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

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.

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.

Eligibility Criteria:
Inclusion Criteria:

* Patients with high risk CVD with LDL-Cholesterol ≤ 4.0mmol\* OR patients with very high risk CVD with LDL-Cholesterol ≤3.5mmol/l\*\*
* Male or female patients over 40 years of age inclusive at screening, with a body weight ≥ 45kg and BMI ≥ 18 - ≤ 40kg/m2
* Palpable brachial arterial pulse, as per study team assessment
* History of stable CV disease, defined as previous myocardial infarction (STEMI or NSTEMI), angioplasty, documented CAD (Stress echo, CT coronary angiography or invasive angiography), stroke, TIA or peripheral vascular disease without a recent event in the last 6 months (i.e. acute coronary syndrome, unstable angina, CABG, PCI, stroke, MI, carotid endarterectomy)
* Stable 'suitable statin therapy' over the last 6 weeks as defined by a "statin equivalent" of Simvastatin 80mg od, Rosuvastatin 20mg/40mg od or Atorvastatin 40/80mg od. If not on stable statin therapy, a willingness to commence statin therapy or, if already on statin therapy, a willingness to increase statin therapy to fit the "statin equivalent" dose required in the study (as open label therapy) during run-in period
* Patients not taking Ezetimibe, or, if on Ezetimibe willingness to be washed out prior to randomisation

High risk is defined as a history of any of the following: acute coronary syndrome (such as myocardial infarction or unstable angina requiring hospitalisation), coronary or other arterial revascularisation procedures, chronic heart disease, ischaemic stroke, peripheral arterial disease.

Very high risk is defined as recurrent cardiovascular events or cardiovascular events in more than 1 vascular bed (that is, polyvascular disease).

Exclusion Criteria:

* Uncontrolled hypertension BP \> 180/110 mmHg on repeated measurements
* Fasting hypertriglyceridemia with fasting TG\>10 mmol/L at screening
* Pregnancy or combined oral contraceptive pill or hormone replacement therapy or childbearing potential
* Any concomitant condition that, at the discretion of the investigator, may affect the participant's ability to complete the study
* Any known sensitivity to Alirocumab or monoclonal antibodies
* Patients with history of hypersensitivity reactions to any of the study drugs
* History of significant LFT's (3xULN ALT or AST elevation) by previous statin treatment
* History of previous myositis associated with statin treatment (i.e. myalgias or asymptomatic CK elevation \> 5 x ULN)
* Type 1 or Type 2 diabetes, which is insulin dependent or on oral hypoglycaemics/diet with HbA1c (DCCT) \> 8% (OR HbA1c (IFCC) \> 64mmol/mol) at screening. Please note: fasting glucose to be checked again at first FDG-PET/CT scan, and if glucose \> 11mol/L at that visit, patients will be excluded from the study
* History of any acute CV event within 6 months prior to the screening period
* Rheumatoid arthritis, connective tissue disorders and other conditions known to be associated with active chronic inflammation (e.g. Inflammatory Bowel Disease)
* Untreated hypothyroidism, known autoimmune myositis
* Patients with CKD (defined as eGFR \< 30 ml/min/1.73m2) at baseline will be excluded from the study
* Participant in a previous research study in the last 3 years which involved exposure to significant ionising radiation (i.e. cumulative research radiation dose \> 5 mSv)
* History of malignancy within the past 5 years (with the exception of localised carcinoma of the skin that has been resected for cure)
* History of alcohol/drug abuse or dependence within 6 months of the study, screening visit 1
* Use of systemic corticosteroids at the time of scanning or a period of 2 weeks prior to screening visit
* Lack of ability to provide informed consent
* An unwillingness for female patients of childbearing potential to use an effective form of contraception (see section 12.2.3)
* Treatment with medications that result in significant drug to drug interactions with study medications. Assignment to a specific statin will be allowed prior to randomisation on a case-to-case basis dependent on the interactions with concomitant medications

Inclusion/Exclusion Criteria for INTENSITY-HIGH PET/MR sub-study (optional)

* Patient meets Inclusion/Exclusion criteria for INTENSITY HIGH
* Patient who fulfills the local imaging centre requirements for being scanned in the PET/MR machine will be enrolled
* Patient is willing to consent to participate in the sub-study