Trial Assessing Long Term USe of PCSK9 Inhibition in Subjects With Genetic LDL Disorders

Study Overview
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Brief Summary
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A study to assess the long term safety and tolerability of evolocumab (AMG 145) in adolescents and adults with severe familial hypercholesterolemia.

Detailed Description
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This phase 2/3 open-label extension study was designed to characterize the safety and tolerability of long-term administration of evolocumab to adults and adolescents with severe FH (HoFH or non-HoFH severe FH). Participants not on lipid apheresis at enrollment or within the prior 8 weeks initiated treatment with evolocumab 420 mg once monthly (QM). Participants on lipid apheresis at enrollment initiated treatment with evolocumab 420 mg once every 2 weeks (Q2W). Dose frequency changes (420 mg QM vs 420 mg Q2W) were permitted at week 12, 24, or other visits with Sponsor approval. Participants with < 5% LDL-C reduction from baseline and serum unbound proprotein convertase subtilisin/kexin type 9 (PCSK9) < 100 ng/mL could discontinue evolocumab. If serum unbound PCSK9 was ≥ 100 ng/mL with QM dosing, the participant could switch to evolocumab 420 mg Q2W treatment. Participants on apheresis with ≥ 5% LDL-C reduction from baseline and serum unbound PCSK9 < 100 ng/mL with Q2W treatment could switch to QM dosing. Participants were to continue to receive open-label evolocumab for up to 5 years or until evolocumab became commercially available in the relevant patient population, whichever occurred first.

Official Title
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A Multicenter, Open-label Study to Assess the Long-term Safety, Tolerability, and Efficacy of Evolocumab (AMG145) on LDL-C in Subjects With Severe Familial Hypercholesterolemia

Conditions
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Severe Familial Hypercholesterolemia

Intervention / Treatment
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* Biological: Evolocumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Participated in Study 20110233 (NCT01588496) or another qualifying evolocumab parent protocol and have a diagnosis of familial hypercholesterolemia. OR Have a diagnosis of familial hypercholesterolemia AND Males and females ≥ 12 to ≤ 80 years of age Stable low-fat diet and lipid-lowering therapies for at least 4 weeks Low-density lipoprotein cholesterol (LDL-C) >= 130 mg/dl (3.4 mmol/L) for subjects without diagnosed coronary heart disease (CHD)/CHD risk equivalent OR LDL-C >= 100 mg/dl (2.6 mmol/L) for subjects with diagnosed CHD or CHD risk equivalent OR apheresis patients have no LDL-C entry requirement Fasting triglycerides ≤ 400 mg/dL(4.5 mmol/L) Body weight of > 40 kg or greater at screening for subjects less than 18 years of age Exclusion Criteria: New York Heart Failure Association (NYHA) class III or IV or last known left ventricular ejection fraction < 30% Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months of screening Planned cardiac surgery or revascularization Uncontrolled cardiac arrhythmia Uncontrolled hypertension

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 80 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 received 420 mg evolocumab every month (participants not on lipid apheresis) or every 2 weeks (participants on lipid apheresis) for up to 5 years. Participants could switch dosing regimens at week 12 or 24 based on LDL-C and serum unbound proprotein convertase subtilisin/kexin type 9 (PCSK9) levels. | Biological: Evolocumab<br>* Evolocumab was administered by subcutaneous injection either once a month (QM) or once every two weeks (Q2W).<br>* Other names: Repatha;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | The severity of each adverse event (AE) was graded according to the National Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE) grading scale, where grade 1 = mild AE, grade 2 = moderate AE, grade 3 = severe AE, grade 4 = life-threatening AE and grade 5 = death due to AE. | From first dose of study drug in Study 20110271 up to 30 days after the last dose or until the end of study date, whichever was earlier; median duration of treatment was 48.7 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) |  | Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216 | 
| Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) |  | Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216 | 
| Percent Change From Baseline in Lipoprotein (a) |  | Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216 | 
| Percent Change From Baseline in Apolipoprotein B |  | Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216 | 
| Percent Change From Baseline in Total Cholesterol/HDL-C Ratio |  | Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216 | 
| Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio |  | Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216 | 
| Percentage of Participants With a 15% or Greater Reduction in LDL-C |  | Baseline and weeks 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216 | 

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