The CHORAL Flow Study (CHORAL)
Primary Purpose
Coronary Artery Disease, Atherosclerosis, Hyperlipidemias
Status
Terminated
Phase
Phase 4
Locations
United Kingdom
Study Type
Interventional
Intervention
Evolocumab
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Coronary Artery Disease focused on measuring Coronary Artery Disease, Atherosclerosis
Eligibility Criteria
Inclusion Criteria:
Patients aged between 18 and 80 years, with a clinical indication for coronary angiography and:
- 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.
- 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.
- at least one other risk factor for vascular disease or established vascular disease.
- 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:
- Patients unable or unwilling to provide written informed consent;
- Patients unable to undergo cardiac catheterisation;
- 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);
- Uncontrolled hypertension (systolic BP >180mmHg or DBP >110mmHg, despite ongoing therapy);
- Clinical heart failure NYHA class III/IV or Ejection Fraction on imaging modality (Echo, MRI) <40%;
- Severe valvular heart disease;
- Severe (>95% diameter) epicardial coronary stenosis;
- Recent (last 12 months) clinically significant cerebrovascular event (including ischaemic or haemorrhagic events);
- End-stage renal failure (eGFR < 30 mL/min/1.73m2);
- Advanced liver disease, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3x ULN
- Current use of PCSK9 inhibitor;
- Malignancy with life expectancy <1y;
- Currently or within last 3 months enrolled on another CTIMP;
- Known allergy to evolocumab or incipients;
- 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.
- 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.
Sites / Locations
- Imperial College NHS Foundation Trust
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Evolocumab
Placebo
Arm Description
Participants will receive evolocumab 140 mg subcutaneous injections once every 2 weeks.
Participants will receive placebo subcutaneous injections once every 2 weeks.
Outcomes
Primary Outcome Measures
Maximal coronary flow velocity changes from baseline to 12 weeks
Measured invasively using a doppler sensor tipped wire
Secondary Outcome Measures
Coronary Flow Reserve (CFR), measured invasively
Hyperaemic Microvascular Resistance, measured invasively
Maximal coronary flow (non-invasive) measured non-invasively using ultrasound (echo)
Coronary Flow Reserve (CFR) (Non-invasive) measured non-invasively using ultrasound (echo)
Full Information
NCT ID
NCT04073134
First Posted
August 27, 2019
Last Updated
March 28, 2023
Sponsor
Imperial College London
1. Study Identification
Unique Protocol Identification Number
NCT04073134
Brief Title
The CHORAL Flow Study
Acronym
CHORAL
Official Title
Cholesterol Reduction With Evolocumab and Coronary MicrovascuLar Function and Coronary Flow: The CHORAL Flow Study
Study Type
Interventional
2. Study Status
Record Verification Date
March 2023
Overall Recruitment Status
Terminated
Why Stopped
Funding withdrawn
Study Start Date
September 11, 2019 (Actual)
Primary Completion Date
March 27, 2022 (Actual)
Study Completion Date
May 27, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Imperial College London
4. Oversight
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
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
CHORAL Flow is a randomised, double blinded, placebo-controlled trial of the effects of evolocumab on coronary flow at 12 weeks.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Coronary Artery Disease, Atherosclerosis, Hyperlipidemias
Keywords
Coronary Artery Disease, Atherosclerosis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
Randomised control Trial
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
12 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Evolocumab
Arm Type
Active Comparator
Arm Description
Participants will receive evolocumab 140 mg subcutaneous injections once every 2 weeks.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Participants will receive placebo subcutaneous injections once every 2 weeks.
Intervention Type
Biological
Intervention Name(s)
Evolocumab
Other Intervention Name(s)
Repatha, AMG 145
Intervention Description
Administered subcutaneously using a spring-based prefilled 1.0 mL autoinjector/pen.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Administered subcutaneously using a spring-based prefilled 1.0 mL autoinjector/pen.
Primary Outcome Measure Information:
Title
Maximal coronary flow velocity changes from baseline to 12 weeks
Description
Measured invasively using a doppler sensor tipped wire
Time Frame
Measured at baseline and after 12 weeks of therapy
Secondary Outcome Measure Information:
Title
Coronary Flow Reserve (CFR), measured invasively
Time Frame
Measured at baseline and after 12 weeks of therapy
Title
Hyperaemic Microvascular Resistance, measured invasively
Time Frame
Measured at baseline and after 12 weeks of therapy
Title
Maximal coronary flow (non-invasive) measured non-invasively using ultrasound (echo)
Time Frame
Measured at baseline and after 12 weeks of therapy and in single-blinded extended treatment arm at 24 weeks
Title
Coronary Flow Reserve (CFR) (Non-invasive) measured non-invasively using ultrasound (echo)
Time Frame
Measured at baseline and after 12 weeks of therapy and in single-blinded extended treatment arm at 24 weeks
Other Pre-specified Outcome Measures:
Title
Coronary wave intensity analysis derived from invasive pressure and flow measurements
Description
Exploratory outcome
Time Frame
Measured at baseline and after 12 weeks of therapy
Title
Exercise coronary flow reserve (CFR) (Non-invasive) measured non-invasively using ultrasound (echo).
Description
Exploratory outcome
Time Frame
Measured at baseline and after 12 weeks of therapy and in single-blinded extended treatment arm at 24 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients aged between 18 and 80 years, with a clinical indication for coronary angiography and:
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.
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.
at least one other risk factor for vascular disease or established vascular disease.
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:
Patients unable or unwilling to provide written informed consent;
Patients unable to undergo cardiac catheterisation;
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);
Uncontrolled hypertension (systolic BP >180mmHg or DBP >110mmHg, despite ongoing therapy);
Clinical heart failure NYHA class III/IV or Ejection Fraction on imaging modality (Echo, MRI) <40%;
Severe valvular heart disease;
Severe (>95% diameter) epicardial coronary stenosis;
Recent (last 12 months) clinically significant cerebrovascular event (including ischaemic or haemorrhagic events);
End-stage renal failure (eGFR < 30 mL/min/1.73m2);
Advanced liver disease, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3x ULN
Current use of PCSK9 inhibitor;
Malignancy with life expectancy <1y;
Currently or within last 3 months enrolled on another CTIMP;
Known allergy to evolocumab or incipients;
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.
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ricardo Petraco, PhD
Organizational Affiliation
Imperial College London
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Henry Seligman, MBBS
Organizational Affiliation
Imperial College London
Official's Role
Study Director
Facility Information:
Facility Name
Imperial College NHS Foundation Trust
City
London
ZIP/Postal Code
W12 0HS
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
No
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The CHORAL Flow Study
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