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 | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10020603 |
E.1.2 | Term | Hypercholesterolaemia |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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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 |
To provide patients with severe hypercholesterolemia at risk for subsequent cardiovascular (CV) events and not adequately controlled with currently available lipid-modifying therapy (LMT) access to alirocumab ahead of commercial availability and to document the overall safety and tolerability of alirocumab in this patient population. |
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E.2.2 | Secondary objectives of the trial |
To document the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C) levels as well as non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (total-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels after 12 weeks of treatment.
To document patient’s acceptability of self-injection (Self Injection Assessment Questionnaire, SIAQ).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Either A, B, C, D, or E below and not adequately controlled with a maximally tolerated dose of statin with or without other LMTs, all at stable doses for at least 4 weeks prior to the screening visit (Week -3):
A. Patients suffering from heterozygous familial hypercholesterolemia (heFH) with LDL-C concentrations ≥160 mg/dL (4.14 mmol/L) despite treatment.
B. Patients suffering from heFH with LDL-C concentrations ≥130 mg/dL (3.36 mmol/L) despite treatment and two or more CV risk factors among this list:
- LDL-C >250 mg/dL (6.46 mmol/L) at the time of the FH diagnosis (before treatment).
- Family history of premature-onset coronary heart disease (CHD; first-degree male relative with onset before age 55 years; first-degree female relative with onset before age 65 years).
- Metabolic syndrome.
- HDL-C <40 mg/dL (1.03 mmol/L).
- Hypertension (blood pressure >140/90 mmHg or drug treatment).
- Lipoprotein a (Lp[a]) ≥50 mg/dL (1.78 µmol/L).
- Tendon xanthoma.
C. Patients suffering from heFH with LDL-C concentrations ≥130 mg/dL (3.36 mmol/L) despite treatment and one of the following characteristics:
- Established CHD or other cardiovascular disease (CVD; history of acute myocardial infarction, ischemic stroke, peripheral arterial disease, coronary or peripheral arterial revascularization, stable or unstable angina, transient ischemic attack, carotid artery stenosis ≥50%, or aortic abdominal aneurysm).
- Drug-treated type 2 diabetes mellitus or type 1 with target organ damage.
- Family history of first- or second-degree relative with very premature onset CHD (first- or second degree male relative with onset before age 45; first- or second-degree female relative with onset before age 55).
D. Non-FH patients suffering from established CHD or other CVD (history of acute myocardial infarction, ischemic stroke, peripheral arterial disease, coronary or peripheral arterial revascularization, stable or unstable angina, transient ischemic attack, carotid artery stenosis ≥50%, or aortic abdominal aneurysm) and with LDL-C concentrations ≥130 mg/dL (3.36 mmol/L).
E. Patients suffering from progressive CVD (coronary artery disease, or peripheral arterial occlusive disease or cerebrovascular disease as documented clinically or by imaging techniques, with a subsequent CV event [acute MI, ischemic stroke, ischemia-driven revascularization, unstable angina, transient ischemic attack] occurring despite stable doses of maximally tolerated LLT) with LDL-C concentrations ≥100 mg/dL (2.59 mmol/L).
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E.4 | Principal exclusion criteria |
Not on a stable dose of LMT (including statin) for at least 4 weeks prior to the screening visit (Week 3) and from screening to enrollment.
Use of a fibrate other than fenofibrate within 4 weeks of the screening visit (Week -3) or between screening and enrollment.
Daily doses above atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg (except for patients on simvastatin 80 mg for more than one year, who are eligible).
Use of statin other than simvastatin, atorvastatin, or rosuvastatin prior to the screening visit (Week -3) or between screening and enrollment, except when there is a documented reason for intolerance to the abovementioned potent statins (in which case the use of a different statin is allowed).
Fasting serum TG >400 mg/dL (>4.52 mmol/L) at the screening visit (Week 3).
Uncontrolled hypertension (>180 mmHg systolic and/or >110 mmHg diastolic at randomization visit).
New York Heart Association Class III or IV congestive heart failure persisting despite treatment.
History of hemorrhagic stroke.
Liver transaminases >3 times the upper limit of normal.
Laboratory evidence of current hepatitis B or C infection.
Creatine kinase >3 times the upper limit of normal.
Estimated glomerular filtration rate <30 mL/min/1.73 m^2.
Pregnant or breastfeeding woman or with childbearing potential without appropriate contraception. Male participant with a female partner of childbearing potential not protected by a highlyeffective method(s) of birth control.
Patients eligible for enrolment into an ongoing clinical study of alirocumab conducted at the same investigational site.
Hypersensitivity to alirocumab or any of the excipients.
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of patients with adverse events |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
a) Assessment of patient’s acceptability of self-injection using Self Injection Assessment Questionnaire (SIAQ)
b) Percent change from baseline in calculated LDL-C levels
c) Percent change from baseline in total-C levels
d) Percent change from baseline in HDL-C levels
e) Percent change from baseline in TG levels
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
a) : Up to 30 months
b), c), d), e): Baseline to week 12 |
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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 | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
provide early access to high-risk patients ahead of alirocumab commercial availability |
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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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 124 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 14 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 15 |