Clinical trial NCT01709500: Study of Alirocumab (REGN727/SAR236553) in Patients With heFH (Heterozygous Familial Hypercholesterolemia) Who Are Not Adequately Controlled With Their LMT (Lipid-Modifying Therapy)
Official title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of REGN727/SAR236553 in Patients With Heterozygous Familial Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Heterozygous Familial Hypercholesterolemia
Lead sponsor: Regeneron Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: Sanofi
First posted: 2012-10-18
Enrollment: 249
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: This is a randomized, double-blind, placebo-controlled, parallel-group, multi-national study alirocumab (REGN727/SAR236553) in patients with Heterozygous Familial Hypercholesterolemia (heFH) who are not adequately controlled with their Lipid-Modifying Therapy (LMT).


Eligibility criteria: Inclusion Criteria:

1. Patients with heFH\* who are not adequately controlled\*\* with a maximally-tolerated daily dose\*\*\* of statin with or without other LMT, at a stable dose prior to the screening visit (week -2).

   \*Diagnosis of heFH must be made either by genotyping or by clinical criteria. For those patients not genotyped, the clinical diagnosis may be based on either the Simon Broome criteria for definite FH (Appendix 1) or the WHO/Dutch Lipid Network criteria with a score of \>8 points (Appendix 2).

   \*\* "Not adequately controlled" is defined as LDL-C ≥70 mg/dL (1.81 mmol/L) at the screening visit (week -2) in patients with a history of documented CVD (Appendix 3), or LDL-C ≥100 mg/dL (2.59 mmol/L) at the screening visit (week -2) in patients without a history of documented CVD.

   \*\*\* "Maximally-tolerated dose" is defined as (any of the following are acceptable):
   * Rosuvastatin 20 mg or 40 mg daily
   * Atorvastatin 40 mg or 80 mg daily
   * Simvastatin 80 mg daily (if already on this dose for \>1 year - see exclusion criterion #7)

   Note: Patients who are not able to be on any of the above statin doses should be treated with the dose of daily atorvastatin, rosuvastatin, or simvastatin which is considered appropriate for the patient, according to the investigator's judgment. Some examples of acceptable reasons for a patient taking a lower statin dose include, but are not limited to: adverse effects on higher doses, advanced age, low body mass index, regional practices, local prescribing information, concomitant medications, co-morbid conditions such as impaired glucose tolerance/impaired fasting glucose. The reason(s) will be documented in the case report form (CRF).
2. Provide signed informed consent

Exclusion Criteria:

1. Patient without diagnosis of heFH made either by genotyping or by clinical criteria
2. LDL-C \<70 mg/dL (\<1.81 mmol/L) at the screening visit (week-2) in patients with history of documented cardiovascular disease
3. LDL-C \<100 mg/dL (\<2.59 mmol/L) at the screening visit (week -2) in patients without history of documented cardiovascular disease
4. Not on a stable dose of LMT (including statin) for at least 4 weeks and/or fenofibrate for at least 6 weeks, as applicable, prior to the screening visit (week -2) and from screening to randomization
5. Currently taking another statin than simvastatin, atorvastatin, or rosuvastatin
6. Simvastatin, atorvastatin, or rosuvastatin is not taken daily or not taken at a registered dose
7. Daily doses above atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg (except for patients on simvastatin 80 mg for more than 1 year, who are eligible)
8. Use of fibrates, other than fenofibrate within 6 weeks of the screening visit (week-2) or between screening and randomization visits
9. Use of nutraceutical products or over-the-counter therapies that may affect lipids which have not been at a stable dose/amount for at least 4 weeks prior to the screening visit (week -2) or between screening and randomization visits
10. Use of red yeast rice products within 4 weeks of the screening visit (week-2), or between screening and randomization visits
11. Patient who has received plasmapheresis treatment within 2 months prior to the screening visit (week -2), or has plans to receive it during the study
12. Recent (within 3 months prior to the screening visit \[week -2\] or between screening and randomization visits) MI, unstable angina leading to hospitalization, percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG), uncontrolled cardiac arrhythmia, stroke, transient ischemic attack (TIA), carotid revascularization, endovascular procedure or surgical intervention for peripheral vascular disease

(The inclusion/exclusion criteria provided above is not intended to contain all considerations relevant to a participant's potential participation in this clinical trial).

