Clinical trial NCT01288443: Efficacy and Safety Evaluation of Alirocumab (SAR236553/REGN727) in Patients With Primary Hypercholesterolemia on Stable Atorvastatin Therapy
Official title: A Randomized, Double-blind, Parallel-group, Placebo-controlled, Multicenter Study Evaluating the Efficacy and Safety of Five Doses and Two Dose Regimens of SAR236553 Over 12 Weeks in Patients With Primary Hypercholesterolemia and LDL-cholesterol ≥ 100 mg/dL (≥ 2.59 mmol/L) on Ongoing Stable Atorvastatin Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hypercholesterolemia
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Regeneron Pharmaceuticals
First posted: 2011-02-02
Enrollment: 183
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Primary Objective:

* To evaluate the effect of alirocumab (SAR236553/REGN727) on low-density lipoprotein cholesterol (LDL-C) levels after 12 weeks of treatment in comparison with placebo in participants with LDL-C ≥ 100 mg/dL (≥ 2.59 mmol/L) on ongoing stable atorvastatin therapy.

Secondary Objectives:

* To evaluate the effects of alirocumab on other lipid levels after 12 weeks of treatment in comparison with placebo
* To evaluate the safety and tolerability of alirocumab
* To evaluate the development of anti-alirocumab antibodies
* To evaluate the pharmacokinetics of alirocumab

Detailed description: The duration of study participation depended on the status of the participant at screening:

* For participants receiving atorvastatin 10 mg, 20 mg, or 40 mg at a stable dose for at least 6 weeks prior to screening, the study participation was to be approximately 21 weeks including a screening period of 1 week, a double-blind treatment period of 12 weeks and a follow-up period of 8 weeks.
* For participants receiving a lipid-lowering treatment other than atorvastatin or not at stable dose of atorvastatin 10 mg, 20 mg, or 40 mg for at least 6 weeks prior to screening, or drug naive participants, the study participation was to be approximately 27 weeks including a screening period of 1 week, a run-in treatment period with atorvastatin 10 mg, 20 mg, or 40 mg at a stable dose of 6 weeks, a double-blind treatment period of 12 weeks, and a follow-up period of 8 weeks.

Eligibility criteria: Inclusion criteria:

* Participants with primary hypercholesterolemia receiving a lipid-lowering treatment other than atorvastatin or not at stable dose of atorvastatin 10 mg, 20 mg, or 40 mg for at least 6 weeks prior to screening period or drug naive participants if they are likely to have low-density lipoprotein cholesterol (LDL-C) ≥ 100 mg/dL (≥ 2.59 mmol/L) at the end of the 6-week run-in treatment period on atorvastatin therapy

OR

* Participants with primary hypercholesterolemia treated with atorvastatin at stable dose of 10 mg, 20 mg, or 40 mg for at least 6 weeks prior to screening period and likely to have LDL-C ≥ 100 mg/dL (≥ 2.59 mmol/L) at the screening visit

Exclusion criteria:

1. LDL-C \< 100 mg/dL (\< 2.59 mmol/L):

   * After the run-in period on atorvastatin (10 mg, 20 mg, or 40 mg) for participants receiving a lipid-lowering treatment other than atorvastatin or not at stable dose of atorvastatin 10 mg, 20 mg, or 40 mg for at least 6 weeks prior to the screening, or drug naive participant

   OR
   * At the first visit for participants who were being treated with stable dose of atorvastatin (10 mg, 20 mg, or 40 mg) for at least 6 weeks prior to screening
2. Participants not previously instructed on a cholesterol-lowering diet
3. Participants with type 1 diabetes
4. Participants with type 2 diabetes treated with insulin
5. Participants with type 2 diabetes and with an glycated hemoglobin (HbA1c) ≥ 8.5% at screening visit (considered poorly controlled)
6. Laboratory findings measured before randomization:

   * Triglycerides (TG) \> 350 mg/dL (\> 3.95 mmol/L) at screening visit
   * Positive serum or urine pregnancy test in females of childbearing potential
7. Pregnant or breast-feeding women
8. Women of childbearing potential with no effective contraceptive method

