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

Regeneron Pharmaceuticals

Status and phase: Completed; Phase 2

Conditions: Hypercholesterolemia

Treatments: Drug: Alirocumab; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT01604824

R727-CL-1018

Details and patient eligibility

About

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.

Enrollment: 23 patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

Inclusion criteria include, but are not limited to the following:

1. Between the ages of 18 and 70 years, inclusive
2. A history of molecularly confirmed PCSK9 GOFm for cohort 1 and a history of molecularly confirmed PCSK9 GOFm or ApoB LOFm
3. 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:

1. Serum triglycerides >350 mg/dL at the screening visit
2. Known to be positive for human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus
3. Pregnant or breast-feeding women.
4. Sexually active man or woman of childbearing potential who is unwilling to practice adequate contraception during the study

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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23 participants in 4 patient groups

GOFm PCSK9 (Cohort 1): Alirocumab From Day 1

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: Alirocumab

GOFm PCSK9 (Cohort 1): Alirocumab From Day 15

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: Alirocumab

GOFm PCSK9 or LOFm ApoB (Cohort 2): Alirocumab from Day 1

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: Alirocumab

GOFm PCSK9 or LOFm ApoB (Cohort 2): Alirocumab from Day 15

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: Alirocumab