Alirocumab and Reverse Cholesterol Transport

Study Overview
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Brief Summary
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Alirocumab is an injectable treatment for elevated blood cholesterol. The hypothesis of this study is that it also increases cholesterol excretion from the body into the stool, a process sometimes called reverse cholesterol transport. A cholesterol metabolic study will be done before and after 6 weeks of alirocumab treatment. If alirocumab increases reverse cholesterol transport, it is possible that this action provides additional protection from cardiovascular disease.

Detailed Description
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This study is a single-site, randomized, placebo-controlled clinical trial in which about 24 subjects are expected to complete an 8-week study period. The performance site is Washington University School of Medicine. Even though alirocumab is an approved drug, the investigators consider this to be a phase I trial because it is a physiological study in which the primary endpoint is change in fecal cholesterol excretion and measures of reverse cholesterol transport. It is not a treatment protocol and uses healthy subjects. Subjects with greater than ideal cholesterol but not taking cholesterol lowering drugs will be studied. All receive whole body cholesterol metabolism tests before and after treatment for 6 weeks with either alirocumab or placebo. Each test takes 2 weeks. On the first day the subjects receive about 35 mg cholesterol-d7 intravenously and blood samples are obtained in order to measure cholesterol turnover rate, pool size, esterification rate, transfer from HDL to LDL and removal from the plasma compartment. Fecal cholesterol excretion and related parameters are measured on days 13 and 14 after a relative steady-state is obtained. During this time the subjects consume a metabolic kitchen diet controlled in cholesterol and phytosterol content and consume oral tracer capsules consisting of cholesterol-d5 and sitostanol-d4. Plasma and stool samples are analyzed by gas chromatography/tandem mass spectrometry to determine daily percent cholesterol excretion from rapidly-mixing body cholesterol pools, fecal cholesterol mass and percent cholesterol absorption. The cholesterol metabolic test is repeated on day 43 and final measurements are made on day 57. Treatment effect, defined as the difference between active and placebo treatments is then calculated. Based on animal data it is expected that alirocumab will increase the efficiency of cholesterol excretion from body pools and the rate of removal of cholesterol ester from plasma.

Official Title
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Effect of Alirocumab on Reverse Cholesterol Transport in Humans

Conditions
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Atherosclerosis, Coronary Heart Disease

Intervention / Treatment
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* Drug: Alirocumab
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy or with stable medical or surgical illnesses LDL>100 mg/dl. Exclusion Criteria: Triglycerides>250 Taking drugs affecting lipid metabolism Elevated liver function tests Diabetes mellitus A1c 6.5% or greater Pregnant Breastfeeding Desire for conception in either sex.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Alirocumab<br>Subjects will receive alirocumab for 6 weeks. | Drug: Alirocumab<br>* 150 mg SQ every 2 weeks<br>* Other names: Praluent;|
| Placebo Comparator: Placebos<br>Subjects will receive placebo for 6 weeks. | Drug: Placebos<br>* Placebo injections SQ every 2 weeks<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in percent cholesterol excretion per day. | Percent cholesterol excretion per day is defined as the percent of endogenous rapidly-mixing cholesterol pools excreted per day into the stool. | Measurements made on days 13-15 (baseline) and days 55-57 (on treatment). | 
| Change from baseline in removal rate of esterified cholesterol from plasma per day. | The removal rate of esterified cholesterol from plasma per day is defined as fractional removal rate of esterified cholesterol from the plasma in pools/day. | Measurements made on days 1-3 (baseline) and days 43-45 (on treatment). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in LDL cholesterol | Reduction in LDL with alirocumab treatment. | Measurements made on day 15 (baseline) and day 57 (on treatment). | 
| Change from baseline in percent cholesterol absorption | Percent cholesterol absorption is defined as the percent of intestinal cholesterol absorbed into the body. | Measurements made on days 13-15 (baseline) and days 55-57 (on treatment). |