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Primary outcomes:
measure: Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis
timeFrame: Baseline to Week 12 (LOCF)
Secondary outcomes:
measure: Absolute Change From Baseline in Calculated LDL-C (mmol/L) at Week 12 - On-Treatment Analysis
timeFrame: Baseline to Week 12 (LOCF)
measure: Absolute Change From Baseline in Calculated LDL-C (mg/dL) at Week 12 - On-Treatment Analysis
timeFrame: Baseline to Week 12 (LOCF)
measure: Percentage of Participants Achieving Calculated LDL-C <100 mg/dL (2.59 mmol/L) and <70 mg/dL (1.81 mmol/L) at Week 12 - On-Treatment Analysis
timeFrame: Week 12 (LOCF)
measure: Percent Change From Baseline in Total Cholesterol, High-density Lipoprotein Cholesterol (HDL-C), Non-HDL-C and Apolipoprotein B (Apo-B) at Week 12 - On-Treatment Analysis
timeFrame: Baseline to Week 12 (LOCF)
measure: Percent Change From Baseline in Fasting Triglycerides and Lipoprotein(a) at Week 12 - On-Treatment Analysis
timeFrame: Baseline to Week 12 (LOCF)
measure: Absolute Change in the Ratio Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) From Baseline to Week 12 - On-Treatment Analysis
timeFrame: Baseline to Week 12 (LOCF)
Other outcomes:
Locations:
city: Tempe
country: United States
facility: Investigational Site Number 840525
state: Arizona
city: Los Angeles
country: United States
facility: Investigational Site Number 840516
state: California
city: Mission Viejo
country: United States
facility: Investigational Site Number 840528
state: California
city: Newport Beach
country: United States
facility: Investigational Site Number 840509
state: California
city: Palm Springs
country: United States
facility: Investigational Site Number 840523
state: California
city: Westlake Village
country: United States
facility: Investigational Site Number 840534
state: California
city: Colorado Springs
country: United States
facility: Investigational Site Number 840530
state: Colorado
city: Aventura
country: United States
facility: Investigational Site Number 840504
state: Florida
city: Aventura
country: United States
facility: Investigational Site Number 840519
state: Florida
city: Jacksonville
country: United States
facility: Investigational Site Number 840514
state: Florida
city: Jupiter
country: United States
facility: Investigational Site Number 840539
state: Florida
city: Miami
country: United States
facility: Investigational Site Number 840502
state: Florida
city: Pembroke Pines
country: United States
facility: Investigational Site Number 840520
state: Florida
city: Ponte Vedra
country: United States
facility: Investigational Site Number 840524
state: Florida
city: Port Orange
country: United States
facility: Investigational Site Number 840536
state: Florida
city: St. Petersburg
country: United States
facility: Investigational Site Number 840507
state: Florida
city: Chicago
country: United States
facility: Investigational Site Number 840527
state: Illinois
city: Evansville
country: United States
facility: Investigational Site Number 840506
state: Indiana
city: Indianapolis
country: United States
facility: Investigational Site Number 840529
state: Indiana
city: Wichita
country: United States
facility: Investigational Site Number 840515
state: Kansas
city: Madisonville
country: United States
facility: Investigational Site Number 840532
state: Kentucky
city: Auburn
country: United States
facility: Investigational Site Number 840535
state: Maine
city: Brockton
country: United States
facility: Investigational Site Number 840503
state: Massachusetts
city: Las Vegas
country: United States
facility: Investigational Site Number 840512
state: Nevada
city: Edison
country: United States
facility: Investigational Site Number 840505
state: New Jersey
city: Rochester
country: United States
facility: Investigational Site Number 840538
state: New York
city: Raleigh
country: United States
facility: Investigational Site Number 840508
state: North Carolina
city: Statesville
country: United States
facility: Investigational Site Number 840522
state: North Carolina
city: Cincinnati
country: United States
facility: Investigational Site Number 840511
state: Ohio
city: Cincinnati
country: United States
facility: Investigational Site Number 840526
state: Ohio
city: Lyndhurst
country: United States
facility: Investigational Site Number 840510
state: Ohio
city: Tulsa
country: United States
facility: Investigational Site Number 840533
state: Oklahoma
city: Eugene
country: United States
facility: Investigational Site Number 840537
state: Oregon
city: Bristol
country: United States
facility: Investigational Site Number 840521
state: Tennessee
city: Bountiful
country: United States
facility: Investigational Site Number 840531
state: Utah
city: Norfolk
country: United States
facility: Investigational Site Number 840517
state: Virginia
city: Richmond
country: United States
facility: Investigational Site Number 840518
state: Virginia
city: Olympia
country: United States
facility: Investigational Site Number 840513
state: Washington
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012 Jun 19;59(25):2344-53. doi: 10.1016/j.jacc.2012.03.007. Epub 2012 Mar 28.
citation: Gaudet D, Kereiakes DJ, McKenney JM, Roth EM, Hanotin C, Gipe D, Du Y, Ferrand AC, Ginsberg HN, Stein EA. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Am J Cardiol. 2014 Sep 1;114(5):711-5. doi: 10.1016/j.amjcard.2014.05.060. Epub 2014 Jun 18.
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: Toth PP, Hamon SC, Jones SR, Martin SS, Joshi PH, Kulkarni KR, Banerjee P, Hanotin C, Roth EM, McKenney JM. Effect of alirocumab on specific lipoprotein non-high-density lipoprotein cholesterol and subfractions as measured by the vertical auto profile method: analysis of 3 randomized trials versus placebo. Lipids Health Dis. 2016 Feb 13;15:28. doi: 10.1186/s12944-016-0197-4.
citation: Koren MJ, Kereiakes D, Pourfarzib R, Winegar D, Banerjee P, Hamon S, Hanotin C, McKenney JM. Effect of PCSK9 Inhibition by Alirocumab on Lipoprotein Particle Concentrations Determined by Nuclear Magnetic Resonance Spectroscopy. J Am Heart Assoc. 2015 Nov 19;4(11):e002224. doi: 10.1161/JAHA.115.002224.