<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03273972</url>
  </required_header>
  <id_info>
    <org_study_id>INTENSITY-LOW</org_study_id>
    <nct_id>NCT03273972</nct_id>
  </id_info>
  <brief_title>INvestigating the Lowest Threshold of Vascular bENefits From LDL Lowering With a PCSK9 InhibiTor in healthY Volunteers</brief_title>
  <official_title>INvestigating the Lowest Threshold of Vascular bENefits From LDL Cholesterol Lowering With a PCSK9 mAb InhibiTor (Alirocumab) in healthY Volunteers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cambridge University Hospitals NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Cambridge</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Cambridge University Hospitals NHS Foundation Trust</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The INTENSITY-LOW study aims to answer if there are any limits to LDL reduction in relation&#xD;
      to benefitting vascular health from a mechanistic viewpoint, and therefore potentially&#xD;
      limitations to primary prevention in healthy volunteers by lowering LDL cholesterol using&#xD;
      PCSK9 therapies. This research is being carried out because it is unclear what the lowest&#xD;
      threshold of LDL cholesterol should be to attain significant reductions in CV risk in healthy&#xD;
      individuals. It is also unknown whether there is a true limit of LDL cholesterol below which&#xD;
      there is no further improvement in endothelial function in healthy people, and, whether this&#xD;
      is associated with a reduction in markers of both systemic and vascular inflammation. This&#xD;
      study will hope to provide evidence that the so-called pleiotropic effects of statins are&#xD;
      actually mediated by a mechanism of LDL-cholesterol lowering per se and not necessarily a&#xD;
      special therapeutic effect of statins.&#xD;
&#xD;
      Defining this may help identify individuals from the general population who may benefit from&#xD;
      more aggressive lipid-lowering treatment than standard statin treatment in terms of CV&#xD;
      morbidity and mortality.&#xD;
&#xD;
      This study will be conducted in healthy volunteers only, where participants will be&#xD;
      randomized to either the Alirocumab arm (which is a therapy designed to lower cholesterol) or&#xD;
      comparator arm. Both Alirocumab and comparator arms will be combined with Atorvastatin&#xD;
      (another therapy designed to lower cholesterol) at the second dosing visit.&#xD;
&#xD;
      In total, thirty healthy individuals will be recruited to this single centre, randomized,&#xD;
      single blind, parallel group, mechanistic physiological study which will be conducted at&#xD;
      Cambridge University Hospitals NHS Foundation Trust/University of Cambridge. This study will&#xD;
      be open to recruitment for one year and the total study duration for each participant will be&#xD;
      approximately 10 weeks. There will be 4 study visits in total with a telephone follow up at&#xD;
      the end of the study. Of these visits, two will be dosing visits and the total duration of&#xD;
      treatment is approx. 4 weeks.&#xD;
&#xD;
      A series of non-invasive haemodynamic assessments and minimally invasive procedures including&#xD;
      blood tests and forearm blood flow measurements will be conducted prior, during and post&#xD;
      dosing to determine if there is an improvement of endothelia vascular function (as measured&#xD;
      by nitric oxide bioavailability) and reduced systemic inflammation. This study is funded by&#xD;
      JP Moulton Charitable Foundation.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 7, 2017</start_date>
  <completion_date type="Actual">October 10, 2018</completion_date>
  <primary_completion_date type="Actual">October 10, 2018</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Randomisation to be performed to a 1:1 ratio.&#xD;
Alirocumab treatment arm:&#xD;
V2: Alirocumab (150mg)&#xD;
V3: Alirocumab (150mg) &amp; Atorvastatin (20mg)&#xD;
Comparator treatment arm&#xD;
V2: Placebo&#xD;
V3: Placebo &amp; Atorvastatin (20mg)</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>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.&#xD;
CRF nurses will also have to collect and store medication in their building. Statin can be stored in a locked cupboard (open label).</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Forearm Blood Flow (FBF) - In response to intra-arterial Acetylcholine infusion, comparing Alirocumab to placebo.</measure>
    <time_frame>4 weeks</time_frame>
