Study of Alirocumab (REGN727/SAR236553) in Patients With Heterozygous Familial Hypercholesterolemia (HeFH) Undergoing Low-density Lipoprotein (LDL) Apheresis Therapy

Phase 3

Completed

• Conditions: Heterozygous Familial Hypercholesterolemia
• Interventions: Drug: Placebo; Drug: Alirocumab

• Registration Number: NCT02326220
• Lead Sponsor: Regeneron Pharmaceuticals

Brief Summary

The primary objective of the study is to evaluate the effect of alirocumab 150 mg every 2 weeks (Q2W) in comparison with placebo on the frequency of low-density lipoprotein (LDL) apheresis treatments in participants with heterozygous familial hypercholesterolemia (HeFH) undergoing weekly or bi-weekly LDL apheresis therapy.

Detailed Description

LDL apheresis removes low-density lipoproteins (LDL) that transport cholesterol in the plasma portion of the blood. This treatment is mainly used for familial hypercholesterolemia, but can be used in other rare diseases. Familial hypercholesterolemia (HeFH) is an inherited genetic condition that causes accumulation of cholesterol in the blood, which can lead to atherosclerosis and heart disease. This treatment is recommended for patients who do not respond to dietary and/or medication control of LDL cholesterol.

Study Timeline

• Study First Submitted: 2014-12-22
• Study First Submitted QC: 2014-12-22
• Study First Posted: 2014-12-29
• Study Start: 2015-03-31
• Primary Completion: 2016-01-31
• Study Completion: 2016-04-30
• Disposition First Submitted: 2017-01-20
• Disposition First Submitted QC: 2017-01-20
• Disposition First Posted: 2017-01-23
• Results First Submitted: 2018-09-24
• Status Verified: 2020-04
• Results First Submitted QC: 2020-04-21
• Last Update Submitted: 2020-04-21
• Results First Posted: 2020-05-01
• Last Update Posted: 2020-05-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 62

Inclusion Criteria

1. Men and women ≥18 years of age at the time of the screening visit
2. Diagnosis of HeFH (Heterozygous familial hypercholesterolemia)
3. Currently undergoing LDL (low-density lipoprotein) apheresis therapy QW (weekly) or Q2W (every 2 weeks) or at least 8 weeks prior to the screening visit

Exclusion Criteria

1. Homozygous FH (familial hypercholesterolemia)
2. Background medical LMT (lipid-modifying therapy) (if applicable) that has not been stable for at least 8 weeks prior to the screening visit
3. LDL apheresis schedule/ apheresis settings that have not been stable for at least 8 weeks prior to the screening visit
4. An LDL apheresis schedule other than QW to Q2W
5. Initiation of a new exercise program or exercise that has not remained stable within 8 weeks prior to the screening visit (week -2)
6. Initiation of a new diet or a diet that has not been stable within 8 weeks prior to the screening visit (week -2)
7. Use of nutraceuticals or over-the-counter therapies known to affect lipids, at a dose/amount that has not been stable for at least 8 weeks prior to the screening visit (week -2), or between the screening and randomization visit
8. Presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins
9. Known history of a positive test for human immunodeficiency virus
10. Use of any active investigational drugs within 1 month or 5 half-lives of screening, whichever is longer
11. Patients who have been treated with at least 1 dose of alirocumab or any other anti-PCSK9 monoclonal antibody in any other clinical studies
12. Pregnant or breastfeeding women

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo Q2W (Double Blind Period)	Placebo	Placebo (for alirocumab) subcutaneous (SC) injection Q2W up to Week 16.
Alirocumab 150 mg Q2W (Double Blind Period)	Alirocumab	Alirocumab 150 mg SC injection Q2W up to Week 16.
Alirocumab 150 Q2W (Open Label Treatment Period)	Alirocumab	Alirocumab 150 mg SC injection Q2W starting from Week 18 up to Week 76.

Primary Outcome Measures

Name	Time	Method
Change in Standardized Rate of Apheresis Treatments From Week 7 to Week 18	Week 7 to Week 18 (before start of open-label treatment)	Rate of apheresis treatments were normalized by the number of planned apheresis treatments according to each participant's established schedule at screening, week -10 to week -2. The normalized rate of apheresis was defined for each participant as the number of actual apheresis treatments received from week 7 to week 18 divided by the number of planned apheresis treatments per randomization strata at baseline (6 for Q2W and 12 for QW).

