Heterozygous Familial Hypercholesterolemia
Conditions
Brief summary
This is a randomized, double-blind, placebo-controlled, parallel-group, multi-national study alirocumab (REGN727/SAR236553) in patients with Heterozygous Familial Hypercholesterolemia (heFH) who are not adequately controlled with their Lipid-Modifying Therapy (LMT).
Interventions
DRUGLMT (atorvastatin, simvastatin, or rosuvastatin)
DRUGalirocumab
Alirocumab administered as a subcutaneous (SC) injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.
DRUGPlacebo
Placebo matched to alirocumab administered as a SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.
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. Patients with heFH\* who are not adequately controlled\*\* with a maximally-tolerated daily dose\*\*\* of statin with or without other LMT, at a stable dose prior to the screening visit (week -2). \*Diagnosis of heFH must be made either by genotyping or by clinical criteria. For those patients not genotyped, the clinical diagnosis may be based on either the Simon Broome criteria for definite FH (Appendix 1) or the WHO/Dutch Lipid Network criteria with a score of \>8 points (Appendix 2). \*\* Not adequately controlled is defined as LDL-C ≥70 mg/dL (1.81 mmol/L) at the screening visit (week -2) in patients with a history of documented CVD (Appendix 3), or LDL-C ≥100 mg/dL (2.59 mmol/L) at the screening visit (week -2) in patients without a history of documented CVD. \*\*\* Maximally-tolerated dose is defined as (any of the following are acceptable): * Rosuvastatin 20 mg or 40 mg daily * Atorvastatin 40 mg or 80 mg daily * Simvastatin 80 mg daily (if already on this dose for \>1 year - see exclusion criterion #7) Note: Patients who are not able to be on any of the above statin doses should be treated with the dose of daily atorvastatin, rosuvastatin, or simvastatin which is considered appropriate for the patient, according to the investigator's judgment. Some examples of acceptable reasons for a patient taking a lower statin dose include, but are not limited to: adverse effects on higher doses, advanced age, low body mass index, regional practices, local prescribing information, concomitant medications, co-morbid conditions such as impaired glucose tolerance/impaired fasting glucose. The reason(s) will be documented in the case report form (CRF). 2. Provide signed informed consent
Exclusion criteria
1. Patient without diagnosis of heFH made either by genotyping or by clinical criteria 2. LDL-C \<70 mg/dL (\<1.81 mmol/L) at the screening visit (week-2) in patients with history of documented cardiovascular disease 3. LDL-C \<100 mg/dL (\<2.59 mmol/L) at the screening visit (week -2) in patients without history of documented cardiovascular disease 4. Not on a stable dose of LMT (including statin) for at least 4 weeks and/or fenofibrate for at least 6 weeks, as applicable, prior to the screening visit (week -2) and from screening to randomization 5. Currently taking another statin than simvastatin, atorvastatin, or rosuvastatin 6. Simvastatin, atorvastatin, or rosuvastatin is not taken daily or not taken at a registered dose 7. Daily doses above atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg (except for patients on simvastatin 80 mg for more than 1 year, who are eligible) 8. Use of fibrates, other than fenofibrate within 6 weeks of the screening visit (week-2) or between screening and randomization visits 9. Use of nutraceutical products or over-the-counter therapies that may affect lipids which have not been at a stable dose/amount for at least 4 weeks prior to the screening visit (week -2) or between screening and randomization visits 10. Use of red yeast rice products within 4 weeks of the screening visit (week-2), or between screening and randomization visits 11. Patient who has received plasmapheresis treatment within 2 months prior to the screening visit (week -2), or has plans to receive it during the study 12. Recent (within 3 months prior to the screening visit \[week -2\] or between screening and randomization visits) MI, unstable angina leading to hospitalization, percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG), uncontrolled cardiac arrhythmia, stroke, transient ischemic attack (TIA), carotid revascularization, endovascular procedure or surgical intervention for peripheral vascular disease (The inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent--to--Treat (ITT) Analysis | From Baseline to Week 52 | Calculated LDL-C values were obtained using the Friedewald formula. Adjusted Least- squares (LS) means and standard errors at Week 24 were obtained from a mixed -effect model with repeated measures (MMRM) to account for missing data. All available post -baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were used in the model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment (ITT analysis). |
| Percent Change From Baseline in Calculated LDL-C at Week 12 - On- Treatment Analysis | From Baseline to Week 52 | Calculated LDL-C values were obtained using the Friedewald formula. Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection) (on-treatment analysis). |
| Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection). |
| Percent Change From Baseline in Non-High -Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection). |
| Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Apo B at Week 12 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Total-C at Week 12 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post baseline data from Week 4 to Week 52 regardless of status on- or off treatment. |
| Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis | From Baseline to Week 52 | Calculated LDL-C values were obtained using the Friedewald formula. Adjusted LS means and standard errors at Week 52 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off treatment (ITT analysis). |
| Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis | From Baseline to Week 52 | Calculated LDL-C values were obtained using the Friedewald formula. Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection) (on-treatment analysis). |
| Percentage of Very High CV Risk Participants Reaching Calculated LDL--C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL--C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis | Up to week 52 | Adjusted percentages at Week 24 were obtained from a multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 52 i.e. up to 21 days after last injection (on-treatment analysis). |
| Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis | Up to Week 52 | Adjusted percentages at Week 24 were obtained from a multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were included in the imputation model (ITT analysis). |
| Percentage of Participants Reaching Calculated LDL--C <70 mg/dL (1.81 mmol/L) at Week 52 - On-Treatment Analysis | Up to Week 52 | Adjusted percentages at Week 52 were obtained from a multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 52 i.e. up to 21 days after last injection (on-treatment analysis). |
| Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis | From Baseline to Week 52 | Adjusted means and standard errors at Week 24 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment. |
| Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment. |
| Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | From Baseline to Week 52 | Adjusted means and standard errors at Week 24 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment. |
| Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment. |
| Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis | From Baseline to Week 52 | Adjusted means and standard errors at Week 12 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment. |
| Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment. |
| Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis | From Baseline to Week 52 | Adjusted means and standard errors at Week 12 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment. |
| Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment. |
| Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis | Up to Week 52 | Adjusted percentages at Week 24 were obtained from a multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were included in the imputation model (ITT analysis). |
Countries
Czechia, Netherlands, Norway, United Kingdom
Participant flow
Recruitment details
The study was conducted at 26 sites in 4 countries. Overall, 322 participants were screened between 28 Nov 2012 and 26 Apr 2013, 73 of whom were screen failures.
Pre-assignment details
Randomization was stratified according to prior history of myocardial infarction or ischemic stroke, and intensity of statin treatment. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 2:1 (alirocumab: placebo) ratio after confirmation of selection criteria.
Participants by arm
| Arm | Count |
|---|---|
| Alirocumab 75 mg/up to 150 mg Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8. | 167 |
| Placebo Placebo matched to alirocumab SC injection for 78--week treatment duration. | 82 |
| Total | 249 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 1 |
| Overall Study | Other | 3 | 1 |
| Overall Study | Poor compliance to protocol | 2 | 1 |
| Overall Study | Randomized but not treated | 0 | 1 |
| Overall Study | Related to IMP administration | 1 | 0 |
| Overall Study | Treatment ongoing | 156 | 78 |
Baseline characteristics
| Characteristic | Alirocumab 75 mg/up to 150 mg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 53.2 years STANDARD_DEVIATION 12.93 | 53.2 years STANDARD_DEVIATION 12.55 | 53.2 years STANDARD_DEVIATION 12.8 |
| Calculated LDL-C in mg/dL | 134.6 mg/dL STANDARD_DEVIATION 41.1 | 134.0 mg/dL STANDARD_DEVIATION 41.4 | 134.4 mg/dL STANDARD_DEVIATION 41.1 |
| Calculated LDL-C in mmol/L | 3.485 mmol/L STANDARD_DEVIATION 1.065 | 3.471 mmol/L STANDARD_DEVIATION 1.071 | 3.480 mmol/L STANDARD_DEVIATION 1.065 |
| Sex: Female, Male Female | 81 Participants | 37 Participants | 118 Participants |
| Sex: Female, Male Male | 86 Participants | 45 Participants | 131 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 65 / 167 | 35 / 81 |
| serious Total, serious adverse events | 10 / 167 | 7 / 81 |
Outcome results
Primary
Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent--to--Treat (ITT) Analysis
Calculated LDL-C values were obtained using the Friedewald formula. Adjusted Least- squares (LS) means and standard errors at Week 24 were obtained from a mixed -effect model with repeated measures (MMRM) to account for missing data. All available post -baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were used in the model.
Time frame: From Baseline to Week 52
Population: ITT population: all randomized participants with one baseline and at least one post-baseline calculated LDL-C value on- or off-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent--to--Treat (ITT) Analysis | -48.7 percent change | Standard Error 1.9 |
| Placebo | Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent--to--Treat (ITT) Analysis | 2.8 percent change | Standard Error 2.8 |
Comparison: Alirocumab group was compared to the placebo group using an appropriate contrast statement.p-value: <0.000195% CI: [-58.1, -44.8]Mixed Models Analysis
Secondary
Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis
Adjusted percentages at Week 24 were obtained from a multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were included in the imputation model (ITT analysis).
