Safety, Tolerability and Efficacy of Evolocumab (AMG 145) in Children With Inherited Elevated Low-density Lipoprotein Cholesterol (Familial Hypercholesterolemia)

Study Overview
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Brief Summary
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The main purpose of this study is to describe the safety and tolerability of 80 weeks of subcutaneous (SC) evolocumab when added to standard of care in children 10 to 17 years of age with familial hypercholesterolemia.

Official Title
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Open-label, Single-Arm, Multicenter Study to Evaluate the Safety, Tolerability and Efficacy of Evolocumab for LDL-C Reduction, as Add-on to Diet and Lipid-lowering Therapy, in Pediatric Subjects From 10 to 17 Years of Age With Heterozygous Familial Hypercholesterolemia (HeFH) or Homozygous Familial Hypercholesterolemia (HoFH)

Conditions
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Familial Hypercholesterolemia

Intervention / Treatment
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* Biological: Evolocumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Heterozygous Familial Hypercholesterolemia (HeFH): -Completed Study 20120123 (NCT02392559) while still on assigned investigational product and did not experience a treatment-related serious adverse event Homozygous Familial Hypercholesterolemia (HoFH): Male or female, ≥ 10 to ≤ 17 years of age at time of enrollment Diagnosis of HoFH On a low-fat diet and receiving background lipid-lowering therapy Lipid-lowering therapy unchanged for ≥ 4 weeks prior to LDL-C screening; fibrates must be stable for at least 6 weeks prior to screening. Fasting LDL-C at screening ≥ 130 mg/dL (3.4 mmol/L) Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) Exclusion Criteria: -Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(s); except Study 20120123 HoFH: Moderate to severe renal dysfunction Active liver disease or hepatic dysfunction, Creatine kinase > 3 times the upper limit of normal (ULN) at screening

