Clinical trial NCT03156621: Study in Participants With Homozygous Familial Hypercholesterolemia (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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Homozygous Familial Hypercholesterolemia
Lead sponsor: Regeneron Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: Sanofi
First posted: 2017-05-17
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility criteria: 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.

Primary outcomes:
measure: Percent Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 12 (Intent-to-Treat [ITT] Estimand)
timeFrame: Baseline to Week 12
Secondary outcomes:
measure: Percent Change in Apolipoprotein (Apo) B From Baseline to Week 12 (ITT Estimand)
timeFrame: Baseline to Week 12
measure: Percent Change in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 12
timeFrame: Baseline to Week 12
measure: Percent Change in Total Cholesterol (TC) From Baseline to Week 12
timeFrame: Baseline to Week 12
measure: Percentage of Participants With ≥15% Reduction in LDL-C at Week 12
timeFrame: At Week 12
measure: Percentage of Participants With ≥30% Reduction in LDL-C at Week 12
timeFrame: At Week 12
measure: Percent Change in Lipoprotein(a) [Lp(a)] From Baseline to Week 12
timeFrame: Baseline to Week 12
measure: Percentage of Participants With ≥50% Reduction in LDL-C at Week 12
timeFrame: At Week 12
measure: Percent Change in HDL-C From Baseline to Week 12 - ITT Analysis
timeFrame: Baseline to Week 12
measure: Percent Change in Fasting Triglycerides (TG) From Baseline to Week 12
timeFrame: Baseline to Week 12
measure: Percent Change in Apo A-1 From Baseline to Week 12 -- ITT Analysis
timeFrame: Baseline to Week 12
measure: Percent Change in LDL-C From Baseline to Week 12 (On-treatment Estimand)
timeFrame: Baseline to Week 12
measure: Percent Change in Apo B From Baseline to Week 12 (On-treatment Estimand)
timeFrame: Baseline to Week 12
measure: Percent Change in Non-HDL-C From Baseline to Week 12 (On-treatment Estimand)
timeFrame: Baseline to Week 12
measure: Percent Change in TC From Baseline to Week 12 (On-treatment Estimand)
timeFrame: Baseline to Week 12
measure: Percent Change in Lp(a) From Baseline to Week 12 (On-treatment Estimand)
timeFrame: Baseline to Week 12
measure: Percent Change in HDL-C From Baseline to Week 12 (On-treatment Estimand)
timeFrame: Baseline to Week 12
measure: Percent Change in Fasting TG From Baseline to Week 12 (On-treatment Estimand)
timeFrame: Baseline to Week 12
measure: Percent Change in Apo A-1 From Baseline to Week 12 (On-treatment Estimand)
timeFrame: Baseline to Week 12
measure: Percentage of Participants With ≥15% Reduction, ≥30% Reduction, and ≥50% Reduction in LDL-C at Week 12 (On-treatment Estimand)
timeFrame: At Week 12
measure: Absolute Change in the Ratio of Apo B/Apo A-1 From Baseline to Week 12 (ITT Estimand)
timeFrame: Baseline to Week 12
measure: Number of Participants With Anti-Drug Antibodies (ADA) to REGN727 Over Time
timeFrame: 26 weeks
measure: Number of Participants With Adverse Events (AEs)
timeFrame: Baseline to week 32 (End of Study)
Other outcomes:
Locations:
city: Boca Raton
country: United States
facility: Regeneron Research Site
state: Florida
city: New York
country: United States
facility: Regeneron Research Site
state: New York
city: Cincinnati
country: United States
facility: Regeneron Research Site
state: Ohio
city: Dallas
country: United States
facility: Regeneron Study Site
state: Texas
city: Innsbruck
country: Austria
facility: Regeneron Research Site
state: Tirol
city: Chicoutimi
country: Canada
facility: Regeneron Research Site
state: Quebec
city: Québec
country: Canada
facility: Regeneron Research Site
state: Quebec
city: Praha
country: Czechia
facility: Regeneron Research Site
city: Marseille
country: France
facility: Regeneron Research Site
city: Paris
country: France
facility: Regeneron Research Site
city: Berlin
country: Germany
facility: Regeneron Research Site
city: Athens
country: Greece
facility: Regeneron Research Site
city: Ioánnina
country: Greece
facility: Regeneron Research Site
city: Napoli
country: Italy
facility: Regeneron Research Site
city: Roma
country: Italy
facility: Regeneron Research Site
city: Nishinomiya
country: Japan
facility: Regeneron Research Site
state: Hyogo
city: Kanazawa
country: Japan
facility: Regeneron Research Site
state: Ishikawa
city: Suita
country: Japan
facility: Regeneron Research Site
state: Osaka
city: Parktown
country: South Africa
facility: Regeneron Research Site
state: Johannesburg
city: Cape Town
country: South Africa
facility: Regeneron Research Site
state: Western Cape
city: Taipei
country: Taiwan
facility: Regeneron Study Site
city: Besevler
country: Turkey
facility: Regeneron Research Site
state: Ankara
city: İzmir
country: Turkey
facility: Regeneron Research Site
state: Bornova
city: Ivano-Frankivs'k
country: Ukraine
facility: Regeneron Research Site
city: Kharkiv
country: Ukraine
facility: Regeneron Research Site
city: Kharkiv
country: Ukraine
facility: Regeneron Research Site
city: Kyiv
country: Ukraine
facility: Regeneron Research Site
city: Kyiv
country: Ukraine
facility: Regeneron Research Site
Study officials:
affiliation: Regeneron Pharmaceuticals
name: Clinical Trial Management
role: STUDY_DIRECTOR
References:
citation: 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.