E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 |
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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 |
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E.1.3 | Condition being studied is a rare disease | No |
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? |
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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? |
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E.2.3 | Trial contains a sub-study | No |
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.
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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.
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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%. |
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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. |
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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.
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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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
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 | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 1 |