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

Phase 2

Completed

• Conditions: Hypercholesterolemia
• Interventions: Drug: Alirocumab; Drug: Placebo

• Registration Number: NCT01604824
• Lead Sponsor: Regeneron Pharmaceuticals

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2012-02-22
• Study First Submitted: 2012-05-22
• Study First Submitted QC: 2012-05-22
• Study First Posted: 2012-05-24
• Primary Completion: 2014-06-02
• Disposition First Submitted: 2015-01-24
• Disposition First Submitted QC: 2015-01-24
• Disposition First Posted: 2015-01-30
• Results First Submitted: 2015-08-20
• Study Completion: 2017-07-28
• Status Verified: 2020-06
• Results First Submitted QC: 2020-06-04
• Last Update Submitted: 2020-06-04
• Results First Posted: 2020-06-17
• Last Update Posted: 2020-06-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 23

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
GOFm PCSK9 (Cohort 1): Alirocumab From Day 1	Alirocumab	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.
GOFm PCSK9 (Cohort 1): Alirocumab From Day 1	Placebo	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.
GOFm PCSK9 or LOFm ApoB (Cohort 2): Alirocumab from Day 1	Placebo	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.
GOFm PCSK9 (Cohort 1): Alirocumab From Day 15	Alirocumab	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.
GOFm PCSK9 (Cohort 1): Alirocumab From Day 15	Placebo	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.
GOFm PCSK9 or LOFm ApoB (Cohort 2): Alirocumab from Day 15	Alirocumab	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.
GOFm PCSK9 or LOFm ApoB (Cohort 2): Alirocumab from Day 15	Placebo	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.
GOFm PCSK9 or LOFm ApoB (Cohort 2): Alirocumab from Day 1	Alirocumab	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.

Primary Outcome Measures

Name	Time	Method
Percent Change in Measured Serum Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 15	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. \[Baseline adjusted least squares (LS) means and standard errors were obtained using analysis of covariance (ANCOVA) model specifying the treatment arm as the fixed effect and the baseline measured LDL-C value as a covariate.\]

Secondary Outcome Measures

Name	Time	Method
Percent Change in Apolipoprotein (Apo) B100 From Baseline to Day 15	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.
Percent Change in Non High-Density Lipoprotein Cholesterol (Non-HDL-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
Percent Change in Total Cholesterol (Total-C) From Baseline to Day 15	Baseline to Day 15