Alirocumab and Reverse Cholesterol Transport

Effect of Alirocumab on Reverse Cholesterol Transport in Humans

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.

Study Overview

• Status: Completed
• Conditions: Atherosclerosis; Coronary Heart Disease
• Intervention / Treatment: Drug: Alirocumab; Drug: Placebos

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Alirocumab; Subjects will receive alirocumab for 6 weeks.	Drug: Alirocumab; 150 mg SQ every 2 weeks; Other Names: Praluent
Placebo Comparator: Placebos; Subjects will receive placebo for 6 weeks.	Drug: Placebos; Placebo injections SQ every 2 weeks; Other Names: Placebo

What is the study measuring?

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).

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Richard E Ostlund, MD, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2017
• Primary Completion (Actual): June 4, 2018
• Study Completion (Actual): July 30, 2018

Study Registration Dates

• First Submitted: December 6, 2016
• First Submitted That Met QC Criteria: January 5, 2017
• First Posted (Estimate): January 9, 2017

Study Record Updates

• Last Update Posted (Actual): November 7, 2018
• Last Update Submitted That Met QC Criteria: November 5, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Atherosclerosis
• Other Study ID Numbers: 201612021

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No plans to share individual data.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No