E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Homozygous familial hypercholesterolemia |
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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 |
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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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objectives of the study are:
- To evaluate the long-term safety and tolerability of evinacumab 15 mg/kg intravenously (IV) administered every 4 weeks (Q4W) in patients with HoFH.
- To evaluate the long-term safety and tolerability of evinacumab 15 mg/kg IV administered Q4W in adolescent patients with HoFH (only applicable to countries enrolling adolescent patients) |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
- To evaluate the effect of evinacumab on lipid parameters (ie, LDL-C, Apo B, non-HDL-C, total cholesterol [TC], and TG) in patients with HoFH
- To evaluate the effect of evinacumab 15 mg/kg IV on lipid parameters (ie, LDL-C, Apo B, non-HDL-C, TC, and TG) in adolescent patients with HoFH (only applicable to countries enrolling adolescent patients)
- 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 |
Genomics Sub-Study, Protocol R1500-CL-1719 Amendment 2A and 2B, Protocol Section 8.2.8.3.
The purpose of the genomic 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 hypercholesterolemia as well as related diseases may also be studied.
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E.3 | Principal inclusion criteria |
1. Male and female patients ≥12 years of age with HoFH. Patients aged ≥12 years old will be enrolled only in countries where permitted by the Regulatory Agency and Institutional Review Board (IRB) or Ethics Committee (EC).
2. Diagnosis of functional HoFH by at least 1 of the following genetic or clinical criteria:
a. Documented functional mutation or mutations in both LDLR alleles
Note: patients who have null receptor mutations on both LDLR alleles, ie, double null, are eligible
b. Presence of homozygous or compound heterozygous mutations in Apo B or PCSK9
Note: patients who are double heterozygous, ie, mutations on different genes (eg, LDLR/PCSK9) and patients with homozygous LDLRAP1 mutations are eligible
c. Untreated TC >500 mg/dL (12.93 mmol/L) and TG <300 mg/dL (3.39 mmol/L) AND both parents with documented TC >250 mg/dL (6.47 mmol) OR cutaneous or tendinous xanthoma before the age of 10 years
3. For patients who have participated in a previous evinacumab or alirocumab study: completion of the study in which they participated.
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 |
Exclusion Criteria for Evinacumab-Naïve Patients
1. Concomitant medications and procedures that have not been stable prior to the baseline visit
2. Any new condition or worsening of an existing condition, which in the opinion of the investigator would make the patient unsuitable for enrollment, or could interfere with the patient participating in or completing the study.
3. History of a MI, unstable angina leading to hospitalization, coronary artery bypass graft surgery, percutaneous coronary intervention, uncontrolled cardiac arrhythmia, carotid surgery or stenting, stroke, transient ischemic attack, valve replacement surgery, carotid revascularization, endovascular procedure or surgical intervention for peripheral vascular disease within 3 months prior to the baseline visit
4. Presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins
5. Newly diagnosed (within 3 months prior to screening visit diabetes mellitus or poorly controlled (HbA1c >9%) diabetes
6. Use of systemic corticosteroids, unless used as replacement therapy for pituitary/adrenal disease with a stable regimen for at least 6 weeks prior to screening visit
7. Use of estrogen or testosterone therapy unless the regimen has been stable 6 weeks prior to the screening visit and no plans to change the regimen during the study
8. Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at the screening visit
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. History of New York Heart Association (NYHA) Class IV heart failure within 12 months before screening
11. Laboratory findings during the screening period (applies to patients undergoing Screening):
• Alanine aminotransferase or aspartate aminotransferase >3 x upper limit of normal (ULN)(1 repeat lab is allowed)
• CPK >3 x ULN (1 repeat lab is allowed)
• Positive serum beta-human chorionic gonadotropin or urine pregnancy test in WOCBP
• TSH >1.5 x ULN of the central laboratory (1 repeat lab is allowed) for patients not on thyroid replacement therapy
• Positive test for hepatitis B surface antigen and/or hepatitis C antibody (associated with a positive HCV RNA polymerase chain reaction)
• eGFR <30 mL/min/1.73 m2 (calculated by central lab)
• Postmenopausal status will be confirmed by measurement of follicle-stimulating hormone (FSH)
12. Member of the clinical site study team and/or his/her immediate family.
13. Pregnant of breastfeeding women
14. Women of child bearing potential (see protocol for more information)
15. Men who are sexually active with WOCBP and are unwilling to use the following forms of medically acceptable birth control during the study drug treatment period and for 24 weeks after the last injection of study drug: vasectomy with medical assessment of surgical success OR consistent use of a condom. Sperm donation is prohibited during the study and for up to 24 weeks after the last injection of study drug.
16. LDL-C level <70 mg/dL at screening visit
17. Use of any active investigational drugs (except alirocumab) within 1 month or 5 half lives prior to the screening visit, whichever is longer.
18. Age <12 years at the screening visit
19. Tanner stage <2 at the screening visit
Exclusion Criteria for Patients from a Previous Evinacumab Study
1. Significant protocol deviation in the previous study based on the investigator’s judgment, such as non-compliance by the patient.
2. Concomitant medications and procedures that have not been stable prior to the baseline visit.
3. Adverse event leading to permanent discontinuation from previous study.
4. Any new condition or worsening of an existing condition, which in the opinion of the investigator would make the patient unsuitable for enrollment, or could interfere with the patient participating in or completing the study.
5. Member of the clinical site study team and/or his/her immediate family.
6. Pregnant of breastfeeding women
7. Women of child bearing potential (see protocol for more information)
8. Men who are sexually active with WOCBP and are unwilling to use the following forms of medically acceptable birth control during the study drug treatment period and for 24 weeks after the last injection of study drug:vasectomy with medical assessment of surgical success OR consistent use of a condom.Sperm donation is prohibited during the study and for up to 24 weeks after the last injection of study drug
9. Age <12 years at the screening visit
10. Tanner stage <2 at the screening visit |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the incidence and severity of treatment-emergent adverse events (TEAEs) and other safety variables during the open-label treatment period. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Overall safety will be assessed by monitoring/evaluation of TEAEs, physical examinations, electrocardiograms (ECG), and clinical safety laboratory tests at pre-specified time points. The potential emergence of anti-evinacumab antibodies will also be evaluated. |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints are:
- The percent and absolute change in LDL-C over time
- The percent and absolute change in Apo B over time
- The percent and absolute change in non-HDL-C over time
- The percent and absolute change in TC over time
- The percent and absolute change in TGs over time |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy will be assessed by clinical laboratory evaluation of lipid levels at pre-specified time points throughout the study. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
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 | 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) | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
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 |
Austria |
Canada |
Czechia |
France |
Germany |
Greece |
Italy |
Japan |
Netherlands |
South Africa |
Ukraine |
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 | 4 |
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 | 4 |
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 | 0 |