Time frame: Up to Week 52
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis | 68.2 percentage of participants |
| Placebo | Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis | 1.2 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.p-value: <0.000195% CI: [31.6, 1820.3]Regression, Logistic
Secondary
Percentage of Participants Reaching Calculated LDL--C <70 mg/dL (1.81 mmol/L) at Week 52 - On-Treatment Analysis
Adjusted percentages at Week 52 were obtained from a multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 52 i.e. up to 21 days after last injection (on-treatment analysis).
Time frame: Up to Week 52
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percentage of Participants Reaching Calculated LDL--C <70 mg/dL (1.81 mmol/L) at Week 52 - On-Treatment Analysis | 68.8 percentage of participants |
| Placebo | Percentage of Participants Reaching Calculated LDL--C <70 mg/dL (1.81 mmol/L) at Week 52 - On-Treatment Analysis | 1.3 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.p-value: <0.000195% CI: [31.4, 1841.7]Regression, Logistic
Secondary
Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis
Adjusted percentages at Week 24 were obtained from a multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were included in the imputation model (ITT analysis).
Time frame: Up to Week 52
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis | 81.4 percentage of participants |
| Placebo | Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis | 11.3 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.p-value: <0.000195% CI: [20.9, 130]Regression, Logistic
Secondary
Percentage of Very High CV Risk Participants Reaching Calculated LDL--C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL--C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis
Adjusted percentages at Week 24 were obtained from a multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 52 i.e. up to 21 days after last injection (on-treatment analysis).
Time frame: Up to week 52
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percentage of Very High CV Risk Participants Reaching Calculated LDL--C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL--C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis | 82.1 percentage of participants |
| Placebo | Percentage of Very High CV Risk Participants Reaching Calculated LDL--C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL--C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis | 11.6 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.p-value: <0.000195% CI: [21.4, 132.6]Regression, Logistic
Secondary
Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time frame: From Baseline to Week 52
Population: Apo A-1 ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis | 0.4 percent change | Standard Error 0.9 |
| Placebo | Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis | -1.9 percent change | Standard Error 1.3 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: =0.147595% CI: [-0.8, 5.5]Mixed Models Analysis
Secondary
Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time frame: From Baseline to Week 52
Population: Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline Apo A-1 value on- or off-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis | 2.8 percent change | Standard Error 0.9 |
| Placebo | Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis | -1.6 percent change | Standard Error 1.3 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: =0.006295% CI: [1.3, 7.5]Mixed Models Analysis
Secondary
Percent Change From Baseline in Apo B at Week 12 - ITT Analysis
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 52
Population: Apo B ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Apo B at Week 12 - ITT Analysis | -35.4 percent change | Standard Error 1.4 |
| Placebo | Percent Change From Baseline in Apo B at Week 12 - ITT Analysis | -0.9 percent change | Standard Error 2 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-39.2, -29.8]Mixed Models Analysis
Secondary
Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis
Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection).
Time frame: From Baseline to Week 52
Population: mITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis | -43.2 percent change | Standard Error 1.4 |
| Placebo | Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis | -3.5 percent change | Standard Error 2 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-44.5, -35.1]Mixed Models Analysis
Secondary
Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 52
Population: Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline Apo B value on- or off-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis | -42.8 percent change | Standard Error 1.4 |
| Placebo | Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis | -3.5 percent change | Standard Error 2 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-44.1, -34.5]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment (ITT analysis).
Time frame: From Baseline to Week 52
Population: ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis | -43.8 percent change | Standard Error 1.8 |
| Placebo | Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis | 4.6 percent change | Standard Error 2.6 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-54.7, -42.2]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated LDL-C at Week 12 - On- Treatment Analysis
Calculated LDL-C values were obtained using the Friedewald formula. Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection) (on-treatment analysis).
Time frame: From Baseline to Week 52
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Calculated LDL-C at Week 12 - On- Treatment Analysis | -44.2 percent change | Standard Error 1.8 |
| Placebo | Percent Change From Baseline in Calculated LDL-C at Week 12 - On- Treatment Analysis | 4.6 percent change | Standard Error 2.6 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-55, -42.5]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis
Calculated LDL-C values were obtained using the Friedewald formula. Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection) (on-treatment analysis).
