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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Alirocumab in Patients With Heterozygous Familial Hypercholesterolemia Undergoing Lipid Apheresis Therapy

Conditions
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Heterozygous Familial Hypercholesterolemia

Intervention / Treatment
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* Drug: Placebo
* Drug: Alirocumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ≥18 years of age at the time of the screening visit Diagnosis of HeFH (Heterozygous familial hypercholesterolemia) 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: Homozygous FH (familial hypercholesterolemia) Background medical LMT (lipid-modifying therapy) (if applicable) that has not been stable for at least 8 weeks prior to the screening visit LDL apheresis schedule/ apheresis settings that have not been stable for at least 8 weeks prior to the screening visit An LDL apheresis schedule other than QW to Q2W Initiation of a new exercise program or exercise that has not remained stable within 8 weeks prior to the screening visit (week -2) Initiation of a new diet or a diet that has not been stable within 8 weeks prior to the screening visit (week -2) 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 Presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins Known history of a positive test for human immunodeficiency virus Use of any active investigational drugs within 1 month or 5 half-lives of screening, whichever is longer Patients who have been treated with at least 1 dose of alirocumab or any other anti-PCSK9 monoclonal antibody in any other clinical studies Pregnant or breastfeeding women

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo Q2W (Double Blind Period)<br>Placebo (for alirocumab) subcutaneous (SC) injection Q2W up to Week 16. | Drug: Placebo<br> <br> |
| Experimental: Alirocumab 150 mg Q2W (Double Blind Period)<br>Alirocumab 150 mg SC injection Q2W up to Week 16. | Drug: Alirocumab<br> <br> * Other names: Praluent®;|
| Experimental: Alirocumab 150 Q2W (Open Label Treatment Period)<br>Alirocumab 150 mg SC injection Q2W starting from Week 18 up to Week 76. | Drug: Alirocumab<br> <br> * Other names: Praluent®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Standardized Rate of Apheresis Treatments From Week 7 to Week 18 | 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). | Week 7 to Week 18 (before start of open-label treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Calculated LDL-C (Pre-apheresis) 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). | Baseline and at Week 6 | 
| Change in Standardized Rate of Apheresis Treatments From Week 15 to Week 18 | 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). | Week 15 up to Week 18 (before the start of open-label treatment dose) | 
| Percent Change From Baseline in Apolipoprotein B (Apo B) (Pre-apheresis) 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). | From Baseline to Week 6 | 
| Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) (Pre-apheresis) 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). | From Baseline to Week 6 | 
| Percent Change From Baseline in Total Cholesterol (Pre-apheresis) 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). | From Baseline to Week 6 | 
| Percent Change From Baseline in Apolipoprotein A (Apo A1) (Pre-apheresis) 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). | From Baseline to Week 6 | 
| Percentage of Participants With At Least (>=) 30% Reduction in Calculated LDL-C (Pre-apheresis) at 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). | From Baseline to Week 6 | 
| Percentage of Participants With At Least (>=) 50% Reduction in Calculated LDL-C (Pre-apheresis) at 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). | From Baseline to Week 6 | 
| Percent Change From Baseline in Calculated LDL-C (Pre-Apheresis) 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). | From Baseline to Week 18 | 
| Percent Change From Baseline in Apolipoprotein B (Apo B) (Pre-apheresis) 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). | From Baseline to Week 18 | 
| Percent Change From Baseline in Non-HDL-C (Pre-apheresis) 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). | From Baseline to Week 18 | 
| Percent Change From Baseline in Total Cholesterol (Pre-apheresis) 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). | From Baseline to Week 18 | 
| Percent Change From Baseline in Apo A1 (Pre-apheresis) 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). | From Baseline to Week 18 | 
| Percentage of Participants With At Least (>=) 30% Reduction in Calculated LDL-C (Pre-apheresis) at 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). | From Baseline to Week 18 | 
| Percentage of Participants With At Least (>=) 50% Reduction in Calculated LDL-C (Pre-apheresis) at 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). | From Baseline to Week 18 | 
| Change From Baseline in W-BQ22 (Well-being Questionnaire) Index Score at 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). | From Baseline to Week 18 | 
| Percent Change From Baseline in Lipoprotein (a) (Lp [a]) (Pre-apheresis) 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). | From Baseline to Week 6 | 
| Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) (Pre-apheresis) 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). | From Baseline to Week 6 | 
| Percent Change From Baseline in Triglyceride (TG) Levels (Pre-apheresis) 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). | From Baseline to Week 6 | 
| Percent Change From Baseline in Lp (a) (Pre-apheresis) 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). | From Baseline to Week 18 | 
| Percent Change From Baseline in HDL-C (Pre-apheresis) 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). | From Baseline to Week 18 | 
| Percent Change From Baseline in TG Levels (Pre-apheresis) 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). | From Baseline to Week 18 |