Trial Evaluating PCSK9 Antibody in Subjects With LDL Receptor Abnormalities

Study Overview
=================
Brief Summary
-----------------
A study to determine the safety, tolerability, and efficacy of evolocumab (AMG 145) in patients with homozygous familial hypercholesterolemia (HoFH).

Detailed Description
-----------------
Study Masking: Part A: Open Label Part B: Double Blind

Official Title
-----------------
2-part, Phase 2/3 Study to Assess the Safety, Tolerability and Efficacy of AMG 145 in Subjects With Homozygous Familial Hypercholesterolemia. Part A - Open-label, Single-arm, Multicenter Pilot Study to Evaluate Safety, Tolerability and Efficacy of AMG 145 in Subjects With Homozygous Familial Hypercholesterolemia. Part B - Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Safety, Tolerability and Efficacy of AMG 145 in Subjects With Homozygous Familial Hypercholesterolemia

Conditions
-----------------
Homozygous Familial Hypercholesterolemia

Intervention / Treatment
-----------------
* Biological: Evolocumab
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males and females ≥ 12 to ≤ 80 years of age Diagnosis of homozygous familial hypercholesterolemia Stable lipid-lowering therapies for at least 4 weeks LDL cholesterol ≥ 130 mg/dl (3.4 mmol/L) Triglyceride ≤ 400 mg/dL (4.5 mmol/L) Bodyweight of ≥ 40 kg at screening. Exclusion Criteria: LDL or plasma apheresis within 8 weeks prior to randomization New York Heart 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 randomization Planned cardiac surgery or revascularization Uncontrolled cardiac arrhythmia Uncontrolled hypertension

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Evolocumab<br>Participants received open-label evolocumab 420 mg subcutaneously once a month for 12 weeks. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;|
| Experimental: Part B: Evolocumab<br>Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;|
| Placebo Comparator: Part B: Placebo<br>Participants received double-blind placebo subcutaneously once a month for 12 weeks. | Drug: Placebo<br>* Administered by subcutaneous injection<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 | LDL-C was quantified using the ultracentrifugation method. | Baseline and Week 12 | 
| Part B: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 | LDL-C was quantified using the ultracentrifugation method. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Change From Baseline in LDL-C at Week 12 | LDL-C was quantified using the ultracentrifugation method. | Baseline and Week 12 | 
| Part A: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 12 |  | Baseline and Week 12 | 
| Part A: Percent Change From Baseline in Apolipoprotein B at Week 12 |  | Baseline and Week 12 | 
| Part A: Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12 |  | Baseline and Week 12 | 
| Part A: Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 12 |  | Baseline and Week 12 | 
| Part A: Percentage of Participants With 15% or Greater Reduction in LDL-C From Baseline at Week 12 | LDL-C was quantified using the ultracentrifugation method. | Baseline and Week 12 | 
| Part A: Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) at Week 12 |  | Baseline and Week 12 | 
| Part B: Percent Change From Baseline in LDL-C at the Mean of Weeks 6 and 12 | LDL-C was quantified using the ultracentrifugation method. | Baseline and Weeks 6 and 12 | 
| Part B: Percent Change From Baseline in Apolipoprotein B at Week 12 |  | Baseline and Week 12 | 
| Part B: Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 6 and 12 |  | Baseline and Weeks 6 and 12 | 
| Part B: Percent Change From Baseline in Lipoprotein (a) at Week 12 |  | Baseline and Week 12 | 
| Part B: Percent Change From Baseline in Lipoprotein (a) at the Mean of Weeks 6 and 12 |  | Baseline and Weeks 6 and 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
hypercholesterolemia, familial hypercholesterolemia, homozygous familial hypercholesterolemia