Hypercholesterolemia
Conditions
Brief summary
Primary Objective: To demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab as add-on therapy to stable daily statin therapy with or without other lipid modifying therapy in comparison with placebo after 24 weeks of treatment in heterozygous familial hypercholesterolemia (HeFH) or high cardiovascular risk participants with hypercholesterolemia. Secondary Objectives: * To evaluate the effect of alirocumab in comparison with placebo on LDL-C after 12 weeks of treatment. * To evaluate the effect of alirocumab on other lipid parameters. * To evaluate the long-term effect of alirocumab in comparison with placebo on LDL-C after 52 weeks of treatment. * To evaluate the safety and tolerability of alirocumab. * To evaluate the development of anti-alirocumab antibodies. * To evaluate the pharmacokinetics of alirocumab.
Detailed description
Total duration per participant of approximately 63 weeks (14 months) (screening: 3 weeks, double-blind treatment period: 52 weeks, and follow-up period: 8 weeks).
Interventions
Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with an auto-injector.
DRUGAlirocumab
Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with an auto-injector.
Statin (pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin) 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
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Participants with heterozygous familial hypercholesterolemia or non-familial hypercholesterolemia who were not adequately controlled with a stable daily dose of statin with or without other lipid modifying therapy, at stable dose prior to the screening visit (Week -3).
Exclusion criteria
1. LDL-C \<100 mg/dL (\<2.59 mmol/L) at the screening visit in participants with heterozygous familial hypercholesterolemia or in participants with non-familial hypercholesterolemia who had a history of documented coronary heart disease as described in Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. 2. LDL-C \<120 mg/dL (\<3.10 mmol/L) at the screening visit in participants with non-familial hypercholesterolemia who had a history of documented diseases or other risk factors as categorized in primary prevention category III as described in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. 3. Not on a stable daily dose of lipid modifying therapy (including statin) within 4 weeks prior to the screening visit or between screening and randomization visits. 4. Age \<20 years at the screening visit. The above information is not intended to contain all considerations relevant to a participants' potential participation in a clinical trial.
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 24 | 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 24 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 24 - On-Treatment Analysis | From Baseline to Week 24 | 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 24 (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 24 | Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline data from Week 4 to Week 24 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 24 | Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection). |
| Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis | From baseline to Week 24 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis | From Baseline to Week 24 | 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 24 (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 24 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 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 24 | Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (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 24 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Apo B at Week 12 - ITT Analysis | From Baseline to Week 24 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis | From Baseline to Week 24 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Total-C at Week 12 - ITT Analysis | From Baseline to Week 24 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis | From Baseline to Week 24 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Apo A1 at Week 12 - ITT Analysis | From Baseline to Week 24 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. |
| Percentage of Participants Reaching Calculated LDL-C Goal at Week 24 - ITT Analysis | Up to Week 24 | Calculated LDL-C goal was defined as: * \<100 mg/dL (2.59 mmol/L) for heFH or non-FH participants who had a history of documented congestive heart disease (CHD), or * \<120 mg/dL (3.10 mmol/L) for non-FH participants who had a history of documented diseases (ischemic stroke, peripheral artery disease, chronic kidney disease or diabetes) or other risk factors as defined in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. Adjusted percentages at Week 24 were obtained from multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment were included in imputation model. |
| Percentage of Participants Reaching Calculated LDL-C Goal at Week 24 - On-Treatment Analysis | Up to Week 24 | Adjusted percentages at Week 24 were from multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 24 (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 24 | Adjusted means and standard errors at Week 24 from a multiple imputation approach followed by robust regression model for handling of missing data. All available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment were included in the imputation model. |
| Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | From Baseline to Week 24 | 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 24 regardless of status on-or off-treatment. |
| Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis | From Baseline to Week 24 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Apo A1 at Week 24 - ITT Analysis | From Baseline to Week 24 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis | From Baseline to Week 24 | 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 24 regardless of status on-or off-treatment. |
| Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis | From Baseline to Week 24 | 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 24 regardless of status on-or off-treatment. |
Other
| 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 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 - On-Treatment Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 52 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). |
Countries
Japan
Participant flow
Recruitment details
The study was conducted at 31 centers in Japan. A total of 319 participants were screened between March 2014 and July 2014, 103 of whom were screen failures. Screen failures were mainly due to exclusion criteria met.
