Hypercholesterolaemia
Conditions
Brief summary
Alirocumab (SAR236553/REGN727) is a fully human monoclonal antibody that binds PCSK9 (proprotein convertase subtilisin/kexin type 9). Primary Objective of the study: To evaluate the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C) levels after 24 weeks of treatment in comparison with placebo. Secondary Objectives: * To evaluate the effect of alirocumab in comparison with placebo on LDL-C at other time points * To evaluate the effects of alirocumab on other lipid parameters * To evaluate the safety and tolerability of alirocumab
Detailed description
The maximum study duration was planned to be 89 weeks per participant including participants who successfully completed the 78-week treatment period had the possibility to join an open-label extension study (LTS13463, NCT01954394) at the end of the treatment period.
Interventions
DRUGAlirocumab
Solution for subcutaneous injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using auto-injector (also known as pre filled pen).
Solution for subcutaneous injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using auto-injector (also known as pre filled pen).
Statin (rosuvastatin, simvastatin or atorvastatin) at stable dose with or without other LMT as clinically indicated.
Sponsors
Regeneron Pharmaceuticals
Sanofi
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
* Participants with heterozygous familial hypercholesterolemia who were not adequately controlled with their lipid-modifying therapy.
Exclusion criteria
* Age \< 18 years * LDL-C \< 160 mg/dL (\< 4.14 mmol/L) at the screening visit (Week-3). * Fasting serum triglycerides \> 400 mg/dL (\> 4.52 mmol/L) during the screening period. * Known history of homozygous familial hypercholesterolemia. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Calculated LDL-C at Week 24 - ITT Analysis | From Baseline to Week 52 | 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 (ITT analysis). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis | From Baseline to Week 52 | 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. |
| 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 Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis | Up to Week 52 | Adjusted percentages at Week 24 from multiple imputation approach including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment. |
| Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis | Up to Week 52 | Adjusted percentages at Week 24 from multiple imputation approach 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 Calculated LDL-C at Week 24 - On-Treatment Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 24 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 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. |
| Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 12 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 Apolipoprotein B (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 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 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. |
| Percentage of Very High Cardiovascular (CV) Risk Participants Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Participants Achieving Calculated LDL-C < 100 mg/dL (<2.59 mmol/L) at Week 24 - ITT Analysis | Up to Week 52 | Very high CV risk participants: Heterozygous Familial Hypercholesterolemia (heFH) participants with coronary heart disease (CHD) or CHD risk equivalents. High CV risk participants: heFH participants without CHD or CHD risk equivalents. CHD risk equivalent: peripheral arterial disease, ischemic stroke, moderate chronic kidney disease (estimated glomerular filtration rate, 30 to \<60 ml/minute/1.73 m\^2 of body-surface area), or diabetes mellitus plus 2 or more additional risk factors (hypertension; ankle-brachial index of ≤0.90; microalbuminuria, macroalbuminuria, or a urinary dipstick result of \>2+ protein; preproliferative or proliferative retinopathy or laser treatment for retinopathy; or a family history of premature CHD). 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. |
| Percentage of Very High CV Risk Participants Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Participants Achieving 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 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. |
| 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 followed by robust regression 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 multiple imputation approach followed by robust regression 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 Apolipoprotein A-1 (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 multiple imputation approach followed by robust regression 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 multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Calculated LDL-C at Week 78 - On-Treatment Analysis | From Baseline to Week 78 | Adjusted LS means and standard errors at Week 78 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 78 i.e. up to 21 days after last injection. |
| Percent Change From Baseline in Calculated LDL-C at Week 78 - ITT Analysis | From Baseline to Week 78 | Adjusted LS means and standard errors at Week 78 from MMRM model including all available post-baseline data from Week 4 to Week 78 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 52 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. |
Countries
Canada, Netherlands, Russia, South Africa, United States
Participant flow
Recruitment details
The study was conducted at 33 centers in 5 countries. A total of 206 participants were screened between June 2012 and May 2013, 99 of whom were screen failures. Screen failures were mainly due to exclusion criteria met.
