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

July 26, 2023 updated by: Joseph Cheriyan, MD, Cambridge University Hospitals NHS Foundation Trust

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

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
30

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
    • Cambridgeshire
      • Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
        • Addenbrooke's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 45 years (Adult)

Accepts Healthy Volunteers

Yes

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: 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.
Other: Written Informed Consent
To be completed prior to conducting any study related procedures
Other: Inclusion/Exclusion check
Eligibility check
Other: Full Clinical Chemistry and Haematology Bloods
Participant required to fast for at least 6-8 hoursprior to visit. (Clear, non-caffeinated fluids are allowed)
Other: Serum sample for systemic markers and lipid sub-fractions
Serum samples may be stored for later analysis.
Other: Pregnancy Test
If applicable for women of child bearing potential
Other: 12 Lead ECG
participant resting supine
Other: Blood Pressure and Heart Rate
Measured in the seated position after 5 minutes rest
Other: Arterial Stiffness
Measure of functional and structural changes which accompanies cardiovascular disease
Other: Central Haemodynamics
Measure of functional and structural changes which accompanies cardiovascular disease
Other: Carotid Intima Media Thickness
Measurements will be repeated three times, and the average of the median values will be recorded
Other: Forearm blood flow studies
Assess and determine vascular function, which can interrogate endothelium dependent and independent mechanisms of nitric oxide bioavailability
Other: Concomitant medication check
Review of medication taken by the participant
Other: Medication compliance check (Pill count)
Ensure prescribed statin has been taken
Other: Physical examination
Check overall health
Other: Medical history
Review of volunteers medial history
Other: AE/SAE review & reporting
Monitor safety from the point of consent
Drug: Dosing
To be performed at the end of the visit following completion all other study visits
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.
Other: Written Informed Consent
To be completed prior to conducting any study related procedures
Other: Inclusion/Exclusion check
Eligibility check
Other: Full Clinical Chemistry and Haematology Bloods
Participant required to fast for at least 6-8 hoursprior to visit. (Clear, non-caffeinated fluids are allowed)
Other: Serum sample for systemic markers and lipid sub-fractions
Serum samples may be stored for later analysis.
Other: Pregnancy Test
If applicable for women of child bearing potential
Other: 12 Lead ECG
participant resting supine
Other: Blood Pressure and Heart Rate
Measured in the seated position after 5 minutes rest
Other: Arterial Stiffness
Measure of functional and structural changes which accompanies cardiovascular disease
Other: Central Haemodynamics
Measure of functional and structural changes which accompanies cardiovascular disease
Other: Carotid Intima Media Thickness
Measurements will be repeated three times, and the average of the median values will be recorded
Other: Forearm blood flow studies
Assess and determine vascular function, which can interrogate endothelium dependent and independent mechanisms of nitric oxide bioavailability
Other: Concomitant medication check
Review of medication taken by the participant
Other: Medication compliance check (Pill count)
Ensure prescribed statin has been taken
Other: Physical examination
Check overall health
Other: Medical history
Review of volunteers medial history
Other: AE/SAE review & reporting
Monitor safety from the point of consent
Drug: Dosing
To be performed at the end of the visit following completion all other study visits

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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
4 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
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
4 weeks
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
4 weeks
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 weeks
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
4 weeks
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
4 weeks
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
4 weeks
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
4 weeks
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
4 weeks
Total and LDL-cholesterol
Time Frame: 4 weeks
Correlation of change in responses to Acetylcholine between groups.
4 weeks
Augmentation Index (an indicator of arterial stiffness)
Time Frame: 4 weeks
Change in Augmentation Index between visits and different treatment regimes.
4 weeks
Pulse Wave Velocity
Time Frame: 4 weeks
Change in aortic Pulse Wave Velocity between visits and different treatment regimes.
4 weeks
Carotid IMT
Time Frame: 4 weeks
Change in Carotid IMT between visits and different treatment regimes.
4 weeks
Systemic inflammation
Time Frame: 4 weeks
Change in lipid profile, hsCRP and other markers of systemic inflammation between visits and different treatment regimes.
4 weeks
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.
4 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Cambridge University Hospitals NHS Foundation Trust

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
University of Cambridge

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Joseph Cheriyan, MBChB, FRCP, MA, Cambridge University Hospitals NHS Trust
  • Principal Investigator: Michalis Kostapanos, MD, PhD, FRSPH, Cambridge University Hospitals NHS Trust

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 7, 2017

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
October 10, 2018

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
October 10, 2018

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 14, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 1, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
September 6, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 27, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 26, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • INTENSITY-LOW

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Only the minimum required participant identifiable information (name and contact details) will be provided to the research team for the purpose of arranging study visits and completing the informed consent process. All delegated research personnel that is responsible to conduct the data/statistical analysis will only analyse data that is anonymised of any patient identifiable data.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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