NCT03355027

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

INvestigating the Lowest Threshold of Vascular bENefits From LDL Cholesterol Lowering With a PCSK9 mAb InhibiTor (Alirocumab) in Patients With Stable Cardiovascular Disease (INTENSITY-HIGH)

• Status: Unknown
• Phase: N/A
• Study type: Interventional
• Enrollment: 60 (actual)
• Sponsor: Cambridge University Hospitals NHS Foundation Trust · Academic / Other
• Sex: All
• Age: 40 Years
• Healthy volunteers: Not accepted

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.

Detailed description

The INTENSITY-HIGH study primarily seeks to explore the physiological mechanisms (mainly using endothelial function and vascular imaging of inflammation) by which secondary prevention in patients with established cardiovascular disease may benefit from even lower LDL levels using PCSK9 therapies. This will then set the basis for potential changes to guidelines about what a "healthy cholesterol" level should be and the targets these should be achieving, or indeed if there is a plateau beyond which there is no further benefit on surrogates of CV disease. Endothelial function can be measured in the peripheral vasculature in a number of different ways, which include venous occlusion plethysmography with intra-arterial infusions of acetylcholine, ischemia flow-mediated endothelium-dependent dilatation (FMD) of the brachial artery, reactive hyperemia peripheral arterial tonometry (RH-PAT) and others. A venous plethysmography measure of forearm blood flow to intra-arterial acetylcholine infusion is the most sensitive and direct measurement of endothelium release of nitric oxides, but is more invasive than other techniques. FMD is non-invasive and measures changes in the brachial artery to ischemia. It is acknowledged that whilst FMD has a larger coefficient variation and is more technician dependent, it is more patient-friendly in that it is of shorter duration procedure wise, is non-invasive and is repeatable over a short period; therefore we have employed this technique in this study to improve chances of patient acceptability. RH-PAT is an alternative non-invasive assessment which measures volume changes at the fingertip (a surrogate of reactive hyperemia), is easy to implement and is not operator dependent. However, as yet it remains not well validated. Therefore, flow mediated dilatation has been selected for this study. Metabolically active inflammatory cells utilize more glucose than non-activated cells, and the degree of metabolic activity can be measured using 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). Cellular FDG uptake is largely irreversible and correlates with glucose usage and macrophage numbers in both tumor cells and atherosclerotic plaques \[38, 39\]. FDG PET imaging has been successfully used to determine culprit plaques responsible for TIA and stroke \[4042\]. The signal has also been shown to be responsive to therapy, with clear reductions in FDG uptake noted in both humans and animal models of atherosclerosis \[43, 44\]. In addition, very recently, it has been shown that FDG-PET/CT is a reliable technique to assess changes in plaque structure with good reproducibility \[40\]. Taken together, these findings suggest a role for FDG PET/CT imaging in the assessment of the antiinflammatory potential of novel compounds such as PCSK9 therapies.

Conditions

• Atherosclerosis
• Cardiovascular Diseases

Interventions

Type	Name	Description
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)

Timeline

• Start date: 2017-11-30
• Primary completion: 2019-09-30
• Completion: 2023-11-30
• First posted: 2017-11-28
• Last updated: 2021-07-23

Locations

1 site across 1 country: United Kingdom