A Study of Alirocumab in Participants With Autosomal Dominant Hypercholesterolemia (ADH) and Gain-of-Function Mutations (GOFm) of the Proprotein Convertase Subtilisin Kexin 9 (PCSK9) Gene or Loss-of-Function Mutations (LOFm) of the Apolipoprotein (Apo) B Gene

Study Overview
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Brief Summary
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The primary objective of the study is to assess the pharmacodynamic (PD) effect of alirocumab on serum low density lipoprotein cholesterol (LDL-C) during 14 weeks of subcutaneous (SC) administered alirocumab in patients with autosomal dominant hypercholesterolemia (ADH) and gain-of-function mutation (GOFm) in 1 or both alleles of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene or with loss-of-function mutation (LOFm) in 1 or more alleles of the apolipoprotein (ApoB) gene.

Official Title
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A Phase 2 Pilot Study With a Randomized Double-Blind Treatment Phase to Evaluate the Pharmacodynamics and Safety of Alirocumab in Patients With Autosomal Dominant Hypercholesterolemia and Gain-of-Function Mutations in 1 or Both Alleles of the PCSK9 Gene or Loss-of-Function Mutations in 1 or More Alleles of the Loss-of-Function Mutations B Gene

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Drug: Alirocumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion criteria include, but are not limited to the following: Between the ages of 18 and 70 years, inclusive A history of molecularly confirmed PCSK9 GOFm for cohort 1 and a history of molecularly confirmed PCSK9 GOFm or ApoB LOFm Plasma LDL-Cholesterol levels ≥70 mg/dL at the screening visit on a lipid-lowering therapy (LLT) regimen stable for at least 28 days Exclusion Criteria: Exclusion criteria include, but are not limited to the following: Serum triglycerides >350 mg/dL at the screening visit Known to be positive for human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus Pregnant or breast-feeding women. Sexually active man or woman of childbearing potential who is unwilling to practice adequate contraception during the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| Experimental: GOFm PCSK9 (Cohort 1): Alirocumab From Day 1<br>Participants with gain-of-function mutation (GOFm) in proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (Cohort 1): Alirocumab 150 mg subcutaneous (SC) injection at Week 0 (Day 1), Week 2 (Day 15), Week 4, 6 and 10 (matching placebo at Week 8, 12 and 14) during the double-blind period (Group A). Afterwards, participants have the possibility to continue in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years. | Drug: Alirocumab<br>* SC injection in the abdomen<br>* Other names: SAR236553;Drug: Placebo<br>* SC injection in the abdomen<br>|
| Experimental: GOFm PCSK9 (Cohort 1): Alirocumab From Day 15<br>Participants with gain-of-function mutation (GOFm) in proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (Cohort 1): Alirocumab 150 mg subcutaneous (SC) injection at Week 2 (Day 15), Week 4, 6, 8 and 12 ([matching placebo at Week 0 (Day 1), 10 and 14]) during the double-blind period (Group B). Afterwards, participants have the possibility to continue in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years. | Drug: Alirocumab<br>* SC injection in the abdomen<br>* Other names: SAR236553;Drug: Placebo<br>* SC injection in the abdomen<br>|
| Experimental: GOFm PCSK9 or LOFm ApoB (Cohort 2): Alirocumab from Day 1<br>Participants with gain-of-function mutation (GOFm) in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene or loss-of-function mutation (LOFm) in the apolipoprotein (Apo) B gene (Cohort 2): Alirocumab 150 mg subcutaneous (SC) injection at Week 0 (Day 1), Week 2 (Day 15), Week 4, 6 and 10 (matching placebo at Week 8, 12 and 14) during the double-blind period (Group C). Afterwards, participants have the possibility to continue in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years. | Drug: Alirocumab<br>* SC injection in the abdomen<br>* Other names: SAR236553;Drug: Placebo<br>* SC injection in the abdomen<br>|
| Experimental: GOFm PCSK9 or LOFm ApoB (Cohort 2): Alirocumab from Day 15<br>Participants with gain-of-function mutation (GOFm) in proprotein convertase subtilisin/kexin type 9 (PCSK9) gene or loss-of-function mutation (LOFm) in apolipoprotein (Apo) B gene (Cohort 2): Alirocumab 150 mg subcutaneous (SC) injection at Week 2 (Day 15), Week 4, 6, 8 and 12 ([matching placebo at Week 0 (Day 1), 10 and 14]) during the double-blind period (Group D). Afterwards, participants have the possibility to continue in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years. | Drug: Alirocumab<br>* SC injection in the abdomen<br>* Other names: SAR236553;Drug: Placebo<br>* SC injection in the abdomen<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Measured Serum Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 15 | By day 15, participants in groups A and C had received 1 subcutaneous (SC) dose of 150 mg alirocumab and participants in group B and D had received 1 SC dose of placebo. [Baseline adjusted least squares (LS) means and standard errors were obtained using analysis of covariance (ANCOVA) model specifying the treatment arm as the fixed effect and the baseline measured LDL-C value as a covariate.] | Baseline to Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Apolipoprotein (Apo) B100 From Baseline to Day 15 | Baseline adjusted LS means and standard errors were obtained using the same ANCOVA model as for primary endpoint specifying the treatment arm as the fixed effect and the parameter value as a covariate. | Baseline to Day 15 | 
| Percent Change in Non High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 15 |  | Baseline to Day 15 | 
| Percent Change in Total Cholesterol (Total-C) From Baseline to Day 15 |  | Baseline to Day 15 | 
| Percent Change in Apolipoprotein (Apo) B100/ ApoA-1 Ratio From Baseline to Day 15 |  | Baseline to Day 15 |