Clinical trial NCT04073134: The CHORAL Flow Study
Official title: Cholesterol Reduction With Evolocumab and Coronary MicrovascuLar Function and Coronary Flow: The CHORAL Flow Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Coronary Artery Disease
Atherosclerosis
Hyperlipidemias
Keywords: Coronary Artery Disease
Atherosclerosis
Lead sponsor: Imperial College London
Sponsor class: OTHER
First posted: 2019-08-29
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomised control Trial
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Maximal coronary flow velocity changes from baseline to 12 weeks
timeFrame: Measured at baseline and after 12 weeks of therapy
Secondary outcomes:
measure: Coronary Flow Reserve (CFR), measured invasively
timeFrame: Measured at baseline and after 12 weeks of therapy
measure: Hyperaemic Microvascular Resistance, measured invasively
timeFrame: Measured at baseline and after 12 weeks of therapy
measure: Maximal coronary flow (non-invasive) measured non-invasively using ultrasound (echo)
timeFrame: Measured at baseline and after 12 weeks of therapy and in single-blinded extended treatment arm at 24 weeks
measure: Coronary Flow Reserve (CFR) (Non-invasive) measured non-invasively using ultrasound (echo)
timeFrame: Measured at baseline and after 12 weeks of therapy and in single-blinded extended treatment arm at 24 weeks
Other outcomes:
measure: Coronary wave intensity analysis derived from invasive pressure and flow measurements
timeFrame: Measured at baseline and after 12 weeks of therapy
measure: Exercise coronary flow reserve (CFR) (Non-invasive) measured non-invasively using ultrasound (echo).
timeFrame: Measured at baseline and after 12 weeks of therapy and in single-blinded extended treatment arm at 24 weeks
Locations:
city: London
country: United Kingdom
facility: Imperial College NHS Foundation Trust
Study officials:
affiliation: Imperial College London
name: Ricardo Petraco, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Imperial College London
name: Henry Seligman, MBBS
role: STUDY_DIRECTOR
References: