E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary Hypercholesterolemia |
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E.1.1.1 | Medical condition in easily understood language |
High blood cholesterol level |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020604 |
E.1.2 | Term | Hypercholesterolemia |
E.1.2 | System Organ Class | 100000004861 |
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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 determine the efficacy, long-term safety, and tolerability of a dosing regimen of 300 mg alirocumab q4w and its potential as a starting regimen. |
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E.2.2 | Secondary objectives of the trial |
* To investigate the pharmacokinetic (PK)/pharmacodynamic (PD) profile of alirocumab from weekly data at steady state and evaluate patients for the development of anti-alirocumab antibodies. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title: As main study
Objectives: To identify genetic associations with clinical or biomarker response to PCSK9 inhibition, hyperlipidaemia of CVD |
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E.3 | Principal inclusion criteria |
1. Men and women > age 18 or legal age of majority with elevated LDL-C.
2. Patients not having adequate control of their hypercholesterolemia, defined as follows: for moderate and high CVD risk, LDL-C ≥100 mg/dL, and for very high CVD risk, LDL-C ≥ 70 mg/dL. Patients who are not on statin therapy must be at moderate CVD risk and must have LDL-C <160 mg/dL (<4.14 mmol/L). Patients who are statin intolerant may be at moderate CVD risk or greater. Patients who are statin intolerant must have LDL-C <160 mg/dL (<4.14 mmol/L), if they are not receiving any other non-statin LMT. There is no upper limit for LDL-C for patients who are statin intolerant and are receiving clinically appropriate
lipid-lowering therapy (as they are already on standard of care). See protocol for CVD risk categories and definition of statin intolerance.
3. If on statin therapy, patients on the following medications/doses for at least 28 days prior to the screening visit are allowed: atorvastatin 40 mg or 80 mg, rosuvastatin 20 mg or 40 mg, or simvastatin 80 mg (must be on stable dose of simvastatin for at least 1 year), or their maximally tolerated dose of 1 of these 3 statins.
4. Willing and able to comply with clinic visits and study-related procedures.
5. Provide signed informed consent. |
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E.4 | Principal exclusion criteria |
1. Patient with homozygous FH (clinically or by previous genotyping)
2. Currently taking a statin that is not atorvastatin, rosuvastatin, or simvastatin
3. Use of fibrates other than fenofibrate within 6 weeks of the screening visit
4. Use of allowed LMTs (eg, omega-3 fatty acids, cholesterol absorption inhibitors [eg, ezetimibe], bile acid resins, niacin, and plant stanols/sterols [such as those found in Benecol®, flax seed oil, or psyllium]) that have not been at a stable dose/regimen for at least 4 weeks prior to the screening visit
5. Use of nutraceutical products or over-the-counter therapies that may affect lipids and that have not been at a stable dose/amount for at least 4 weeks prior to the screening visit
6. Use of red yeast rice products within 4 weeks of the screening visit or between screening and randomization visits
7. Uncontrolled hypothyroidism
8. Uncontrolled blood pressure (systolic blood pressure >160 mm Hg or diastolic blood pressure >100 mm Hg) at the screening visit
9. Patient who has received plasmapheresis treatment within 2 months prior to the screening visit, or has plans to receive it during the study
10. Recent (within 3 months prior to the screening visit) myocardial infarction, unstable angina leading to hospitalization, percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG), uncontrolled cardiac arrhythmia, stroke, transient ischemic attack, carotid revascularization, endovascular procedure or surgical intervention for peripheral vascular disease