Pre-assignment details
Randomization was stratified according to prior history of myocardial infarction (MI) or ischemic stroke, and intensity of statin treatment. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 1:2 ratio (placebo:alirocumab) after confirmation of selection criteria. 107 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Q2W Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks. | 35 |
| Alirocumab 150 mg Q2W Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks. | 72 |
| Total | 107 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 |
| Overall Study | Consent withdrawn by participant | 1 | 1 |
| Overall Study | Last visit outside protocol visit window | 1 | 10 |
| Overall Study | Other than specified above | 1 | 2 |
| Overall Study | Participants moved | 0 | 4 |
| Overall Study | Poor compliance to protocol | 1 | 4 |
| Overall Study | Site closure | 3 | 5 |
Baseline characteristics
| Characteristic | Alirocumab 150 mg Q2W | Total | Placebo Q2W |
|---|---|---|---|
| Age, Continuous | 49.8 years STANDARD_DEVIATION 14.2 | 50.6 years STANDARD_DEVIATION 13.3 | 52.1 years STANDARD_DEVIATION 11.2 |
| Calculated LDL-C in mg/dL | 196.3 mg/dL STANDARD_DEVIATION 57.9 | 197.8 mg/dL STANDARD_DEVIATION 53.4 | 201 mg/dL STANDARD_DEVIATION 43.4 |
| Calculated low density lipoprotein cholesterol (LDL-C) in mmol/L | 5.083 mmol/L STANDARD_DEVIATION 1.499 | 5.123 mmol/L STANDARD_DEVIATION 1.382 | 5.205 mmol/L STANDARD_DEVIATION 1.125 |
| Sex: Female, Male Female | 37 Participants | 50 Participants | 13 Participants |
| Sex: Female, Male Male | 35 Participants | 57 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 35 | 39 / 72 |
| serious Total, serious adverse events | 4 / 35 | 10 / 72 |
Outcome results
Primary
Percent Change From Baseline in Calculated LDL-C at Week 24 - ITT Analysis
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 (ITT analysis).
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 |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 24 - ITT Analysis | -6.6 percent change | Standard Error 4.9 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 24 - ITT Analysis | -45.7 percent change | Standard Error 3.5 |
Comparison: Alirocumab group was compared to placebo group using an appropriate contrast statement.p-value: <0.000195% CI: [-51.1, -27.1]Mixed Models Analysis
Secondary
Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis
Adjusted percentages at Week 24 from multiple imputation approach including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time frame: Up to Week 52
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Q2W | Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis | 2.9 percentage of participants |
| Alirocumab 150 mg Q2W | Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis | 32.4 percentage of participants |
Secondary
Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis
Adjusted percentages at Week 24 from multiple imputation approach including available post-baseline on-treatment data from Week 4 to Week 52 i.e. up to 21 days after last injection.
Time frame: Up to Week 52
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Q2W | Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis | 2.9 percentage of participants |
| Alirocumab 150 mg Q2W | Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis | 32.6 percentage of participants |
Secondary
Percentage of Very High Cardiovascular (CV) Risk Participants Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Participants Achieving Calculated LDL-C < 100 mg/dL (<2.59 mmol/L) at Week 24 - ITT Analysis
Very high CV risk participants: Heterozygous Familial Hypercholesterolemia (heFH) participants with coronary heart disease (CHD) or CHD risk equivalents. High CV risk participants: heFH participants without CHD or CHD risk equivalents. CHD risk equivalent: peripheral arterial disease, ischemic stroke, moderate chronic kidney disease (estimated glomerular filtration rate, 30 to \<60 ml/minute/1.73 m\^2 of body-surface area), or diabetes mellitus plus 2 or more additional risk factors (hypertension; ankle-brachial index of ≤0.90; microalbuminuria, macroalbuminuria, or a urinary dipstick result of \>2+ protein; preproliferative or proliferative retinopathy or laser treatment for retinopathy; or a family history of premature CHD). 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.
Time frame: Up to Week 52
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Q2W | Percentage of Very High Cardiovascular (CV) Risk Participants Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Participants Achieving Calculated LDL-C < 100 mg/dL (<2.59 mmol/L) at Week 24 - ITT Analysis | 5.7 percentage of participants |
| Alirocumab 150 mg Q2W | Percentage of Very High Cardiovascular (CV) Risk Participants Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Participants Achieving Calculated LDL-C < 100 mg/dL (<2.59 mmol/L) at Week 24 - ITT Analysis | 41.0 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: 0.001695% CI: [2.5, 53.5]Regression, Logistic
Secondary
Percentage of Very High CV Risk Participants Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Participants Achieving Calculated LDL-C < 100 mg/dL (<2.59 mmol/L) at Week 24 - On-Treatment Analysis
Adjusted percentages at Week 24 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.
Time frame: Up to Week 52
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Q2W | Percentage of Very High CV Risk Participants Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Participants Achieving Calculated LDL-C < 100 mg/dL (<2.59 mmol/L) at Week 24 - On-Treatment Analysis | 5.7 percentage of participants |
| Alirocumab 150 mg Q2W | Percentage of Very High CV Risk Participants Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Participants Achieving Calculated LDL-C < 100 mg/dL (<2.59 mmol/L) at Week 24 - On-Treatment Analysis | 41.4 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: 0.001495% CI: [2.6, 54.9]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 |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis | 1.1 percent change | Standard Error 2.2 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis | 4.6 percent change | Standard Error 1.5 |
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 |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Apo B at Week 12 - ITT Analysis | -9 percent change | Standard Error 3.7 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Apo B at Week 12 - ITT Analysis | -39.2 percent change | Standard Error 2.6 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-39.2, -21.1]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 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: Participants of the mITT population with one baseline and at least one post-baseline Apo B value on-treatment (Apo B mITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis | -8.7 percent change | Standard Error 3.9 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis | -38.9 percent change | Standard Error 2.8 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-39.7, -20.7]Mixed Models Analysis
Secondary
Percent Change From Baseline in Apolipoprotein A-1 (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 of the ITT population with one baseline and at least one post-baseline Apo A-1 value on-or off-treatment (Apo A-1 ITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 24 - ITT Analysis | 2 percent change | Standard Error 2.1 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 24 - ITT Analysis | 5.6 percent change | Standard Error 1.5 |
Secondary
Percent Change From Baseline in Apolipoprotein B (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 of the ITT population with one baseline and at least one post-baseline Apo B value on- or off-treatment (Apo B ITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 24 - ITT Analysis | -8.7 percent change | Standard Error 3.8 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 24 - ITT Analysis | -39 percent change | Standard Error 2.7 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-39.7, -20.9]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.
