Clinical trial NCT06784557: Effect of Ezetimibe on Gut Microbiota
Official title: Gut Microbiota Alteration With Atorvastatin/Ezetimibe Combination in Patients With Atherosclerotic Cardiovascular Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Atherosclerotic Cardiovascular Disease With Dyslipidemia
Lead sponsor: Yonsei University
Sponsor class: OTHER
First posted: 2025-01-20
Enrollment: 110
Sex: ALL
Minimum age (years): 19
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Ezetimibe exerts its primary effects by inhibiting intestinal cholesterol absorption through the NPC1L1 protein. Beyond this, its impact on gut microbiota remains an area of interest. Gut microbiota has been implicated in cholesterol metabolism and CVD pathogenesis through metabolic and non-metabolic pathways. Modulating gut microbiota has been explored as a potential strategy to prevent CVDs.

Despite its intestinal mechanism, the influence of ezetimibe on gut microbiota composition has not been thoroughly investigated. Future studies are needed to elucidate its potential interactions with gut microbial communities and their implications for cholesterol metabolism and cardiovascular health.

Detailed description: 1. Study Period The clinical trial spans 12 weeks to analyze baseline data and changes after treatment.

   The study starts upon IRB approval, with participant recruitment concluding within 24 months and the entire study wrapping up within 48 months.
2. Study Design This is an investigator-initiated, prospective, single-center, open-label, randomized clinical trial.

   It involves 110 coronary artery disease (CAD) patients in need of lipid-lowering therapy, divided into two groups:

   Experimental Group (n=55): Moderate-intensity statin (Atorvastatin 20 mg) combined with Ezetimibe 10 mg.

   Control Group (n=55): High-intensity statin monotherapy (Atorvastatin 40 mg). Primary Outcome: Changes in gut microbiota composition. Secondary Outcomes: Changes in blood lipid levels and inflammatory biomarkers.
3. Methods 3.1. Screening and Enrollment Participants are screened for eligibility based on inclusion and exclusion criteria.

   After providing informed consent, participants are randomized into two groups (1:1 ratio) using a permuted block randomization method.

   For those on prior statin or Ezetimibe therapy, a 2-week washout period is required before enrollment.

   3.2. Study Medication

   Participants receive their assigned treatment for 12 weeks, with medications administered orally once daily at consistent times, irrespective of meals:

   High-Intensity Statin Group: Atorvastatin 40 mg. Combination Therapy Group: Atorvastatin 20 mg + Ezetimibe 10 mg. 3.3. Follow-Up Baseline data, including demographic details, blood tests, and stool samples, are collected at enrollment.

   After 12 weeks of treatment, follow-up includes clinical evaluations, blood tests, and stool sample collection for post-treatment analysis.
4. Efficacy Evaluation 4.1. Primary Endpoint

Gut Microbiota Analysis:

Stool samples are analyzed using 16S rRNA sequencing.

Statistical tests compare microbiota differences:

Between groups at baseline (T-test or Mann-Whitney test). Pre- and post-treatment within groups (Paired t-test or Wilcoxon test). Intergroup changes over time (ANOVA test). 4.2. Secondary Endpoint Similar statistical methods are applied to assess changes in blood lipid levels and inflammatory biomarkers.

4.3. Subgroup Analysis

Specific subgroups undergo additional analysis:

Subgroup 1: Low-risk CAD patients (10-year ASCVD risk \<7.5%). Subgroup 2: Patients with poor response to therapy (LDL \>70 mg/dL after 12 weeks).

Subgroup 3: Recurrent CAD patients despite optimal therapy. Subgroup stool samples are analyzed using shotgun metagenomic sequencing for detailed microbial insights.

Eligibility criteria: Inclusion Criteria:

* Age: 19 to 80 years old
* Criteria for Diagnosis of Coronary Artery Disease:

Patients diagnosed with coronary artery disease through coronary angiography, or

Patients who require high-intensity lipid-lowering therapy according to current guidelines:

Clinical atherosclerotic cardiovascular disease, LDL cholesterol ≥ 190 mg/dL, LDL 70-189 mg/dL in diabetic patients, 10-year calculated atherosclerotic cardiovascular disease risk ≥ 7.5%

- Voluntary Consent: Individuals who have voluntarily agreed to participate in the study and signed the consent form.

Exclusion Criteria:

* Patients with active liver disease or liver disease with AST/ALT levels elevated more than twice the upper limit of normal.
* Individuals with allergies or hypersensitivity to HMG-CoA reductase inhibitors or ezetimibe.
* Individuals with a history of adverse reactions to HMG-CoA reductase inhibitors or ezetimibe.
* Pregnant, breastfeeding, or women of childbearing potential.
* Organ transplant recipients or individuals scheduled for organ transplantation.
* Patients with active malignant tumors.
* Patients with inflammatory bowel disease.
* Patients with wasting diseases, autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis), or connective tissue diseases (e.g., systemic sclerosis, polymyositis, and dermatomyositis).
* Patients with a history of taking antibiotics, probiotics, or ezetimibe within 3 months prior to study screening.
* Patients who have undergone gastrointestinal surgery within the past year.
* Patients who do not understand the study content or are unable to provide consent.

Primary outcomes:
measure: Changes in Gut Microbiota After 12 Weeks of Treatment
timeFrame: 12 weeks
Secondary outcomes:
measure: Changes in Blood Lipid Levels and Inflammatory Biomarker Levels After 12 Weeks of Treatment
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Severance hospital, Yonsei University College of Medicine
Study officials:
References: