INvestigating the Lowest Threshold of Vascular bENefits From LDL Lowering With a PCSK9 InhibiTor in healthY Volunteers
Condition: Atherosclerosis; Cardiovascular Diseases
MeSH terms: Cardiovascular Diseases; Atherosclerosis
Study type: Interventional

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.
    


Intervention name(s): Written Informed Consent; Inclusion/Exclusion check; Full Clinical Chemistry and Haematology Bloods; Serum sample for systemic markers and lipid sub-fractions; Pregnancy Test; 12 Lead ECG; Blood Pressure and Heart Rate; Arterial Stiffness; Central Haemodynamics; Carotid Intima Media Thickness; Forearm blood flow studies; Concomitant medication check; Medication compliance check (Pill count); Physical examination; Medical history; AE/SAE review & reporting; Dosing
Intervention type(s): Other; Other; Other; Other; Other; Other; Other; Other; Other; Other; Other; Other; Other; Other; Other; Other; Drug
Intervention description(s): To be completed prior to conducting any study related procedures; Eligibility check; Participant required to fast for at least 6-8 hoursprior to visit. (Clear, non-caffeinated fluids are allowed); Serum samples may be stored for later analysis.; If applicable for women of child bearing potential; participant resting supine; Measured in the seated position after 5 minutes rest; Measure of functional and structural changes which accompanies cardiovascular disease; Measure of functional and structural changes which accompanies cardiovascular disease; Measurements will be repeated three times, and the average of the median values will be recorded; Assess and determine vascular function, which can interrogate endothelium dependent and independent mechanisms of nitric oxide bioavailability; Review of medication taken by the participant; Ensure prescribed statin has been taken; Check overall health; Review of volunteers medial history; Monitor safety from the point of consent; To be performed at the end of the visit following completion all other study visits
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomisation to be performed to a 1:1 ratio.
Alirocumab treatment arm:
V2: Alirocumab (150mg)
V3: Alirocumab (150mg) & Atorvastatin (20mg)
Comparator treatment arm
V2: Placebo
V3: Placebo & Atorvastatin (20mg)
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: Healthy Volunteers; Low Density Lipoprotein Cholesterol (LDL); PCSK9; Alirocumab; Forearm Blood Flow; Arterial Stiffness; Carotid Intima Media Thickness; Inflammation; Endothelial function