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Investigating the Lowest Threshold of Vascular Benefits From LDL Cholesterol Lowering in Patients With Stable CV Disease (INTENSITY-HIGH)

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ClinicalTrials.gov Identifier: NCT03355027
Recruitment Status : Recruiting
First Posted : November 28, 2017
Last Update Posted : June 8, 2018
Sponsor:
Collaborator:
University of Cambridge
Information provided by (Responsible Party):
Joseph Cheriyan, MD, Cambridge University Hospitals NHS Foundation Trust

Brief Summary:

The INTENSITY-HIGH study aims to answer if there are any limits to LDL reduction in relation to benefiting vascular health, exploring the mechanisms by which secondary prevention in patients with established heart disease may benefit from even lower LDL levels. By using PCSK9 inhibitors such as Alirocumab, very low LDL cholesterol levels not previously encountered in statin trials, can be achieved in patients with established heart disease on top of intensive statin treatment.

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 stable cardiovascular patients. It is unknown whether there is a true limit of LDL cholesterol below which there is no further improvement in endothelial function in stable cardiovascular patients, and, whether this is associated with a reduction in markers of both systemic and vascular inflammation.

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 patients with stable cardiovascular disease, where they will be randomized to receive either a combination of Alirocumab and statin, or Ezetimibe plus statin. 60 patients will be recruited to this single center, randomized, open label, parallel group, mechanistic physiological study which will be conducted at Cambridge University Hospitals NHS Foundation Trust. In order to be eligible for enrollment to the study, some patients may have to complete a 4 week washout period on a suitable statin therapy. The total study duration for each participant will be approximately 14 weeks, where a series of non-invasive vascular studies and medical imaging assessments which will be conducted to observe vascular/systemic inflammation and to assess endothelial vascular function.This study is funded by JP Moulton Charitable Foundation.


Condition or disease Intervention/treatment Phase
Atherosclerosis Cardiovascular Diseases Drug: Alirocumab 150 MG/ML Drug: Ezetimibe 10Mg Tablet Drug: Atorvastatin 40Mg Tablet Drug: Atorvastatin 80Mg Tablet Drug: Rosuvastatin 20Mg Tablet Drug: Rosuvastatin 40Mg Tablet Drug: Simvastatin 80mg Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Randomisation to be performed to a 1:1 ratio.

Alirocumab treatment arm*:

Alirocumab (150mg) & Statin (either: Simvastatin 80mg od, Rosuvastatin 20mg/40mg od or Atorvastatin 40/80mg od)

*May be required to complete a 4 week washout period on a statin before entering the study: Simvastatin 80mg od, Rosuvastatin 20mg/40mg od or Atorvastatin 40/80mg od.

Comparator treatment arm*:

Ezetimibe (10mg) & Statin (either: Simvastatin 80mg od, Rosuvastatin 20mg/40mg od or Atorvastatin 40/80mg od)

*May be required to complete a 4 week washout period on a statin before entering the study: Simvastatin 80mg od, Rosuvastatin 20mg/40mg od or Atorvastatin 40/80mg od.

Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: INvestigating the Lowest Threshold of Vascular bENefits From LDL Cholesterol Lowering With a PCSK9 mAb InhibiTor (Alirocumab) in Patients With Stable Cardiovascular Disease (INTENSITY-HIGH)
Actual Study Start Date : November 30, 2017
Estimated Primary Completion Date : March 31, 2019
Estimated Study Completion Date : May 8, 2019


Arm Intervention/treatment
Experimental: Alirocumab Treatment Arm
30 patients with stable cardiovascular disease to receive Alirocumab 150mg & prescribed one of the following: Atorvastatin 40mg/80mg or Simvastatin 80mg or Rosuvastatin 20mg/40mg. Dosing and dispensing to be performed at V3, V4, V5 and V6.
Drug: Alirocumab 150 MG/ML
Dosing to be performed by subcutaneous injection in clinic
Other Name: Praluent

Drug: Atorvastatin 40Mg Tablet
Patients will be instructed to take once daily at night. Atorvastatin will be the preferred statin option for those with eGFR < 60 ml/min/1.73m2. Patient may be required to complete a 4 week run-in period on a statin prior to entering the study (dependent on eligibility)