11. Planning to undergo scheduled PCI, CABG, or carotid or peripheral revascularization during the study
12. Known history of a hemorrhagic stroke
13. History of New York Heart Association Class III or IV heart failure within 12 months prior to the screening visit.
14. Newly diagnosed diabetes (within 3 months prior to the screening visit) or poorly controlled diabetes (hemoglobin A1c [HbA1c] >9% at the screening visit)
15. History of bariatric surgery within 12 months prior to the screening visit
16. Unstable weight, defined by a variation >5 kg within 2 months prior to the screening visit
17. Known history of loss of function of PCSK9 (ie, genetic mutation or sequence variation)
18. Use of systemic corticosteroids, unless used as replacement therapy for pituitary/adrenal disease with a stable regimen for at least 6 weeks prior to randomization
19. Use of continuous estrogen or testosterone hormone replacement therapy, unless the regimen has been stable for 6 weeks prior to the screening visit and there are no plans to change the regimen during the study
20. History of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer
21. Known history of positive test for human immunodeficiency virus (HIV)
22. Has been previously treated with at least 1 dose of alirocumab or any other anti-PCSK9 monoclonal antibody in other clinical studies
23. Has taken any active investigational drugs within 1 month or 5 half-lives, whichever is longer; however, patients who have taken anti-PCSK9 therapy at any time are excluded
24. Conditions/situations such as:
Any clinically significant abnormality identified at the time of screening that in the judgment of the investigator or any sub-investigator would preclude safe completion of the study or constrain assessment of endpoints, such as major systemic diseases or patients with short life expectancy.
Patients considered by the investigator or any sub-investigator to be inappropriate for this study for any reason, eg:
o Those patients deemed unable to meet specific protocol requirements, such as scheduled visits.
o Those patients the investigator deems unable to administer or tolerate long-term injections.
Investigator or any sub-investigator, pharmacist, study coordinator, other study staff, or relative thereof directly involved in the conduct of the protocol.
Presence of any other conditions (eg, geographic or social), actual or anticipated, that the investigator feels would restrict or limit the patient’s participation for the duration of the study.
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E.5 End points |
E.5.1 | Primary end point(s) |
*The percent change in calculated LDL-C from baseline to week 24 in the intent-to-treat(ITT) population, using all LDL-C values regardless of adherence to treatment (ITT estimand).
*The percent change in calculated LDL-C from baseline to averaged weeks 21 to 24 in the ITT population, using all LDL-C values regardless of adherence to treatment (ITT estimand). |
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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) |
*The percent change in calculated LDL-C from baseline to week 24 in the mITT population, using all LDL-C values during the efficacy treatment period (on-treatment estimand).
*The percent change in calculated LDL-C from baseline to week 12 (ITT estimand).
*The percent change in calculated LDL-C from baseline to week 12 (ontreatment estimand).
*The percent change in ApoB from baseline to week 24 (ITT estimand).
*The percent change in ApoB from baseline to week 24 (on-treatment estimand).
*The percent change in non-HDL-C from baseline to week 24 (ITT estimand).
*The percent change in non-HDL-C from baseline to week 24 (on-treatment estimand).
*The percent change in total-C from baseline to week 24 (ITT estimand).
*The percent change in ApoB from baseline to week 12 (ITT estimand).
*The percent change in non-HDL-C from baseline to week 12 (ITT estimand).
*The percent change in total-C from baseline to week 12 (ITT estimand).
*The proportion of very high CV risk patients reaching calculated LDL-C <70 mg/dL (1.81 mmol/L), or moderate or high CV risk patients reaching calculated LDL-C <100 mg/dL (2.59 mmol/L) at week 24 (ITT estimand).
*The proportion of very high CV risk patients reaching calculated LDL-C <70 mg/dL (1.81 mmol/L), or moderate or high CV risk patients reaching calculated LDL-C <100 mg/dL (2.59 mmol/L) at week 24 (ontreatment estimand).
*The proportion of patients reaching calculated LDL-C <70 mg/dL at week 24 (ITT estimand).
*The proportion of patients reaching calculated LDL-C <70 mg/dL at week 24 (on-treatment estimand).
*The percent change in Lp(a) from baseline to week 24 (ITT estimand).
*The percent change in Lp(a) from baseline to week 12 (ITT estimand).
*The percent change in HDL-C from baseline to week 24 (ITT estimand).
*The percent change in HDL-C from baseline to week 12 (ITT estimand).
*The percent change in fasting TG from baseline to week 24 (ITT estimand).
*The percent change in fasting TG from baseline to week 12 (ITT estimand).
*The percent change in ApoA-1 from baseline to week 24 (ITT estimand).
*The percent change in ApoA-1 from baseline to week 12 (ITT estimand). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
* At week 24
* From baseline to week 12
*From baseline to week 24 |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
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.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
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 |
Bulgaria |
Canada |
Hungary |
Israel |
Norway |
Poland |
Slovakia |
South Africa |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |