Hypercholesterolemia
Conditions
Keywords
Non-statin LMT, Low dose statin
Brief summary
Primary Objective: To demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab administration as add-on therapy to non-statin lipid modifying therapy (LMT) including diet therapy alone or the lowest strength of statin in comparison with placebo after 12 weeks of treatment in participants with hypercholesterolemia. Secondary Objective: * To evaluate the effect of two treatment regimens of alirocumab on other lipid parameters: apolipoprotein B (Apo-B), non-high-density lipoprotein cholesterol (non HDL-C), total cholesterol (TC), lipoprotein (a) (Lp\[a\]), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and apolipoprotein A-1 (Apo A-1). * To evaluate the safety and tolerability of alirocumab administration. * To evaluate the development of anti-alirocumab antibodies. * To evaluate the pharmacokinetic and pharmacodynamic profiles of alirocumab administration. * To evaluate the long-term safety in participants receiving open-label alirocumab administration.
Detailed description
The duration of study per participant was approximately 71 weeks consisting of a run-in period (4 weeks), a screening period (3 weeks), a double-blind treatment period (12 weeks), and an open-label treatment period (52 weeks).
Interventions
DRUGAlirocumab
Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector.
DRUGPlacebo
Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector.
DRUGAtorvastatin
Atorvastatin 5 mg tablet orally.
DRUGNon-statin Lipid-Modifying Therapy
Ezetimibe, Bezafibrate or Fenofibrate at stable dose as background therapy.
OTHERDiet Alone
Stable cholesterol-lowering diet as background therapy.
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 No maximum
Healthy volunteers
No
Inclusion criteria
: Participants with hypercholesterolemia (heFH or non-FH) receiving non statin LMTs or the lowest strength of statin.
Exclusion criteria
* LDL-C \<100 mg/dL (\<2.59 mmol/L) at the screening visit (Week -3) in participants with heFH or in participants with non-FH who have a history of documented coronary heart disease. * LDL-C \<120 mg/dL (\<3.10 mmol/L) at the screening visit (Week -3) in participants with non-FH participants who had a history of documented diseases or other risk factors classified as primary prevention category III as defined in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. * Not on a stable dose of LMT (including diet therapy alone) in the run-in period or the screening period. * Fasting serum TGs \>400 mg/dL (\>4.52 mmol/L) at the screening period. * Systolic blood pressure (BP) \>160 mmHg or diastolic BP \>100 mmHg at the run-in visit (Week -7) or the screening visit (Week -3) or the randomization visit (Week 0). The above information was 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 12- Intent to Treat (ITT) Analysis | From Baseline to Week 12 | Adjusted Least-squares (LS) means and standard errors at Week 12 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 12 regardless of status on- or off-treatment were used in the model (ITT analysis). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Non-HDL-C at Week 12- On-treatment Analysis | From Baseline to Week 12 | 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 12 (i.e. up to 21 days after last double-blind injection). |
| Percent Change From Baseline in Calculated LDL-C at Week 12- On-Treatment Analysis | From Baseline to Week 12 | 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 12 (i.e. up to 21 days after last double-blind injection). |
| Percent Change From Baseline in Calculated LDL-C to Averaged Week 10 to 12: ITT Analysis | From Baseline to Week 12 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 12 regardless of status on- or off-treatment and assigning a weight of 0.5 for Week 10 and 12 time points. |
| Percent Change From Baseline in Calculated LDL-C to Averaged Week 10 to 12- On-Treatment Analysis | From Baseline to Week 12 | 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 12 (i.e. up to 21 days after last double-blind injection) and assigning a weight of 0.5 for Week 10 and 12 time points. |
| Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 12: ITT Analysis | From Baseline to Week 12 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 12 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Apo-B at Week 12- On-Treatment Analysis | From Baseline to Week 12 | Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including available post-baseline on-treatment data at from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection). |
| Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 12: ITT Analysis | From Baseline to Week 12 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 12 regardless of status on- or off-treatment. |
| Percentage of Participants Reaching Calculated LDL-C Goal at Week 12- ITT Analysis | Up to Week 12 | Calculated LDL-C goal was defined as calculated LDL-C \<100 mg/dL (2.59 mmol/L) for heterozygous familiar hypercholesterolemia (heFH) participants or non-familial hypercholesterolemia (non-FH) participants who had a history of documented CHD, or \<120 mg/dL (3.10 mmol/L) for non-FH participants who had a history of documented diseases or other risk factors as defined in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. Adjusted percentages at Week 12 were obtained from multiple imputation approach for handling of missing data. All available post-baseline data from Week 4 to Week 12 regardless of status on- or off-treatment were included in the imputation model. |
| Percentage of Participants Reaching Calculated LDL-C Goal at Week 12- On-Treatment Analysis | Up to Week 12 | Calculated LDL-C goal was defined as calculated LDL-C \<100 mg/dL (2.59 mmol/L) for heFH participants or non-FH participants who had a history of documented CHD, or \<120 mg/dL (3.10 mmol/L) for non-FH participants who had a history of documented diseases or other risk factors as defined in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. Adjusted percentages at Week 12 from multiple imputation approach including available post-baseline on-treatment data from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection). |
| Percent Change From Baseline in Lipoprotein (a) at Week 12: ITT Analysis | From Baseline to Week 12 | Adjusted means and standard errors at Week 12 were obtained from multiple imputation approach followed by robust regression model for handling of missing data. All available post-baseline data from Week 4 to Week 12 regardless of status on- or off-treatment were included in the imputation model. |
| Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 12- ITT Analysis | From Baseline to Week 12 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 12 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Fasting Triglycerides (TGs) at Week 12: ITT Analysis | From Baseline to Week 12 | 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 12 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 12: ITT Analysis | From Baseline to Week 12 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 12 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Total Cholesterol (Total-C) at Week 12- ITT Analysis | From Baseline to Week 12 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 12 regardless of status on- or off-treatment. |
Other
| Measure | Time frame |
|---|---|
| Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis | Baseline, Weeks 20, 24, 36, 48 and 64 |
Countries
Japan
Participant flow
Recruitment details
The study was conducted at 30 active centers in Japan. Overall 241 participants were screened between 30 November 2015 and 19 October 2016, of whom 78 were screen failures and 163 were randomized. Screen failures were mainly due to exclusion criteria met.
Pre-assignment details
Randomization stratified per background statin therapy (Yes/No). No statin also stratified per background fibrate/ezetimibe therapy (Yes/No), 'Yes' =fibrate/ezetimibe, 'No' =diet therapy alone. Randomization followed 1:1:1 ratio (Alirocumab 150 mg Q4W: Alirocumab 150 mg Q2W: Placebo Q2W).
