E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Persistent Hypercholesterolemia Despite Maximally Tolerated Lipid Modifying Therapy |
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E.1.1.1 | Medical condition in easily understood language |
Hypercholesterolemia, also called dyslipidemia, is the presence of high levels of cholesterol in the blood, despite previous and concomitant treatment with Maximally Tolerated Lipid Modifying Therapy |
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E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
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 |
The primary objective of the study is to evaluate the reduction of LDL-C by evinacumab in comparison to placebo after 16 weeks in patients with primary hypercholesterolemia (HeFH, or non-HeFH with a history of clinical ASCVD) with persistent hypercholesterolemia despite receiving maximally-tolerated lipid-modifying treatment (LMT). Persistent hypercholesterolemia is defined as LDL-C ≥70 mg/dL (1.81 mmol/L) for those patients with clinical ASCVD and LDL-C ≥100 mg/dL (2.59 mmol/L) for those patients without clinical ASCVD. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the dose-response effect of evinacumab on other lipid parameters (ie, apolipoprotein [Apo] B, non-high-density lipoprotein cholesterol [non-HDL-C], total cholesterol [TC], Lp(a), HDL-C, triglycerides [TGs], ApoA1, apolipoprotein CIII [ApoCIII], and total Angiopoietin-like 3 [ANGPTL3]) in patients with primary hypercholesterolemia • To evaluate the safety and tolerability of SC and IV doses of evinacumab in patients with primary hypercholesterolemia • To assess systemic serum concentrations of evinacumab in patients with primary hypercholesterolemia • To evaluate the potential development of anti-evinacumab 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 |
An optional genomic sub-study will be conducted to identify genomic associations with clinical or biomarker response, other clinical outcome measures and possible AEs. Title : Genomic sub-study optional. Version and date: R1500-CL-1643.01, 22Jun2017 Objectives: The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or biomarker response, other clinical outcome measures and possible AEs. In addition, associations between genomic variants and prognosis or progression of as well as other diseases may also be studied. These data may be used or combined with data collected from other studies to identify and validate genomic markers related to the study drug or and other diseases. Analyses may include sequence determination or single nucleotide polymorphism studies of candidate genes and surrounding genomic regions. Other methods, including whole exome sequencing, whole-genome sequencing, DNA copy number variation. The list of methods may be expanded to include novel methodology that may be developed during the course of this study or sample storage period.
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E.3 | Principal inclusion criteria |
1. Men and women, ages 18 through 80 at the screening visit 2. Diagnosis of primary hypercholesterolemia, either HeFH or non-HeFH with clinical ASCVD 3. A history of clinical ASCVD, for those patients who are non-HeFH. 4. Receiving a stable maximally tolerated statin (± ezetimibe) for at least 4 weeks at screening 5. Receiving alirocumab 150 mg SC Q2W, OR evolocumab 140 mg SC Q2W or 420 mg SC Q4W for at least 8 weeks prior to the screening visit 6. Serum LDL-C ≥ 100 mg/dL at screening (1 repeat lab is allowed) 7. Provide signed informed consent
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E.4 | Principal exclusion criteria |
1. Known history of homozygous FH (clinically, or by previous genotyping) 2. Presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins 3. Newly diagnosed diabetes (within 3 months prior to screening) 4. Use of thyroid medications (except for replacement therapy which has been stable for at least 12 weeks before screening) 5. Laboratory findings during screening period (not including randomization labs): - Triglycerides > 400 mg/dL (> 4.52 mmol/L) for patients without a known history of diabetes mellitus; OR Triglycerides > 300 mg/dL (> 3.39 mmol/L) for patients with a known history of diabetes mellitus - Positive test for Hepatitis B surface antigen and/or Hepatitis C antibody (associated with a positive HCV ribonucleic acid [RNA] polymerase chain reaction) - Positive serum beta-human chorionic gonadotropin or urine pregnancy test in women of childbearing potential - Estimated glomerular filtration rate < 30 mL/min/1.73 m^2 - TSH > 1.5 x upper limit normal (ULN) - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 x ULN - Creatinine phosphokinase (CPK) > 3 x ULN at screening (1 repeat lab is allowed) 6. Systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg at screening visit or time of randomization 7. History of heart failure (New York Heart Association [NYHA] Class II-IV) within 12 months before screening 8. History of MI, unstable angina leading to hospitalization, CABG surgery, PCI, uncontrolled cardiac arrhythmia, carotid surgery or stenting, stroke, TIA, carotid revascularization, endovascular procedure or surgical intervention for peripheral vascular disease within 3 months prior screening 9. 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) 10. Having received LDL apheresis within 2 months before screening 11. Pregnant or breast-feeding women 12. Women of childbearing potential who are unwilling to practice a highly effective birth control method 13. Sexually active men unwilling to use acceptable birth control |
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E.5 End points |
E.5.1 | Primary end point(s) |
Percent change in calculated low-density lipoprotein cholesterol (LDL-C) from baseline to week 16 in the intent-to-treat (ITT) population, using all LDL-C values regardless of adherence to treatment |
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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) |
• Percent change in ApoB from baseline to week 16 • Percent change in non-HDL-C from baseline to week 16 • Percent change in TC from baseline to week 16 • Proportion of patients with ≥ 30% reduction in calculated LDL-C at week 16 • Proportion of patients with ≥ 50% reduction in calculated LDL-C at week 16 • Percent change in TGs from baseline to week 16 • Percent change in Lp(a) from baseline to week 16 • Proportion of patients with calculated LDL-C < 100 mg/dL (2.59 mmol/L) at week 16 • Proportion of patients with calculated LDL-C < 70 mg/dL (1.81 mmol/L) at week 16 • Proportion of patients with calculated LDL-C < 50 mg/dL (1.30 mmol/L) at week 16 • Percent change in calculated LDL-C, ApoB, non-HDL-C, TC, TG, and Lp(a) from baseline to week 24 (only applicable to those patients receiving IV route of study treatment administration)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline and Week 16 for all endpoints except last endpoint regarding the Percent change in calculated LDL-C, ApoB, non-HDL-C, TC, TG, and Lp(a) that will be calculated on Baseline and 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 | Yes |
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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
dose ranging study to assess varying doses of SC and IV regimens |
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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 | 7 |
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 | 38 |
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 |
Australia |
Canada |
Israel |
New Zealand |
Russian Federation |
South Africa |
United States |
Austria |
Czechia |
Denmark |
Italy |
Netherlands |
Norway |
Poland |
Spain |
Sweden |
United Kingdom |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 10 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 10 |