    <description>Change in FBF ratio, as measured by absolute &amp; percent change in venous occlusion plethysmography</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Forearm Blood Flow in response to intra-arterial Acetylcholine infusion, comparing Alirocumab to statin.</measure>
    <time_frame>4 weeks</time_frame>
    <description>Change in FBF ratio, as measured by absolute &amp; percent change in venous occlusion plethysmography</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Forearm blood flow in response to intra-arterial Acetylcholine infusion, comparing Alirocumab with statin to statin alone.</measure>
    <time_frame>4 weeks</time_frame>
    <description>Change in FBF ratio, as measured by absolute &amp; percent change in venous occlusion plethysmography</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Forearm blood flow in response to intra-arterial Sodium Nitroprusside, comparing Alirocumab to placebo.</measure>
    <time_frame>4 weeks</time_frame>
    <description>Change in FBF ratio, as measured by absolute &amp; percent change in venous occlusion plethysmography</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Forearm blood flow in response to intra-arterial Sodium Nitroprusside, comparing Alirocumab to statin.</measure>
    <time_frame>4 weeks</time_frame>
    <description>Change in FBF ratio, as measured by absolute &amp; percent change in venous occlusion plethysmography</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Forearm blood flow in response to intra-arterial Sodium Nitroprusside, comparing Alirocumab with statin to statin alone.</measure>
    <time_frame>4 weeks</time_frame>
    <description>Change in FBF ratio, as measured by absolute &amp; percent change in venous occlusion plethysmography</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Forearm blood flow in response to intra-arterial L-NMMA infusion, comparing Alirocumab to placebo.</measure>
    <time_frame>4 weeks</time_frame>
    <description>Change in FBF ratio, as measured by absolute &amp; percent change in venous occlusion plethysmography</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Forearm blood flow in response to intra-arterial L-NMMA infusion, comparing Alirocumab to statin.</measure>
    <time_frame>4 weeks</time_frame>
    <description>Change in FBF ratio, as measured by absolute &amp; percent change in venous occlusion plethysmography</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Forearm blood flow in response to intra-arterial L-NMMA infusion, comparing Alirocumab with statin to statin alone.</measure>
    <time_frame>4 weeks</time_frame>
    <description>Change in FBF ratio, as measured by absolute &amp; percent change in venous occlusion plethysmography</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total and LDL-cholesterol</measure>
    <time_frame>4 weeks</time_frame>
    <description>Correlation of change in responses to Acetylcholine between groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Augmentation Index (an indicator of arterial stiffness)</measure>
    <time_frame>4 weeks</time_frame>
    <description>Change in Augmentation Index between visits and different treatment regimes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pulse Wave Velocity</measure>
    <time_frame>4 weeks</time_frame>
    <description>Change in aortic Pulse Wave Velocity between visits and different treatment regimes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Carotid IMT</measure>
    <time_frame>4 weeks</time_frame>
    <description>Change in Carotid IMT between visits and different treatment regimes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systemic inflammation</measure>
    <time_frame>4 weeks</time_frame>
    <description>Change in lipid profile, hsCRP and other markers of systemic inflammation between visits and different treatment regimes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Physical examination, vital signs, ECG, laboratory tests and adverse event assessment to determine Safety and tolerability parameters</measure>
    <time_frame>4 weeks</time_frame>
    <description>Including physical examination, blood pressure, heart rate, 12-lead electrocardiograms (ECGs), clinical laboratory tests side effects and adverse event reporting.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Atherosclerosis</condition>
  <condition>Cardiovascular Diseases</condition>
  <arm_group>
    <arm_group_label>Alirocumab Treatment Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Comparator Treatment Arm</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Written Informed Consent</intervention_name>
    <description>To be completed prior to conducting any study related procedures</description>
    <arm_group_label>Alirocumab Treatment Arm</arm_group_label>