Pre-assignment details
Randomization was stratified according to heterozygous familial hypercholesterolemia (heFH) population. Assignment to treatment arms was done using an Interactive Web Response System in 1:2 (Placebo: Alirocumab) ratio after confirmation of selection criteria. 216 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Q2W Placebo (for alirocumab) SC injection Q2W added to stable LMT for 52 weeks. | 72 |
| Alirocumab 75 mg/Up to 150 mg Q2W Alirocumab 75 mg SC injection Q2W added to stable LMT for 52 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥ 100 mg/dL (2.59 mmol/L) or ≥ 120 mg/dL (3.10 mmol/L) at Week 8 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. | 144 |
| Total | 216 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 7 |
| Overall Study | Consent withdrawn by participant | 2 | 1 |
| Overall Study | Participant moved | 0 | 2 |
| Overall Study | Poor compliance to protocol | 0 | 1 |
| Overall Study | Randomized but not treated | 0 | 1 |
Baseline characteristics
| Characteristic | Alirocumab 75 mg/Up to 150 mg Q2W | Total | Placebo Q2W |
|---|---|---|---|
| Age, Continuous | 60.3 years STANDARD_DEVIATION 9.7 | 60.8 years STANDARD_DEVIATION 9.5 | 61.8 years STANDARD_DEVIATION 9 |
| Calculated LDL-C in mg/dL | 140.9 mg/dL STANDARD_DEVIATION 26.8 | 141.2 mg/dL STANDARD_DEVIATION 26.7 | 141.6 mg/dL STANDARD_DEVIATION 26.7 |
| Calculated LDL-C in mmol/L | 3.650 mmol/L STANDARD_DEVIATION 0.693 | 3.656 mmol/L STANDARD_DEVIATION 0.691 | 3.668 mmol/L STANDARD_DEVIATION 0.691 |
| Sex: Female, Male Female | 60 Participants | 85 Participants | 25 Participants |
| Sex: Female, Male Male | 84 Participants | 131 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 44 / 72 | 97 / 143 |
| serious Total, serious adverse events | 9 / 72 | 10 / 143 |
Outcome results
Primary
Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (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 24 regardless of status on- or off-treatment were used in the model (ITT analysis).
Time frame: From Baseline to Week 24
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 - Intent-to-Treat (ITT Analysis) | 1.6 percent change | Standard Error 1.8 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT Analysis) | -62.5 percent change | Standard Error 1.3 |
Comparison: Alirocumab group was compared to placebo group using an appropriate contrast statement.p-value: <0.000195% CI: [-68.5, -59.8]Mixed Models Analysis
Secondary
Percentage of Participants Reaching Calculated LDL-C Goal at Week 24 - ITT Analysis
Calculated LDL-C goal was defined as: * \<100 mg/dL (2.59 mmol/L) for heFH or non-FH participants who had a history of documented congestive heart disease (CHD), or * \<120 mg/dL (3.10 mmol/L) for non-FH participants who had a history of documented diseases (ischemic stroke, peripheral artery disease, chronic kidney disease or diabetes) or other risk factors as defined in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. Adjusted percentages at Week 24 were obtained from multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment were included in imputation model.
Time frame: Up to Week 24
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Q2W | Percentage of Participants Reaching Calculated LDL-C Goal at Week 24 - ITT Analysis | 10.2 percentage of participants |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percentage of Participants Reaching Calculated LDL-C Goal at Week 24 - ITT Analysis | 96.7 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [105.6, 2886.8]Regression, Logistic
Secondary
Percentage of Participants Reaching Calculated LDL-C Goal at Week 24 - On-Treatment Analysis
Adjusted percentages at Week 24 were from multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection).
