Investigating the Lowest Threshold of Vascular Benefits From LDL Cholesterol Lowering in Patients With Stable CV Disease

Summary

The INTENSITY-HIGH study aims to answer if there are any limits to LDL reduction in relation to benefiting vascular health, exploring the mechanisms by which secondary prevention in patients with established heart disease may benefit from even lower LDL levels. By using PCSK9 inhibitors such as Alirocumab, very low LDL cholesterol levels not previously encountered in statin trials, can be achieved in patients with established heart disease on top of intensive statin treatment.

This research is being carried out because it is unclear what the lowest threshold of LDL cholesterol should be to attain significant reductions in CV risk in stable cardiovascular patients. It is unknown whether there is a true limit of LDL cholesterol below which there is no further improvement in endothelial function in stable cardiovascular patients, and, whether this is associated with a reduction in markers of both systemic and vascular inflammation.

Defining this may help identify individuals from the general population who may benefit from more aggressive lipid lowering treatment than standard statin treatment in terms of CV morbidity and mortality.

This study will be conducted in patients with stable cardiovascular disease, where they will be randomized to receive either a combination of Alirocumab and statin, or Ezetimibe plus statin. 60 patients will be recruited to this single center, randomized, open label, parallel group, mechanistic physiological study which will be conducted at Cambridge University Hospitals NHS Foundation Trust. In order to be eligible for enrollment to the study, some patients may have to complete a 4 week washout period on a suitable statin therapy. The total study duration for each participant will be approximately 14 weeks, where a series of non-invasive vascular studies and medical imaging assessments which will be conducted to observe vascular/systemic inflammation and to assess endothelial vascular function.This study is funded by JP Moulton Charitable Foundation.

Conditions

• Atherosclerosis
• Cardiovascular Diseases

Interventions

DRUG

Alirocumab 150 MG/ML

Dosing to be performed by subcutaneous injection in clinic

DRUG

Ezetimibe 10Mg Tablet

Patients will be instructed to take once daily at night.

DRUG

Atorvastatin 40Mg Tablet

Patients will be instructed to take once daily at night. Atorvastatin will be the preferred statin option for those with eGFR \< 60 ml/min/1.73m2. Patient may be required to complete a 4 week run-in period on a statin prior to entering the study (dependent on eligibility)

DRUG

Atorvastatin 80Mg Tablet

Patients will be instructed to take once daily at night. Atorvastatin will be the preferred statin option for those with eGFR \< 60 ml/min/1.73m2. Patient may be required to complete a 4 week run-in period on a statin prior to entering the study (dependent on eligibility)

DRUG

Rosuvastatin 20Mg Tablet

Patients will be instructed to take once daily at night. Rosuvastatin only to be prescribed if atorvastatin and simvastatin are not previously tolerated. Patient may be required to complete a 4 week run-in period on a statin prior to entering the study (dependent on eligibility)

DRUG

Rosuvastatin 40Mg Tablet

Patients will be instructed to take once daily at night. Rosuvastatin only to be prescribed if atorvastatin and simvastatin are not previously tolerated. Patient may be required to complete a 4 week run-in period on a statin prior to entering the study (dependent on eligibility)

DRUG

Simvastatin 80mg

Patients will be instructed to take once daily at night. Patient may be required to complete a 4 week run-in period on a statin prior to entering the study (dependent on eligibility)

Sponsors & Collaborators

• University of Cambridge

  collaborator OTHER

• Cambridge University Hospitals NHS Foundation Trust

  lead OTHER

Principal Investigators

• Joseph Cheriyan, MBChB, FRCP, MA · Cambridge University Hospitals NHS Trust

• Michalis Kostapanos, MD, PhD, FRSPH · Cambridge University Hospitals NHS Trust

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

40 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2017-11-30

Primary Completion

2019-09-30

Completion

2023-11-30

Countries

• United Kingdom

Study Locations