Participants by arm
| Arm | Count |
|---|---|
| Alirocumab 150 mg Q4W In DBTP, participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks. Participants who completed DBTP were entered in OLTP and received alirocumab 150 mg Q4W up to additional 52 weeks (up to Week 64). Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. | 54 |
| Alirocumab 150 mg Q2W In DBTP, participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks. Participants who completed DBTP were entered in OLTP and received alirocumab 150 mg Q4W up to additional 52 weeks (up to Week 64). Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. | 53 |
| Placebo Q2W In DBTP, participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks. Participants who completed DBTP were entered in OLTP and received alirocumab 150 mg Q4W up to additional 52 weeks (up to Week 64). Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. | 56 |
| Total | 163 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-blind Treatment | Adverse Event | 0 | 1 | 0 |
| Double-blind Treatment | Family Matter | 0 | 1 | 0 |
| Double-blind Treatment | Participant withdrew consent | 0 | 0 | 1 |
| Open-label Treatment | Adverse Event | 2 | 2 | 3 |
| Open-label Treatment | Entered but not treated | 0 | 1 | 1 |
| Open-label Treatment | Participant withdrew consent | 0 | 0 | 4 |
| Open-label Treatment | Physician Decision | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Alirocumab 150 mg Q4W | Alirocumab 150 mg Q2W | Placebo Q2W | Total |
|---|---|---|---|---|
| Age, Continuous | 62.6 years STANDARD_DEVIATION 9.8 | 63.6 years STANDARD_DEVIATION 10.4 | 64.6 years STANDARD_DEVIATION 10 | 63.6 years STANDARD_DEVIATION 10.1 |
| Calculated LDL-C in mg/dL | 154.2 mg/dL STANDARD_DEVIATION 59.5 | 149.2 mg/dL STANDARD_DEVIATION 31.1 | 149.4 mg/dL STANDARD_DEVIATION 32.6 | 150.9 mg/dL STANDARD_DEVIATION 42.8 |
| Calculated LDL-C in mmol/L | 3.993 mmol/L STANDARD_DEVIATION 1.541 | 3.865 mmol/L STANDARD_DEVIATION 0.806 | 3.870 mmol/L STANDARD_DEVIATION 0.844 | 3.909 mmol/L STANDARD_DEVIATION 1.109 |
| Race/Ethnicity, Customized Asian | 54 Participants | 53 Participants | 56 Participants | 163 Participants |
| Sex: Female, Male Female | 21 Participants | 20 Participants | 19 Participants | 60 Participants |
| Sex: Female, Male Male | 33 Participants | 33 Participants | 37 Participants | 103 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 56 | 0 / 54 | 1 / 53 | 0 / 158 |
| other Total, other adverse events | 14 / 56 | 11 / 54 | 13 / 53 | 72 / 158 |
| serious Total, serious adverse events | 1 / 56 | 1 / 54 | 2 / 53 | 12 / 158 |
Outcome results
Primary
Percent Change From Baseline in Calculated LDL-C at Week 12- Intent to Treat (ITT) Analysis
Adjusted Least-squares (LS) means and standard errors at Week 12 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 12 regardless of status on- or off-treatment were used in the model (ITT analysis).
Time frame: From Baseline to Week 12
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 150 mg Q4W | Percent Change From Baseline in Calculated LDL-C at Week 12- Intent to Treat (ITT) Analysis | -43.8 percent change | Standard Error 2.2 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 12- Intent to Treat (ITT) Analysis | -70.1 percent change | Standard Error 2.3 |
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 12- Intent to Treat (ITT) Analysis | -4.3 percent change | Standard Error 2.2 |
Comparison: Alirocumab 150 mg Q4W group was compared to placebo group using an appropriate contrast statement.p-value: <0.000197.5% CI: [-46.5, -32.4]Mixed Models Analysis
Comparison: Alirocumab 150 mg Q2W group was compared to placebo group using an appropriate contrast statement.p-value: <0.000197.5% CI: [-72.9, -58.7]Mixed Models Analysis
Comparison: Alirocumab 150 mg Q4W group was compared to Alirocumab 150 mg Q2W group using an appropriate contrast statement.95% CI: [-32.5, -20]
Secondary
Percentage of Participants Reaching Calculated LDL-C Goal at Week 12- ITT Analysis
Calculated LDL-C goal was defined as calculated LDL-C \<100 mg/dL (2.59 mmol/L) for heterozygous familiar hypercholesterolemia (heFH) participants or non-familial hypercholesterolemia (non-FH) participants who had a history of documented CHD, or \<120 mg/dL (3.10 mmol/L) for non-FH participants who had a history of documented diseases or other risk factors as defined in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. Adjusted percentages at Week 12 were obtained from multiple imputation approach for handling of missing data. All available post-baseline data from Week 4 to Week 12 regardless of status on- or off-treatment were included in the imputation model.
