Study in Participants With Homozygous Familial Hypercholesterolemia (HoFH)

Homozygous Familial Hypercholesterolemia Clinical Trial

— ODYSSEY HoFH  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03156621
• Other study ID #: R727-CL-1628
• Secondary ID: 2017-000351-95
• Status: Completed
• Phase: Phase 3
• Start date: October 3, 2017
• Est. completion date: February 13, 2020

Study information

• Verified date: June 2021
• Source: Regeneron Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 69
• Est. completion date: February 13, 2020
• Est. primary completion date: September 27, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Homozygous Familial Hypercholesterolemia
• Hypercholesterolemia
• Hyperlipoproteinemia Type II

Intervention

Drug:
• Alirocumab
Alirocumab SC Q2W
• Placebo
Matching placebo SC Q2W

Locations

Country	Name	City	State
Austria	Regeneron Research Site	Innsbruck	Tirol
Canada	Regeneron Research Site	Chicoutimi	Quebec
Canada	Regeneron Research Site	Québec	Quebec
Czechia	Regeneron Research Site	Praha
France	Regeneron Research Site	Marseille
France	Regeneron Research Site	Paris
Germany	Regeneron Research Site	Berlin
Greece	Regeneron Research Site	Athens
Greece	Regeneron Research Site	Ioánnina
Italy	Regeneron Research Site	Napoli
Italy	Regeneron Research Site	Roma
Japan	Regeneron Research Site	Kanazawa	Ishikawa
Japan	Regeneron Research Site	Nishinomiya	Hyogo
Japan	Regeneron Research Site	Suita	Osaka
South Africa	Regeneron Research Site	Cape Town	Western Cape
South Africa	Regeneron Research Site	Parktown	Johannesburg
Taiwan	Regeneron Study Site	Taipei
Turkey	Regeneron Research Site	Besevler	Ankara
Turkey	Regeneron Research Site	Izmir	Bornova
Ukraine	Regeneron Research Site	Ivano-Frankivs'k
Ukraine	Regeneron Research Site	Kharkiv
Ukraine	Regeneron Research Site	Kharkiv
Ukraine	Regeneron Research Site	Kyiv
Ukraine	Regeneron Research Site	Kyiv
United States	Regeneron Research Site	Boca Raton	Florida
United States	Regeneron Research Site	Cincinnati	Ohio
United States	Regeneron Study Site	Dallas	Texas
United States	Regeneron Research Site	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Regeneron Pharmaceuticals	Sanofi

Countries where clinical trial is conducted

United States,  Austria,  Canada,  Czechia,  France,  Germany,  Greece,  Italy,  Japan,  South Africa,  Taiwan,  Turkey,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	Percentage of Participants With =15% Reduction in LDL-C at Week 12	ITT estimand	At Week 12
Secondary	Percentage of Participants With =30% Reduction in LDL-C at Week 12	ITT estimand	At Week 12
Secondary	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
Secondary	Percentage of Participants With =50% Reduction in LDL-C at Week 12	ITT estimand	At Week 12
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Percentage of Participants With =15% Reduction, =30% Reduction, and =50% Reduction in LDL-C at Week 12 (On-treatment Estimand)		At Week 12
Secondary	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
Secondary	Number of Participants With Anti-Drug Antibodies (ADA) to REGN727 Over Time		26 weeks
Secondary	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)