Atherosclerosis, Cardiovascular Diseases
Conditions
Keywords
Healthy Volunteers, Low Density Lipoprotein Cholesterol (LDL), PCSK9, Alirocumab, Forearm Blood Flow, Arterial Stiffness, Carotid Intima Media Thickness, Inflammation, Endothelial function
Brief 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.
Interventions
To be completed prior to conducting any study related procedures
OTHERInclusion/Exclusion check
Eligibility check
OTHERFull Clinical Chemistry and Haematology Bloods
Participant required to fast for at least 6-8 hoursprior to visit. (Clear, non-caffeinated fluids are allowed)
OTHERSerum sample for systemic markers and lipid sub-fractions
Serum samples may be stored for later analysis.
OTHERPregnancy Test
If applicable for women of child bearing potential
OTHER12 Lead ECG
participant resting supine
Measured in the seated position after 5 minutes rest
OTHERArterial Stiffness
Measure of functional and structural changes which accompanies cardiovascular disease
OTHERCentral Haemodynamics
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
OTHERForearm blood flow studies
Assess and determine vascular function, which can interrogate endothelium dependent and independent mechanisms of nitric oxide bioavailability
OTHERConcomitant medication check
Review of medication taken by the participant
OTHERMedication compliance check (Pill count)
Ensure prescribed statin has been taken
OTHERPhysical examination
Check overall health
OTHERMedical history
Review of volunteers medial history
OTHERAE/SAE review & reporting
Monitor safety from the point of consent
DRUGDosing
To be performed at the end of the visit following completion all other study visits
Sponsors
University of Cambridge
Cambridge University Hospitals NHS Foundation Trust
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Masking description
Independent CRF research nurse to perform the drug administration. CRF nurse will be unblinded whilst the rest of the study team (including the CI/PI) are blinded. This will involve the ACRC nurse bringing the injection in a sealed box to the room, preparing a shield (so the volunteer is blinded), administering the injection (via alirocumab pen or placebo - saline in insulin syringe) and then putting the syringe back in the sealed box and removing the screen. They have to ensure none of the study team are aware of the Rx as well as the patient. CRF nurses will also have to collect and store medication in their building. Statin can be stored in a locked cupboard (open label).
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)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Apparently healthy male or female individuals * Age 18-45 years old inclusive at screening * Body weight ≥ 45kg and BMI 18 -29.9 kg/m2 * Fasting LDL-C \< 4.1 mmol/l, TG \<1.7 mmol/l and HDL-C ≥ 1.0 mmol for men and ≥1.3 mmol for women * Palpable brachial arterial pulse, as per study team assessment * Not currently eligible for statin therapy according to current treatment criteria
Exclusion criteria
* History of established CV disease (Coronary Heart Disease, Cerebrovascular Disease, Peripheral Vascular Disease or Abdominal Aortic Aneurysm) * Lipid lowering treatment at screening or within 6 weeks before screening * Pregnancy at any study visit * Ongoing anticoagulation therapy with warfarin or any of the DOAC/NOAC's * History of hypersensitivity to any of the study drugs/any known sensitivity to alirocumab or monoclonal antibodies * History of alcohol or drug abuse or dependence within 6 months of the study at screening * Current or previous history of regular smoking (defined as 1 pack-year) within the last 10 years. * History of hypertension or sustained BP ≥140/90 mmHg on repeated measurements at screening * History of type 1 or 2 diabetes or HbA1c ≥ 48 mmol/mol (6.5%) at screening * Chronic kidney disease defined as eGFR \<60ml/min/1.73m2 at screening * Biological first-degree relatives who have experienced stroke, TIA, myocardial infarction or peripheral vascular disease (incident event at an age younger than: 55 for male and 65 for female relatives) * History of autoimmune inflammatory conditions * Lack of ability to provide informed consent * TSH \>5.0 mu/l at screening * Clinically significant liver disease on the basis of screening bloods or history * History of myositis/rhabdomyolysis * Any concomitant condition that, at the discretion of the investigator, may affect the participants' ability to complete the study or the study results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forearm Blood Flow (FBF) - In response to intra-arterial Acetylcholine infusion, comparing Alirocumab to placebo. | 4 weeks | Change in FBF ratio, as measured by absolute & percent change in venous occlusion plethysmography |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Forearm blood flow in response to intra-arterial Acetylcholine infusion, comparing Alirocumab with statin to statin alone. | 4 weeks | Change in FBF ratio, as measured by absolute & percent change in venous occlusion plethysmography |
| Forearm blood flow in response to intra-arterial Sodium Nitroprusside, comparing Alirocumab to placebo. | 4 weeks | Change in FBF ratio, as measured by absolute & percent change in venous occlusion plethysmography |
| Forearm blood flow in response to intra-arterial Sodium Nitroprusside, comparing Alirocumab to statin. | 4 weeks | Change in FBF ratio, as measured by absolute & percent change in venous occlusion plethysmography |
| Forearm blood flow in response to intra-arterial Sodium Nitroprusside, comparing Alirocumab with statin to statin alone. | 4 weeks | Change in FBF ratio, as measured by absolute & percent change in venous occlusion plethysmography |
| Forearm blood flow in response to intra-arterial L-NMMA infusion, comparing Alirocumab to placebo. | 4 weeks | Change in FBF ratio, as measured by absolute & percent change in venous occlusion plethysmography |
| Forearm blood flow in response to intra-arterial L-NMMA infusion, comparing Alirocumab to statin. | 4 weeks | Change in FBF ratio, as measured by absolute & percent change in venous occlusion plethysmography |
| Forearm Blood Flow in response to intra-arterial Acetylcholine infusion, comparing Alirocumab to statin. | 4 weeks | Change in FBF ratio, as measured by absolute & percent change in venous occlusion plethysmography |
| Total and LDL-cholesterol | 4 weeks | Correlation of change in responses to Acetylcholine between groups. |
| Augmentation Index (an indicator of arterial stiffness) | 4 weeks | Change in Augmentation Index between visits and different treatment regimes. |
| Pulse Wave Velocity | 4 weeks | Change in aortic Pulse Wave Velocity between visits and different treatment regimes. |
| Carotid IMT | 4 weeks | Change in Carotid IMT between visits and different treatment regimes. |
| Systemic inflammation | 4 weeks | Change in lipid profile, hsCRP and other markers of systemic inflammation between visits and different treatment regimes. |
| Physical examination, vital signs, ECG, laboratory tests and adverse event assessment to determine Safety and tolerability parameters | 4 weeks | Including physical examination, blood pressure, heart rate, 12-lead electrocardiograms (ECGs), clinical laboratory tests side effects and adverse event reporting. |
| Forearm blood flow in response to intra-arterial L-NMMA infusion, comparing Alirocumab with statin to statin alone. | 4 weeks | Change in FBF ratio, as measured by absolute & percent change in venous occlusion plethysmography |
Countries
United Kingdom
Outcome results
None listed