    <arm_group_label>Comparator Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Inclusion/Exclusion check</intervention_name>
    <description>Eligibility check</description>
    <arm_group_label>Alirocumab Treatment Arm</arm_group_label>
    <arm_group_label>Comparator Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Full Clinical Chemistry and Haematology Bloods</intervention_name>
    <description>Participant required to fast for at least 6-8 hoursprior to visit. (Clear, non-caffeinated fluids are allowed)</description>
    <arm_group_label>Alirocumab Treatment Arm</arm_group_label>
    <arm_group_label>Comparator Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Serum sample for systemic markers and lipid sub-fractions</intervention_name>
    <description>Serum samples may be stored for later analysis.</description>
    <arm_group_label>Alirocumab Treatment Arm</arm_group_label>
    <arm_group_label>Comparator Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Pregnancy Test</intervention_name>
    <description>If applicable for women of child bearing potential</description>
    <arm_group_label>Alirocumab Treatment Arm</arm_group_label>
    <arm_group_label>Comparator Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>12 Lead ECG</intervention_name>
    <description>participant resting supine</description>
    <arm_group_label>Alirocumab Treatment Arm</arm_group_label>
    <arm_group_label>Comparator Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Blood Pressure and Heart Rate</intervention_name>
    <description>Measured in the seated position after 5 minutes rest</description>
    <arm_group_label>Alirocumab Treatment Arm</arm_group_label>
    <arm_group_label>Comparator Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Arterial Stiffness</intervention_name>
    <description>Measure of functional and structural changes which accompanies cardiovascular disease</description>
    <arm_group_label>Alirocumab Treatment Arm</arm_group_label>
    <arm_group_label>Comparator Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Central Haemodynamics</intervention_name>
    <description>Measure of functional and structural changes which accompanies cardiovascular disease</description>
    <arm_group_label>Alirocumab Treatment Arm</arm_group_label>
    <arm_group_label>Comparator Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Carotid Intima Media Thickness</intervention_name>
    <description>Measurements will be repeated three times, and the average of the median values will be recorded</description>
    <arm_group_label>Alirocumab Treatment Arm</arm_group_label>
    <arm_group_label>Comparator Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Forearm blood flow studies</intervention_name>
    <description>Assess and determine vascular function, which can interrogate endothelium dependent and independent mechanisms of nitric oxide bioavailability</description>
    <arm_group_label>Alirocumab Treatment Arm</arm_group_label>
    <arm_group_label>Comparator Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Concomitant medication check</intervention_name>
    <description>Review of medication taken by the participant</description>
    <arm_group_label>Alirocumab Treatment Arm</arm_group_label>
    <arm_group_label>Comparator Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Medication compliance check (Pill count)</intervention_name>
    <description>Ensure prescribed statin has been taken</description>
    <arm_group_label>Alirocumab Treatment Arm</arm_group_label>
    <arm_group_label>Comparator Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Physical examination</intervention_name>
    <description>Check overall health</description>
    <arm_group_label>Alirocumab Treatment Arm</arm_group_label>
    <arm_group_label>Comparator Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Medical history</intervention_name>
    <description>Review of volunteers medial history</description>
    <arm_group_label>Alirocumab Treatment Arm</arm_group_label>
    <arm_group_label>Comparator Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>AE/SAE review &amp; reporting</intervention_name>
    <description>Monitor safety from the point of consent</description>
    <arm_group_label>Alirocumab Treatment Arm</arm_group_label>
    <arm_group_label>Comparator Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dosing</intervention_name>
    <description>To be performed at the end of the visit following completion all other study visits</description>
    <arm_group_label>Alirocumab Treatment Arm</arm_group_label>
    <arm_group_label>Comparator Treatment Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Apparently healthy male or female individuals&#xD;
&#xD;
          -  Age 18-45 years old inclusive at screening&#xD;
