Trial Assessing Efficacy, Safety and Tolerability of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition in Paediatric Subjects With Genetic Low-Density Lipoprotein (LDL) Disorders

Study Overview
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Brief Summary
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A study to assess safety and efficacy of evolocumab (AMG-145) in paediatric subjects aged 10-17 years diagnosed with heterozygous familial hypercholesterolemia.

Detailed Description
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A study to evaluate the effect of 24 weeks of subcutaneous (SC) evolocumab compared with placebo, when added to standard of care, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in pediatric subjects 10 to 17 years of age with heterozygous familial hypercholesterolemia (HeFH).

Official Title
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Double-blind, Randomized, Multicenter, Placebo-Controlled Study to Characterize the Efficacy, Safety, and Tolerability of 24 Weeks of Evolocumab for LDL-C Reduction in Pediatric Subjects 10 to 17 Years of Age With HeFH

Conditions
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Heterozygous Familial Hypercholesterolemia

Intervention / Treatment
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* Drug: Evolocumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥ 10 to ≤ 17 years of age (before 18th birthday) Diagnosis of heterozygous familial hypercholesterolemia On an approved statin with stable optimized dose for ≥ 4 weeks Other lipid-lowering therapy stable for ≥ 4 weeks (fibrates must be stable for ≥ 6 weeks) Fasting LDL-C ≥ 130 mg/dL (3.4 mmol/L) Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) Exclusion Criteria: Type 1 diabetes, or type 2 diabetes that is or poorly controlled Uncontrolled hyperthyroidism or hypothyroidism Cholesterylester transfer protein (CETP) inhibitor in the last 12 months, or mipomersen or lomitapide in the last 5 months Previously received evolocumab or any other investigational therapy to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9). Lipid apheresis within the last 12 weeks prior to screening. Homozygous familial hypercholesterolemia

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Matching subcutaneous injection every 4 weeks (QM) | Drug: Placebo<br>* Dose of subcutaneous placebo treatment every 4 weeks<br>|
| Experimental: EvoMab 420 mg QM<br>Evolocumab subcutaneous injection QM | Drug: Evolocumab<br>* Dose of subcutaneous evolocumab every 4 weeks<br>* Other names: AMG 145; EvoMab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Week 24 in LDL-C | Least squares mean is from the repeated measures model which includes treatment group, stratification factors of age and screening LDL-C (from interactive voice response system [IVRS]), scheduled visit and the interaction of treatment with scheduled visit as covariates. The model uses an unstructured covariance. | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Percent Change From Baseline to Mean of Weeks 22 and 24 in LDL-C | Least squares mean is from the repeated measures model which includes treatment group, stratification factors of age and screening LDL-C (from IVRS), scheduled visit and the interaction of treatment with scheduled visit as covariates. | Baseline, Week 22, Week 24 | 
| Change From Baseline to Week 24 in LDL-C | Least squares mean is from the repeated measures model which includes treatment group, stratification factors of age and screening LDL-C (from IVRS), scheduled visit and the interaction of treatment with scheduled visit as covariates. | Baseline, Week 24 | 
| Percent Change From Baseline to Week 24 in Non-HDL-C | Least squares mean is from the repeated measures model which includes treatment group, stratification factors of age and screening LDL-C (from IVRS), scheduled visit and the interaction of treatment with scheduled visit as covariates | Baseline, Week 24 | 
| Percent Change From Baseline to Week 24 in Apoliprotein-B (ApoB) | Least squares mean is from the repeated measures model which includes treatment group, stratification factors of age and screening LDL-C (from IVRS), scheduled visit and the interaction of treatment with scheduled visit as covariates. | Baseline, Week 24 | 
| Percent Change From Baseline to Week 24 in Total Cholesterol/HDL-C Ratio | Least squares mean is from the repeated measures model which includes treatment group, stratification factors of age and screening LDL-C (from IVRS), scheduled visit and the interaction of treatment with scheduled visit as covariates. | Baseline, Week 24 | 
| Percent Change From Baseline to Week 24 in ApoB:ApoA1 Ratio | Least squares mean is from the repeated measures model which includes treatment group, stratification factors of age and screening LDL-C (from IVRS), scheduled visit and the interaction of treatment with scheduled visit as covariates. | Baseline, Week 24 | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation (DC), Fatal TEAEs, and Device-Related TEAEs | An adverse event (AE) is defined as any untoward medical occurrence that does not necessarily have a causal relationship with study treatment. An SAE is defined as an adverse event that: is fatal; is a life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or other medically important serious event. Events were graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grading scale (1=mild; 2=moderate; 3=severe; 4=life-threatening; 5=death). Events were defined as treatment emergent if they occurred after the first dose of study drug and up to and including 30 days after the last dose or the end of study date, whichever is earlier. | From first dose of study drug up to and including 30 days after the last dose or end of study date (Week 24), whichever was earlier. Mean (SD) duration on study was 5.664 (0.278) and 5.608 (0.137) months for Placebo and EvoMab arms, respectively. | 
| Number of Participants With Maximum Post-Baseline Laboratory Toxicities of Grade ≥ 3 | Laboratory toxicity grading was based on NCI CTCAE grading. Grade 3 indicates severe toxicity and Grade 4 indicates life-threatening toxicity. Values representing a worsening from baseline are shown. | Week 24 | 
| Change From Baseline Over Time in Systolic Blood Pressure |  | Baseline, Week 4, Week 12, Week 20, Week 22, Week 24 | 
| Change From Baseline Over Time in Diastolic Blood Pressure |  | Baseline, Week 4, Week 12, Week 20, Week 22, Week 24 | 
| Change From Baseline Over Time in Heart Rate |  | Baseline, Week 4, Week 12, Week 20, Week 22, Week 24 | 
| Number of Participants Testing Positive for Anti-Evolocumab Antibodies |  | up to Week 24 | 
| Serum Evolocumab Concentrations Over Time |  | Week 12, Week 22, Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Paediatric, Hypercholesterolemia, Elevated Cholesterol, High Cholesterol, Heterozygous Familial Hypercholesterolemia, PCSK9 mutations, pediatric, Childhood Familial Hypercholesterolemia