INvestigating the Lowest Threshold of Vascular bENefits From LDL Lowering With a PCSK9 InhibiTor in healthY Volunteers

Summary

The INTENSITY-LOW study aims to answer if there are any limits to LDL reduction in relation to benefitting vascular health from a mechanistic viewpoint, and therefore potentially limitations to primary prevention in healthy volunteers by lowering LDL cholesterol using PCSK9 therapies. 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 healthy individuals. It is also unknown whether there is a true limit of LDL cholesterol below which there is no further improvement in endothelial function in healthy people, and, whether this is associated with a reduction in markers of both systemic and vascular inflammation. This study will hope to provide evidence that the so-called pleiotropic effects of statins are actually mediated by a mechanism of LDL-cholesterol lowering per se and not necessarily a special therapeutic effect of statins.

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 healthy volunteers only, where participants will be randomized to either the Alirocumab arm (which is a therapy designed to lower cholesterol) or comparator arm. Both Alirocumab and comparator arms will be combined with Atorvastatin (another therapy designed to lower cholesterol) at the second dosing visit.

In total, thirty healthy individuals will be recruited to this single centre, randomized, single blind, parallel group, mechanistic physiological study which will be conducted at Cambridge University Hospitals NHS Foundation Trust/University of Cambridge. This study will be open to recruitment for one year and the total study duration for each participant will be approximately 10 weeks. There will be 4 study visits in total with a telephone follow up at the end of the study. Of these visits, two will be dosing visits and the total duration of treatment is approx. 4 weeks.

A series of non-invasive haemodynamic assessments and minimally invasive procedures including blood tests and forearm blood flow measurements will be conducted prior, during and post dosing to determine if there is an improvement of endothelia vascular function (as measured by nitric oxide bioavailability) and reduced systemic inflammation. This study is funded by JP Moulton Charitable Foundation.

Conditions

• Atherosclerosis
• Cardiovascular Diseases

Interventions

OTHER

Written Informed Consent

To be completed prior to conducting any study related procedures

OTHER

Inclusion/Exclusion check

Eligibility check

OTHER

Full Clinical Chemistry and Haematology Bloods

Participant required to fast for at least 6-8 hoursprior to visit. (Clear, non-caffeinated fluids are allowed)

OTHER

Serum sample for systemic markers and lipid sub-fractions

Serum samples may be stored for later analysis.

OTHER

Pregnancy Test

If applicable for women of child bearing potential

OTHER

12 Lead ECG

participant resting supine

OTHER

Blood Pressure and Heart Rate

Measured in the seated position after 5 minutes rest

OTHER

Arterial Stiffness

Measure of functional and structural changes which accompanies cardiovascular disease

OTHER

Central Haemodynamics

Measure of functional and structural changes which accompanies cardiovascular disease

OTHER

Carotid Intima Media Thickness

Measurements will be repeated three times, and the average of the median values will be recorded

OTHER

Forearm blood flow studies

Assess and determine vascular function, which can interrogate endothelium dependent and independent mechanisms of nitric oxide bioavailability

OTHER

Concomitant medication check

Review of medication taken by the participant

OTHER

Medication compliance check (Pill count)

Ensure prescribed statin has been taken

OTHER

Physical examination

Check overall health

OTHER

Medical history

Review of volunteers medial history

OTHER

AE/SAE review & reporting

Monitor safety from the point of consent

DRUG

Dosing

To be performed at the end of the visit following completion all other study visits

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

DOUBLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

45 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2017-09-07

Primary Completion

2018-10-10

Completion

2018-10-10

Countries

• United Kingdom

Study Locations