Drug: Atorvastatin 80Mg Tablet
Patients will be instructed to take once daily at night. Atorvastatin will be the preferred statin option for those with eGFR < 60 ml/min/1.73m2. Patient may be required to complete a 4 week run-in period on a statin prior to entering the study (dependent on eligibility)

Drug: Rosuvastatin 20Mg Tablet
Patients will be instructed to take once daily at night. Rosuvastatin only to be prescribed if atorvastatin and simvastatin are not previously tolerated. Patient may be required to complete a 4 week run-in period on a statin prior to entering the study (dependent on eligibility)

Drug: Rosuvastatin 40Mg Tablet
Patients will be instructed to take once daily at night. Rosuvastatin only to be prescribed if atorvastatin and simvastatin are not previously tolerated. Patient may be required to complete a 4 week run-in period on a statin prior to entering the study (dependent on eligibility)

Drug: Simvastatin 80mg
Patients will be instructed to take once daily at night. Patient may be required to complete a 4 week run-in period on a statin prior to entering the study (dependent on eligibility)

Active Comparator: Comparator Treatment Arm
30 patients with stable cardiovascular disease to receive Ezetimibe 10mg & prescribed one of the following: Atorvastatin 40mg/80mg or Simvastatin 80mg or Rosuvastatin 20mg/40mg. Dosing and dispensing to be performed at V3, V4, V5 and V6.
Drug: Ezetimibe 10Mg Tablet
Patients will be instructed to take once daily at night.

Drug: Atorvastatin 40Mg Tablet
Patients will be instructed to take once daily at night. Atorvastatin will be the preferred statin option for those with eGFR < 60 ml/min/1.73m2. Patient may be required to complete a 4 week run-in period on a statin prior to entering the study (dependent on eligibility)

Drug: Atorvastatin 80Mg Tablet
Patients will be instructed to take once daily at night. Atorvastatin will be the preferred statin option for those with eGFR < 60 ml/min/1.73m2. Patient may be required to complete a 4 week run-in period on a statin prior to entering the study (dependent on eligibility)

Drug: Rosuvastatin 20Mg Tablet
Patients will be instructed to take once daily at night. Rosuvastatin only to be prescribed if atorvastatin and simvastatin are not previously tolerated. Patient may be required to complete a 4 week run-in period on a statin prior to entering the study (dependent on eligibility)

Drug: Rosuvastatin 40Mg Tablet
Patients will be instructed to take once daily at night. Rosuvastatin only to be prescribed if atorvastatin and simvastatin are not previously tolerated. Patient may be required to complete a 4 week run-in period on a statin prior to entering the study (dependent on eligibility)

Drug: Simvastatin 80mg
Patients will be instructed to take once daily at night. Patient may be required to complete a 4 week run-in period on a statin prior to entering the study (dependent on eligibility)




Primary Outcome Measures :
  1. Vascular inflammation (Standard Uptake Value) - Carotid artery [ Time Frame: 8 weeks ]
    Change in vascular inflammation in the carotid artery between Alirocumab and Ezetimibe treatment regimes (Vascular inflammation will be quantified by calculating the Standard Uptake Value [SUV])

  2. Vascular inflammation (Tissue to Background Ratio TBR) - Carotid artery [ Time Frame: 8 weeks ]
    Change in vascular inflammation in the carotid artery between Alirocumab and Ezetimibe treatment regimes (Vascular inflammation will be quantified by calculating the Tissue to Background Ratio [TBR])

  3. Vascular inflammation (Standard Uptake Value) - Aortic artery [ Time Frame: 8 weeks ]
    Change in vascular inflammation in the aortic artery between Alirocumab and Ezetimibe treatment regimes (Vascular inflammation will be quantified by calculating the Standard Uptake Value [SUV])

  4. Vascular inflammation (Tissue to Background Ratio TBR) - Aortic artery [ Time Frame: 8 weeks ]
    Change in vascular inflammation in the aortic artery between Alirocumab and Ezetimibe treatment regimes (Vascular inflammation will be quantified by calculating the Tissue to Background Ratio [TBR])