&#xD;
          -  Body weight ≥ 45kg and BMI 18 -29.9 kg/m2&#xD;
&#xD;
          -  Fasting LDL-C &lt; 4.1 mmol/l, TG &lt;1.7 mmol/l and HDL-C ≥ 1.0 mmol for men and ≥1.3 mmol&#xD;
             for women&#xD;
&#xD;
          -  Palpable brachial arterial pulse, as per study team assessment&#xD;
&#xD;
          -  Not currently eligible for statin therapy according to current treatment criteria&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of established CV disease (Coronary Heart Disease, Cerebrovascular Disease,&#xD;
             Peripheral Vascular Disease or Abdominal Aortic Aneurysm)&#xD;
&#xD;
          -  Lipid lowering treatment at screening or within 6 weeks before screening&#xD;
&#xD;
          -  Pregnancy at any study visit&#xD;
&#xD;
          -  Ongoing anticoagulation therapy with warfarin or any of the DOAC/NOAC's&#xD;
&#xD;
          -  History of hypersensitivity to any of the study drugs/any known sensitivity to&#xD;
             alirocumab or monoclonal antibodies&#xD;
&#xD;
          -  History of alcohol or drug abuse or dependence within 6 months of the study at&#xD;
             screening&#xD;
&#xD;
          -  Current or previous history of regular smoking (defined as 1 pack-year) within the&#xD;
             last 10 years.&#xD;
&#xD;
          -  History of hypertension or sustained BP ≥140/90 mmHg on repeated measurements at&#xD;
             screening&#xD;
&#xD;
          -  History of type 1 or 2 diabetes or HbA1c ≥ 48 mmol/mol (6.5%) at screening&#xD;
&#xD;
          -  Chronic kidney disease defined as eGFR &lt;60ml/min/1.73m2 at screening&#xD;
&#xD;
          -  Biological first-degree relatives who have experienced stroke, TIA, myocardial&#xD;
             infarction or peripheral vascular disease (incident event at an age younger than: 55&#xD;
             for male and 65 for female relatives)&#xD;
&#xD;
          -  History of autoimmune inflammatory conditions&#xD;
&#xD;
          -  Lack of ability to provide informed consent&#xD;
&#xD;
          -  TSH &gt;5.0 mu/l at screening&#xD;
&#xD;
          -  Clinically significant liver disease on the basis of screening bloods or history&#xD;
&#xD;
          -  History of myositis/rhabdomyolysis&#xD;
&#xD;
          -  Any concomitant condition that, at the discretion of the investigator, may affect the&#xD;
             participants' ability to complete the study or the study results&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Joseph Cheriyan, MBChB, FRCP, MA</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cambridge University Hospitals NHS Trust</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Michalis Kostapanos, MD, PhD, FRSPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cambridge University Hospitals NHS Trust</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Addenbrooke's Hospital</name>
      <address>
        <city>Cambridge</city>
        <state>Cambridgeshire</state>
        <zip>CB2 0QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>August 14, 2017</study_first_submitted>
  <study_first_submitted_qc>September 1, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 6, 2017</study_first_posted>
  <last_update_submitted>July 26, 2023</last_update_submitted>
  <last_update_submitted_qc>July 26, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 27, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Cambridge University Hospitals NHS Foundation Trust</investigator_affiliation>
    <investigator_full_name>Joseph Cheriyan, MD</investigator_full_name>
    <investigator_title>Consultant Physician &amp; Clinical Pharmacologist/Associate Lecturer</investigator_title>
  </responsible_party>
  <keyword>Healthy Volunteers</keyword>
  <keyword>Low Density Lipoprotein Cholesterol (LDL)</keyword>
  <keyword>PCSK9</keyword>
  <keyword>Alirocumab</keyword>
  <keyword>Forearm Blood Flow</keyword>
  <keyword>Arterial Stiffness</keyword>
  <keyword>Carotid Intima Media Thickness</keyword>
  <keyword>Inflammation</keyword>
  <keyword>Endothelial function</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cardiovascular Diseases</mesh_term>
    <mesh_term>Atherosclerosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_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.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03273972
org study id: INTENSITY-LOW
nct id: NCT03273972
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
allocation: Randomized
intervention model: Parallel Assignment
intervention 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)
primary purpose: Basic Science
masking: Double (Participant, Investigator)
masking description: 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).
