Study in Participants With Homozygous Familial Hypercholesterolemia (HoFH) (ODYSSEY HoFH)

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

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

Study Overview

• Status: Completed
• Conditions: Homozygous Familial Hypercholesterolemia
• Intervention / Treatment: Drug: Alirocumab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Tirol
    • Innsbruck, Tirol, Austria, 6020
      • Regeneron Research Site
• Canada
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Regeneron Research Site
    • Québec, Quebec, Canada, GIV 4W2
      • Regeneron Research Site
• Czechia
  • Praha, Czechia, 128 08
    • Regeneron Research Site
• France
  • Marseille, France, 13285
    • Regeneron Research Site
  • Paris, France, 75651
    • Regeneron Research Site
• Germany
  • Berlin, Germany, 12200
    • Regeneron Research Site
• Greece
  • Athens, Greece, 17674
    • Regeneron Research Site
  • Ioánnina, Greece, 45500
    • Regeneron Research Site
• Italy
  • Napoli, Italy, 80131
    • Regeneron Research Site
  • Roma, Italy, 00161
    • Regeneron Research Site
• Japan
  • Hyogo
    • Nishinomiya, Hyogo, Japan, 662-0918
      • Regeneron Research Site
  • Ishikawa
    • Kanazawa, Ishikawa, Japan, 920-8641
      • Regeneron Research Site
  • Osaka
    • Suita, Osaka, Japan, 565-8565
      • Regeneron Research Site
• South Africa
  • Johannesburg
    • Parktown, Johannesburg, South Africa, 2000
      • Regeneron Research Site
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7925
      • Regeneron Research Site
• Taiwan
  • Taipei, Taiwan, 11217
    • Regeneron Study Site
• Turkey
  • Ankara
    • Besevler, Ankara, Turkey, 06500
      • Regeneron Research Site
  • Bornova
    • İzmir, Bornova, Turkey, 35040
      • Regeneron Research Site
• Ukraine
  • Ivano-Frankivs'k, Ukraine, 76005
    • Regeneron Research Site
  • Kharkiv, Ukraine, 61039
    • Regeneron Research Site
  • Kharkiv, Ukraine, 61176
    • Regeneron Research Site
  • Kyiv, Ukraine, 03680
    • Regeneron Research Site
  • Kyiv, Ukraine, 02166
    • Regeneron Research Site
• United States
  • Florida
    • Boca Raton, Florida, United States, 33434
      • Regeneron Research Site
  • New York
    • New York, New York, United States, 10029
      • Regeneron Research Site
  • Ohio
    • Cincinnati, Ohio, United States, 45227
      • Regeneron Research Site
  • Texas
    • Dallas, Texas, United States, 78226
      • Regeneron Study Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

1. 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):

   1. Documented homozygous or compound heterozygous mutations in both low-density lipoprotein receptor (LDLR) alleles
   2. Presence of homozygous or compound heterozygous mutations in Apo B, PCSK9 or LDL receptor adaptor protein 1 (LDLRAP1)
   3. Presence of double heterozygous mutations, i.e, mutations on different genes in the LDLR, Apo B or PCSK9 alleles
   4. 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
2. Receiving a stable dose of a statin at the screening visit (documentation if statin ineffective or patient unable to tolerate statin)
3. 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:

1. Documented evidence of a null mutation in both LDLR alleles
2. Use of a PCSK9 inhibitor within 10 weeks from screening visit
3. 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.
4. 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.
5. 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.
6. 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
7. Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at the screening visit (1 repeat measurement is allowed).
8. LDL-C level <70 mg/dL (1.81 mmol/L) at the screening visit
9. 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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Alirocumab SC Q2W; 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; Alirocumab SC Q2W; Other Names: SAR236553; REGN727; PRALUENT®
EXPERIMENTAL: Placebo SC Q2W; 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; Alirocumab SC Q2W; Other Names: SAR236553; REGN727; PRALUENT®; Drug: Placebo; Matching placebo SC Q2W

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Regeneron Pharmaceuticals
• Collaborators: Sanofi

Publications and helpful links

General Publications

• Blom DJ, Harada-Shiba M, Rubba P, Gaudet D, Kastelein JJP, Charng MJ, Pordy R, Donahue S, Ali S, Dong Y, Khilla N, Banerjee P, Baccara-Dinet M, Rosenson RS. Efficacy and Safety of Alirocumab in Adults With Homozygous Familial Hypercholesterolemia: The ODYSSEY HoFH Trial. J Am Coll Cardiol. 2020 Jul 14;76(2):131-142. doi: 10.1016/j.jacc.2020.05.027.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 3, 2017
• Primary Completion (ACTUAL): September 27, 2019
• Study Completion (ACTUAL): February 13, 2020

Study Registration Dates

• First Submitted: May 15, 2017
• First Submitted That Met QC Criteria: May 15, 2017
• First Posted (ACTUAL): May 17, 2017

Study Record Updates

• Last Update Posted (ACTUAL): June 29, 2021
• Last Update Submitted That Met QC Criteria: June 7, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Hypercholesterolemia; Hyperlipoproteinemia Type II
• Other Study ID Numbers: R727-CL-1628; 2017-000351-95 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No