Back to resultsA 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
Primary Purpose
Hypercholesterolemia
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Alirocumab
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Hypercholesterolemia
Eligibility Criteria
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
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Experimental
Arm Label
GOFm PCSK9 (Cohort 1): Alirocumab From Day 1
GOFm PCSK9 (Cohort 1): Alirocumab From Day 15
GOFm PCSK9 or LOFm ApoB (Cohort 2): Alirocumab from Day 1
GOFm PCSK9 or LOFm ApoB (Cohort 2): Alirocumab from Day 15
Arm 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.
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.
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.
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.
Outcomes
Primary Outcome Measures
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.]
Secondary Outcome Measures
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.
Percent Change in Non High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 15
Percent Change in Total Cholesterol (Total-C) From Baseline to Day 15
Percent Change in Apolipoprotein (Apo) B100/ ApoA-1 Ratio From Baseline to Day 15
Full Information
NCT ID
NCT01604824
First Posted
May 22, 2012
Last Updated
June 4, 2020
Sponsor
Regeneron Pharmaceuticals
Collaborators
Sanofi
1. Study Identification
Unique Protocol Identification Number
NCT01604824
Brief Title
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
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
June 2020
Overall Recruitment Status
Completed
Study Start Date
February 22, 2012 (Actual)
Primary Completion Date
June 2, 2014 (Actual)
Study Completion Date
July 28, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Regeneron Pharmaceuticals
Collaborators
Sanofi
4. Oversight
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypercholesterolemia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
23 (Actual)
8. Arms, Groups, and Interventions
Arm Title
GOFm PCSK9 (Cohort 1): Alirocumab From Day 1
Arm Type
Experimental
Arm 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.
Arm Title
GOFm PCSK9 (Cohort 1): Alirocumab From Day 15
Arm Type
Experimental
Arm 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.
Arm Title
GOFm PCSK9 or LOFm ApoB (Cohort 2): Alirocumab from Day 1
Arm Type
Experimental
Arm 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.
Arm Title
GOFm PCSK9 or LOFm ApoB (Cohort 2): Alirocumab from Day 15
Arm Type
Experimental
Arm 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.
Intervention Type
Drug
Intervention Name(s)
Alirocumab
Other Intervention Name(s)
Praluent®, REGN727, SAR236553
Intervention Description
SC injection in the abdomen
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
SC injection in the abdomen
Primary Outcome Measure Information:
Title
Percent Change in Measured Serum Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 15
Description
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.]
Time Frame
Baseline to Day 15
Secondary Outcome Measure Information:
Title
Percent Change in Apolipoprotein (Apo) B100 From Baseline to Day 15
Description
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.
Time Frame
Baseline to Day 15
Title
Percent Change in Non High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 15
Time Frame
Baseline to Day 15
Title
Percent Change in Total Cholesterol (Total-C) From Baseline to Day 15
Time Frame
Baseline to Day 15
Title
Percent Change in Apolipoprotein (Apo) B100/ ApoA-1 Ratio From Baseline to Day 15
Time Frame
Baseline to Day 15
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trial Management
Organizational Affiliation
Regeneron Pharmaceuticals
Official's Role
Study Director
Facility Information:
City
Salt Lake City
State/Province
Utah
Country
United States
City
Lille
State/Province
Cedex
Country
France
City
Nantes
State/Province
Cedex
Country
France
City
Paris
Country
France
12. IPD Sharing Statement
Citations:
PubMed Identifier
31767518
Citation
Hopkins PN, Krempf M, Bruckert E, Donahue S, Yang F, Zhang Y, DiCioccio AT. Pharmacokinetic and pharmacodynamic assessment of alirocumab in patients with familial hypercholesterolemia associated with proprotein convertase subtilisin/kexin type 9 gain-of-function or apolipoprotein B loss-of-function mutations. J Clin Lipidol. 2019 Nov-Dec;13(6):970-978. doi: 10.1016/j.jacl.2019.10.007. Epub 2019 Oct 21.
Results Reference
derived
PubMed Identifier
26374825
Citation
Hopkins PN, Defesche J, Fouchier SW, Bruckert E, Luc G, Cariou B, Sjouke B, Leren TP, Harada-Shiba M, Mabuchi H, Rabes JP, Carrie A, van Heyningen C, Carreau V, Farnier M, Teoh YP, Bourbon M, Kawashiri MA, Nohara A, Soran H, Marais AD, Tada H, Abifadel M, Boileau C, Chanu B, Katsuda S, Kishimoto I, Lambert G, Makino H, Miyamoto Y, Pichelin M, Yagi K, Yamagishi M, Zair Y, Mellis S, Yancopoulos GD, Stahl N, Mendoza J, Du Y, Hamon S, Krempf M, Swergold GD. Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody. Circ Cardiovasc Genet. 2015 Dec;8(6):823-31. doi: 10.1161/CIRCGENETICS.115.001129. Epub 2015 Sep 15.
Results Reference
derived
Learn more about this trial
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
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