Efficacy and Safety Evaluation of Alirocumab (SAR236553/REGN727) When Co-administered With High Dose of Atorvastatin in Patients With Primary Hypercholesterolemia

• Sponsor: Sanofi
• Collaborator: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Sanofi

Study Description

Brief Summary:

Primary Objective:

To evaluate the effect of alirocumab (SAR236553/REGN727) on low-density lipoprotein cholesterol (LDL-C) levels compared with placebo when co-administered with 80 mg of atorvastatin after 8 weeks of treatment in participants with LDL-C ≥ 100mg/dL (≥ 2.59 mmol/L) on atorvastatin 10 mg.

Secondary Objectives:

• To evaluate the effects of alirocumab on other lipid levels in comparison with placebo, when co-administered with 80 mg of atorvastatin after 8 weeks of treatment.
• To evaluate the efficacy of alirocumab when co-administered with a high dose of atorvastatin (80 mg) versus atorvastatin 10 mg.
• To evaluate the safety and tolerability of alirocumab when co-administered with 2 different doses of atorvastatin.
• To evaluate the development of anti-alirocumab antibodies.
• To evaluate the pharmacokinetics of alirocumab.

Condition or disease	Intervention/treatment	Phase
Hypercholesterolemia	Drug: Alirocumab; Drug: Placebo (for alirocumab); Drug: Atorvastatin; Drug: Placebo (for atorvastatin)	Phase 2

Detailed Description:

The duration of study participation depended on the status of the patient at screening:

• For participants receiving atorvastatin 10 mg at stable dose for at least 6 weeks prior to screening, the study participation was to be approximately 17 weeks including a screening period of 1 week, a double-blind treatment period of 8 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 for at least 6 weeks prior to screening, or drug naive participants, the study participation was to be approximately 23 weeks with a screening period of 1 week, a run-in treatment period with atorvastatin 10 mg of 6 weeks, a double-blind treatment period of 8 weeks and a follow-up period of 8 weeks.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 92 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Parallel-group, Placebo-controlled, Fixed Dose/Dose Regimen, Multicenter Study Evaluating the Efficacy and Safety of SAR236553 When Co-administered With 80 mg of Atorvastatin Over 8 Weeks in Patients With Primary Hypercholesterolemia and LDL-cholesterol ≥ 100 mg/dL (≥2.59 mmol/L) on Atorvastatin 10 mg
• Study Start Date: January 2011
• Actual Primary Completion Date: September 2011
• Actual Study Completion Date: September 2011

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo + Atorvastatin 80 mg; Placebo (for alirocumab) subcutaneous (SC) administration every 2 weeks (Q2W) in combination with atorvastatin 80 mg orally once daily for 8 weeks.	Drug: Placebo (for alirocumab); One SC injection in the abdomen only.; Drug: Atorvastatin; Over-encapsulated tablet orally once daily in the evening with dinner.
Experimental: Alirocumab + Atorvastatin 10 mg; Alirocumab 150 mg SC administration Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.	Drug: Alirocumab; One subcutaneous (SC) injection in the abdomen only.; Other Names: SAR236553; REGN727; Drug: Atorvastatin; Over-encapsulated tablet orally once daily in the evening with dinner.; Drug: Placebo (for atorvastatin); One over-encapsulated tablet of placebo for atorvastatin orally once daily in the evening with dinner.
Experimental: Alirocumab + Atorvastatin 80 mg; Alirocumab 150 mg SC administration Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.	Drug: Alirocumab; One subcutaneous (SC) injection in the abdomen only.; Other Names: SAR236553; REGN727; Drug: Atorvastatin; Over-encapsulated tablet orally once daily in the evening with dinner.

Outcome Measures

Primary Outcome Measures :

1. Percent Change From Baseline in Calculated LDL-C at Week 8 - On-treatment Analysis [ Time Frame: From Baseline to Week 8 (LOCF) ]
   Calculated LDL-C values were obtained using the Friedewald formula. Baseline adjusted least squares (LS) means and standard errors were estimated using an analysis of covariance (ANCOVA) model including available post-baseline data on treatment from first investigational product (IP) injection up to 21 days after last IP injection (on-treatment analysis). Missing Week 8 data were imputed by last observation carried forward [LOCF] method.