Secondary Outcome Measures :
  1. Endothelial-dependent vasodilatation (as measured by Flow Mediated Dilatation using high-resolution vascular ultrasound) [ Time Frame: 8 weeks ]
    Comparing the effects of Alirocumab or Ezetimibe treatment regimes on Flow Mediated Dilatation (a surrogate of endothelial-dependent vasodilatation)

  2. Endothelial-independent vasodilatation (as measured by Flow Mediated Dilatation using high-resolution vascular ultrasound) [ Time Frame: 8 weeks ]
    Comparing the effects of Alirocumab or Ezetimibe treatment regimes on sublingual glyceryl trinitrate (GTN) response to Flow Mediated Dilatation (a surrogate of endothelial-independent vasodilatation)

  3. Augmentation index (an indicator of arterial stiffness) [ Time Frame: 8 weeks ]
    Change in Augmentation Index between visits and between Alirocumab or Ezetimibe treatment regimes

  4. Pulse wave velocity [ Time Frame: 8 weeks ]
    Change in aortic Pulse Wave Velocity between visits and between Alirocumab or Ezetimibe treatment regimes

  5. Carotid IMT [ Time Frame: 8 weeks ]
    Change in Carotid IMT between visits and between Alirocumab or Ezetimibe treatment regimes

  6. Systemic inflammation [ Time Frame: 8 weeks ]
    Change in systemic inflammation (as measured by lipid profile) between visits and between Alirocumab or Ezetimibe treatment regimes

  7. Systemic inflammation [ Time Frame: 8 weeks ]
    Change in systemic inflammation (as measured by hsCRP) between visits and between Alirocumab or Ezetimibe treatment regimes

  8. Systemic inflammation [ Time Frame: 8 weeks ]
    Change in systemic inflammation (as measured by MMP9) between visits and between Alirocumab or Ezetimibe treatment regimes

  9. Systemic inflammation [ Time Frame: 8 weeks ]
    Change in systemic inflammation (as measured by IL2) between visits and between Alirocumab or Ezetimibe treatment regimes

  10. Systemic inflammation [ Time Frame: 8 weeks ]
    Change in systemic inflammation (as measured by IL6) between visits and between Alirocumab or Ezetimibe treatment regimes

  11. Systemic inflammation [ Time Frame: 8 weeks ]
    Change in systemic inflammation (as measured by oxLDL lipid subfractions) between visits and between Alirocumab or Ezetimibe treatment regimes



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with high risk CVD with LDL-Cholesterol ≤ 4.0mmol* OR patients with very high risk CVD with LDL-Cholesterol ≤3.5mmol/l**
  • Male or female patients over 40 years of age inclusive at screening, with a body weight ≥ 45kg and BMI ≥ 18 - ≤ 40kg/m2
  • Palpable brachial arterial pulse, as per study team assessment
  • History of stable CV disease, defined as previous myocardial infarction (STEMI or NSTEMI), angioplasty, documented CAD (Stress echo, CT coronary angiography or invasive angiography), stroke, TIA or peripheral vascular disease without a recent event in the last 6 months (i.e. acute coronary syndrome, unstable angina, CABG, PCI, stroke, MI, carotid endarterectomy)
  • Stable 'suitable statin therapy' over the last 6 weeks as defined by a "statin equivalent" of Simvastatin 80mg od, Rosuvastatin 20mg/40mg od or Atorvastatin 40/80mg od. If not on stable statin therapy, a willingness to commence statin therapy or, if already on statin therapy, a willingness to increase statin therapy to fit the "statin equivalent" dose required in the study (as open label therapy) during run-in period
  • Patients not taking Ezetimibe, or, if on Ezetimibe willingness to be washed out prior to randomisation

High risk is defined as a history of any of the following: acute coronary syndrome (such as myocardial infarction or unstable angina requiring hospitalisation), coronary or other arterial revascularisation procedures, chronic heart disease, ischaemic stroke, peripheral arterial disease.

Very high risk is defined as recurrent cardiovascular events or cardiovascular events in more than 1 vascular bed (that is, polyvascular disease).