Time frame: Up to Week 24
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Q2W | Percentage of Participants Reaching Calculated LDL-C Goal at Week 24 - On-Treatment Analysis | 10.6 percentage of participants |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percentage of Participants Reaching Calculated LDL-C Goal at Week 24 - On-Treatment Analysis | 97.9 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [137.8, 13578.3]Regression, Logistic
Secondary
Percent Change From Baseline in Apo A1 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 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 24
Population: Apo A1 ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Apo A1 at Week 12 - ITT Analysis | -4.8 percent change | Standard Error 1.1 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Apo A1 at Week 12 - ITT Analysis | 1.5 percent change | Standard Error 0.8 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [3.6, 9]Mixed Models Analysis
Secondary
Percent Change From Baseline in Apo A1 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 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 24
Population: Participants of the ITT population with one baseline and at least one post-baseline Apo A1 value on- or off-treatment (Apo A1 ITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Apo A1 at Week 24 - ITT Analysis | -2.6 percent change | Standard Error 1.6 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Apo A1 at Week 24 - ITT Analysis | 1.4 percent change | Standard Error 1.1 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: 0.038295% CI: [0.2, 7.9]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 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 24
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 | -3.3 percent change | Standard Error 1.5 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Apo B at Week 12 - ITT Analysis | -54.6 percent change | Standard Error 1.1 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-54.9, -47.6]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 24 (i.e. up to 21 days after last injection).
Time frame: From Baseline to Week 24
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 | -2.1 percent change | Standard Error 1.7 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis | -55.9 percent change | Standard Error 1.2 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-57.8, -49.8]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 24 regardless of status on- or off-treatment.
Time frame: From baseline to Week 24
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 (Apo) B at Week 24 - ITT Analysis | -1.6 percent change | Standard Error 1.7 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis | -55.0 percent change | Standard Error 1.2 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-57.5, -49.1]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 available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 24
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 | -2.7 percent change | Standard Error 1.6 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis | -64.2 percent change | Standard Error 1.1 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-65.3, -57.7]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 24 (i.e. up to 21 days after last injection).
Time frame: From Baseline to Week 24
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 | -2.8 percent change | Standard Error 1.5 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 12 - On-treatment Analysis | -64.8 percent change | Standard Error 1.1 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-65.8, -58.3]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 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection) (on-treatment analysis).
Time frame: From Baseline to Week 24
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 | 1.7 percent change | Standard Error 1.7 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis | -63.7 percent change | Standard Error 1.2 |
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: [-69.4, -61.3]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 24 regardless of status on-or off-treatment.
Time frame: From Baseline to Week 24
Population: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis | 2.4 percent change | Standard Error 3.7 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis | -13.1 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: 0.000795% CI: [-24.4, -6.6]Regression, Robust
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 24 regardless of status on-or off-treatment.
Time frame: From Baseline to Week 24
Population: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | 6.7 percent change | Standard Error 3.7 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | -15.3 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: [-30.9, -13.1]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 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 24
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 | -1.8 percent change | Standard Error 1.2 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis | 4.7 percent change | Standard Error 0.8 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [3.7, 9.3]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 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 24
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 | 2.1 percent change | Standard Error 1.5 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis | 7.9 percent change | Standard Error 1.1 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: 0.00295% CI: [2.1, 9.4]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 24 regardless of status on-or off-treatment.
Time frame: From Baseline to Week 24
Population: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis | -0.5 percent change | Standard Error 2.4 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis | -41.9 percent change | Standard Error 1.7 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-47, -35.7]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 followed by robust regression model for handling of missing data. All available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment were included in the imputation model.
Time frame: From Baseline to Week 24
Population: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis | 2.5 percent change | Standard Error 2.5 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis | -39.5 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: [-48, -36]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 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 24
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 | -1.7 percent change | Standard Error 1.4 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis | -56.3 percent change | Standard Error 1 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-57.9, -51.1]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 24 (i.e. up to 21 days after last injection).
Time frame: From Baseline to Week 24
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 | 2.6 percent change | Standard Error 1.6 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis | -56.0 percent change | Standard Error 1.1 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-62.3, -54.8]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 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 24
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 | 2.6 percent change | Standard Error 1.6 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis | -54.9 percent change | Standard Error 1.2 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-61.5, -53.5]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 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 24
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 | -2.1 percent change | Standard Error 1.1 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Total-C at Week 12 - ITT Analysis | -41.1 percent change | Standard Error 0.8 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-41.7, -36.4]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 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 24
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 | 2.0 percent change | Standard Error 1.3 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis | -39.5 percent change | Standard Error 0.9 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-44.6, -38.4]Mixed Models Analysis
Other Pre-specified
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 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 | -3.6 Percent change | Standard Error 1.9 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis | -62.5 Percent change | Standard Error 1.4 |
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 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 |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis | -3.4 Percent change | Standard Error 1.7 |
| Alirocumab 75 mg/Up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis | -64.6 Percent change | Standard Error 1.2 |