Heterozygous Familial Hypercholesterolemia
Conditions
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.
Interventions
DRUGPlacebo
DRUGAlirocumab
Sponsors
Sanofi
Regeneron Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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). |
| 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). |
| 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). |
Countries
Germany, United States
Participant flow
Recruitment details
The study was conducted in Germany and the United States between 09 Mar 2015 and 20 Apr 2016. A total of 76 participants were screened, of which 62 were enrolled and randomized in the study.
Pre-assignment details
Randomization was stratified according to the frequency of the apheresis procedure (every 7 or 14 days) and lipoprotein (a) (Lp \[a\]) levels (normal or elevated). Assignment to treatment arms was done using an Interactive Voice/Web Response System in 1:2 ratio to placebo or alirocumab 150 mg Q2W.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Q2W (Double Blind Period) Placebo (for alirocumab) SC injection Q2W up to Week 16. Apheresis frequency was fixed (weekly or bi-weekly) until Week 6, then it was adjusted according to the response to treatment. (Participants undergoing LDL apheresis therapy every 1 or 2 weeks were enrolled in this study while maintaining background lipid modifying therapy (LMT) treatment throughout the study. All participants were being treated with the maximally tolerated clinically-relevant LMT). | 21 |
| Alirocumab 150 mg Q2W (Double Blind Period) Alirocumab 150 mg SC injection Q2W up to Week 16. Apheresis frequency was fixed (weekly or bi-weekly) until Week 6, then it was adjusted according to the response to treatment. (Participants undergoing LDL apheresis therapy every 1 or 2 weeks were enrolled in this study while maintaining background lipid modifying therapy (LMT) treatment throughout the study. All participants were being treated with the maximally tolerated clinically-relevant LMT). | 41 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-blind Treatment Period | Adverse Event | 1 | 2 | 0 |
| Double-blind Treatment Period | Protocol Violation | 0 | 1 | 0 |
| Double-blind Treatment Period | Withdrawal by Subject | 0 | 1 | 0 |
| Open-label Treatment Period | Lost to Follow-up | 0 | 0 | 1 |
| Open-label Treatment Period | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo Q2W (Double Blind Period) | Alirocumab 150 mg Q2W (Double Blind Period) | Total |
|---|---|---|---|
| Age, Continuous | 57 years STANDARD_DEVIATION 10.5 | 59.5 years STANDARD_DEVIATION 9.2 | 58.7 years STANDARD_DEVIATION 9.7 |
| Apolipoprotein A1 (Apo-A1) | 145.8 mg/dL STANDARD_DEVIATION 32.5 | 140.1 mg/dL STANDARD_DEVIATION 25.5 | 142.1 mg/dL STANDARD_DEVIATION 27.9 |
| Apolipoprotein B (Apo-B) | 145.8 mg/dL STANDARD_DEVIATION 34 | 135.2 mg/dL STANDARD_DEVIATION 36.4 | 138.8 mg/dL STANDARD_DEVIATION 35.7 |
| Calculated low-density lipoprotein cholesterol (LDL-C) | 191.6 mg/dL STANDARD_DEVIATION 68.9 | 175.1 mg/dL STANDARD_DEVIATION 54.6 | 180.7 mg/dL STANDARD_DEVIATION 59.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 41 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Frequency in which participants are undergoing LDL apheresis Every 2 weeks | 12 Treatments | 23 Treatments | 35 Treatments |
| Frequency in which participants are undergoing LDL apheresis Every week | 9 Treatments | 18 Treatments | 27 Treatments |
| High-density lipoprotein cholesterol (HDL-C) | 47.8 mg/dL STANDARD_DEVIATION 17.3 | 46.6 mg/dL STANDARD_DEVIATION 16.2 | 47.0 mg/dL STANDARD_DEVIATION 16.4 |
| Lipoprotein a [Lp(a)] | 45.7 mg/dL STANDARD_DEVIATION 49.5 | 43.0 mg/dL STANDARD_DEVIATION 54.5 | 43.9 mg/dL STANDARD_DEVIATION 52.4 |
| Measured LDL-C | 195.0 mg/dL STANDARD_DEVIATION 66.9 | 174.0 mg/dL STANDARD_DEVIATION 51.4 | 181.1 mg/dL STANDARD_DEVIATION 57.4 |
| Non-high-density lipoprotein cholesterol (HDL-C) | 224.5 mg/dL STANDARD_DEVIATION 68 | 210.3 mg/dL STANDARD_DEVIATION 62.8 | 215.1 mg/dL STANDARD_DEVIATION 64.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 21 Participants | 39 Participants | 60 Participants |
| Sex: Female, Male Female | 11 Participants | 15 Participants | 26 Participants |
| Sex: Female, Male Male | 10 Participants | 26 Participants | 36 Participants |
| Total-cholesterol (Total-C) | 272.3 mg/dL STANDARD_DEVIATION 73.6 | 256.9 mg/dL STANDARD_DEVIATION 60.6 | 262.1 mg/dL STANDARD_DEVIATION 65.1 |
| Triglycerides (TGs) | 164.4 mg/dL STANDARD_DEVIATION 61.4 | 176.0 mg/dL STANDARD_DEVIATION 87.2 | 172.1 mg/dL STANDARD_DEVIATION 79 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 41 | 0 / 29 |
| other Total, other adverse events | 10 / 21 | 22 / 41 | 2 / 29 |
| serious Total, serious adverse events | 2 / 21 | 4 / 41 | 1 / 29 |
Outcome results
Primary
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).
