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Completed

NCT Number: NCT03273972

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

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.

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Key information

Conditions

Atherosclerosis Arterial Occlusive Diseases Arteriosclerosis Cardiovascular Diseases Inflammation Pathologic Processes Pathological Conditions, Signs and Symptoms Vascular Diseases

Age range

18 year–45 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Addenbrooke's Hospital

Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Written Informed Consent

Other

To be completed prior to conducting any study related procedures

Inclusion/Exclusion check

Other

Eligibility check

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)

Serum sample for systemic markers and lipid sub-fractions

Other

Serum samples may be stored for later analysis.

Pregnancy Test

Other

If applicable for women of child bearing potential

12 Lead ECG

Other

participant resting supine

Blood Pressure and Heart Rate

Other

Measured in the seated position after 5 minutes rest

Arterial Stiffness

Other

Measure of functional and structural changes which accompanies cardiovascular disease

Central Haemodynamics

Other

Measure of functional and structural changes which accompanies cardiovascular disease

Carotid Intima Media Thickness

Other

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

Forearm blood flow studies

Other

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

Concomitant medication check

Other

Review of medication taken by the participant

Medication compliance check (Pill count)

Other

Ensure prescribed statin has been taken

physical examination

Other

Check overall health

Medical history

Other

Review of volunteers medial history

AE/SAE review & reporting

Other

Monitor safety from the point of consent

Dosing

Drug

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

Primary outcomes

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

    Time frame: 4 weeks

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

Secondary outcomes

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

    Time frame: 4 weeks

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

  2. Forearm blood flow in response to intra-arterial Acetylcholine infusion, comparing Alirocumab with statin to statin alone.

    Time frame: 4 weeks

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

  3. Forearm blood flow in response to intra-arterial Sodium Nitroprusside, comparing Alirocumab to placebo.

    Time frame: 4 weeks

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

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

    Time frame: 4 weeks

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

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

    Time frame: 4 weeks

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

  6. Forearm blood flow in response to intra-arterial L-NMMA infusion, comparing Alirocumab to placebo.

    Time frame: 4 weeks

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

  7. Forearm blood flow in response to intra-arterial L-NMMA infusion, comparing Alirocumab to statin.

    Time frame: 4 weeks

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

  8. Forearm blood flow in response to intra-arterial L-NMMA infusion, comparing Alirocumab with statin to statin alone.

    Time frame: 4 weeks

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

  9. Total and LDL-cholesterol

    Time frame: 4 weeks

    Correlation of change in responses to Acetylcholine between groups.

  10. Augmentation Index (an indicator of arterial stiffness)

    Time frame: 4 weeks

    Change in Augmentation Index between visits and different treatment regimes.

  11. Pulse Wave Velocity

    Time frame: 4 weeks

    Change in aortic Pulse Wave Velocity between visits and different treatment regimes.

  12. Carotid IMT

    Time frame: 4 weeks

    Change in Carotid IMT between visits and different treatment regimes.

  13. Systemic inflammation

    Time frame: 4 weeks

    Change in lipid profile, hsCRP and other markers of systemic inflammation between visits and different treatment regimes.

  14. Physical examination, vital signs, ECG, laboratory tests and adverse event assessment to determine Safety and tolerability parameters

    Time frame: 4 weeks

    Including physical examination, blood pressure, heart rate, 12-lead electrocardiograms (ECGs), clinical laboratory tests side effects and adverse event reporting.

Sponsors and collaborators

Lead sponsor

Cambridge University Hospitals NHS Foundation Trust

Other

Collaborators

  • University of Cambridge

Registry information

Official study title

INvestigating the Lowest Threshold of Vascular bENefits From LDL Cholesterol Lowering With a PCSK9 mAb InhibiTor (Alirocumab) in healthY Volunteers

Important dates

Study start
2017
Primary completion
2018
Study completion
2018
First posted
Sep 6, 2017
Registry last updated
Jul 27, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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