Study in Participants With Homozygous Familial Hypercholesterolemia (HoFH)

Phase 3

Completed

Conditions: Homozygous Familial Hypercholesterolemia

Interventions: Drug: Alirocumab
Drug: Placebo

Registration Number: NCT03156621

Lead Sponsor: Regeneron Pharmaceuticals

Brief Summary: 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

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 69

Inclusion Criteria

Not provided

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo SC Q2W	Placebo	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
Placebo SC Q2W	Alirocumab	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
Alirocumab SC Q2W	Alirocumab	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

Primary Outcome Measures

Name	Time	Method
Percent Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 12 (Intent-to-Treat [ITT] Estimand)	Baseline to Week 12	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With ≥50% Reduction in LDL-C at Week 12	At Week 12	ITT estimand
Percent Change in Non-HDL-C From Baseline to Week 12 (On-treatment Estimand)	Baseline to Week 12	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.
Percent Change in Apo A-1 From Baseline to Week 12 -- ITT Analysis	Baseline to Week 12	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.
Percent Change in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 12	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.
Percent Change in Lipoprotein(a) [Lp(a)] From Baseline to Week 12	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.
Percent Change in HDL-C From Baseline to Week 12 - ITT Analysis	Baseline to Week 12	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.
Percent Change in Apo B From Baseline to Week 12 (On-treatment Estimand)	Baseline to Week 12	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.
Percent Change in Lp(a) From Baseline to Week 12 (On-treatment Estimand)	Baseline to Week 12	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.
Percent Change in Total Cholesterol (TC) From Baseline to Week 12	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.
Percentage of Participants With ≥15% Reduction in LDL-C at Week 12	At Week 12	ITT estimand
Percent Change in TC From Baseline to Week 12 (On-treatment Estimand)	Baseline to Week 12	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.
Percent Change in Apo A-1 From Baseline to Week 12 (On-treatment Estimand)	Baseline to Week 12	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.
Percent Change in Apolipoprotein (Apo) B From Baseline to Week 12 (ITT Estimand)	Baseline to Week 12	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.
Percentage of Participants With ≥30% Reduction in LDL-C at Week 12	At Week 12	ITT estimand
Percent Change in Fasting Triglycerides (TG) From Baseline to Week 12	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.
Percent Change in LDL-C From Baseline to Week 12 (On-treatment Estimand)	Baseline to Week 12	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.
Percent Change in HDL-C From Baseline to Week 12 (On-treatment Estimand)	Baseline to Week 12	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.
Percent Change in Fasting TG From Baseline to Week 12 (On-treatment Estimand)	Baseline to Week 12	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.
Percentage of Participants With ≥15% Reduction, ≥30% Reduction, and ≥50% Reduction in LDL-C at Week 12 (On-treatment Estimand)	At Week 12
Number of Participants With Adverse Events (AEs)	Baseline to week 32 (End of Study)	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.
Absolute Change in the Ratio of Apo B/Apo A-1 From Baseline to Week 12 (ITT Estimand)	Baseline to Week 12	Ratio of Apo B/Apo A1 at week 12 minus ratio of Apo B/Apo A1 at baseline
Number of Participants With Anti-Drug Antibodies (ADA) to REGN727 Over Time	26 weeks