Time frame: Week 7 to Week 18 (before start of open-label treatment)
Population: Primary intent-to-treat (ITT) population defined as all randomized participants and were analyzed according to the treatment group allocated by randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Change in Standardized Rate of Apheresis Treatments From Week 7 to Week 18 | 0.806 Treatments | Standard Deviation 0.191 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Change in Standardized Rate of Apheresis Treatments From Week 7 to Week 18 | 0.128 Treatments | Standard Deviation 0.242 |
Comparison: Analysis was performed using the ranked analysis of covariance (ANCOVA) model with baseline frequency of the apheresis procedure (QW or Q2W) and Lp(a) levels (normal or elevated) as fixed effect and the baseline LDL-C level as a covariate. Hodges-Lehmann estimator of median difference (median of all pairwise differences; CI is Moses distribution free CI.~p-value is derived from the rank-based ANCOVA model. The model includes the baseline LDL-C value and stratification factors per IVRS.p-value: <0.000195% CI: [0.667, 0.833]ANCOVA
Secondary
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).
Time frame: From Baseline to Week 18
Population: Analysis was performed on Well-Being analysis set included all randomized and treated participants with complete baseline and complete post-baseline evaluations of the 22-question well-being questionnaire.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Change From Baseline in W-BQ22 (Well-being Questionnaire) Index Score at Week 18 | -1.43 scores on a scale | Standard Error 1.441 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Change From Baseline in W-BQ22 (Well-being Questionnaire) Index Score at Week 18 | 0.91 scores on a scale | Standard Error 1.04 |
Secondary
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).
Time frame: Week 15 up to Week 18 (before the start of open-label treatment dose)
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Change in Standardized Rate of Apheresis Treatments From Week 15 to Week 18 | 0.774 Treatments | Standard Deviation 0.315 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Change in Standardized Rate of Apheresis Treatments From Week 15 to Week 18 | 0.165 Treatments | Standard Deviation 0.334 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [0.5, 1]ANCOVA
Secondary
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).
Time frame: From Baseline to Week 18
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Q2W (Double Blind Period) | Percentage of Participants With At Least (>=) 30% Reduction in Calculated LDL-C (Pre-apheresis) at Week 18 | 0 percentage of participants |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percentage of Participants With At Least (>=) 30% Reduction in Calculated LDL-C (Pre-apheresis) at Week 18 | 65.9 percentage of participants |
Secondary
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).
Time frame: From Baseline to Week 6
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Q2W (Double Blind Period) | Percentage of Participants With At Least (>=) 30% Reduction in Calculated LDL-C (Pre-apheresis) at Week 6 | 4.8 percentage of participants |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percentage of Participants With At Least (>=) 30% Reduction in Calculated LDL-C (Pre-apheresis) at Week 6 | 95.1 percentage of participants |
Secondary
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).
Time frame: From Baseline to Week 18
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Q2W (Double Blind Period) | Percentage of Participants With At Least (>=) 50% Reduction in Calculated LDL-C (Pre-apheresis) at Week 18 | 0 percentage of participants |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percentage of Participants With At Least (>=) 50% Reduction in Calculated LDL-C (Pre-apheresis) at Week 18 | 43.9 percentage of participants |
Secondary
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).
Time frame: From Baseline to Week 6
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Q2W (Double Blind Period) | Percentage of Participants With At Least (>=) 50% Reduction in Calculated LDL-C (Pre-apheresis) at Week 6 | 0 percentage of participants |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percentage of Participants With At Least (>=) 50% Reduction in Calculated LDL-C (Pre-apheresis) at Week 6 | 63.4 percentage of participants |
Secondary
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).
Time frame: From Baseline to Week 18
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Percent Change From Baseline in Apo A1 (Pre-apheresis) to Week 18 | -0.7 Percent change | Standard Error 3.4 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percent Change From Baseline in Apo A1 (Pre-apheresis) to Week 18 | 7.8 Percent change | Standard Error 2.4 |
Secondary
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).
Time frame: From Baseline to Week 6
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Percent Change From Baseline in Apolipoprotein A (Apo A1) (Pre-apheresis) to Week 6 | 0 Percent change | Standard Error 3.3 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percent Change From Baseline in Apolipoprotein A (Apo A1) (Pre-apheresis) to Week 6 | 4.2 Percent change | Standard Error 2.4 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: 0.301295% CI: [-3.9, 12.3]MMRM
Secondary
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).
Time frame: From Baseline to Week 18
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Percent Change From Baseline in Apolipoprotein B (Apo B) (Pre-apheresis) to Week 18 | 1.7 percent change | Standard Error 4.8 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percent Change From Baseline in Apolipoprotein B (Apo B) (Pre-apheresis) to Week 18 | -33.8 percent change | Standard Error 3.5 |
Secondary
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).
