Investigating the Lowest Threshold of Vascular Benefits From LDL Cholesterol Lowering in Patients With Stable CV Disease

NCT03355027 | Unknown

• 1 other identifier: INTENSITY-HIGH
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

Atherosclerosis; Cardiovascular Diseases

Keywords

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

Outcome Measures

Primary Outcomes (4)

• Vascular inflammation (Standard Uptake Value) - Carotid artery

  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 \[SUV\])

  8 weeks

• Vascular inflammation (Tissue to Background Ratio TBR) - Carotid artery

  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 \[TBR\])

  8 weeks

• Vascular inflammation (Standard Uptake Value) - Aortic artery

  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 \[SUV\])

  8 weeks

• Vascular inflammation (Tissue to Background Ratio TBR) - Aortic artery

  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 \[TBR\])

  8 weeks

Secondary Outcomes (11)

• Endothelial-dependent vasodilatation (as measured by Flow Mediated Dilatation using high-resolution vascular ultrasound)

  8 weeks

• Endothelial-independent vasodilatation (as measured by Flow Mediated Dilatation using high-resolution vascular ultrasound)

  8 weeks

• Augmentation index (an indicator of arterial stiffness)

  8 weeks

• Pulse wave velocity

  8 weeks

• Carotid IMT

  8 weeks

Study Arms (2)

Alirocumab Treatment Arm

EXPERIMENTAL

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; Drug: Atorvastatin 40Mg Tablet; Drug: Atorvastatin 80Mg Tablet; Drug: Rosuvastatin 20Mg Tablet; Drug: Rosuvastatin 40Mg Tablet; Drug: Simvastatin 80mg

Comparator Treatment Arm

ACTIVE COMPARATOR

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; Drug: Atorvastatin 40Mg Tablet; Drug: Atorvastatin 80Mg Tablet; Drug: Rosuvastatin 20Mg Tablet; Drug: Rosuvastatin 40Mg Tablet; Drug: Simvastatin 80mg

Interventions

Alirocumab 150 MG/ML DRUG

Dosing to be performed by subcutaneous injection in clinic

Also known as: Praluent

Alirocumab Treatment Arm

Ezetimibe 10Mg Tablet DRUG

Patients will be instructed to take once daily at night.

Also known as: Ezetrol

Comparator Treatment Arm

Atorvastatin 40Mg Tablet DRUG

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)

Alirocumab Treatment Arm; Comparator Treatment Arm

Atorvastatin 80Mg Tablet DRUG

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)

Alirocumab Treatment Arm; Comparator Treatment Arm

Rosuvastatin 20Mg Tablet DRUG

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)

Also known as: Crestor

Alirocumab Treatment Arm; Comparator Treatment Arm

Rosuvastatin 40Mg Tablet DRUG

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)

Also known as: Crestor

Alirocumab Treatment Arm; Comparator Treatment Arm

Simvastatin 80mg DRUG

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)

Alirocumab Treatment Arm; Comparator Treatment Arm

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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)

Sponsors & Collaborators

• Cambridge University Hospitals NHS Foundation Trust: lead
• University of Cambridge: collaborator

Study Sites (1)

Addenbrooke's Hospital

Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

Location

Related Publications (1)

• Cacciottolo PJ, Kostapanos MS, Hernan Sancho E, Pavey H, Kaloyirou F, Vamvaka E, Helmy J, Hubsch A, McEniery CM, Wilkinson IB, Cheriyan J. 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): protocol and study rationale for a randomised, open label, parallel group, mechanistic study. BMJ Open. 2021 Apr 13;11(4):e037457. doi: 10.1136/bmjopen-2020-037457.

  PMID: 33849844 DERIVED

MeSH Terms

Conditions

Atherosclerosis; Cardiovascular Diseases; Inflammation

Interventions

alirocumab; Ezetimibe; Tablets; Atorvastatin; Rosuvastatin Calcium; Simvastatin

Condition Hierarchy (Ancestors)

Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Azetidines; Azetines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Dosage Forms; Pharmaceutical Preparations; Pyrroles; Azoles; Heptanoic Acids; Fatty Acids; Lipids; Sulfonamides; Amides; Organic Chemicals; Fluorobenzenes; Hydrocarbons, Fluorinated; Hydrocarbons, Halogenated; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrimidines; Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds

Study Officials

• Joseph Cheriyan, MBChB, FRCP, MA

  Cambridge University Hospitals NHS Trust

  PRINCIPAL INVESTIGATOR

• Michalis Kostapanos, MD, PhD, FRSPH

  Cambridge University Hospitals NHS Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Consultant Physician & Clinical Pharmacologist/Associate Lecturer

Model Details: 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.

Study Record Dates

• First Submitted: October 6, 2017
• First Posted: November 28, 2017
• Study Start: November 30, 2017
• Primary Completion: September 30, 2019
• Study Completion: November 30, 2023
• Last Updated: July 23, 2021

Record last verified: 2021-07

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)