Secondary Outcome Measures :

1. Absolute Change From Baseline in Calculated LDL-C (mmol/L) at Week 8 - On-treatment Analysis [ Time Frame: From baseline to Week 8 (LOCF) ]
   Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
2. Absolute Change From Baseline in Calculated LDL-C (mg/dL) at Week 8 - On-treatment Analysis [ Time Frame: From baseline to Week 8 (LOCF) ]
   Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
3. Percentage of Participants Achieving Calculated LDL-C <100 mg/dL (2.59 mmol/L) and < 70 mg/dL (1.81 mmol/L) at Week 8 - On-treatment Analysis [ Time Frame: Week 8 (LOCF) ]
4. Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis [ Time Frame: From baseline to Week 8 (LOCF) ]
   Since the assumptions of normal distribution and equality of variances were not verified for the lipid parameters, percent changes were expressed as median (interquartile range).
5. Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 8 - On-treatment Analysis [ Time Frame: From Baseline to Week 8 (LOCF) ]
   Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
6. Absolute Change in the Ratio Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) From Baseline to Week 8 - On-treatment Analysis [ Time Frame: From Baseline to Week 8 (LOCF) ]
   Adjusted LS means and standard errors were estimated using the same ANCOVA as for primary endpoint.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

- Participants receiving a lipid-lowering treatment other than atorvastatin/ or not at stable dose of atorvastatin 10 mg for at least 6 weeks prior to screening, or drug naive participants with primary hypercholesterolemia 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 stable dose of atorvastatin 10 mg for at least 6 weeks prior to screening and likely to have low-density lipoprotein cholesterol (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) at Week -1 (V1):

   • After the run-in period on atorvastatin 10 mg for participants receiving a lipid lowering treatment other than atorvastatin/ or not at stable dose of atorvastatin 10 mg for at least 6 weeks prior to the screening period, or drug naive participants.

   OR

   • At the first visit for participants who are being treated with atorvastatin 10 mg at stable dose for at least 6 weeks prior to screening visit.
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 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.

Contacts and Locations

Locations

United States, Arizona

Investigational Site Number 840616

Mesa, Arizona, United States, 85206

Investigational Site Number 840601

Tucson, Arizona, United States, 85710

United States, California

Investigational Site Number 840610

Los Angeles, California, United States, 90057

Investigational Site Number 840608

Newport Beach, California, United States, 92660

United States, Florida

Investigational Site Number 840603

Doral, Florida, United States, 33166

Investigational Site Number 840611

Jacksonville, Florida, United States, 32223

Investigational Site Number 840618

Jupiter, Florida, United States, 33458

Investigational Site Number 840612

Miami, Florida, United States, 33138

Investigational Site Number 840614

Miami, Florida, United States, 33138

Investigational Site Number 840607

St. Petersburg, Florida, United States, 33609

United States, Illinois

Investigational Site Number 840605

Chicago, Illinois, United States, 60610

Investigational Site Number 840619

Chicago, Illinois, United States, 60610

United States, New Jersey

Investigational Site Number 840604

Edison, New Jersey, United States, 08817

United States, New York

Investigational Site Number 840606

Rochester, New York, United States, 14609

United States, Ohio

Investigational Site Number 840615

Cincinnati, Ohio, United States, 45219

Investigational Site Number 840617

Cincinnati, Ohio, United States, 45219

United States, Oregon

Investigational Site Number 840602

Eugene, Oregon, United States, 97404

United States, Virginia

Investigational Site Number 840621

Richmond, Virginia, United States, 23227

United States, Washington

Investigational Site Number 840609

Olympia, Washington, United States, 98502

United States, Wisconsin

Investigational Site Number 840613

Oregon, Wisconsin, United States, 53575

Sponsors and Collaborators

Sanofi

Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

More Information

Publications of Results:

Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012 Nov 15;367(20):1891-900. doi: 10.1056/NEJMoa1201832. Epub 2012 Oct 31.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT01288469 History of Changes
• Other Study ID Numbers: DFI11566; U1111-1117-9994 ( Other Identifier: UTN )
• First Posted: February 2, 2011
• Results First Posted: September 24, 2015
• Last Update Posted: September 24, 2015
• Last Verified: January 2015

Keywords provided by Sanofi:

10020603

Additional relevant MeSH terms:

Hypercholesterolemia; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Atorvastatin; Antibodies, Monoclonal; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors; Immunologic Factors; Physiological Effects of Drugs