Time frame: From Baseline to Week 6
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Percent Change From Baseline in Apolipoprotein B (Apo B) (Pre-apheresis) to Week 6 | 1.2 Percent change | Standard Error 3 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percent Change From Baseline in Apolipoprotein B (Apo B) (Pre-apheresis) to Week 6 | -42.8 Percent change | Standard Error 2.1 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-51.3, -36.6]MMRM
Secondary
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).
Time frame: Baseline and at Week 6
Population: Analysis was performed on ITT population that included all randomized particpants with baseline and at least one post-baseline pre-apheresis calculated LDL-C value up to week 6, analyzed according to the treatment group allocated by randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Percent Change From Baseline in Calculated LDL-C (Pre-apheresis) at Week 6 | 1.6 percent change in mmol/L | Standard Error 3.1 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percent Change From Baseline in Calculated LDL-C (Pre-apheresis) at Week 6 | -53.7 percent change in mmol/L | Standard Error 2.3 |
Comparison: A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.p-value: <0.000195% CI: [-63, -47.5]MMRM
Secondary
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).
Time frame: From Baseline to Week 18
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Percent Change From Baseline in Calculated LDL-C (Pre-Apheresis) to Week 18 | 4 Percent change | Standard Error 6.2 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percent Change From Baseline in Calculated LDL-C (Pre-Apheresis) to Week 18 | -42.3 Percent change | Standard Error 4.5 |
Secondary
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).
Time frame: From Baseline to Week 18
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Percent Change From Baseline in HDL-C (Pre-apheresis) to Week 18 | 2.4 Percent change | Standard Error 5 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percent Change From Baseline in HDL-C (Pre-apheresis) to Week 18 | 10.9 Percent change | Standard Error 3.6 |
Secondary
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).
Time frame: From Baseline to Week 6
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) (Pre-apheresis) to Week 6 | 4 percent change | Standard Error 3.4 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) (Pre-apheresis) to Week 6 | 9.3 percent change | Standard Error 2.4 |
Secondary
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).
Time frame: From Baseline to Week 6
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Percent Change From Baseline in Lipoprotein (a) (Lp [a]) (Pre-apheresis) to Week 6 | -4 percent change | Standard Error 5.1 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percent Change From Baseline in Lipoprotein (a) (Lp [a]) (Pre-apheresis) to Week 6 | -18.1 percent change | Standard Error 3.7 |
Secondary
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).
Time frame: From Baseline to Week 18
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Percent Change From Baseline in Lp (a) (Pre-apheresis) to Week 18 | -1.2 Percent change | Standard Error 8 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percent Change From Baseline in Lp (a) (Pre-apheresis) to Week 18 | -6.1 Percent change | Standard Error 5.9 |
Secondary
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).
Time frame: From Baseline to Week 18
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Percent Change From Baseline in Non-HDL-C (Pre-apheresis) to Week 18 | 4.7 Percent change | Standard Error 5.6 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percent Change From Baseline in Non-HDL-C (Pre-apheresis) to Week 18 | -35.7 Percent change | Standard Error 4.1 |
Secondary
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).
Time frame: From Baseline to Week 6
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) (Pre-apheresis) to Week 6 | 2.8 Percent change | Standard Error 2.9 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) (Pre-apheresis) to Week 6 | -47.1 Percent change | Standard Error 2.1 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-57.3, -42.7]MMRM
Secondary
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).
Time frame: From Baseline to Week 18
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Percent Change From Baseline in TG Levels (Pre-apheresis) to Week 18 | 4.1 Percent change | Standard Error 7.9 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percent Change From Baseline in TG Levels (Pre-apheresis) to Week 18 | -2.4 Percent change | Standard Error 5.8 |
Secondary
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).
Time frame: From Baseline to Week 18
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Percent Change From Baseline in Total Cholesterol (Pre-apheresis) to Week 18 | 4.7 Percent change | Standard Error 4.7 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percent Change From Baseline in Total Cholesterol (Pre-apheresis) to Week 18 | -27.1 Percent change | Standard Error 3.4 |
Secondary
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).
Time frame: From Baseline to Week 6
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Percent Change From Baseline in Total Cholesterol (Pre-apheresis) to Week 6 | 3.1 Percent change | Standard Error 2.5 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percent Change From Baseline in Total Cholesterol (Pre-apheresis) to Week 6 | -36.4 Percent change | Standard Error 1.8 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-45.6, -33.2]MMRM
Secondary
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).
Time frame: From Baseline to Week 6
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W (Double Blind Period) | Percent Change From Baseline in Triglyceride (TG) Levels (Pre-apheresis) to Week 6 | 3 percent change | Standard Error 5.6 |
| Alirocumab 150 mg Q2W (Double Blind Period) | Percent Change From Baseline in Triglyceride (TG) Levels (Pre-apheresis) to Week 6 | -12.9 percent change | Standard Error 4 |