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AtherosclerosisNCT03273972

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

A study testing Written Informed Consent, Inclusion/Exclusion check and Full Clinical Chemistry and Haematology Bloods in people with Atherosclerosis and Cardiovascular Diseases, run by Cambridge University Hospitals NHS Foundation Trust at 1 site in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 45 yearsHealthy volunteers can take part
Conditions the study is for
Atherosclerosis, Cardiovascular Diseases
What is being tested?
Written Informed Consent, Inclusion/Exclusion check and Full Clinical Chemistry and Haematology Bloods
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
1 siteUnited Kingdom
Study dates
7 Sep 2017to 10 Oct 2018
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 45 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 17Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

United Kingdom1 site
  • Addenbrooke's Hospital

    Cambridge, Cambridgeshire, CB2 0QQ

Other trials in United Kingdom

About this study

Official title: 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.

Read more

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.

Being tested
Written Informed Consent, Inclusion/Exclusion check, Full Clinical Chemistry and Haematology Bloods, Serum sample for systemic markers and lipid sub-fractions, Pregnancy Test
Keywords
Healthy Volunteers, Low Density Lipoprotein Cholesterol (LDL), PCSK9, Alirocumab, Forearm Blood Flow, Arterial Stiffness, Carotid Intima Media Thickness, Inflammation, Endothelial function
Medical subject headings
Atherosclerosis, Cardiovascular Diseases, Inflammation

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Written Informed ConsentOther

    To be completed prior to conducting any study related procedures

  • Inclusion/Exclusion checkOther

    Eligibility check

  • Full Clinical Chemistry and Haematology BloodsOther

    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-fractionsOther

    Serum samples may be stored for later analysis.

  • Pregnancy TestOther

    If applicable for women of child bearing potential

  • 12 Lead ECGOther

    participant resting supine

  • Blood Pressure and Heart RateOther

    Measured in the seated position after 5 minutes rest

  • Arterial StiffnessOther

    Measure of functional and structural changes which accompanies cardiovascular disease

  • Central HaemodynamicsOther

    Measure of functional and structural changes which accompanies cardiovascular disease

  • Carotid Intima Media ThicknessOther

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

  • Forearm blood flow studiesOther

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

  • Concomitant medication checkOther

    Review of medication taken by the participant

  • Medication compliance check (Pill count)Other

    Ensure prescribed statin has been taken

  • Physical examinationOther

    Check overall health

  • Medical historyOther

    Review of volunteers medial history

  • AE/SAE review & reportingOther

    Monitor safety from the point of consent

  • DosingDrug

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

Study groups in NCT03273972
Study groupRoleWhat they receive
Alirocumab Treatment ArmExperimentalV2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
Receives: 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 ArmOtherV2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
Receives: 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

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    Measured: 4 weeks

Secondary outcomes (14)
  1. Forearm Blood Flow in response to intra-arterial Acetylcholine infusion, comparing Alirocumab to statin.

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

    Measured: 4 weeks

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

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

    Measured: 4 weeks

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

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

    Measured: 4 weeks

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

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

    Measured: 4 weeks

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

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

    Measured: 4 weeks

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

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

    Measured: 4 weeks

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

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

    Measured: 4 weeks

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

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

    Measured: 4 weeks

  9. Total and LDL-cholesterol

    Correlation of change in responses to Acetylcholine between groups.

    Measured: 4 weeks

  10. Augmentation Index (an indicator of arterial stiffness)

    Change in Augmentation Index between visits and different treatment regimes.

    Measured: 4 weeks

  11. Pulse Wave Velocity

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

    Measured: 4 weeks

  12. Carotid IMT

    Change in Carotid IMT between visits and different treatment regimes.

    Measured: 4 weeks

  13. Systemic inflammation

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

    Measured: 4 weeks

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

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

    Measured: 4 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Sep 2017
  2. Study start7 Sep 2017
  3. Primary completion10 Oct 2018
  4. Study completion10 Oct 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Parallel groups
Model description
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)
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
30 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03273972
Sponsor's protocol ID
INTENSITY-LOW
Status last verified
Jul 2023
First submitted
14 Aug 2017
Last updated
27 Jul 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No: 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.

Questions about this trial

What is this clinical trial studying?

A study testing Written Informed Consent, Inclusion/Exclusion check and Full Clinical Chemistry and Haematology Bloods in people with Atherosclerosis and Cardiovascular Diseases, run by Cambridge University Hospitals NHS Foundation Trust at 1 site in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 27 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Forearm Blood Flow (FBF) - In response to intra-arterial Acetylcholine infusion, comparing Alirocumab to placebo. (time frame: 4 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Jul 2023.

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