Investigating the lowest threshold of vascular benefits from LDL cholesterol lowering with a PCSK9 mAb inhibitor (alirocumab) in healthy volunteers – a mechanistic physiological study (INTENSITY-LOW): protocol and study rationale

Figures & data

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Primary outcome measure Change in forearm blood flow ratio (additionally absolute and % change, based on data), as measured by venous occlusion plethysmography, in response to intra-arterial acetylcholine (Ach) infusion, comparing alirocumab with placebo.

Secondary outcome measures Change in forearm blood flow ratio additionally absolute and % change, based on data), as measured by venous occlusion plethysmography, in response to intra-arterial Ach infusion, comparing alirocumab with statin. Change in forearm blood flow ratio additionally absolute and % change, based on data), as measured by venous occlusion plethysmography, in response to intra-arterial Ach infusion, comparing alirocumab with statin with statin alone. Change in forearm blood flow ratio (additionally absolute and % change, based on data), as measured by venous occlusion plethysmography, in response to intra-arterial sodium nitroprusside (SNP), comparing alirocumab with placebo. Change in forearm blood flow ratio additionally absolute and % change, based on data), as measured by venous occlusion plethysmography, in response to intra-arterial SNP, comparing alirocumab with statin. Change in forearm blood flow ratio (additionally absolute and % change, based on data), as measured by venous occlusion plethysmography, in response to intra-arterial SNP, comparing alirocumab with statin with statin alone. Change in forearm blood flow ratio (additionally absolute and % change, based on data), as measured by venous occlusion plethysmography, in response to intra-arterial L-N^G-monomethyl arginine acetate (L-NMMA) infusion, comparing alirocumab with placebo. Change in forearm blood flow ratio (additionally absolute and % change, based on data), as measured by venous occlusion plethysmography, in response to intra-arterial L-NMMA infusion, comparing alirocumab with statin. Change in forearm blood flow ratio (additionally absolute and % change, based on data), as measured by venous occlusion plethysmography, in response to intra-arterial L-NMMA infusion, comparing alirocumab with statin with statin alone. Correlation of change in total and LDL-cholesterol to change in responses to Ach between groups. Change in Augmentation Index (an indicator of arterial stiffness) between visits and different treatment regimes. Change in aortic Pulse Wave Velocity between visits and different treatment regimes. Change in carotid intima media thickness (IMT) between visits and different treatment regimes. Change in lipid profile, high sensitivity C-reactive protein (hsCRP) and other markers of systemic inflammation between visits and different treatment regimes. Safety and tolerability parameters, including physical examination, blood pressure, heart rate, 12-lead electrocardiograms (ECGs), clinical laboratory tests side effects and adverse event reporting.

Figure 1. Synopsis of the study design. After a screening visit all eligible volunteers will attend V2 in which they will have pre-dose blood tests and vascular studies, and then will be randomized to either single sc dose of alirocumab 150 mg or placebo. They will then attend V3 14 ± 3 days later to have pre-dose blood tests and vascular studies and be administered another sc dose of alirocumab 150 mg or placebo. After this all participants in both groups (alirocumab and placebo group) will be prescribed atorvastatin 20 mg once nightly for 14 days. They will then attend V4 for post-dose blood tests and vascular studies. A follow up visit (V5) will take place 7–14 days later. Abbreviations. SC, subcutaneously; V1, Visit 1; V2, Visit 2; V3, Visit 3; V4, Visit 4; V5, Visit 5.

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Inclusion criteria:

Apparently healthy male or female individuals Age 18-45 years old (inclusive) at screening Body weight ≥45kg and body mass index (BMI) 18.0 - 29.9 kg/m^2 Fasting low density lipoprotein cholesterol (LDL-C) <4.1 mmol/l, triglycerides (TG) <1.7 mmol/l and high density lipoprotein (HDL)-cholesterol ≥1.0 mmol for men and ≥1.3 mmol for women Palpable brachial arterial pulse Not currently eligible for statin therapy according to current treatment criteria

Exclusion criteria:

The presence of ANY of the following will preclude participant inclusion: History of established cardiovascular 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. Women of childbearing potential will be included in the study provided that they are not pregnant at any stage (from screening to the end of the study) and are sexually abstinent (if this is the preferred lifestyle) or use of highly effective methods of contraception^26 Ongoing anticoagulation therapy with warfarin or any of the new oral anticoagulants 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 blood pressure ≥140/90 mmHg on repeated measurements at screening History of type 1 or 2 diabetes or glycated hemoglobin (HbA1c) ≥48 mmol/mol (6.5%) at screening Chronic kidney disease defined as an estimated glomerular filtration rate <60 ml/min/1.73m^2 Biological first-degree relatives who have experienced stroke, transient ischemic attack, 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 Thyroid stimulating hormone > 5.0 mU/l at screening Clinically significant liver disease based on 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

Figure 2. Ach, SNP and L-NMMA infusion pattern in FBF studies. FBF will be measured at baseline and after 20 mins of saline intra-arterial infusion at a rate 1 ml/min. Following this, 3 different concentrations of Ach will be infused intra-arterially at the same rate for 6 mins each. At the last 3 mins of each infusion period FBF will be measured. After 30 mins of washout 2 different concentrations of SNP will be infused intra-arterially for 6 mins each, and FBF will be measured again at the last 3 mins of each infusion period. Following 30 mins washout period 2 different concentrations of L-NMMA will be infused intra-arterially for 6 mins each, and FBF will be measured again at the last 3 mins of each infusion period. A final 10 min of saline will then be infused. BP and heart rate will be recorded at baseline, and at the end of each infusion. ¹Blood pressure and heart rate recorded at baseline and at the end of each infusion. ²Basal FBF recorded after 20-min Saline infusion. ³Forearm blood flow recorded after each dose of challenge agent for 3 min. Abbreviations. Ach, acetylcholine; SNP, sodium nitroprusside; L-NMMA, L-N^G-monomethyl-arginine acetate; FBF, forearm blood flow.

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Withdrawal of informed consent Blood results that determine that the participant is ineligible to continue further participation in the study The investigator determines that continuation of study treatment/procedures would result in a significant safety risk to the participant If the participant experiences a serious adverse event (SAE), which would affect their ability to participate in the study (at the discretion of the principal investigator) Pregnancy Any protocol deviation that results in a significant risk to the participants’ safety Noncompliance with treatment or procedures Lost to follow-up Study closed/terminated Any other reason, at the discretion of principal investigator

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