Study in Participants With Homozygous Familial Hypercholesterolemia (HoFH)

Study Overview
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Brief Summary
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The primary objective of the study is to demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) with alirocumab subcutaneous (SC) every 2 weeks (Q2W) in comparison to placebo after 12 weeks of treatment. The secondary objectives of the study are: To evaluate the effect of alirocumab Q2W on other lipid parameters (ie, apolipoprotein [Apo] A-1 and B, non-high-density lipoprotein cholesterol [non-HDL-C], total-cholesterol [TC], proportion of participants with 15%, 30%, and 50% LDL-C reductions, Lp(a), HDL-C, triglycerides [TG]) in participants with HoFH To evaluate the safety and tolerability of alirocumab SC Q2W in participants with HoFH To assess the pharmacokinetics of alirocumab SC Q2W in participants with HoFH To assess the potential development of anti-drug (alirocumab) antibodies

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Alirocumab in Patients With Homozygous Familial Hypercholesterolemia

Conditions
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Homozygous Familial Hypercholesterolemia

Intervention / Treatment
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* Drug: Alirocumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Note: The information listed below is not intended to contain all considerations relevant to a patient's potential participation in this clinical trial, therefore not all inclusion/exclusion criteria are listed. Key Inclusion Criteria Diagnosis of HoFH by at least 1 of the following genotype or clinical criteria (all patients on LDL apheresis must be diagnosed based on genotype): Documented homozygous or compound heterozygous mutations in both low-density lipoprotein receptor (LDLR) alleles Presence of homozygous or compound heterozygous mutations in Apo B, PCSK9 or LDL receptor adaptor protein 1 (LDLRAP1) Presence of double heterozygous mutations, i.e, mutations on different genes in the LDLR, Apo B or PCSK9 alleles Untreated TC >500 mg/dL (12.93 mmol/L) and TG <300 mg/dL (3.39 mmol/L) AND Both parents with history of TC >250 mg/dL (6.46 mmol/L) OR cutaneous or tendinous xanthoma before age 10 Receiving a stable dose of a statin at the screening visit (documentation if statin ineffective or patient unable to tolerate statin) If undergoing LDL apheresis, must have initiated LDL apheresis at least 3 months prior to screening and must have been on a stable weekly (every 7 days) or every other week (every 14 days) schedule or stable settings for at least 8 weeks Key Exclusion Criteria: Documented evidence of a null mutation in both LDLR alleles Use of a PCSK9 inhibitor within 10 weeks from screening visit Background medical lipid modifying therapy (LMT) that has not been stable for at least 4 weeks (6 weeks for fibrates, 24 weeks for mipomersen, 12 weeks for maximum tolerated dose of lomitapide) before the screening visit. LDL apheresis schedule/apheresis settings that have not been stable for at least 8 weeks before the screening visit or an apheresis schedule/settings that is not anticipated to be stable over the next 24 weeks. Use of nutraceuticals or over-the-counter (OTC) therapies known to affect lipids, at a dose/amount that has not been stable for at least 4 weeks prior to the screening visit or between the screening and randomization visits. Chronic use of systemic corticosteroids, unless on a stable regimen of 10 mg daily prednisone equivalent or less for at least 6 weeks prior to randomization. Note: topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are not considered as 'systemic' and are allowed Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at the screening visit (1 repeat measurement is allowed). LDL-C level <70 mg/dL (1.81 mmol/L) at the screening visit History of a myocardial infarction (MI), unstable angina leading to hospitalization, coronary artery bypass graft surgery, percutaneous coronary intervention , uncontrolled cardiac arrhythmia, carotid surgery or stenting, stroke, transient ischemic attack, valve replacement surgery, carotid revascularization, endovascular procedure or surgical intervention for peripheral vascular disease within 3 months prior to the screening visit.

