The CHORAL Flow Study (CHORAL)

Cholesterol Reduction With Evolocumab and Coronary MicrovascuLar Function and Coronary Flow: The CHORAL Flow Study

CHORAL Flow is a randomised, double blinded, placebo-controlled trial of the effects of evolocumab on coronary flow at 12 weeks.

Study Overview

• Status: Terminated
• Conditions: Coronary Artery Disease; Atherosclerosis; Hyperlipidemias
• Intervention / Treatment: Biological: Evolocumab; Drug: Placebo

Detailed Description

Evolocumab is a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor which has been shown in the Fourier Trial to reduce major cardiovascular events in statin-treated patients with raised LDL cholesterol compared to placebo. The precise mechanisms via which evolocumab therapy impacts cardiovascular outcomes remain unknown. Coronary blood flow is a powerful predictor of clinical outcomes across a wide range of cardio-circulatory disorders as well as within normal subjects. Improvement in coronary microvascular function and coronary flow, therefore, could potentially represent one of the core pathways via which evolocumab offers cardiovascular protection. In the CHORAL Flow Study patients will undergo invasive and non-invasive physiological assessment with coronary flow measurements before and after 12 weeks of therapy with evolocumab or placebo. Patients in the treatment arm will go on to have a further non-invasive assessment of coronary flow at 24 weeks of therapy in a single blinded fashion.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, W12 0HS
    • Imperial College NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Patients aged between 18 and 80 years, with a clinical indication for coronary angiography and:

1. willing to provide consent: Provide written (signed and dated) informed consent and be capable of understanding the study and co-operating with treatment and follow-up.
2. raised levels of fasting (>9h) LDL-cholesterol (≥2mmol/L) either on optimal statin therapy (90% of overall sample) or intolerants to statins (restricted to 10% of overall sample). Optimal statin therapy will be defined as at least 4 weeks of atorvastatin 40mg or more, with no change in statin dose during this period.
3. at least one other risk factor for vascular disease or established vascular disease.
4. willing and able to use a highly effective method of contraception from screening until 15 weeks after the last dose of IP if a woman of childbearing potential.

Exclusion Criteria:

1. Patients unable or unwilling to provide written informed consent;
2. Patients unable to undergo cardiac catheterisation;
3. Patients with contraindication to adenosine (severe asthma, second or third degree atrioventricular block, heart rate lower than 40/min at rest, previous formal diagnosis of long QT syndrome, acute decompensated heart failure, severe hypotension, advanced (stage IV) or decompensated chronic obstructive pulmonary disease (COPD);
4. Uncontrolled hypertension (systolic BP >180mmHg or DBP >110mmHg, despite ongoing therapy);
5. Clinical heart failure NYHA class III/IV or Ejection Fraction on imaging modality (Echo, MRI) <40%;
6. Severe valvular heart disease;
7. Severe (>95% diameter) epicardial coronary stenosis;
8. Recent (last 12 months) clinically significant cerebrovascular event (including ischaemic or haemorrhagic events);
9. End-stage renal failure (eGFR < 30 mL/min/1.73m2);
10. Advanced liver disease, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3x ULN
11. Current use of PCSK9 inhibitor;
12. Malignancy with life expectancy <1y;
13. Currently or within last 3 months enrolled on another CTIMP;
14. Known allergy to evolocumab or incipients;
15. Women of childbearing potential who are unwilling or unable to use a highly effective method of contraception from screening until 15 weeks after the last dose of IP.
16. Subject is pregnant or breast feeding or planning to become pregnant or to breastfeed during screening, during treatment with IP and/ or within 15 weeks after the end of treatment with IP.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Evolocumab; Participants will receive evolocumab 140 mg subcutaneous injections once every 2 weeks.	Biological: Evolocumab; Administered subcutaneously using a spring-based prefilled 1.0 mL autoinjector/pen.; Other Names: Repatha; AMG 145
Placebo Comparator: Placebo; Participants will receive placebo subcutaneous injections once every 2 weeks.	Drug: Placebo; Administered subcutaneously using a spring-based prefilled 1.0 mL autoinjector/pen.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal coronary flow velocity changes from baseline to 12 weeks	Measured invasively using a doppler sensor tipped wire	Measured at baseline and after 12 weeks of therapy

Secondary Outcome Measures

Outcome Measure	Time Frame
Coronary Flow Reserve (CFR), measured invasively	Measured at baseline and after 12 weeks of therapy
Hyperaemic Microvascular Resistance, measured invasively	Measured at baseline and after 12 weeks of therapy
Maximal coronary flow (non-invasive) measured non-invasively using ultrasound (echo)	Measured at baseline and after 12 weeks of therapy and in single-blinded extended treatment arm at 24 weeks
Coronary Flow Reserve (CFR) (Non-invasive) measured non-invasively using ultrasound (echo)	Measured at baseline and after 12 weeks of therapy and in single-blinded extended treatment arm at 24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Coronary wave intensity analysis derived from invasive pressure and flow measurements	Exploratory outcome	Measured at baseline and after 12 weeks of therapy
Exercise coronary flow reserve (CFR) (Non-invasive) measured non-invasively using ultrasound (echo).	Exploratory outcome	Measured at baseline and after 12 weeks of therapy and in single-blinded extended treatment arm at 24 weeks

Collaborators and Investigators

• Sponsor: Imperial College London
• Investigators: Principal Investigator: Ricardo Petraco, PhD, Imperial College London; Study Director: Henry Seligman, MBBS, Imperial College London

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2019
• Primary Completion (Actual): March 27, 2022
• Study Completion (Actual): May 27, 2022

Study Registration Dates

• First Submitted: August 27, 2019
• First Submitted That Met QC Criteria: August 28, 2019
• First Posted (Actual): August 29, 2019

Study Record Updates

• Last Update Posted (Actual): August 6, 2024
• Last Update Submitted That Met QC Criteria: August 5, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Coronary Artery Disease; Atherosclerosis
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Lipid Metabolism Disorders; Dyslipidemias; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Atherosclerosis; Hyperlipidemias; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Protease Inhibitors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Serine Proteinase Inhibitors; PCSK9 Inhibitors; Evolocumab
• Other Study ID Numbers: 18HH4626; 2018-002483-11 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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