Time frame: Up to Week 12
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alirocumab 150 mg Q4W | Percentage of Participants Reaching Calculated LDL-C Goal at Week 12- ITT Analysis | 85.2 percentage of participants |
| Alirocumab 150 mg Q2W | Percentage of Participants Reaching Calculated LDL-C Goal at Week 12- ITT Analysis | 96.2 percentage of participants |
| Placebo Q2W | Percentage of Participants Reaching Calculated LDL-C Goal at Week 12- ITT Analysis | 14.3 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [13.9, 268.9]Regression, Logistic
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [33.3, 2382.2]Regression, Logistic
Secondary
Percentage of Participants Reaching Calculated LDL-C Goal at Week 12- On-Treatment Analysis
Calculated LDL-C goal was defined as calculated LDL-C \<100 mg/dL (2.59 mmol/L) for heFH participants or non-FH participants who had a history of documented CHD, or \<120 mg/dL (3.10 mmol/L) for non-FH participants who had a history of documented diseases or other risk factors as defined in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. Adjusted percentages at Week 12 from multiple imputation approach including available post-baseline on-treatment data from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection).
Time frame: Up to Week 12
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alirocumab 150 mg Q4W | Percentage of Participants Reaching Calculated LDL-C Goal at Week 12- On-Treatment Analysis | 85.2 percentage of participants |
| Alirocumab 150 mg Q2W | Percentage of Participants Reaching Calculated LDL-C Goal at Week 12- On-Treatment Analysis | 96.2 percentage of participants |
| Placebo Q2W | Percentage of Participants Reaching Calculated LDL-C Goal at Week 12- On-Treatment Analysis | 10.8 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [19, 556.8]Regression, Logistic
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [47.9, 5230.9]Regression, Logistic
Secondary
Percent Change From Baseline in Apo-B at Week 12- On-Treatment Analysis
Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including available post-baseline on-treatment data at from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection).
Time frame: From Baseline to Week 12
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 |
|---|---|---|---|
| Alirocumab 150 mg Q4W | Percent Change From Baseline in Apo-B at Week 12- On-Treatment Analysis | -31.8 percent change | Standard Error 2 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Apo-B at Week 12- On-Treatment Analysis | -58.0 percent change | Standard Error 2 |
| Placebo Q2W | Percent Change From Baseline in Apo-B at Week 12- On-Treatment Analysis | -4.6 percent change | Standard Error 1.9 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [-33.5, -20.9]Mixed Models Analysis
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [-59.7, -47.1]Mixed Models Analysis
Secondary
Percent Change From Baseline in Apolipoprotein A-1 (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 12 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 12
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 |
|---|---|---|---|
| Alirocumab 150 mg Q4W | Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 12: ITT Analysis | 6.8 percent change | Standard Error 1.6 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 12: ITT Analysis | 9.1 percent change | Standard Error 1.7 |
| Placebo Q2W | Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 12: ITT Analysis | 2.9 percent change | Standard Error 1.6 |
Secondary
Percent Change From Baseline in Apolipoprotein B (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 12 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 12
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 |
|---|---|---|---|
| Alirocumab 150 mg Q4W | Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 12: ITT Analysis | -32.2 percent change | Standard Error 2 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 12: ITT Analysis | -57.9 percent change | Standard Error 2 |
| Placebo Q2W | Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 12: ITT Analysis | -6.0 percent change | Standard Error 2 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [-32.5, -19.9]Mixed Models Analysis
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [-58.3, -45.5]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 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection).
Time frame: From Baseline to Week 12
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 150 mg Q4W | Percent Change From Baseline in Calculated LDL-C at Week 12- On-Treatment Analysis | -43.4 percent change | Standard Error 2.1 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 12- On-Treatment Analysis | -70.1 percent change | Standard Error 2.2 |
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 12- On-Treatment Analysis | -2.8 percent change | Standard Error 2.1 |
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 0.025 level. Hierarchical procedure for comparisons of Alirocumab 150 mg Q4W versus Placebo Q2W and Alirocumab 150 mg Q2W versus Placebo Q2W were processed separately.p-value: <0.000197.5% CI: [-47.4, -33.8]Mixed Models Analysis
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [-74.2, -60.5]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated LDL-C to Averaged Week 10 to 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 12 regardless of status on- or off-treatment and assigning a weight of 0.5 for Week 10 and 12 time points.
