INvestigating the Lowest Threshold of Vascular bENefits From LDL Lowering With a PCSK9 InhibiTor in healthY Volunteers

NCT03273972 | Completed

• 1 other identifier: INTENSITY-LOW
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (1)

• Forearm Blood Flow (FBF) - In response to intra-arterial Acetylcholine infusion, comparing Alirocumab to placebo.

  Change in FBF ratio, as measured by absolute \& percent change in venous occlusion plethysmography

  4 weeks

Secondary Outcomes (14)

• Forearm Blood Flow in response to intra-arterial Acetylcholine infusion, comparing Alirocumab to statin.

  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 Sodium Nitroprusside, comparing Alirocumab to statin.

  4 weeks

• Forearm blood flow in response to intra-arterial Sodium Nitroprusside, comparing Alirocumab with statin to statin alone.

  4 weeks

Study Arms (2)

Alirocumab Treatment Arm

EXPERIMENTAL

V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.

Other: Written Informed Consent; Other: Inclusion/Exclusion check; Other: Full Clinical Chemistry and Haematology Bloods; Other: Serum sample for systemic markers and lipid sub-fractions; Other: Pregnancy Test; Other: 12 Lead ECG; Other: Blood Pressure and Heart Rate; Other: Arterial Stiffness; Other: Central Haemodynamics; Other: Carotid Intima Media Thickness; Other: Forearm blood flow studies; Other: Concomitant medication check; Other: Medication compliance check (Pill count); Other: Physical examination; Other: Medical history; Other: AE/SAE review & reporting; Drug: Dosing

Comparator Treatment Arm

OTHER

V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.

Other: Written Informed Consent; Other: Inclusion/Exclusion check; Other: Full Clinical Chemistry and Haematology Bloods; Other: Serum sample for systemic markers and lipid sub-fractions; Other: Pregnancy Test; Other: 12 Lead ECG; Other: Blood Pressure and Heart Rate; Other: Arterial Stiffness; Other: Central Haemodynamics; Other: Carotid Intima Media Thickness; Other: Forearm blood flow studies; Other: Concomitant medication check; Other: Medication compliance check (Pill count); Other: Physical examination; Other: Medical history; Other: AE/SAE review & reporting; Drug: Dosing

Interventions

Written Informed Consent OTHER

To be completed prior to conducting any study related procedures

Alirocumab Treatment Arm; Comparator Treatment Arm

Inclusion/Exclusion check OTHER

Eligibility check

Alirocumab Treatment Arm; Comparator Treatment Arm

Full Clinical Chemistry and Haematology Bloods OTHER

Participant required to fast for at least 6-8 hoursprior to visit. (Clear, non-caffeinated fluids are allowed)

Alirocumab Treatment Arm; Comparator Treatment Arm

Serum sample for systemic markers and lipid sub-fractions OTHER

Serum samples may be stored for later analysis.

Alirocumab Treatment Arm; Comparator Treatment Arm

Pregnancy Test OTHER

If applicable for women of child bearing potential

Alirocumab Treatment Arm; Comparator Treatment Arm

12 Lead ECG OTHER

participant resting supine

Alirocumab Treatment Arm; Comparator Treatment Arm

Blood Pressure and Heart Rate OTHER

Measured in the seated position after 5 minutes rest

Alirocumab Treatment Arm; Comparator Treatment Arm

Arterial Stiffness OTHER

Measure of functional and structural changes which accompanies cardiovascular disease

Alirocumab Treatment Arm; Comparator Treatment Arm

Central Haemodynamics OTHER

Measure of functional and structural changes which accompanies cardiovascular disease

Alirocumab Treatment Arm; Comparator Treatment Arm

Carotid Intima Media Thickness OTHER

Measurements will be repeated three times, and the average of the median values will be recorded

Alirocumab Treatment Arm; Comparator Treatment Arm

Forearm blood flow studies OTHER

Assess and determine vascular function, which can interrogate endothelium dependent and independent mechanisms of nitric oxide bioavailability

Alirocumab Treatment Arm; Comparator Treatment Arm

Concomitant medication check OTHER

Review of medication taken by the participant

Alirocumab Treatment Arm; Comparator Treatment Arm

Medication compliance check (Pill count) OTHER

Ensure prescribed statin has been taken

Alirocumab Treatment Arm; Comparator Treatment Arm

Physical examination OTHER

Check overall health

Alirocumab Treatment Arm; Comparator Treatment Arm

Medical history OTHER

Review of volunteers medial history

Alirocumab Treatment Arm; Comparator Treatment Arm

AE/SAE review & reporting OTHER

Monitor safety from the point of consent

Alirocumab Treatment Arm; Comparator Treatment Arm

Dosing DRUG

To be performed at the end of the visit following completion all other study visits

Alirocumab Treatment Arm; Comparator Treatment Arm

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Cambridge University Hospitals NHS Foundation Trust: lead
• University of Cambridge: collaborator

Study Sites (1)

Addenbrooke's Hospital

Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

Location

MeSH Terms

Conditions

Atherosclerosis; Cardiovascular Diseases; Inflammation

Interventions

Pregnancy Tests; Blood Pressure; Heart Rate; Vascular Stiffness; Carotid Intima-Media Thickness; Restraint, Physical; Health Records, Personal; Biomarkers, Pharmacological

Condition Hierarchy (Ancestors)

Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Obstetrical and Gynecological; Investigative Techniques; Vital Signs; Physical Examination; Hemodynamics; Cardiovascular Physiological Phenomena; Circulatory and Respiratory Physiological Phenomena; Ultrasonography, Carotid Arteries; Ultrasonography; Diagnostic Imaging; Diagnostic Techniques, Cardiovascular; Behavior Control; Therapeutics; Immobilization; Medical Records; Records; Data Collection; Epidemiologic Methods; Biomarkers; Biological Factors

Study Officials

• Joseph Cheriyan, MBChB, FRCP, MA

  Cambridge University Hospitals NHS Trust

  PRINCIPAL INVESTIGATOR

• Michalis Kostapanos, MD, PhD, FRSPH

  Cambridge University Hospitals NHS Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: 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).
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Consultant Physician & Clinical Pharmacologist/Associate Lecturer

Model Details: 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)

Study Record Dates

• First Submitted: August 14, 2017
• First Posted: September 6, 2017
• Study Start: September 7, 2017
• Primary Completion: October 10, 2018
• Study Completion: October 10, 2018
• Last Updated: July 27, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)