Time frame: From Baseline to Week 52
Population: ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis | -6.6 percent change | Standard Error 4.6 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis | -46.9 percent change | Standard Error 3.2 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-51.4, -29.3]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis
Adjusted LS means and standard errors at Week 12 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 |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis | -6.6 percent change | Standard Error 4.6 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis | -46.9 percent change | Standard Error 3.2 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-51.4, -29.2]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis
Adjusted LS means and standard errors at Week 24 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 |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis | -6.6 percent change | Standard Error 5 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis | -45.5 percent change | Standard Error 3.5 |
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: [-51, -26.9]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis
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.
Time frame: From Baseline to Week 52
Population: ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis | -3 percent change | Standard Error 5.9 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis | -42.1 percent change | Standard Error 4.2 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-53.6, -24.6]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 multiple imputation approach followed by robust regression 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: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis | -4.4 percent change | Standard Error 5.1 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis | -9.4 percent change | Standard Error 3.7 |
Secondary
Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis
Adjusted means and standard errors at Week 24 from multiple imputation approach followed by robust regression 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: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | -1.9 percent change | Standard Error 4.8 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | -10.5 percent change | Standard Error 3.3 |
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 |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis | 8.0 percent change | Standard Error 3.4 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis | 7.9 percent change | Standard Error 2.4 |
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 of the ITT population with one baseline and at least one post-baseline HDL-C value on-or off-treatment (HDL-C ITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis | 3.9 percent change | Standard Error 2.7 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis | 7.5 percent change | Standard Error 1.9 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: 0.274595% CI: [-2.9, 10.2]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 multiple imputation approach followed by robust regression 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: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis | -1.5 percent change | Standard Error 5.1 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis | -23.2 percent change | Standard Error 3.6 |
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 followed by robust regression 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: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis | -8.7 percent change | Standard Error 5 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis | -23.5 percent change | Standard Error 3.7 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: 0.016495% CI: [-26.9, -2.7]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 |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis | -6.9 percent change | Standard Error 4.3 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis | -41.4 percent change | Standard Error 3 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-44.8, -24.1]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 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: Participants of the mITT population with one baseline and at least one post-baseline non-HDL-C value on-treatment (non-HDL-C mITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis | -6.1 percent change | Standard Error 4.3 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis | -41.7 percent change | Standard Error 3.1 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-46.2, -24.9]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 of the ITT population with one baseline and at least one post-baseline non-HDL-C value on- or off-treatment (non-HDL-C ITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis | -6.2 percent change | Standard Error 4.3 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis | -41.9 percent change | Standard Error 3.1 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-46.3, -25.3]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 |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Total-C at Week 12 - ITT Analysis | -5.2 percent change | Standard Error 3.5 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Total-C at Week 12 - ITT Analysis | -33 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: <0.000195% CI: [-36.2, -19.4]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 of the ITT population with one baseline and at least one post-baseline total-C value on- or off-treatment (total-C ITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis | -4.8 percent change | Standard Error 3.6 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis | -33.2 percent change | Standard Error 2.6 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-37.3, -19.6]Mixed Models Analysis
Other Pre-specified
Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis
Adjusted LS means and standard errors at Week 52 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 |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis | -2.9 percent change | Standard Error 6.1 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis | -42.0 percent change | Standard Error 4.4 |
Other Pre-specified
Percent Change From Baseline in Calculated LDL-C at Week 78 - ITT Analysis
Adjusted LS means and standard errors at Week 78 from MMRM model including all available post-baseline data from Week 4 to Week 78 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 78
Population: ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 78 - ITT Analysis | 1.2 percent change | Standard Error 6.4 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 78 - ITT Analysis | -37.9 percent change | Standard Error 4.5 |
Other Pre-specified
Percent Change From Baseline in Calculated LDL-C at Week 78 - On-Treatment Analysis
Adjusted LS means and standard errors at Week 78 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 78 i.e. up to 21 days after last injection.
Time frame: From Baseline to Week 78
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 78 - On-Treatment Analysis | -0.2 percent change | Standard Error 6.2 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 78 - On-Treatment Analysis | -40.9 percent change | Standard Error 4.5 |