Efficacy and Safety Evaluation of Alirocumab (SAR236553/REGN727) in Patients With Primary Hypercholesterolemia on Stable Atorvastatin Therapy in Japan

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

Study Description

Brief Summary:

Alirocumab (SAR236553/REGN727) is a fully human monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9).

Primary Objective of the study:

To evaluate the effect of alirocumab 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

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

Detailed Description:

The duration of study participation depended on the status of the participant at screening: 21 to 27 weeks including a screening/run-in period of 1 to 7 weeks, a double-blind treatment period of 12 weeks, followed by an 8-week follow-up period.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled Study Evaluating the Efficacy and Safety of Three Doses of SAR236553 (REGN727) Over 12 Weeks in Patients With Primary Hypercholesterolemia and LDL-cholesterol ≥100 mg/dL (≥2.59 mmol/L) on Ongoing Stable Atorvastatin Therapy
• Study Start Date: March 2013
• Actual Primary Completion Date: January 2014
• Actual Study Completion Date: January 2014

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Placebo (for alirocumab) every 2 weeks (Q2W) for 12-weeks in combination with atorvastatin stable dose.	Drug: Placebo (for alirocumab); Two subcutaneous (SC) injections in the abdomen only Route of administration: subcutaneous injection (1 mL) in the abdomen; Drug: Atorvastatin; Orally once daily at a stable dose of 5 to 20 mg as background therapy Route of administration: oral administration in the evening
Experimental: Alirocumab 50 mg Q2W; Alirocumab 50 mg Q2W for 12-weeks in combination with atorvastatin stable dose.	Drug: Alirocumab; Two SC injections in the abdomen only; Other Names: SAR236553; RGEN727; Drug: Atorvastatin; Orally once daily at a stable dose of 5 to 20 mg as background therapy Route of administration: oral administration in the evening
Experimental: Alirocumab 75 mg Q2W; Alirocumab 75 mg Q2W for 12-weeks in combination with atorvastatin stable dose.	Drug: Alirocumab; Two SC injections in the abdomen only; Other Names: SAR236553; RGEN727; Drug: Atorvastatin; Orally once daily at a stable dose of 5 to 20 mg as background therapy Route of administration: oral administration in the evening
Placebo Comparator: Alirocumab 150 mg Q2W; Alirocumab 150 mg Q2W for 12-weeks in combination with atorvastatin stable dose.	Drug: Alirocumab; Two SC injections in the abdomen only; Other Names: SAR236553; RGEN727; Drug: Atorvastatin; Orally once daily at a stable dose of 5 to 20 mg as background therapy Route of administration: oral administration in the evening

Outcome Measures

Primary Outcome Measures :

1. Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis [ Time Frame: Baseline to Week 12 (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 12 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 12 - On-Treatment Analysis [ Time Frame: Baseline to Week 12 (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 12 - On-Treatment Analysis [ Time Frame: Baseline to Week 12 (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 12 - On-Treatment Analysis [ Time Frame: Week 12 (LOCF) ]
4. 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 [ Time Frame: Baseline to Week 12 (LOCF) ]
   Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
5. Percent Change From Baseline in Fasting Triglycerides and Lipoprotein (a) at Week 12 - On-Treatment Analysis [ Time Frame: Baseline to Week 12 (LOCF) ]
   Since the assumptions of normal distribution and equality of variances were not verified for the lipid parameters, percent changes were expressed as median (inter-quartile range).
6. Absolute Change From Baseline in Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) Ratio at Week 12 - On-Treatment Analysis [ Time Frame: From Baseline to Week 12 (LOCF) ]
   Adjusted LS mean and standard errors were estimated using the same ANCOVA as for primary endpoint.

Eligibility Criteria

• Ages Eligible for Study: 20 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria :

- Participants with primary hypercholesterolemia treated with atorvastatin at stable dose of 5-20 mg for at least 6 weeks prior to screening and likely to have LDL-C ≥100 mg/dL (≥2.59 mmol/L) at the screening visit.

OR

- Participants with primary hypercholesterolemia who were receiving a lipid-lowering treatment other than atorvastatin, or who were not at stable dose of atorvastatin 5-20 mg for at least 6 weeks prior to screening if they were likely to have LDL-C ≥100 mg/dL (≥2.59 mmol/L) after a 6-week run-in treatment period on atorvastatin therapy.

Exclusion criteria:

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

   • at screening visit for participants who were being treated with stable dose of atorvastatin 5-20 mg for at least 6 weeks prior to screening OR
   • at the end of the 6-week run-in period on atorvastatin for participants receiving a lipid lowering treatment other than atorvastatin, or not at stable dose of atorvastatin 5-20 mg for at least 6 weeks prior to screening
2. Participants with type 1 diabetes
3. Participants with type 2 diabetes treated with insulin, or without, and considered poorly controlled at screening.

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

Japan

Investigational Site Number 392002

Koganei-Shi, Japan

Investigational Site Number 392001

Shinjuku-Ku, Japan

Investigational Site Number 392003

Suita-Shi, Japan

Investigational Site Number 392004

Suita-Shi, Japan

Sponsors and Collaborators

Sanofi

Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

More Information

Publications of Results:

Teramoto T, Kobayashi M, Uno K, Takagi Y, Matsuoka O, Sugimoto M, Inoue S, Minami F, Baccara-Dinet MT. Efficacy and Safety of Alirocumab in Japanese Subjects (Phase 1 and 2 Studies). Am J Cardiol. 2016 Jul 1;118(1):56-63. doi: 10.1016/j.amjcard.2016.04.011. Epub 2016 Apr 21.

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.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT01812707 History of Changes
• Other Study ID Numbers: DFI12361; U1111-1134-4749 ( Other Identifier: UTN )
• First Posted: March 18, 2013
• Results First Posted: September 24, 2015
• Last Update Posted: October 4, 2016
• Last Verified: August 2015

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