measure: Forearm Blood Flow (FBF) - In response to intra-arterial Acetylcholine infusion, comparing Alirocumab to placebo.
time frame: 4 weeks
description: Change in FBF ratio, as measured by absolute & percent change in venous occlusion plethysmography
measure: Forearm Blood Flow in response to intra-arterial Acetylcholine infusion, comparing Alirocumab to statin.
time frame: 4 weeks
description: Change in FBF ratio, as measured by absolute & percent change in venous occlusion plethysmography
measure: Forearm blood flow in response to intra-arterial Acetylcholine infusion, comparing Alirocumab with statin to statin alone.
time frame: 4 weeks
description: Change in FBF ratio, as measured by absolute & percent change in venous occlusion plethysmography
measure: Forearm blood flow in response to intra-arterial Sodium Nitroprusside, comparing Alirocumab to placebo.
time frame: 4 weeks
description: Change in FBF ratio, as measured by absolute & percent change in venous occlusion plethysmography
measure: Forearm blood flow in response to intra-arterial Sodium Nitroprusside, comparing Alirocumab to statin.
time frame: 4 weeks
description: Change in FBF ratio, as measured by absolute & percent change in venous occlusion plethysmography
measure: Forearm blood flow in response to intra-arterial Sodium Nitroprusside, comparing Alirocumab with statin to statin alone.
time frame: 4 weeks
description: Change in FBF ratio, as measured by absolute & percent change in venous occlusion plethysmography
measure: Forearm blood flow in response to intra-arterial L-NMMA infusion, comparing Alirocumab to placebo.
time frame: 4 weeks
description: Change in FBF ratio, as measured by absolute & percent change in venous occlusion plethysmography
measure: Forearm blood flow in response to intra-arterial L-NMMA infusion, comparing Alirocumab to statin.
time frame: 4 weeks
description: Change in FBF ratio, as measured by absolute & percent change in venous occlusion plethysmography
measure: Forearm blood flow in response to intra-arterial L-NMMA infusion, comparing Alirocumab with statin to statin alone.
time frame: 4 weeks
description: Change in FBF ratio, as measured by absolute & percent change in venous occlusion plethysmography
measure: Total and LDL-cholesterol
time frame: 4 weeks
description: Correlation of change in responses to Acetylcholine between groups.
measure: Augmentation Index (an indicator of arterial stiffness)
time frame: 4 weeks
description: Change in Augmentation Index between visits and different treatment regimes.
measure: Pulse Wave Velocity
time frame: 4 weeks
description: Change in aortic Pulse Wave Velocity between visits and different treatment regimes.
measure: Carotid IMT
time frame: 4 weeks
description: Change in Carotid IMT between visits and different treatment regimes.
measure: Systemic inflammation
time frame: 4 weeks
description: Change in lipid profile, hsCRP and other markers of systemic inflammation between visits and different treatment regimes.
measure: Physical examination, vital signs, ECG, laboratory tests and adverse event assessment to determine Safety and tolerability parameters
time frame: 4 weeks
description: Including physical examination, blood pressure, heart rate, 12-lead electrocardiograms (ECGs), clinical laboratory tests side effects and adverse event reporting.
arm group label: Alirocumab Treatment Arm
arm group type: Experimental
description: V2: Day 1 - Alirocumab 150mg (subcutaneous injection) V3: Day 15 +/- 3 days - Alirocumab 150mg (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
arm group label: Comparator Treatment Arm
arm group type: Other
description: V2: Day 1 - Placebo (subcutaneous injection) V3: Day 15 +/- 3 days - Placebo (subcutaneous injection) plus Atorvastatin 20mg (oral) approx. 14 days prescription.
