Clinical Trials Register

Summary
EudraCT Number:	2018-002483-11
Sponsor's Protocol Code Number:	18HH4626
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-03-21
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2018-002483-11

A.3

Full title of the trial

CHOlesterol Reduction with Evolocumab and coronAry microvascuLar function: The CHORAL Flow Study

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Does Evolocumab increase blood flow in coronary arteries?

A.3.2

Name or abbreviated title of the trial where available

Evolocumab and coronary flow: The CHORAL Flow Study

A.4.1

Sponsor's protocol code number

18HH4626

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04073134

A.5.4

Other Identifiers

Name:

EudraCT

Number:

2018-002483-11

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Imperial College London
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Amgen Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Imperial College London
B.5.2	Functional name of contact point	Keith Boland
B.5.3	Address:
B.5.3.1	Street Address	JRCO Room 221 Medical School Building
B.5.3.2	Town/ city	St Marys Campus
B.5.3.3	Post code	W12 0HS
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	020 7594 9480
B.5.6	E-mail	k.boland@imperial.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Repatha
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Europe B.V.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Repatha
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Coronary artery disease

E.1.1.1

Medical condition in easily understood language

Coronary artery disease

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10005422
E.1.2	Term	Blood cholesterol
E.1.2	System Organ Class	10022891 - Investigations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10002434
E.1.2	Term	Angiogram coronary
E.1.2	System Organ Class	10022891 - Investigations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

This study aims to show the effect of strong anti-cholesterol medicines called PCSK9 inhibitors on the flow of blood inside the coronary arteries that supply blood to heart muscle. Our main research question will be: Does treatment with PCSK9 inhibitors improves the flow of blood in coronary arteries and in the smaller blood vessels that they supply?

E.2.2

Secondary objectives of the trial

Our secondary research question will be: By what mechanism does treatment with PCSK9 inhibitors affect flow of blood in these arteries?

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

III.2.2 Inclusion Criteria

Patients aged ≥18 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 (≥1.8mmol/L) either on optimal statin therapy (90% of overall sample) or intolerants to statins (restricted to 10% of overall sample).
3. At least one other risk factor for vascular disease or established vascular disease.
Optimal statin therapy will be defined as at least 4 weeks of atorvastatin 20mg or more, with no change in statin dose during this period.
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.

Definition of vascular risk factors
1. Diabetes (type I or type II), formally diagnosed, on therapy;
2. Current cigarette smoking;
3. Diagnosis of hypertension, on treatment;
4. Early family history of established vascular disease (brother or father with vascular disease before 55yo or sister or mother with vascular disease before 65yo);
5. Most recent LDL-C ≥ 3.4 mmol/L despite at least 40mg of atorvastatin.

Definition of established vascular disease
1. Previously documented coronary disease, stable or unstable.
1.1 History of acute coronary syndrome;
1.2 Previous coronary revascularisation;
1.3 Clinical syndrome of stable angina;
1.4 Previous documented at least one moderate coronary stenosis on coronary angiography.
2. Previously formally diagnosed symptomatic peripheral vascular disease;
3. Previously documented cerebrovascular ischaemic event;

Definition of childbearing potential
A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

Definition of highly effective contraception methods
Methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods. Such methods include: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal). Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable). Intrauterine device (IUD), intrauterine hormone-releasing system ( IUS), bilateral tubal occlusion, vasectomised partner, sexual abstinence. Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical success. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse from screening until 15 weeks after last dose of IMP. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and is preferred and usual lifestyle of the participant. Periodic abstinence (calendar, symptothermal and postovulation methods are not acceptable.

E.4

Principal exclusion criteria

III.2.3 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 recipients;
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.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the study will be maximal coronary flow velocity (in cm/s) measured invasively, 12 weeks after Evolocumab therapy. It is hypothesized that Evolocumab will augment maximal coronary flow by at least 10%.

E.5.1.1

Timepoint(s) of evaluation of this end point

Coronary flow velocity will be measured at baseline and after three months of therapy.

E.5.2

Secondary end point(s)

1. Coronary Flow Reserve (CFR), measured invasively, 12 weeks after evolocumab therapy; It is hypothesized that Evolocumab will augment CFR.
2. Hyperaemic Microvascular Resistance (HMR, in mmHg/cm/s), measured invasively, 12 weeks after Evolocumab therapy. It is hypothesized that Evolocumab will reduce HMR.
3. Adenosine-mediated maximal coronary flow velocity (in cm/s) and coronary flow reserve, measured non-invasively, 12 weeks after Evolocumab therapy; It is hypothesized that Evolocumab will augment coronary flow when measured non-invasively.

Exploratory endpoints

4. Quantification of the effect of Evolocumab on Coronary Waves (using Wave Intensity Analysis, derived from invasive pressure and flow data)15. It is plausible to speculate that Evolocumab therapy will increase coronary suction.
5. Adenosine-mediated maximal coronary flow velocity (in cm/s) and coronary flow reserve, measured non-invasively, 6 months after Evolocumab therapy. It is plausible to speculate that Evolocumab therapy will increase coronary flow further (when compared to baseline and 12 weeks follow up).
6. Exercise-induced maximal coronary flow velocity (in cm/s) and coronary flow reserve, measured non-invasively, 12 weeks and 6 months after Evolocumab therapy; It is plausible to speculate that Evolocumab therapy will increase exercise-induced maximal coronary flow.

7. Seattle Angina questionnaire score - it is plausible to speculate improving coronary blood flow may improve angina scores.

8. Canadian Cardiovascular Society Angina Score - it is plausible to speculate improving coronary blood flow may improve angina scores.

E.5.2.1

Timepoint(s) of evaluation of this end point

These measures will be recorded at baseline, after 3 months of therapy and non-invasive measures will be recorded again after a further 3 months of therapy in the treatment arm only.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1