INvestigating the Lowest Threshold of Vascular bENefits From LDL Cholesterol Lowering With a PCSK9 mAb InhibiTor (Alirocumab) in healthY Volunteers
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Forearm Blood Flow (FBF) - In response to intra-arterial Acetylcholine infusion, comparing Alirocumab to placebo.
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
盲法说明
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).
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Alirocumab Treatment Arm
V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Full Clinical Chemistry and Haematology Bloods (Other)
Alirocumab Treatment Arm
V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Written Informed Consent (Other)
Alirocumab Treatment Arm
V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Inclusion/Exclusion check (Other)
Alirocumab Treatment Arm
V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Serum sample for systemic markers and lipid sub-fractions (Other)
Alirocumab Treatment Arm
V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Pregnancy Test (Other)
Alirocumab Treatment Arm
V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: 12 Lead ECG (Other)
Alirocumab Treatment Arm
V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Blood Pressure and Heart Rate (Other)
Alirocumab Treatment Arm
V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Arterial Stiffness (Other)
Alirocumab Treatment Arm
V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Central Haemodynamics (Other)
Alirocumab Treatment Arm
V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Carotid Intima Media Thickness (Other)
Alirocumab Treatment Arm
V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Forearm blood flow studies (Other)
Alirocumab Treatment Arm
V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Concomitant medication check (Other)
Alirocumab Treatment Arm
V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Medication compliance check (Pill count) (Other)
Alirocumab Treatment Arm
V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Physical examination (Other)
Alirocumab Treatment Arm
V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Medical history (Other)
Alirocumab Treatment Arm
V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: AE/SAE review & reporting (Other)
Alirocumab Treatment Arm
V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Dosing (Drug)
Comparator Treatment Arm
V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Written Informed Consent (Other)
Comparator Treatment Arm
V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Inclusion/Exclusion check (Other)
Comparator Treatment Arm
V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Physical examination (Other)
Comparator Treatment Arm
V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Full Clinical Chemistry and Haematology Bloods (Other)
Comparator Treatment Arm
V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Serum sample for systemic markers and lipid sub-fractions (Other)
Comparator Treatment Arm
V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Pregnancy Test (Other)
Comparator Treatment Arm
V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: 12 Lead ECG (Other)
Comparator Treatment Arm
V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Blood Pressure and Heart Rate (Other)
Comparator Treatment Arm
V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Arterial Stiffness (Other)
Comparator Treatment Arm
V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Central Haemodynamics (Other)
Comparator Treatment Arm
V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Carotid Intima Media Thickness (Other)
Comparator Treatment Arm
V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Forearm blood flow studies (Other)
Comparator Treatment Arm
V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Concomitant medication check (Other)
Comparator Treatment Arm
V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Medication compliance check (Pill count) (Other)
Comparator Treatment Arm
V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Medical history (Other)
Comparator Treatment Arm
V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: AE/SAE review & reporting (Other)
Comparator Treatment Arm
V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
干预措施: Dosing (Drug)
结局指标
主要结局
Forearm Blood Flow (FBF) - In response to intra-arterial Acetylcholine infusion, comparing Alirocumab to placebo.
时间窗: 4 weeks
Change in FBF ratio, as measured by absolute \& percent change in venous occlusion plethysmography
次要结局
- Carotid IMT(4 weeks)
- Augmentation Index (an indicator of arterial stiffness)(4 weeks)
- Forearm blood flow in response to intra-arterial Sodium Nitroprusside, comparing Alirocumab with statin to statin alone.(4 weeks)
- Forearm blood flow in response to intra-arterial Acetylcholine infusion, comparing Alirocumab with statin to statin alone.(4 weeks)
- Forearm blood flow in response to intra-arterial Sodium Nitroprusside, comparing Alirocumab to placebo.(4 weeks)
- Forearm blood flow in response to intra-arterial L-NMMA infusion, comparing Alirocumab with statin to statin alone.(4 weeks)
- Total and LDL-cholesterol(4 weeks)
- Forearm blood flow in response to intra-arterial Sodium Nitroprusside, comparing Alirocumab to statin.(4 weeks)
- Forearm blood flow in response to intra-arterial L-NMMA infusion, comparing Alirocumab to placebo.(4 weeks)
- Forearm blood flow in response to intra-arterial L-NMMA infusion, comparing Alirocumab to statin.(4 weeks)
- Physical examination, vital signs, ECG, laboratory tests and adverse event assessment to determine Safety and tolerability parameters(4 weeks)
- Forearm Blood Flow in response to intra-arterial Acetylcholine infusion, comparing Alirocumab to statin.(4 weeks)
- Pulse Wave Velocity(4 weeks)
- Systemic inflammation(4 weeks)
研究者
Joseph Cheriyan, MD
Consultant Physician & Clinical Pharmacologist/Associate Lecturer
Cambridge University Hospitals NHS Foundation Trust