Randomized Comparison of Morning Versus Bedtime Administration of Statins: a Cardiovascular Circadian Chronotherapy (C3) Trial (STATIN-C3)

Statins inhibit hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase which catalyzes the rate-limiting step in cholesterol synthesis. This in turn leads to reductions in concentrations of low-density lipoprotein (LDL) cholesterol and C-reactive protein which reduces the risk of incident atherosclerotic events among individuals both with and without a history of atherosclerotic cardiovascular Several pilot studies have suggested potential benefits of taking statin in the evening rather than in the morning.

The primary objective of this study is to examine whether statin administration at bedtime versus in the morning provides a superior reduction in the incidence of major adverse cardiovascular events among patients with or without established atherosclerotic cardiovascular disease, who are already taking statin.

Study Overview

• Status: Not yet recruiting
• Conditions: Drug Effect; Atherosclerosis Cardiovascular Disease; Cardiovascular Diseases (CVD)
• Intervention / Treatment: Drug: Statin in the evening (such as Simvastatin, Atorvastatin, Rosuvastatin, Pravastatin); Drug: Statin in the morning (such as Simvastatin, Atorvastatin, Rosuvastatin, Pravastatin)

Detailed Description

The study is a pragmatic, registry-based, open-label, randomized controlled trial combining the utilization of the Danish nationwide health registries and the official Danish electronic letter system (Digital Post/eBoks) into an innovative, decentralized trial requiring no study visits from participants. The nationwide health registries will be used for identification of potential participants and data collection, including baseline information and follow-up data, while the electronic letter system will be used for sending recruitment letters and communicating with participants. Study participants will provide electronic informed consent from home before inclusion and randomization.

The trial will include patients currently in statin treatment regardless of the presence or absence of established cardiovascular disease. Participants will be randomized 1:1 to either statin administration at bedtime or in the morning. The trial is event-driven.

• Study Type: Interventional
• Enrollment (Estimated): 42000
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Manan Pareek, MD and PhD; Phone Number: +4525536900; Email: mananpareek@dadlnet.dk

Study Locations

• Denmark
  • Hellerup, Denmark, 2900
    • Center for Translational Cardiology and Pragmatic Randomized Trials, Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte
    • Contact: Sine Højlund Christensen, MSc; Phone Number: +4524595177; Email: sine.hoejlund.christensen@regionh.dk
    • Contact: Niklas Dyrby Johansen, MD, PhD; Phone Number: +4520204794; Email: niklas.dyrby.johansen@regionh.dk
    • Contact: Manan Pareek, MD and PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age >=18 years
• Current treatment with atorvastatin 10-80 mg, rosuvastatin 5-40 mg, simvastatin 10-80 mg or pravastatin 20-40 mg (as recorded in the Danish National Prescription Registry and confirmed by the participant via questionnaire)
• Signed informed consent

Exclusion Criteria:

• none

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Statin at bedtime; Statin in the current prescribed dose	Drug: Statin in the evening (such as Simvastatin, Atorvastatin, Rosuvastatin, Pravastatin); Participants will be instructed to take their Statin daily at approx. 8PM-12AM.
Experimental: Statin in the morning; Statin in the current prescribed dose	Drug: Statin in the morning (such as Simvastatin, Atorvastatin, Rosuvastatin, Pravastatin); Participants will be instructed to take their statin upon awakening/or with their breakfast (approx. 6AM-10AM).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of hospitalization for myocardial infarction, hospitalization for stroke or cardiovascular death	For Hospitalizations: Inpatient, at least 1 night	Will be assessed in a time-to-first-event approach from date of randomization until end of study (up til 5 years).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospitalization for myocardial infarction	Inpatient, at least 1 night	Will be assessed in a time-to-first-event approach from date of randomization until end of study (up til 5 years).
Hospitalization for stroke	Inpatient, at least 1 night	Will be assessed in a time-to-first-event approach from date of randomization until end of study (up til 5 years).
Cardiovascular death		Will be assessed in a time-to-first-event approach from date of randomization until end of study (up til 5 years).
All-cause death		Will be assessed in a time-to-first-event approach from date of randomization until end of study (up til 5 years).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospitalization for unstable angina	Inpatient, at least 1 night	Will be assessed in a time-to-first-event approach from date of randomization until end of study (up til 5 years).
Coronary revascularization		Will be assessed in a time-to-first-event approach from date of randomization until end of study (up til 5 years).
Any arterial revascularization		Will be assessed in a time-to-first-event approach from date of randomization until end of study (up til 5 years).
Any venous thromboembolism	The incidence of Any venous thromboembolism	Will be assessed in a time-to-first-event approach from date of randomization until end of study (up til 5 years).
Hospitalization for heart failure	The incidence of Hospitalization for heartfailure. For hospitalizations: Inpatient, at least 1 night	Will be assessed in a time-to-first-event approach from date of randomization until end of study (up til 5 years).
Hospitalization for rhabdomyolysis	The incidence of Hospitalization for rhabdomyolysis, Inpatient, at least 1 night.	From date of randomization until end of study (up til 5 years)
Any incident cancer	The incidence of any cancer	From date of randomization until end of study (up til 5 years)
Any incident renal disorder	The incidence of any renal disorder	From date of randomization until end of study (up til 5 years)
Any incident hepatic disorder	The incidence of any hepatic disorder	From date of randomization until end of study (up til 5 years)
Bleeding episodes requiring hospitalization	The incidence of any bleeding episodes requiring hospitalization. For hospitalizations: Inpatient, at least 1 night.	From date of randomization until end of study (up til 5 years)
Any Incident Diabetes mellitus	The incidence of diabetes mellitus	From date of randomization until end of study (up til 5 years)
Plasma Lipid levels		From date of randomization until end of study (up til 5 years)
Plasma C-reactive protein level		From date of randomization until end of study (up til 5 years)
Time of day of hospitalization for myocardial infarction	The time of hospitalization will be expressed as the hour of the beginning of the hospitalization	From date of randomization until end of study (up til 5 years)
Time of day of hospitalization for stroke	The time of hospitalization will expressed as the hour of the beginning of the hospitalization.	From date of randomization until end of study (up til 5 years)

Collaborators and Investigators

• Sponsor: Tor Biering-Sørensen
• Collaborators: Herlev and Gentofte Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): February 28, 2025
• Primary Completion (Estimated): March 28, 2028
• Study Completion (Estimated): March 28, 2028

Study Registration Dates

• First Submitted: February 20, 2025
• First Submitted That Met QC Criteria: February 26, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 26, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Cardiovascular disease; Prevention; Randomized Controlled Trial; Outcomes; Circadian Rhythm; Statin; Pragmatic
• Additional Relevant MeSH Terms: Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Cardiovascular Diseases; Atherosclerosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Atorvastatin; Rosuvastatin Calcium; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin; Pravastatin
• Other Study ID Numbers: STATIN-C3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Baseline and endpoint data will be collected from Danish administrative health registries, which are subject to Danish legislation and can only be made available to a third party under certain conditions. Please contact the sponsor in case of any inquiries.

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