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Evolocumab<br>Participants receive 420 mg evolocumab administered by subcutaneous injection every 4 weeks (QM) for up to 80 weeks. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: AMG 145;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An adverse event is defined as any untoward medical occurrence in a clinical trial participant, not necessarily having a causal relationship with study treatment. A serious AE is as an AE that met at least 1 of the following criteria: fatal; life threatening; required in-patient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. AEs were graded for severity using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0: Grade 1: Mild; asymptomatic or mild symptoms; Grade 2: Moderate; minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening consequences; urgent intervention indicated; Grade 5: Death related to AE. | From first dose of evolocumab in this study up to and including 30 days after the last dose or up to the end of study date, whichever was earlier; up to 80 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Week 80 in Low-density Lipoprotein Cholesterol (LDL-C) in HeFH Participants | For HeFH participants baseline was defined as the baseline value of the parent study 20120123. | Baseline and week 80 | 
| Percent Change From Baseline to Week 80 in Low-density Lipoprotein Cholesterol (LDL-C) in HoFH Participants | For HoFH participants baseline was defined as the baseline value in this study (20120124). | Baseline and week 80 | 
| Percent Change From Baseline to Week 80 in Non-HDL-C in HeFH Participants | For HeFH participants baseline was defined as the baseline value of the parent study 20120123. | Baseline and week 80 | 
| Percent Change From Baseline to Week 80 in Non-HDL-C in HoFH Participants | For HoFH participants baseline was defined as the baseline value in this study (20120124). | Baseline and week 80 | 
| Percent Change From Baseline to Week 80 in Apolipoprotein B in HeFH Participants | For HeFH participants baseline was defined as the baseline value in the parent study 20120123. | Baseline and week 80 | 
| Percent Change From Baseline to Week 80 in Apolipoprotein B in HoFH Participants | For HoFH participants baseline was defined as the baseline value in this study (20120124). | Baseline and week 80 | 
| Percent Change From Baseline to Week 80 in Total Cholesterol/HDL-C Ratio in HeFH Participants | For HeFH participants baseline was defined as the baseline value in the parent study 20120123. | Baseline and week 80 | 
| Percent Change From Baseline to Week 80 in Total Cholesterol/HDL-C Ratio in HoFH Participants | For HoFH participants baseline was defined as the baseline value in this study (20120124). | Baseline and week 80 | 
| Percent Change From Baseline to Week 80 in Apolipoprotein B / Apolipoprotein A1 Ratio in HeFH Participants | For HeFH participants baseline was defined as the baseline value in the parent study 20120123. | Baseline and week 80 | 
| Percent Change From Baseline to Week 80 in Apolipoprotein B/Apolipoprotein A1 Ratio in HoFH Participants | For HoFH participants baseline was defined as the baseline value in this study (20120124). | Baseline and week 80 | 
| Change From Baseline to Week 80 in LDL-C in HeFH Participants | For HeFH participants baseline was defined as the baseline value of the parent study 20120123. | Baseline and week 80 | 
| Change From Baseline to Week 80 in LDL-C in HoFH Participants | For HoFH participants baseline was defined as the baseline value in this study (20120124). | Baseline and week 80 | 
| Change From Baseline to Week 80 in Estradiol Levels | For HeFH participants baseline was defined as the baseline value in the parent study 20120123. For HoFH participants baseline was defined as the baseline value in this study (20120124). | Baseline and week 80 | 
| Change From Baseline to Week 80 in Testosterone Levels | For HeFH participants baseline was defined as the baseline value in the parent study 20120123. For HoFH participants baseline was defined as the baseline value in this study (20120124). | Baseline and week 80 | 
| Change From Baseline to Week 80 in Follicle Stimulating Hormone (FSH) Levels | For HeFH participants baseline was defined as the baseline value in the parent study 20120123. For HoFH participants baseline was defined as the baseline value in this study (20120124). | Baseline and week 80 | 
| Change From Baseline to Week 80 in Luteinizing Hormone (LH) Levels | For HeFH participants baseline was defined as the baseline value in the parent study 20120123. For HoFH participants baseline was defined as the baseline value in this study (20120124). | Baseline and week 80 | 
| Change From Baseline to Week 80 in Adenocorticotropic Hormone (ACTH) Levels | For HeFH participants baseline was defined as the baseline value in the parent study 20120123. For HoFH participants baseline was defined as the baseline value in this study (20120124). | Baseline and week 80 | 
| Change From Baseline to Week 80 in Dehydroepiandrosterone Sulfate (DHEA-S) Levels | For HeFH participants baseline was defined as the baseline value in the parent study 20120123. For HoFH participants baseline was defined as the baseline value in this study (20120124). | Baseline and week 80 | 
| Change From Baseline to Week 80 in Cortisol Levels | For HeFH participants baseline was defined as the baseline value in the parent study 20120123. For HoFH participants baseline was defined as the baseline value in this study (20120124). | Baseline and week 80 | 
| Number of Participants With Liver Function Test Abnormalities at Week 80 | Liver function tests included alanine aminotransferase (ALT) levels, aspartate aminotransferase (AST) levels and total bilirubin levels. | Week 80 | 
| Number of Participants With Abnormalities in Levels of Creatine Kinase (CK) at Week 80 | The number of participants with levels of creatine kinase greater than 5 times the upper limit of normal (ULN) and greater than 10 times the ULN, measured by the central laboratory. | Week 80 | 
| Change From Baseline to Week 80 in Carotid Intima-media Thickness (cIMT) | Carotid intima-media thickness measures the thickness of the intima and media, the inner two layers of the carotid artery, and is used to determine the extent of plaque buildup in the walls of the arteries (atherosclerosis) supplying blood to the head. CIMT was measured by ultrasonography and analyzed at a core laboratory. The largest values measured in the left common carotid artery (LCCA) and the right common carotid artery (RCCA) are averaged in this analysis. | Baseline and week 80 | 
| Change From Baseline in Height at Weeks 24, 48, and 80 |  | Baseline and weeks 24, 48, and 80 | 
| Change From Baseline in Weight at Weeks 24, 48, and 80 |  | Baseline and weeks 24, 48, and 80 | 
| Number of Participants With Change in Tanner Staging From Baseline to Week 80 | Pubertal growth and sexual maturity was assessed separately for males and females using the 5 Tanner stages where stage 1 = prepubertal and stage 5 = mature. The number of participants with any change in Tanner Stage from baseline is reported. | Baseline and week 80 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypercholesterolemia, Elevated Cholesterol, High Cholesterol, PCSK9 mutations, Severe Familial Hypercholesterolemia, evolocumab, Repatha, Heterozygous Familial Hypercholesterolemia, Homozygous Familial Hypercholesterolemia, Pediatric, Paediatric