intervention type: Other
intervention name: Written Informed Consent
description: To be completed prior to conducting any study related procedures
arm group label: Alirocumab Treatment Arm
arm group label: Comparator Treatment Arm
intervention type: Other
intervention name: Inclusion/Exclusion check
description: Eligibility check
arm group label: Alirocumab Treatment Arm
arm group label: Comparator Treatment Arm
intervention type: Other
intervention name: Full Clinical Chemistry and Haematology Bloods
description: Participant required to fast for at least 6-8 hoursprior to visit. (Clear, non-caffeinated fluids are allowed)
arm group label: Alirocumab Treatment Arm
arm group label: Comparator Treatment Arm
intervention type: Other
intervention name: Serum sample for systemic markers and lipid sub-fractions
description: Serum samples may be stored for later analysis.
arm group label: Alirocumab Treatment Arm
arm group label: Comparator Treatment Arm
intervention type: Other
intervention name: Pregnancy Test
description: If applicable for women of child bearing potential
arm group label: Alirocumab Treatment Arm
arm group label: Comparator Treatment Arm
intervention type: Other
intervention name: 12 Lead ECG
description: participant resting supine
arm group label: Alirocumab Treatment Arm
arm group label: Comparator Treatment Arm
intervention type: Other
intervention name: Blood Pressure and Heart Rate
description: Measured in the seated position after 5 minutes rest
arm group label: Alirocumab Treatment Arm
arm group label: Comparator Treatment Arm
intervention type: Other
intervention name: Arterial Stiffness
description: Measure of functional and structural changes which accompanies cardiovascular disease
arm group label: Alirocumab Treatment Arm
arm group label: Comparator Treatment Arm
intervention type: Other
intervention name: Central Haemodynamics
description: Measure of functional and structural changes which accompanies cardiovascular disease
arm group label: Alirocumab Treatment Arm
arm group label: Comparator Treatment Arm
intervention type: Other
intervention name: Carotid Intima Media Thickness
description: Measurements will be repeated three times, and the average of the median values will be recorded
arm group label: Alirocumab Treatment Arm
arm group label: Comparator Treatment Arm
intervention type: Other
intervention name: Forearm blood flow studies
description: Assess and determine vascular function, which can interrogate endothelium dependent and independent mechanisms of nitric oxide bioavailability
arm group label: Alirocumab Treatment Arm
arm group label: Comparator Treatment Arm
intervention type: Other
intervention name: Concomitant medication check
description: Review of medication taken by the participant
arm group label: Alirocumab Treatment Arm
arm group label: Comparator Treatment Arm
intervention type: Other
intervention name: Medication compliance check (Pill count)
description: Ensure prescribed statin has been taken
arm group label: Alirocumab Treatment Arm
arm group label: Comparator Treatment Arm
intervention type: Other
intervention name: Physical examination
description: Check overall health
arm group label: Alirocumab Treatment Arm
arm group label: Comparator Treatment Arm
intervention type: Other
intervention name: Medical history
description: Review of volunteers medial history
arm group label: Alirocumab Treatment Arm
arm group label: Comparator Treatment Arm
intervention type: Other
intervention name: AE/SAE review & reporting
description: Monitor safety from the point of consent
arm group label: Alirocumab Treatment Arm
arm group label: Comparator Treatment Arm
intervention type: Drug
intervention name: Dosing
description: To be performed at the end of the visit following completion all other study visits
arm group label: Alirocumab Treatment Arm
arm group label: Comparator Treatment Arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Joseph Cheriyan, MBChB, FRCP, MA
role: Principal Investigator
affiliation: Cambridge University Hospitals NHS Trust
last name: Michalis Kostapanos, MD, PhD, FRSPH
role: Principal Investigator
affiliation: Cambridge University Hospitals NHS Trust
facility: 
country: United Kingdom
responsible party type: Principal Investigator
investigator affiliation: Cambridge University Hospitals NHS Foundation Trust
investigator full name: Joseph Cheriyan, MD
investigator title: Consultant Physician & Clinical Pharmacologist/Associate Lecturer
mesh term: Cardiovascular Diseases
mesh term: Atherosclerosis
sharing ipd: No
ipd 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.