Ages Eligible for Study
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Minimum Age: 18 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: Alirocumab SC Q2W<br>Alirocumab SC every 2 weeks (Q2W) from baseline (day 1) through week 10 during the double-blind treatment period Starting at week 12, and continuing through week 22, participants will receive open-label alirocumab SC Q2W | Drug: Alirocumab<br>* Alirocumab SC Q2W<br>* Other names: SAR236553;|
| Experimental: Placebo SC Q2W<br>Matching placebo SC Q2W from baseline through week 10 during the double-blind treatment period Starting at week 12, and continuing through week 22, participants will receive open-label alirocumab SC Q2W | Drug: Alirocumab<br>* Alirocumab SC Q2W<br>* Other names: SAR236553;Drug: Placebo<br>* Matching placebo SC Q2W<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 12 (Intent-to-Treat [ITT] Estimand) | The percent change in LDL-C from baseline to week 12 is defined as: 100x (LDL-C value at week 12 - LDL-C value at baseline) / LDL-C value at baseline. | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Apolipoprotein (Apo) B From Baseline to Week 12 (ITT Estimand) | ITT estimand; The percent change in Apo B from baseline to week 12 is defined as: 100x (Apo B value at week 12 - Apo B value at baseline) / Apo B value at baseline. | Baseline to Week 12 | 
| Percent Change in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 12 | ITT estimand; The percent change in non-HDL-C from baseline to week 12 is defined as: 100x (non-HDL-C value at week 12 - non-HDL-C value at baseline) / non-HDL-C value at baseline. | Baseline to Week 12 | 
| Percent Change in Total Cholesterol (TC) From Baseline to Week 12 | ITT estimand; The percent change in TC from baseline to week 12 is defined as: 100x (TC value at week 12 - TC value at baseline) / TC value at baseline. | Baseline to Week 12 | 
| Percentage of Participants With ≥15% Reduction in LDL-C at Week 12 | ITT estimand | At Week 12 | 
| Percentage of Participants With ≥30% Reduction in LDL-C at Week 12 | ITT estimand | At Week 12 | 
| Percent Change in Lipoprotein(a) [Lp(a)] From Baseline to Week 12 | ITT estimand; The percent change in Lp(a) from baseline to week 12 is defined as: 100x (Lp(a) value at week 12 - Lp(a) value at baseline) / Lp(a) value at baseline. | Baseline to Week 12 | 
| Percentage of Participants With ≥50% Reduction in LDL-C at Week 12 | ITT estimand | At Week 12 | 
| Percent Change in HDL-C From Baseline to Week 12 - ITT Analysis | ITT estimand; The percent change in HDL-C from baseline to week 12 is defined as: 100x (HDL-C value at week 12 - HDL-C value at baseline) / HDL-C value at baseline. | Baseline to Week 12 | 
| Percent Change in Fasting Triglycerides (TG) From Baseline to Week 12 | ITT estimand; The percent change in TG from baseline to week 12 is defined as: 100x (TG value at week 12 - TG value at baseline) / TG value at baseline. | Baseline to Week 12 | 
| Percent Change in Apo A-1 From Baseline to Week 12 -- ITT Analysis | ITT estimand; The percent change in Apo A-1 from baseline to week 12 is defined as: 100x (Apo A-1 value at week 12 - Apo A-1 value at baseline) / Apo A-1 value at baseline. | Baseline to Week 12 | 
| Percent Change in LDL-C From Baseline to Week 12 (On-treatment Estimand) | Percent change for LDL-C from baseline to Week 12 during the efficacy treatment period, which is defined as the time from the first double-blind investigational study drug injection up to 21 days after the last double-blind investigational study drug injection, or the first dose of the open-label investigational study drug, whichever is earlier. | Baseline to Week 12 | 
| Percent Change in Apo B From Baseline to Week 12 (On-treatment Estimand) | Percent change for Apo B from baseline to Week 12 during the efficacy treatment period, which is defined as the time from the first double-blind investigational study drug injection up to 21 days after the last double-blind investigational study drug injection, or the first dose of the open-label nvestigational study drug, whichever is earlier. | Baseline to Week 12 | 
| Percent Change in Non-HDL-C From Baseline to Week 12 (On-treatment Estimand) | Percent change for non-HDL-C from baseline to Week 12 during the efficacy treatment period, which is defined as the time from the first double-blind investigational study drug injection up to 21 days after the last double-blind investigational study drug injection, or the first dose of the open-label investigational study drug, whichever is earlier. | Baseline to Week 12 | 
| Percent Change in TC From Baseline to Week 12 (On-treatment Estimand) | Percent change for TC from baseline to Week 12 during the efficacy treatment period, which is defined as the time from the first double-blind investigational study drug injection up to 21 days after the last double-blind investigational study drug injection, or the first dose of the open-label investigational study drug, whichever is earlier. | Baseline to Week 12 | 
| Percent Change in Lp(a) From Baseline to Week 12 (On-treatment Estimand) | Percent change for LP(a) from baseline to Week 12 during the efficacy treatment period, which is defined as the time from the first double-blind investigational study drug injection up to 21 days after the last double-blind investigational study drug injection, or the first dose of the open-label investigational study drug, whichever is earlier. | Baseline to Week 12 | 
| Percent Change in HDL-C From Baseline to Week 12 (On-treatment Estimand) | Percent change for HDL-C from baseline to Week 12 during the efficacy treatment period, which is defined as the time from the first double-blind investigational study drug injection up to 21 days after the last double-blind investigational study drug injection, or the first dose of the open-label investigational study drug, whichever is earlier. | Baseline to Week 12 | 
| Percent Change in Fasting TG From Baseline to Week 12 (On-treatment Estimand) | Percent change for fasting TG from baseline to Week 12 during the efficacy treatment period, which is defined as the time from the first double-blind investigational study drug injection up to 21 days after the last double-blind investigational study drug injection, or the first dose of the open-label investigational study drug, whichever is earlier. | Baseline to Week 12 | 
| Percent Change in Apo A-1 From Baseline to Week 12 (On-treatment Estimand) | Percent change for Apo A-1 from baseline to Week 12 during the efficacy treatment period, which is defined as the time from the first double-blind investigational study drug injection up to 21 days after the last double-blind investigational study drug injection, or the first dose of the open-label investigational study drug, whichever is earlier. | Baseline to Week 12 | 
| Percentage of Participants With ≥15% Reduction, ≥30% Reduction, and ≥50% Reduction in LDL-C at Week 12 (On-treatment Estimand) |  | At Week 12 | 
| Absolute Change in the Ratio of Apo B/Apo A-1 From Baseline to Week 12 (ITT Estimand) | Ratio of Apo B/Apo A1 at week 12 minus ratio of Apo B/Apo A1 at baseline | Baseline to Week 12 | 
| Number of Participants With Anti-Drug Antibodies (ADA) to REGN727 Over Time |  | 26 weeks | 
| Number of Participants With Adverse Events (AEs) | All AEs will be recorded from time of informed consent to end of study. Only treatment-emergent adverse events (TEAE) will be reported. Double-blind TEAE observation period is defined as time from first dose of double-blind study drug to last dose of double-blind study drug +70 days, or up to day before first dose of open-label study drug administration, whichever is earlier. Open-label TEAE observation period is defined as time from first open-label study treatment administration to last open-label study treatment administration +70 days. | Baseline to week 32 (End of Study) |