Effects of Selective Inhibition of Cholesterol Absorption With Ezetimibe on Intestinal Cholesterol Homeostasis in Dyslipidemic Men With Insulin-resistance - a Pilot Study

NCT01849068 | Completed Phase 3 Results

• 1 other identifier: INAF-B13-04-1195
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Metabolic Syndrome X

Outcome Measures

Primary Outcomes (1)

• 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)

Secondary Outcomes (3)

• Change in Intestinal mRNA Expression Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions

  At the end of the two 12-week interventions (Week 12 and 24)

• Change in Intestinal Protein Levels of LDL Receptor Between the Two 12-week Interventions

  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

  At the end of the two 12-week interventions (Week 12 and 24)

Study Arms (2)

Ezetimibe

EXPERIMENTAL

Drug: Ezetimibe

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Ezetimibe DRUG

Ezetimibe 10 mg/d for 12 weeks

Also known as: Ezetrol

Ezetimibe

Placebo DRUG

Placebo for 12 weeks

Placebo

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Men aged between 18-60 years
• Waist circumference \> 102 cm
• HDL-cholesterol \< 1.1 mmol/L
• Triglycerides \> 1.7 mmol/L
• Fasting blood glucose \> 6.1 mmol/L
• Normal blood pressure (\<130/85)

You may not qualify if:

• Women
• Men \< 18 or \> 60 years
• Smokers (\> 1 cigarette/day)
• Body weight variation \> 10% during the last 6 months prior to the study baseline
• Subjects with a previous history of cardiovascular disease
• Subjects with type 2 diabetes
• Subjects with a monogenic dyslipidemia
• Subjects on hypertension medications or medications known to affect lipoprotein metabolism or the integrity of gastrointestinal mucosa
• Subjects with endocrine or gastrointestinal disorders
• History of alcohol or drug abuse within the past 2 years
• Subjects who are in a situation or have any condition that, in the opinion of the investigator, may interfere with optimal participation in the study.

Sponsors & Collaborators

• Laval University: lead

Study Sites (1)

Laval University

Québec, Quebec, G1V 0A6, Canada

Location

MeSH Terms

Conditions

Metabolic Syndrome

Interventions

Ezetimibe

Condition Hierarchy (Ancestors)

Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Azetidines; Azetines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Patrick Couture MD, PhD, FRCP
• Organization: Laval University

patrick.couture@crchul.ulaval.ca

418-654-2106

Study Officials

• Patrick Couture, MD, FRCP, PhD

  Laval University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, FRCP, PhD

Study Record Dates

• First Submitted: May 6, 2013
• First Posted: May 8, 2013
• Study Start: June 1, 2013
• Primary Completion: June 1, 2015
• Study Completion: February 1, 2016
• Last Updated: April 12, 2016
• Results First Posted: April 12, 2016

Record last verified: 2016-03

Locations

CA (1)