Exclusion Criteria:

  • Uncontrolled hypertension BP > 180/110 mmHg on repeated measurements
  • Fasting hypertriglyceridemia with fasting TG>10 mmol/L at screening
  • Pregnancy or combined oral contraceptive pill or hormone replacement therapy or childbearing potential
  • Any concomitant condition that, at the discretion of the investigator, may affect the participant's ability to complete the study
  • Any known sensitivity to Alirocumab or monoclonal antibodies
  • Patients with history of hypersensitivity reactions to any of the study drugs
  • History of significant LFT's (3xULN ALT or AST elevation) by previous statin treatment
  • History of previous myositis associated with statin treatment (i.e. myalgias or asymptomatic CK elevation > 5 x ULN)
  • Type 1 or Type 2 diabetes, which is insulin dependent or on oral hypoglycaemics/diet with HbA1c (DCCT) > 8% (OR HbA1c (IFCC) > 64mmol/mol) at screening. Please note: fasting glucose to be checked again at first FDG-PET/CT scan, and if glucose > 11mol/L at that visit, patients will be excluded from the study
  • History of any acute CV event within 6 months prior to the screening period
  • Rheumatoid arthritis, connective tissue disorders and other conditions known to be associated with active chronic inflammation (e.g. Inflammatory Bowel Disease)
  • Untreated hypothyroidism, known autoimmune myositis
  • Patients with CKD (defined as eGFR < 30 ml/min/1.73m2) at baseline will be excluded from the study
  • Participant in a previous research study in the last 3 years which involved exposure to significant ionising radiation (i.e. cumulative research radiation dose > 5 mSv)
  • History of malignancy within the past 5 years (with the exception of localised carcinoma of the skin that has been resected for cure)
  • History of alcohol/drug abuse or dependence within 6 months of the study, screening visit 1
  • Use of systemic corticosteroids at the time of scanning or a period of 2 weeks prior to screening visit
  • Lack of ability to provide informed consent
  • An unwillingness for female patients of childbearing potential to use an effective form of contraception (see section 12.2.3)
  • Treatment with medications that result in significant drug to drug interactions with study medications. Assignment to a specific statin will be allowed prior to randomisation on a case-to-case basis dependent on the interactions with concomitant medications

Inclusion/Exclusion Criteria for INTENSITY-HIGH PET/MR sub-study (optional)

  • Patient meets Inclusion/Exclusion criteria for INTENSITY HIGH
  • Patient who fulfills the local imaging centre requirements for being scanned in the PET/MR machine will be enrolled
  • Patient is willing to consent to participate in the sub-study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03355027


Contacts
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Contact: Paul Cacciottolo 01223 256653 pjc99@medschl.cam.ac.uk
Contact: Joseph Cheriyan, MBChB, FRCP, MA jc403@medschl.cam.ac.uk

Locations
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United Kingdom
Addenbrooke's Hospital Recruiting
Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
Contact: Paul Cacciottolo    01223256653    pjc99@medschl.cam.ac.uk   
Principal Investigator: Joseph Cheriyan, MBChB, MA, FRCP         
Sponsors and Collaborators
Cambridge University Hospitals NHS Foundation Trust
University of Cambridge
Investigators
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Principal Investigator: Joseph Cheriyan, MBChB, FRCP, MA Cambridge University Hospitals NHS Trust
Principal Investigator: Michalis Kostapanos, MD, PhD, FRSPH Cambridge University Hospitals NHS Trust

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Responsible Party: Joseph Cheriyan, MD, Consultant Physician & Clinical Pharmacologist/Associate Lecturer, Cambridge University Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT03355027     History of Changes
Other Study ID Numbers: INTENSITY-HIGH
First Posted: November 28, 2017    Key Record Dates
Last Update Posted: June 8, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
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.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Joseph Cheriyan, MD, Cambridge University Hospitals NHS Foundation Trust:
Low Density Lipoprotein Cholesterol (LDL)
PCSK9
Alirocumab
Flow Mediated Dilatation
Arterial Stiffness
Carotid Intima Media Thickness
Inflammation
Endothelial function
FDG PET-CT
PET-MR
Ezetimibe
Additional relevant MeSH terms:
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Atherosclerosis
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Atorvastatin
Rosuvastatin Calcium
Simvastatin
Ezetimibe
Antibodies, Monoclonal
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors
Immunologic Factors
Physiological Effects of Drugs