Time frame: From Baseline to Week 12
Population: ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 150 mg Q4W | Percent Change From Baseline in Calculated LDL-C to Averaged Week 10 to 12: ITT Analysis | -54.2 percent change | Standard Error 1.9 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C to Averaged Week 10 to 12: ITT Analysis | -69.9 percent change | Standard Error 1.9 |
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C to Averaged Week 10 to 12: ITT Analysis | -3.7 percent change | Standard Error 1.9 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [-56.6, -44.5]Mixed Models Analysis
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [-72.3, -60.1]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated LDL-C to Averaged Week 10 to 12- On-Treatment Analysis
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 12 (i.e. up to 21 days after last double-blind injection) and assigning a weight of 0.5 for Week 10 and 12 time points.
Time frame: From Baseline to Week 12
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 150 mg Q4W | Percent Change From Baseline in Calculated LDL-C to Averaged Week 10 to 12- On-Treatment Analysis | -54.0 percent change | Standard Error 1.9 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C to Averaged Week 10 to 12- On-Treatment Analysis | -69.9 percent change | Standard Error 1.9 |
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C to Averaged Week 10 to 12- On-Treatment Analysis | -2.6 percent change | Standard Error 1.9 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [-57.4, -45.4]Mixed Models Analysis
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [-73.3, -61.3]Mixed Models Analysis
Secondary
Percent Change From Baseline in Fasting Triglycerides (TGs) 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 12 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 12
Population: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 150 mg Q4W | Percent Change From Baseline in Fasting Triglycerides (TGs) at Week 12: ITT Analysis | -0.6 percent change | Standard Error 3.7 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Fasting Triglycerides (TGs) at Week 12: ITT Analysis | -18.0 percent change | Standard Error 3.8 |
| Placebo Q2W | Percent Change From Baseline in Fasting Triglycerides (TGs) at Week 12: ITT Analysis | -6.4 percent change | Standard Error 3.7 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: 0.264597.5% CI: [-5.9, 17.7]Regression, Robust
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: 0.029997.5% CI: [-23.5, 0.4]Regression, Robust
Secondary
Percent Change From Baseline in High Density Lipoprotein Cholesterol (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 12 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 12
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 |
|---|---|---|---|
| Alirocumab 150 mg Q4W | Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 12- ITT Analysis | 7.7 percent change | Standard Error 1.8 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 12- ITT Analysis | 9.9 percent change | Standard Error 1.8 |
| Placebo Q2W | Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 12- ITT Analysis | 2.0 percent change | Standard Error 1.8 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: 0.024197.5% CI: [0, 11.3]Mixed Models Analysis
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: 0.002297.5% CI: [2.1, 13.5]Mixed Models Analysis
Secondary
Percent Change From Baseline in Lipoprotein (a) at Week 12: ITT Analysis
Adjusted means and standard errors at Week 12 were obtained from multiple imputation approach followed by robust regression model for handling of missing data. All available post-baseline data from Week 4 to Week 12 regardless of status on- or off-treatment were included in the imputation model.
Time frame: From Baseline to Week 12
Population: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 150 mg Q4W | Percent Change From Baseline in Lipoprotein (a) at Week 12: ITT Analysis | -31.7 percent change | Standard Error 3.3 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Lipoprotein (a) at Week 12: ITT Analysis | -49.6 percent change | Standard Error 3.3 |
| Placebo Q2W | Percent Change From Baseline in Lipoprotein (a) at Week 12: ITT Analysis | 1.3 percent change | Standard Error 3.3 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [-43.4, -22.5]Regression, Robust
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [-61.5, -40.3]Regression, Robust
Secondary
Percent Change From Baseline in Non-HDL-C at Week 12- On-treatment Analysis
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 12 (i.e. up to 21 days after last double-blind injection).
