INvestigating the Lowest Threshold of Vascular bENefits From LDL Lowering With a PCSK9 InhibiTor in healthY Volunteers
- Conditions
- AtherosclerosisCardiovascular Diseases
- Interventions
- Other: Written Informed ConsentOther: Inclusion/Exclusion checkOther: Full Clinical Chemistry and Haematology BloodsOther: Serum sample for systemic markers and lipid sub-fractionsOther: Pregnancy TestOther: 12 Lead ECGOther: Blood Pressure and Heart RateOther: Arterial StiffnessOther: Central HaemodynamicsOther: Carotid Intima Media ThicknessOther: Forearm blood flow studiesOther: Concomitant medication checkOther: Medication compliance check (Pill count)Other: Physical examinationOther: Medical historyOther: AE/SAE review & reportingDrug: Dosing
- Registration Number
- NCT03273972
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 30
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Alirocumab Treatment Arm Medical history V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Comparator Treatment Arm Dosing V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Alirocumab Treatment Arm 12 Lead ECG V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Alirocumab Treatment Arm Blood Pressure and Heart Rate V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Alirocumab Treatment Arm Forearm blood flow studies V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Comparator Treatment Arm Medical history V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Alirocumab Treatment Arm Written Informed Consent V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Alirocumab Treatment Arm Full Clinical Chemistry and Haematology Bloods V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Alirocumab Treatment Arm Arterial Stiffness V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Alirocumab Treatment Arm Dosing V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Comparator Treatment Arm Inclusion/Exclusion check V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Comparator Treatment Arm Serum sample for systemic markers and lipid sub-fractions V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Comparator Treatment Arm Pregnancy Test V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Comparator Treatment Arm Blood Pressure and Heart Rate V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Alirocumab Treatment Arm Inclusion/Exclusion check V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Alirocumab Treatment Arm Carotid Intima Media Thickness V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Alirocumab Treatment Arm Medication compliance check (Pill count) V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Alirocumab Treatment Arm AE/SAE review & reporting V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Comparator Treatment Arm 12 Lead ECG V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Comparator Treatment Arm Forearm blood flow studies V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Alirocumab Treatment Arm Serum sample for systemic markers and lipid sub-fractions V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Alirocumab Treatment Arm Pregnancy Test V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Alirocumab Treatment Arm Central Haemodynamics V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Alirocumab Treatment Arm Concomitant medication check V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Alirocumab Treatment Arm Physical examination V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Comparator Treatment Arm Full Clinical Chemistry and Haematology Bloods V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Comparator Treatment Arm Central Haemodynamics V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Comparator Treatment Arm Written Informed Consent V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Comparator Treatment Arm Carotid Intima Media Thickness V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Comparator Treatment Arm AE/SAE review & reporting V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Comparator Treatment Arm Arterial Stiffness V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Comparator Treatment Arm Concomitant medication check V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Comparator Treatment Arm Medication compliance check (Pill count) V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription. Comparator Treatment Arm Physical examination V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method Carotid IMT 4 weeks Change in Carotid IMT between visits and different treatment regimes.
Augmentation Index (an indicator of arterial stiffness) 4 weeks Change in Augmentation Index between visits and different treatment regimes.
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 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 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
Total and LDL-cholesterol 4 weeks Correlation of change in responses to Acetylcholine between groups.
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 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
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 Acetylcholine infusion, comparing Alirocumab to statin. 4 weeks Change in FBF ratio, as measured by absolute \& percent change in venous occlusion plethysmography
Pulse Wave Velocity 4 weeks Change in aortic Pulse Wave Velocity 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.
Trial Locations
- Locations (1)
Addenbrooke's Hospital
🇬🇧Cambridge, Cambridgeshire, United Kingdom