Time frame: From Baseline to Week 52
Population: Modified ITT (mITT) population: all randomized and treated participants with one baseline and at least one post-baseline calculated LDL-C value on-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis | -49.4 percent change | Standard Error 1.9 |
| Placebo | Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis | 2.7 percent change | Standard Error 2.7 |
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 5% level.p-value: <0.000195% CI: [-58.7, -45.6]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis
Calculated LDL-C values were obtained using the Friedewald formula. Adjusted LS means and standard errors at Week 52 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off treatment (ITT analysis).
Time frame: From Baseline to Week 52
Population: ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis | -50.3 percent change | Standard Error 2.3 |
| Placebo | Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis | 8.4 percent change | Standard Error 3.3 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-66.8, -50.8]Mixed Models Analysis
Secondary
Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis
Adjusted means and standard errors at Week 12 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time frame: From Baseline to Week 52
Population: Fasting triglycerides ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis | -8.1 percent change | Standard Error 2.2 |
| Placebo | Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis | 0.6 percent change | Standard Error 3.1 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a robust regression model.p-value: =0.02495% CI: [-16.1, -1.1]Regression, Robust
Secondary
Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis
Adjusted means and standard errors at Week 24 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time frame: From Baseline to Week 52
Population: Participants analyzed: participants of the ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | -10.4 percent change | Standard Error 2 |
| Placebo | Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | 0.5 percent change | Standard Error 2.8 |
Comparison: Testing according to the hierarchical testing procedure. Statistical analysis used a multiple imputation approach followed by a robust regression model.p-value: =0.001295% CI: [-17.5, -4.3]Regression, Robust
Secondary
Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time frame: From Baseline to Week 52
Population: HDL-C ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis | 6.0 percent change | Standard Error 1 |
| Placebo | Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis | -0.8 percent change | Standard Error 1.6 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: =0.014795% CI: [0.9, 7.8]Mixed Models Analysis
Secondary
Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time frame: From Baseline to Week 52
Population: Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline HDL-C value on- or off-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis | 6.0 percent change | Standard Error 1.2 |
| Placebo | Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis | -0.8 percent change | Standard Error 1.6 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: =0.000995% CI: [2.8, 10.7]Mixed Models Analysis
Secondary
Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis
Adjusted means and standard errors at Week 12 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time frame: From Baseline to Week 52
Population: Lipoprotein (a) ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis | -24.7 percent change | Standard Deviation 1.7 |
| Placebo | Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis | -5.6 percent change | Standard Deviation 2.5 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a robust regression model.p-value: <0.000195% CI: [-25, -13.1]Regression, Robust
Secondary
Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis
Adjusted means and standard errors at Week 24 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time frame: From Baseline to Week 52
Population: Participants analyzed: participants of the ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis | -30.3 percent change | Standard Error 1.8 |
| Placebo | Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis | -10 percent change | Standard Error 2.5 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a robust regression model.p-value: <0.000195% CI: [-26.4, -14.2]Regression, Robust
Secondary
Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 52
Population: Non-HDL-C ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis | -37.9 percent change | Standard Error 1.7 |
| Placebo | Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis | 4.1 percent change | Standard Error 2.4 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-47.8, -36.2]Mixed Models Analysis
Secondary
Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis
Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection).
Time frame: From Baseline to Week 52
Population: mITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis | -43.2 percent change | Standard Error 1.7 |
| Placebo | Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis | 3.1 percent change | Standard Error 2.5 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-52.3, -40.4]Mixed Models Analysis
Secondary
Percent Change From Baseline in Non-High -Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 52
Population: Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline non-HDL-C value on- or off-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Non-High -Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis | -42.6 percent change | Standard Error 1.8 |
| Placebo | Percent Change From Baseline in Non-High -Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis | 3.1 percent change | Standard Error 2.5 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-51.8, -39.7]Mixed Models Analysis
Secondary
Percent Change From Baseline in Total-C at Week 12 - ITT Analysis
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post baseline data from Week 4 to Week 52 regardless of status on- or off treatment.
Time frame: From Baseline to Week 52
Population: Total--C ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Total-C at Week 12 - ITT Analysis | -26.6 percent change | Standard Error 1.3 |
| Placebo | Percent Change From Baseline in Total-C at Week 12 - ITT Analysis | 3.4 percent change | Standard Error 1.9 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-34.5, -25.4]Mixed Models Analysis
Secondary
Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 52
Population: Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline total-C value on- or off-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg/up to 150 mg | Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis | -30.6 percent change | Standard Error 1.4 |
| Placebo | Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis | 2.1 percent change | Standard Error 1.9 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-37.4, -28.1]Mixed Models Analysis