Time frame: From Baseline to Week 12
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 |
|---|---|---|---|
| Alirocumab 150 mg Q4W | Percent Change From Baseline in Non-HDL-C at Week 12- On-treatment Analysis | -35.9 percent change | Standard Error 1.9 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Non-HDL-C at Week 12- On-treatment Analysis | -61.1 percent change | Standard Error 2 |
| Placebo Q2W | Percent Change From Baseline in Non-HDL-C at Week 12- On-treatment Analysis | -3.5 percent change | Standard Error 1.9 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [-38.6, -26.3]Mixed Models Analysis
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [-63.8, -51.4]Mixed Models Analysis
Secondary
Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (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 12 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 12
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 |
|---|---|---|---|
| Alirocumab 150 mg Q4W | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 12: ITT Analysis | -36.2 percent change | Standard Error 2 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 12: ITT Analysis | -61.1 percent change | Standard Error 2 |
| Placebo Q2W | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 12: ITT Analysis | -4.9 percent change | Standard Error 2 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [-37.7, -25]Mixed Models Analysis
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [-62.5, -49.8]Mixed Models Analysis
Secondary
Percent Change From Baseline in Total Cholesterol (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 12 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 12
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 |
|---|---|---|---|
| Alirocumab 150 mg Q4W | Percent Change From Baseline in Total Cholesterol (Total-C) at Week 12- ITT Analysis | -25.8 percent change | Standard Error 1.5 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Total Cholesterol (Total-C) at Week 12- ITT Analysis | -44.7 percent change | Standard Error 1.6 |
| Placebo Q2W | Percent Change From Baseline in Total Cholesterol (Total-C) at Week 12- ITT Analysis | -3.3 percent change | Standard Error 1.5 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [-27.4, -17.6]Mixed Models Analysis
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.000197.5% CI: [-46.4, -36.5]Mixed Models Analysis
Other Pre-specified
Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis
Time frame: Baseline, Weeks 20, 24, 36, 48 and 64
Population: Open-label treatment (OLT) population included all randomized participants who received at least one dose or part of dose of open-label investigational medicinal product. Here, number analyzed signifies participants with available data at each specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alirocumab 150 mg Q4W | Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis | Week 48 | -48.6 Percent change | Standard Deviation 21.6 |
| Alirocumab 150 mg Q4W | Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis | Week 36 | -49.2 Percent change | Standard Deviation 19.4 |
| Alirocumab 150 mg Q4W | Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis | Week 20 | -42.1 Percent change | Standard Deviation 20.1 |
| Alirocumab 150 mg Q4W | Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis | Week 24 | -39.7 Percent change | Standard Deviation 20.4 |
| Alirocumab 150 mg Q4W | Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis | Week 64 | -44.3 Percent change | Standard Deviation 22.8 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis | Week 36 | -51.5 Percent change | Standard Deviation 19.6 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis | Week 20 | -47.8 Percent change | Standard Deviation 24.2 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis | Week 24 | -46.0 Percent change | Standard Deviation 20 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis | Week 48 | -53.9 Percent change | Standard Deviation 17.6 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis | Week 64 | -55.2 Percent change | Standard Deviation 17.5 |
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis | Week 64 | -58.1 Percent change | Standard Deviation 19.6 |
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis | Week 48 | -57.8 Percent change | Standard Deviation 17.4 |
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis | Week 20 | -45.5 Percent change | Standard Deviation 20.5 |
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis | Week 36 | -56.2 Percent change | Standard Deviation 18.8 |
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis | Week 24 | -47.8 Percent change | Standard Deviation 21.7 |