KF2023#1-Trial: Influence of Statin Intake on Cellular Readouts

A majority of high-risk patients does not achieve their cholesterol target levels and most of these patients do not receive more effective combination therapy, which goes beyond statin monotherapy. Large interindividual differences in treatment outcomes have been observed for patients receiving statins. Statins block cholesterol synthesis and increase cellular low-density lipoprotein (LDL) uptake. Importantly, LDL uptake is highly divergent in individuals.The aim of this trial is to investigate how atorvastatin influences leukocyte readouts of LDL uptake and lipid storage in humans. The trial is a single-arm, open-label, interventional trial. A total of 15 healthy volunteers will receive 40 mg atorvastatin once a day for 4 weeks. The participants will provide blood samples before starting the atorvastatin intervention, each week when taking atorvastatin, and one week after the end of the intervention for the measurement of leukocyte readouts of LDL uptake and lipid storage.

Study Overview

• Status: Recruiting
• Conditions: Pharmacodynamics
• Intervention / Treatment: Drug: Atorvastatin

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Mikko Niemi, MD, PhD; Phone Number: +35894711; Email: mikko.niemi@hus.fi
• Study Contact Backup: Name: Anssi Mykkänen, MD; Phone Number: +35894711; Email: anssi.mykkanen@hus.fi

Study Locations

• Finland
  • Helsinki, Finland, 00290
    • Recruiting
    • Department of Clinical Pharmacology
    • Contact: Mikko Niemi, MD, PhD; Phone Number: +35894711; Email: mikko.niemi@hus.fi
    • Contact: Anssi Mykkänen, MD; Phone Number: +35894711; Email: anssi.mykkanen@hus.fi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. a signed written informed consent
2. age 18-40 years
3. healthy, and
4. Accepted results from laboratory tests (blood haemoglobin, basic blood count and blood platelets, alanine aminotransferase, alkaline phosphatase, glutamyl transferase, creatinine, plasma potassium and sodium). Negative pregnancy test result (serum human chorionic gonadotropin) for women.
5. Fully vaccinated against COVID-19.

Exclusion Criteria:

1. significant disease
2. smoking
3. SLCO1B1 poor function genotype
4. oral contraception or other continuous medication
5. pregnancy, planning of pregnancy or breastfeeding
6. participating in a clinical trial less than 3 months ago
7. donating blood less than 3 months ago
8. marked obesity
9. anticipated difficulties in drawing blood samples
10. weight less than 45 kg
11. BMI less than 18.5 kg/m2 or
12. inadequate Finnish language skills

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Atorvastatin; atorvastatin 40 mg daily for 28 days	Drug: Atorvastatin; one 40 mg atorvastatin tablet once daily for 28 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lipid trafficking score LT-Mo	The primary outcome measurement is the "lipid trafficking score LT-Mo" is a combination of LDL uptake and lipid droplet quantifications in monocytes. The participants provide blood samples before starting the atorvastatin intervention, each week when taking atorvastatin (4 times in total), and one week after the end of the intervention.	Baseline and once a week for 5 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Leukocyte LDL uptake	Systematic quantification of leukocyte uptake of low-density lipoprotein (LDL). Leukocytes are exposed to fluorescently labelled LDL particles and internalized LDL particles are quantified with microscopy and automated image analysis. The specific readouts are overall fluorescent LDL intensity and the number of endosomal organelles filled with fluorescent LDL particles for monocyte and lymphocyte subpopulations.	Baseline and once a week for 5 weeks
Leukocyte lipid storage	A systematic semi-automated approach is used to quantify cellular lipid droplets, dedicated storage organelles for lipids. Individual lipid droplets, their size and area are quantified in each cell and either used as individual readouts or combined with LDL uptake readouts to derive lipid trafficking scores.	Baseline and once a week for 5 weeks
Atorvastatin plasma concentration	The plasma concentrations of atorvastatin and its metabolites will be quantified with liquid chromatography tandem mass spectrometry (LC-MS/MS) from plasma samples.	Once a week during the 4 week atorvastatin treatment

Collaborators and Investigators

• Sponsor: Mikko Niemi
• Collaborators: University of Helsinki

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2024
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: May 6, 2024
• First Submitted That Met QC Criteria: June 17, 2024
• First Posted (Actual): June 21, 2024

Study Record Updates

• Last Update Posted (Actual): June 21, 2024
• Last Update Submitted That Met QC Criteria: June 17, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin
• Other Study ID Numbers: KF2023#1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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