Ezetimibe has been shown to inhibit cholesterol absorption and several lines of evidence from in vitro systems and animal models suggest that this effect is associated with an increase in low-density lipoprotein (LDL) receptor expression in the small intestine. The impact of a treatment with ezetimibe on intestinal gene expression and protein mass levels of LDL receptor and other key genes involved in intestinal cholesterol homeostasis will be examined in dyslipidemic men with insulin-resistance. In the present study, gene expression studies and protein mass levels will be assessed on duodenal biopsies by real-time polymerase chain reaction (rt-PCR) and liquid chromatography-mass spectrometry (LC-MS/MS), respectively. The primary objective of this proposal is to examine the effects of ezetimibe on intestinal gene expression (rt-PCR) and protein mass levels (LC-MS/MS) of LDL receptor in dyslipidemic men with insulin-resistance. The secondary objective is to examine the impact of ezetimibe treatment on intestinal gene expression and protein mass levels of sterol regulatory element-binding protein (SREBP)-2, Niemann-Pick C1-Like1 (NPC1L1), ATP binding cassette gene (ABCG)-5/8, proprotein convertase subtilisin/kexin type 9 (PCSK9) and 3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA) reductase.
Primary hypothesis Treatment with ezetimibe 10 mg/day will significantly increase duodenal mRNA and protein mass levels of LDL receptor in dyslipidemic men with insulin-resistance.
Secondary hypothesis Treatment with ezetimibe 10 mg/day will significantly increase duodenal mRNA and protein mass levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA reductase in dyslipidemic men with insulin-resistance.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ezetimibe | Experimental |
| |
| Placebo | Placebo Comparator |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ezetimibe | Drug | Ezetimibe 10 mg/d for 12 weeks |
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| Measure | Description | Time Frame |
|---|---|---|
| Change in Intestinal mRNA Expression Levels of LDL Receptor Between the Two 12-week Interventions | We combined the results at the end of each ezetimibe phase from both sequence (average and standard deviation). We combined the results at the end of each placebo phase from both sequence (average and standard deviation). | At the end of the two 12-week interventions (Week 12 and 24) |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Intestinal mRNA Expression Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions | We combined the results at the end of each ezetimibe phase from both sequence (average and standard deviation). We combined the results at the end of each placebo phase from both sequence (average and standard deviation). | At the end of the two 12-week interventions (Week 12 and 24) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Patrick Couture, MD, FRCP, PhD | Laval University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Laval University | Québec | Quebec | G1V 0A6 | Canada |
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| ID | Title | Description |
|---|---|---|
| FG000 | Ezetimibe First, Then Placebo | First intervention: Ezetimibe 10 mg/d for 12 weeks Second intervention: Placebo for 12 weeks |
| FG001 | Placebo First, Then Ezetimibe | First intervention: Placebo for 12 weeks Second intervention: Ezetimibe 10 mg/d for 12 weeks |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Placebo | Drug | Placebo for 12 weeks |
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| Change in Intestinal Protein Levels of LDL Receptor Between the Two 12-week Interventions | We combined the results at the end of each ezetimibe phase from both sequence (average and standard deviation). We combined the results at the end of each placebo phase from both sequence (average and standard deviation). | At the end of the two 12-week interventions (Week 12 and 24) |
| Change in Protein Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions | We combined the results at the end of each ezetimibe phase from both sequence (average and standard deviation). We combined the results at the end of each placebo phase from both sequence (average and standard deviation). | At the end of the two 12-week interventions (Week 12 and 24) |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Ezetimibe First Then Placebo | First intervention: Ezetimibe 10 mg/d for 12 weeks Second intervention: Placebo 12 weeks |
| BG001 | Placebo First Then Ezetimibe | First intervention: Placebo for 12 weeks Second intervention: Ezetimibe 12 weeks |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Intestinal mRNA Expression Levels of LDL Receptor Between the Two 12-week Interventions | We combined the results at the end of each ezetimibe phase from both sequence (average and standard deviation). We combined the results at the end of each placebo phase from both sequence (average and standard deviation). | Posted | Mean | Standard Deviation | #copies/100000 copies housekeeping gene | At the end of the two 12-week interventions (Week 12 and 24) |
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| Secondary | Change in Intestinal mRNA Expression Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions | We combined the results at the end of each ezetimibe phase from both sequence (average and standard deviation). We combined the results at the end of each placebo phase from both sequence (average and standard deviation). | Posted | Mean | Standard Deviation | #copies/100000 copies housekeeping gene | At the end of the two 12-week interventions (Week 12 and 24) |
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| Secondary | Change in Intestinal Protein Levels of LDL Receptor Between the Two 12-week Interventions | We combined the results at the end of each ezetimibe phase from both sequence (average and standard deviation). We combined the results at the end of each placebo phase from both sequence (average and standard deviation). | Data will never be analyzed because the mRNA expression of LDL receptor is sufficient. | Posted | At the end of the two 12-week interventions (Week 12 and 24) |
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| Secondary | Change in Protein Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions | We combined the results at the end of each ezetimibe phase from both sequence (average and standard deviation). We combined the results at the end of each placebo phase from both sequence (average and standard deviation). | Data will never be analyzed because the mRNA expression of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA reductase are sufficient. | Posted | At the end of the two 12-week interventions (Week 12 and 24) |
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Ezetimibe | Ezetimibe 10 mg/d for 12 weeks Ezetimibe 10 mg/d for 12 weeks | 0 | 20 | 0 | 20 | ||
| EG001 | Placebo | Placebo for 12 weeks Placebo for 12 weeks | 0 | 20 | 0 | 20 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Patrick Couture MD, PhD, FRCP | Laval University | 418-654-2106 | patrick.couture@crchul.ulaval.ca |
| ID | Term |
|---|---|
| D024821 | Metabolic Syndrome |
| ID | Term |
|---|---|
| D007333 | Insulin Resistance |
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D000069438 | Ezetimibe |
| ID | Term |
|---|---|
| D001384 | Azetidines |
| D001385 | Azetines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| >=65 years |
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| Male |
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