Primary outcomes:
measure: Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent--to--Treat (ITT) Analysis
timeFrame: From Baseline to Week 52
Secondary outcomes:
measure: Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Calculated LDL-C at Week 12 - On- Treatment Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Non-High -Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Apo B at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Total-C at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis
timeFrame: Up to Week 52
measure: Percentage of Very High CV Risk Participants Reaching Calculated LDL--C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL--C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis
timeFrame: Up to week 52
measure: Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis
timeFrame: Up to Week 52
measure: Percentage of Participants Reaching Calculated LDL--C <70 mg/dL (1.81 mmol/L) at Week 52 - On-Treatment Analysis
timeFrame: Up to Week 52
measure: Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
Other outcomes:
Locations:
city: Hradec Kralove
country: Czech Republic
city: Praha 2
country: Czech Republic
city: Praha 5
country: Czech Republic
city: Praha 8
country: Czech Republic
city: Trutnov
country: Czech Republic
city: Vyskov
country: Czech Republic
city: Alkmaar
country: Netherlands
city: Amsterdam
country: Netherlands
city: Apeldoorn
country: Netherlands
city: Enschede
country: Netherlands
city: Goes
country: Netherlands
city: Groningen
country: Netherlands
city: Hoogeveen
country: Netherlands
city: Hoorn
country: Netherlands
city: Rotterdam
country: Netherlands
city: Sittard- Geleen
country: Netherlands
city: Utrecht (2 locations)
country: Netherlands
city: Venlo
country: Netherlands
city: Waalwijk
country: Netherlands
city: Oslo
country: Norway
city: Cardiff
country: United Kingdom
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
city: Middlesex
country: United Kingdom
city: Newcastle upon Tyne
country: United Kingdom
city: West Bromwich
country: United Kingdom
Study officials:
affiliation: Regeneron Pharmaceuticals
name: Clinical Trial Management
role: STUDY_DIRECTOR
References:
citation: Mahmood T, Minnier J, Ito MK, Li QH, Koren A, Kam IW, Fazio S, Shapiro MD. Discordant responses of plasma low-density lipoprotein cholesterol and lipoprotein(a) to alirocumab: A pooled analysis from 10 ODYSSEY Phase 3 studies. Eur J Prev Cardiol. 2021 Jul 23;28(8):816-822. doi: 10.1177/2047487320915803. Epub 2020 Apr 10.
citation: Leiter LA, Tinahones FJ, Karalis DG, Bujas-Bobanovic M, Letierce A, Mandel J, Samuel R, Jones PH. Alirocumab safety in people with and without diabetes mellitus: pooled data from 14 ODYSSEY trials. Diabet Med. 2018 Dec;35(12):1742-1751. doi: 10.1111/dme.13817. Epub 2018 Oct 9.
citation: Defesche JC, Stefanutti C, Langslet G, Hopkins PN, Seiz W, Baccara-Dinet MT, Hamon SC, Banerjee P, Kastelein JJP. Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia. J Clin Lipidol. 2017 Nov-Dec;11(6):1338-1346.e7. doi: 10.1016/j.jacl.2017.08.016. Epub 2017 Sep 4.
citation: Kastelein JJ, Hovingh GK, Langslet G, Baccara-Dinet MT, Gipe DA, Chaudhari U, Zhao J, Minini P, Farnier M. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody alirocumab vs placebo in patients with heterozygous familial hypercholesterolemia. J Clin Lipidol. 2017 Jan-Feb;11(1):195-203.e4. doi: 10.1016/j.jacl.2016.12.004. Epub 2016 Dec 28.
citation: Ray KK, Ginsberg HN, Davidson MH, Pordy R, Bessac L, Minini P, Eckel RH, Cannon CP. Reductions in Atherogenic Lipids and Major Cardiovascular Events: A Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab With Control. Circulation. 2016 Dec 13;134(24):1931-1943. doi: 10.1161/CIRCULATIONAHA.116.024604. Epub 2016 Oct 24.
citation: Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R, Blom D, Civeira F, Krempf M, Lorenzato C, Zhao J, Pordy R, Baccara-Dinet MT, Gipe DA, Geiger MJ, Farnier M. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015 Nov 14;36(43):2996-3003. doi: 10.1093/eurheartj/ehv370. Epub 2015 Sep 1.
citation: Kastelein JJ, Robinson JG, Farnier M, Krempf M, Langslet G, Lorenzato C, Gipe DA, Baccara-Dinet MT. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies. Cardiovasc Drugs Ther. 2014 Jun;28(3):281-9. doi: 10.1007/s10557-014-6523-z.