Secondary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Calculated LDL-C (Pre-apheresis) at Week 6	Baseline and at Week 6	Adjusted Least-squares (LS) means and standard errors at Week 6 were obtained from a mixed-effect model with repeated measures (MMRM) to account for missing data. All available post-baseline data from Week 2 to Week 18 regardless of status on or off-treatment were used in the model (ITT analysis).
Change in Standardized Rate of Apheresis Treatments From Week 15 to Week 18	Week 15 up to Week 18 (before the start of open-label treatment dose)	Rate of apheresis treatments were normalized by the rate by the number of actual apheresis treatments according to received from week 15 to week 18 divided by the planned apheresis treatments per randomization strata at baseline (2 for Q2W and 4 for QW). Only legitimate apheresis treatment skipping per point-of-care LDL-C value is counted as "apheresis not occurred". Missing apheresis treatment information (any reason) from week 7 to week 18 is assigned an outcome of the apheresis treatment occurred at the visit (i.e. impute 1 apheresis treatment for that visit).
Percent Change From Baseline in Apolipoprotein B (Apo B) (Pre-apheresis) to Week 6	From Baseline to Week 6	Adjusted LS means and standard errors at Week 6 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis).
Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) (Pre-apheresis) to Week 6	From Baseline to Week 6	Adjusted LS means and standard errors at Week 6 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis).
Percent Change From Baseline in Total Cholesterol (Pre-apheresis) to Week 6	From Baseline to Week 6	Adjusted LS means and standard errors at Week 6 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis).
Percent Change From Baseline in Apolipoprotein A (Apo A1) (Pre-apheresis) to Week 6	From Baseline to Week 6	Adjusted LS means and standard errors at Week 6 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis).
Percentage of Participants With At Least (>=) 30% Reduction in Calculated LDL-C (Pre-apheresis) at Week 6	From Baseline to Week 6	Percentage of participants at Week 6 was obtained from a last observation carried forward (LOCF) model for handling of missing data. All available post-baseline data regardless of status on- or off-treatment were used in the model (ITT analysis).
Percentage of Participants With At Least (>=) 50% Reduction in Calculated LDL-C (Pre-apheresis) at Week 6	From Baseline to Week 6	Percentage of participants at Week 6 was obtained from LOCF model for handling of missing data. All available post-baseline data regardless of status on- or off-treatment were used in the model (ITT analysis).
Percent Change From Baseline in Calculated LDL-C (Pre-Apheresis) to Week 18	From Baseline to Week 18	Adjusted LS means and standard errors at Week 18 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis).
Percent Change From Baseline in Apolipoprotein B (Apo B) (Pre-apheresis) to Week 18	From Baseline to Week 18	Adjusted LS means and standard errors at Week 18 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis).
Percent Change From Baseline in Non-HDL-C (Pre-apheresis) to Week 18	From Baseline to Week 18	Adjusted LS means and standard errors at Week 18 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis).
Percent Change From Baseline in Total Cholesterol (Pre-apheresis) to Week 18	From Baseline to Week 18	Adjusted LS means and standard errors at Week 18 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis).
Percent Change From Baseline in Apo A1 (Pre-apheresis) to Week 18	From Baseline to Week 18	Adjusted LS means and standard errors at Week 18 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis).
Percentage of Participants With At Least (>=) 30% Reduction in Calculated LDL-C (Pre-apheresis) at Week 18	From Baseline to Week 18	Percentage of participants at Week 18 was obtained from LOCF model for handling of missing data. All available post-baseline data regardless of status on- or off-treatment were used in the model (ITT analysis).
Percentage of Participants With At Least (>=) 50% Reduction in Calculated LDL-C (Pre-apheresis) at Week 18	From Baseline to Week 18	Percentage of participants at Week 18 was obtained from LOCF model for handling of missing data. All available post-baseline data regardless of status on- or off-treatment were used in the model (ITT analysis).
Change From Baseline in W-BQ22 (Well-being Questionnaire) Index Score at Week 18	From Baseline to Week 18	The W-BQ22 (well-being) questionnaire was a standardized and generic instrument used for measuring the impact of hypercholesterolemia and treatment on well-being of participants. The general well-being score was calculated as the sum of 22 questions in the W-BQ22 questionnaire (each question scored from 0 to 3 \[0 = not at all and 3 = all the time\]). Total score for 22 questions range from 0 to 66 \[0 = worst condition and 66 = best well-being condition).
Percent Change From Baseline in Lipoprotein (a) (Lp [a]) (Pre-apheresis) to Week 6	From Baseline to Week 6	Adjusted means and standard errors at Week 6 from a multiple imputation approach followed by robust regression model including all available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis).
Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) (Pre-apheresis) to Week 6	From Baseline to Week 6	Adjusted LS means and standard errors at Week 6 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis).
Percent Change From Baseline in Triglyceride (TG) Levels (Pre-apheresis) to Week 6	From Baseline to Week 6	Adjusted means and standard errors at Week 6 from a multiple imputation approach followed by robust regression model including all available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis).
Percent Change From Baseline in Lp (a) (Pre-apheresis) to Week 18	From Baseline to Week 18	Adjusted means and standard errors at Week 18 from a multiple imputation approach followed by robust regression model including all available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis).
Percent Change From Baseline in HDL-C (Pre-apheresis) to Week 18	From Baseline to Week 18	Adjusted LS means and standard errors at Week 18 were obtained from MMRM to account for missing data. All available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis).
Percent Change From Baseline in TG Levels (Pre-apheresis) to Week 18	From Baseline to Week 18	Adjusted means and standard errors at Week 18 from a multiple imputation approach followed by robust regression model including all available post-baseline data from Week 2 (pre-apheresis) to Week 18 (pre-apheresis) regardless of status on- or off-treatment were used in the model (ITT analysis).