Clinical trial NCT03273972: INvestigating the Lowest Threshold of Vascular bENefits From LDL Lowering With a PCSK9 InhibiTor in healthY Volunteers
Official title: INvestigating the Lowest Threshold of Vascular bENefits From LDL Cholesterol Lowering With a PCSK9 mAb InhibiTor (Alirocumab) in healthY Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Atherosclerosis
Cardiovascular Diseases
Keywords: Healthy Volunteers
Low Density Lipoprotein Cholesterol (LDL)
PCSK9
Alirocumab
Forearm Blood Flow
Arterial Stiffness
Carotid Intima Media Thickness
Inflammation
Endothelial function
Lead sponsor: Cambridge University Hospitals NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: University of Cambridge
First posted: 2017-09-06
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
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)
Primary purpose: BASIC_SCIENCE

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.


Eligibility criteria: 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

Primary outcomes:
measure: Forearm Blood Flow (FBF) - In response to intra-arterial Acetylcholine infusion, comparing Alirocumab to placebo.
timeFrame: 4 weeks
Secondary outcomes:
measure: Forearm Blood Flow in response to intra-arterial Acetylcholine infusion, comparing Alirocumab to statin.
timeFrame: 4 weeks
measure: Forearm blood flow in response to intra-arterial Acetylcholine infusion, comparing Alirocumab with statin to statin alone.
timeFrame: 4 weeks
measure: Forearm blood flow in response to intra-arterial Sodium Nitroprusside, comparing Alirocumab to placebo.
timeFrame: 4 weeks
measure: Forearm blood flow in response to intra-arterial Sodium Nitroprusside, comparing Alirocumab to statin.
timeFrame: 4 weeks
measure: Forearm blood flow in response to intra-arterial Sodium Nitroprusside, comparing Alirocumab with statin to statin alone.
timeFrame: 4 weeks
measure: Forearm blood flow in response to intra-arterial L-NMMA infusion, comparing Alirocumab to placebo.
timeFrame: 4 weeks
measure: Forearm blood flow in response to intra-arterial L-NMMA infusion, comparing Alirocumab to statin.
timeFrame: 4 weeks
measure: Forearm blood flow in response to intra-arterial L-NMMA infusion, comparing Alirocumab with statin to statin alone.
timeFrame: 4 weeks
measure: Total and LDL-cholesterol
timeFrame: 4 weeks
measure: Augmentation Index (an indicator of arterial stiffness)
timeFrame: 4 weeks
measure: Pulse Wave Velocity
timeFrame: 4 weeks
measure: Carotid IMT
timeFrame: 4 weeks
measure: Systemic inflammation
timeFrame: 4 weeks
measure: Physical examination, vital signs, ECG, laboratory tests and adverse event assessment to determine Safety and tolerability parameters
timeFrame: 4 weeks
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: Cambridgeshire
Study officials:
affiliation: Cambridge University Hospitals NHS Trust
name: Joseph Cheriyan, MBChB, FRCP, MA
role: PRINCIPAL_INVESTIGATOR
affiliation: Cambridge University Hospitals NHS Trust
name: Michalis Kostapanos, MD, PhD, FRSPH
role: PRINCIPAL_INVESTIGATOR
References: