Dyslipidemia
Conditions
Brief summary
Primary Objective: To demonstrate the superiority of alirocumab in comparison with usual care in the reduction of non-high-density lipoprotein cholesterol (non-HDL-C) in participants with type 2 diabetes and mixed dyslipidemia at high cardiovascular risk with non-HDL-C not adequately controlled with maximally tolerated statin therapy. Secondary Objectives: * To demonstrate whether alirocumab is superior in comparison with usual care in its effects on other lipid parameters (ie, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), total cholesterol (Total -C), lipoprotein a (Lp\[a\]), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), triglyceride rich lipoproteins (TGRLs), apolipoprotein A-1 (Apo A-1), apolipoprotein C-III (Apo C-III), lipid subfractions by nuclear magnetic resonance (NMR) spectroscopy (ie, LDL-C particle size and LDL, very low-density lipoprotein \[VLDL\], HDL, and intermediate-density lipoprotein \[IDL\] particle number). * To assess changes in glycemic parameters with alirocumab vs. usual care treatment. * To demonstrate the safety and tolerability of alirocumab. * To evaluate treatment acceptance of alirocumab. * To evaluate proprotein convertase subtilisin kexin type 9 (PCSK9) concentrations and antibody development. * To demonstrate the superiority of alirocumab vs. fenofibrate on non-HDL-C and other lipid parameters (subgroup analysis).
Detailed description
The maximum study duration was approximately 9 months per participant, including a 6 month treatment period, a screening period of up to 3 weeks, and an 8 week safety observation period. For the purpose of scientific communication, a first-step analysis (both efficacy and safety) was performed at the Week 24 cut-off date. A second-step analysis was performed once all participants had completed the study to include a final update of the safety analysis.
Interventions
DRUGAlirocumab
Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector.
DRUGStatins
Statins at stable dose without other LMT as clinically indicated.
DRUGEzetimibe
Pharmaceutical form: tablet Route of administration: oral
DRUGFenofibrate
Pharmaceutical form: tablet Route of administration: oral
DRUGNicotinic acid
Pharmaceutical form: tablet Route of administration: oral
DRUGOmega-3 fatty acids
Pharmaceutical form: tablet Route of administration: oral
Insulin (injectable or inhaled) or other antihyperglycemic drugs as clinically indicated.
Sponsors
Regeneron Pharmaceuticals
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with type 2 diabetes and mixed dyslipidemia whose non-HDL-C was not adequately controlled with a stable, maximum dose/regimen of statin that was tolerated by the participant. * 18 years of age or more. * Documented history of atherosclerotic cardiovascular disease (ASCVD) or at least one additional cardiovascular risk factor. * Non-HDL-C of 100 mg/dL or greater. * Triglycerides greater than or equal to 150 mg/dL and less than 500 mg/dL. * Stable anti-hyperglycemic agents for at least 3 months prior to the screening visit and between screening and randomization (including stable insulin dose defined as no variation more than 30% in daily insulin dose within the preceding 3 months, as judged by the Investigator). * No change in weight of more than 5 kg within the prior 3 months. * On stable dose of medications that are known to influence weight and/or lipids within the last 3 months.
Exclusion criteria
* Use of any lipid modifying therapies other than statins within the last 4 weeks (eg, ezetimibe, fenofibrate, nicotinic acid, omega-3 fatty acids, etc.) or use of over the counter products/nutraceuticals known to impact lipids (eg, red yeast rice) within the last 4 weeks. * Currently drinking more than 2 standard alcoholic drinks per day. * Body Mass Index (BMI) \>45 kg/m² or currently enrolled in a weight loss program and still in active phase of weight loss. * Glycosylated hemoglobin (HbA1c) 9% or greater. 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 Non-HDL-C at Week 24: Overall 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 8 to Week 24 regardless of status on- or off-treatment were used in the model (ITT analysis). |
| Percent Change From Baseline in Non-HDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | 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 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Non-HDL-C at Week 12: Overall 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 8 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Non-HDL-C at Week 12: ITT- Intent to Prescribe Fenofibrate Stratum | 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 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. |
| Percent Change From Baseline in Measured LDL-C at Week 12: Overall ITT Analysis | From Baseline to Week 24 | Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Measured LDL-C at Week 12: ITT- Intent to Prescribe Fenofibrate Stratum | From Baseline to Week 24 | Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. |
| Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24: Overall 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 8 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Apo B at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | 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 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. |
| Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 : Overall 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 8 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Total-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | 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 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. |
| Percent Change From Baseline in Lipoprotein(a) at Week 24 : Overall ITT Analysis | From Baseline to Week 24 | Adjusted means and standard errors at Week 24 were obtained from multiple imputation approach followed by robust regression model for handling of missing data. All available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment were included in the imputation model. |
| Percent Change From Baseline in Measured Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24: Overall ITT Analysis | From Baseline to Week 24 | Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Fasting Triglycerides at Week 24: Overall 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 8 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Fasting Triglycerides at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | 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 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. |
| Percent Change From Baseline in HDL-C at Week 24 : Overall 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 8 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in HDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | 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 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. |
| Percent Change From Baseline in LDL-C Particle Number at Week 24: Overall ITT Analysis | From Baseline to Week 24 | LDL-C particle number was calculated from lipid subfractions by nuclear magnetic resonance (NMR) spectroscopy. Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in LDL-C Particle Number at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | From Baseline to Week 24 | LDL-C particle number was calculated from lipid subfractions by NMR spectroscopy. Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. |
| Absolute Change From Baseline in Hemoglobin A1c (HbA1c) at Week 12 and 24 : Overall ITT Analysis | Baseline, Week 12 and 24 | Absolute change = HbA1c value at specified week minus HbA1c value at baseline. |
| Absolute Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 and 24 : Overall ITT Analysis | Baseline, Week 12 and 24 | Absolute change = FPG value at specified week minus FPG value at baseline. |
| Absolute Change From Baseline in Number of Glucose-Lowering Treatments at Week 12 and 24 : Overall ITT Analysis | Baseline, Week 12 and 24 | Glucose lowering treatment was calculated for non-insulin treatments as one for each unique treatment received and for insulin treatment as one in total for all participants who have taken one or more treatments. Absolute change = number of glucose-lowering treatments at specified week minus baseline value. |
| Percent Change From Baseline in Lipoprotein(a) at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | 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 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. |
| Percent Change From Baseline in Measured LDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | From Baseline to Week 24 | Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. |
Countries
Australia, Brazil, Finland, Germany, Israel, Italy, Kuwait, Lebanon, Norway, Sweden, Switzerland, Turkey (Türkiye), United Arab Emirates, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 119 centers in 15 countries. A total of 864 participants were screened between March 2016 and September 2016, 451 of whom were screen failures. Screen failures were mainly due to inclusion criteria not met.
Pre-assignment details
Randomization was stratified by investigator's choice of usual care therapy, which was pre-specified prior to randomization. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 2:1 ratio (alirocumab: usual care) after confirmation of selection criteria. 413 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W Alirocumab 75 mg SC injection Q2W added to insulin or other antihyperglycemic drugs, stable maximally tolerated dose of statin therapy without other LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when non-HDL-C levels \>=100 mg/dL (2.59 mmol/L) at Week 8. | 276 |
| Usual Care Participants on usual care continued on insulin or other antihyperglycemic drugs, stable maximally tolerated dose of statin therapy without additional LMT or with either ezetimibe, fenofibrate, omega-3 fatty acids or nicotinic acid as per Investigator's judgment for 24 weeks. | 137 |
| Total | 413 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 4 |
| Overall Study | Other than specified above | 10 | 3 |
| Overall Study | Poor compliance to study protocol | 1 | 0 |
| Overall Study | Randomized but not treated | 1 | 0 |
| Overall Study | Withdrawal by Subject | 9 | 1 |
Baseline characteristics
| Characteristic | Total | Usual Care | Alirocumab 75 mg Q2W/Up to 150 mg Q2W |
|---|---|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 9.2 | 64.1 years STANDARD_DEVIATION 8.8 | 62.8 years STANDARD_DEVIATION 9.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 49 Participants | 14 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 363 Participants | 123 Participants | 240 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Intent to Prescribe Treatment Ezetimibe | 156 Participants | 52 Participants | 104 Participants |
| Intent to Prescribe Treatment Fenofibrate | 72 Participants | 24 Participants | 48 Participants |
| Intent to Prescribe Treatment Nicotinic acid | 3 Participants | 1 Participants | 2 Participants |
| Intent to Prescribe Treatment No additional LMT | 118 Participants | 39 Participants | 79 Participants |
| Intent to Prescribe Treatment Omega-3 fatty acids | 64 Participants | 21 Participants | 43 Participants |
| Non-HDL-C | 4.073 mmol/L STANDARD_DEVIATION 1.221 | 4.2 mmol/L STANDARD_DEVIATION 1.2 | 4.0 mmol/L STANDARD_DEVIATION 1.2 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 4 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian/Oriental | 10 Participants | 7 Participants | 3 Participants |
| Race/Ethnicity, Customized Black | 22 Participants | 6 Participants | 16 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 7 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized White/Caucasian | 370 Participants | 123 Participants | 247 Participants |
| Sex: Female, Male Female | 197 Participants | 68 Participants | 129 Participants |
| Sex: Female, Male Male | 216 Participants | 69 Participants | 147 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 275 | 0 / 137 |
| other Total, other adverse events | 37 / 275 | 27 / 137 |
| serious Total, serious adverse events | 26 / 275 | 12 / 137 |
Outcome results
Primary
Percent Change From Baseline in Non-HDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
Time frame: From Baseline to Week 24
Population: ITT population. Here, 'Number of participants analyzed' = participants from intent to prescribe fenofibrate stratum who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Non-HDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | -41.7 Percent change | Standard Error 3.4 |
| Usual Care | Percent Change From Baseline in Non-HDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | -8.5 Percent change | Standard Error 4.8 |
Comparison: Alirocumab group was compared to usual care group for the intent to prescribe fenofibrate using an appropriate contrast statement.p-value: <0.000197.5% CI: [-46.6, -19.9]Mixed Models Analysis
Primary
Percent Change From Baseline in Non-HDL-C at Week 24: Overall 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 8 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 non-HDL-C value on- or off-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Non-HDL-C at Week 24: Overall Intent-to-treat (ITT) Analysis | -37.3 Percent change | Standard Error 3 |
| Usual Care | Percent Change From Baseline in Non-HDL-C at Week 24: Overall Intent-to-treat (ITT) Analysis | -4.7 Percent change | Standard Error 3.3 |
Comparison: Alirocumab group was compared to usual care group using an appropriate contrast statement.p-value: <0.000197.5% CI: [-38.1, -27]Mixed Models Analysis
Secondary
Absolute Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 and 24 : Overall ITT Analysis
Absolute change = FPG value at specified week minus FPG value at baseline.
Time frame: Baseline, Week 12 and 24
Population: ITT population. Here, 'Number Analyzed' = participants with available data at the specified time points for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Absolute Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 and 24 : Overall ITT Analysis | Change at Week 12 | 0.45 mmol/L | Standard Deviation 2.43 |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Absolute Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 and 24 : Overall ITT Analysis | Change at Week 24 | 0.68 mmol/L | Standard Deviation 2.54 |
| Usual Care | Absolute Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 and 24 : Overall ITT Analysis | Change at Week 12 | 0.21 mmol/L | Standard Deviation 1.86 |
| Usual Care | Absolute Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 and 24 : Overall ITT Analysis | Change at Week 24 | 0.03 mmol/L | Standard Deviation 2.54 |
Secondary
Absolute Change From Baseline in Hemoglobin A1c (HbA1c) at Week 12 and 24 : Overall ITT Analysis
Absolute change = HbA1c value at specified week minus HbA1c value at baseline.
Time frame: Baseline, Week 12 and 24
Population: ITT population. Here, 'Number Analyzed' = participants with available data at the specified time points for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Absolute Change From Baseline in Hemoglobin A1c (HbA1c) at Week 12 and 24 : Overall ITT Analysis | Change at Week 12 | 0.59 mmol/mol | Standard Deviation 6.82 |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Absolute Change From Baseline in Hemoglobin A1c (HbA1c) at Week 12 and 24 : Overall ITT Analysis | Change at Week 24 | 2.84 mmol/mol | Standard Deviation 8.04 |
| Usual Care | Absolute Change From Baseline in Hemoglobin A1c (HbA1c) at Week 12 and 24 : Overall ITT Analysis | Change at Week 12 | 0.43 mmol/mol | Standard Deviation 5.7 |
| Usual Care | Absolute Change From Baseline in Hemoglobin A1c (HbA1c) at Week 12 and 24 : Overall ITT Analysis | Change at Week 24 | 2.40 mmol/mol | Standard Deviation 8.19 |
Secondary
Absolute Change From Baseline in Number of Glucose-Lowering Treatments at Week 12 and 24 : Overall ITT Analysis
Glucose lowering treatment was calculated for non-insulin treatments as one for each unique treatment received and for insulin treatment as one in total for all participants who have taken one or more treatments. Absolute change = number of glucose-lowering treatments at specified week minus baseline value.
Time frame: Baseline, Week 12 and 24
Population: ITT population. Here, 'Number Analyzed' = participants with available data at the specified time points for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Absolute Change From Baseline in Number of Glucose-Lowering Treatments at Week 12 and 24 : Overall ITT Analysis | Change at Week 12 | 0.04 Glucose lowering treatments | Standard Deviation 0.3 |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Absolute Change From Baseline in Number of Glucose-Lowering Treatments at Week 12 and 24 : Overall ITT Analysis | Change at Week 24 | 0.07 Glucose lowering treatments | Standard Deviation 0.37 |
| Usual Care | Absolute Change From Baseline in Number of Glucose-Lowering Treatments at Week 12 and 24 : Overall ITT Analysis | Change at Week 12 | 0.04 Glucose lowering treatments | Standard Deviation 0.19 |
| Usual Care | Absolute Change From Baseline in Number of Glucose-Lowering Treatments at Week 12 and 24 : Overall ITT Analysis | Change at Week 24 | 0.04 Glucose lowering treatments | Standard Deviation 0.23 |
Secondary
Percent Change From Baseline in Apo B at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
Time frame: From Baseline to Week 24
Population: Apo-B ITT population.Here, 'Number of participants analyzed' = participants from intent to prescribe fenofibrate stratum who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Apo B at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | -38.9 Percent change | Standard Error 3.1 |
| Usual Care | Percent Change From Baseline in Apo B at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | -3.8 Percent change | Standard Error 4.4 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint of ITT- intent to prescribe fenofibrate stratum was statistically significant).p-value: <0.000197.5% CI: [-47.4, -22.9]Mixed Models Analysis
Secondary
Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24: Overall ITT Analysis
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 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 |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24: Overall ITT Analysis | -33.8 Percent change | Standard Error 2.7 |
| Usual Care | Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24: Overall ITT Analysis | -1.6 Percent change | Standard Error 3 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint of overall ITT analysis was statistically significant).p-value: <0.000197.5% CI: [-37.3, -27.2]Mixed Models Analysis
Secondary
Percent Change From Baseline in Fasting Triglycerides at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum
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 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
Time frame: From Baseline to Week 24
Population: ITT population. Here, 'Number of participants analyzed' = participants from intent to prescribe fenofibrate stratum who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Fasting Triglycerides at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | -15.4 Percent change | Standard Error 4.7 |
| Usual Care | Percent Change From Baseline in Fasting Triglycerides at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | -24.4 Percent change | Standard Error 6.6 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint of ITT- intent to prescribe fenofibrate stratum was statistically significant).p-value: 0.265197.5% CI: [-9.1, 27.1]Regression, Robust
Secondary
Percent Change From Baseline in Fasting Triglycerides at Week 24: Overall 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 8 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 |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Fasting Triglycerides at Week 24: Overall ITT Analysis | -13.0 Percent change | Standard Error 2 |
| Usual Care | Percent Change From Baseline in Fasting Triglycerides at Week 24: Overall ITT Analysis | -8.8 Percent change | Standard Error 2.8 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint of overall ITT analysis was statistically significant).p-value: 0.219197.5% CI: [-11.8, 3.4]Regression, Robust
Secondary
Percent Change From Baseline in HDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
Time frame: From Baseline to Week 24
Population: HDL-C ITT population. Here, 'Number of participants analyzed' = participants from intent to prescribe fenofibrate stratum who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in HDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | 13.5 Percent change | Standard Error 2.9 |
| Usual Care | Percent Change From Baseline in HDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | 12.3 Percent change | Standard Error 4.1 |
Secondary
Percent Change From Baseline in HDL-C at Week 24 : Overall ITT Analysis
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 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 |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in HDL-C at Week 24 : Overall ITT Analysis | 14.5 Percent change | Standard Error 2.5 |
| Usual Care | Percent Change From Baseline in HDL-C at Week 24 : Overall ITT Analysis | 8.2 Percent change | Standard Error 2.7 |
Secondary
Percent Change From Baseline in LDL-C Particle Number at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum
LDL-C particle number was calculated from lipid subfractions by NMR spectroscopy. Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
Time frame: From Baseline to Week 24
Population: LDL-C particle number ITT population. Here, 'Number of participants analyzed' = participants from intent to prescribe fenofibrate stratum who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in LDL-C Particle Number at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | -45.4 Percent change | Standard Error 3.5 |
| Usual Care | Percent Change From Baseline in LDL-C Particle Number at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | -2.9 Percent change | Standard Error 5 |
Secondary
Percent Change From Baseline in LDL-C Particle Number at Week 24: Overall ITT Analysis
LDL-C particle number was calculated from lipid subfractions by nuclear magnetic resonance (NMR) spectroscopy. Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 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 LDL-C particle number on- or off-treatment (LDL-C particle number ITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in LDL-C Particle Number at Week 24: Overall ITT Analysis | -41.6 Percent change | Standard Error 3 |
| Usual Care | Percent Change From Baseline in LDL-C Particle Number at Week 24: Overall ITT Analysis | -3.9 Percent change | Standard Error 3.4 |
Secondary
Percent Change From Baseline in Lipoprotein(a) at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum
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 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
Time frame: From Baseline to Week 24
Population: ITT population. Here, 'Number of participants analyzed' = participants from intent to prescribe fenofibrate stratum who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Lipoprotein(a) at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | -18.9 Percent change | Standard Error 4.4 |
| Usual Care | Percent Change From Baseline in Lipoprotein(a) at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | 3.9 Percent change | Standard Error 6.6 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint of ITT- intent to prescribe fenofibrate stratum was statistically significant).p-value: 0.00497.5% CI: [-40.6, -5]Regression, Robust
Secondary
Percent Change From Baseline in Lipoprotein(a) at Week 24 : Overall ITT Analysis
Adjusted means and standard errors at Week 24 were obtained from multiple imputation approach followed by robust regression model for handling of missing data. All available post-baseline data from Week 8 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 |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Lipoprotein(a) at Week 24 : Overall ITT Analysis | -23.7 Percent change | Standard Error 1.9 |
| Usual Care | Percent Change From Baseline in Lipoprotein(a) at Week 24 : Overall ITT Analysis | 3.7 Percent change | Standard Error 2.6 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint of overall ITT analysis was statistically significant).p-value: <0.000197.5% CI: [-34.6, -20.1]Regression, Robust
Secondary
Percent Change From Baseline in Measured LDL-C at Week 12: ITT- Intent to Prescribe Fenofibrate Stratum
Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
Time frame: From Baseline to Week 24
Population: LDL-C ITT population. Here, 'Number of participants analyzed' = participants from intent to prescribe fenofibrate stratum who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Measured LDL-C at Week 12: ITT- Intent to Prescribe Fenofibrate Stratum | -44.3 Percent change | Standard Error 3.6 |
| Usual Care | Percent Change From Baseline in Measured LDL-C at Week 12: ITT- Intent to Prescribe Fenofibrate Stratum | 5.4 Percent change | Standard Error 5.1 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint of ITT-intent to prescribe fenofibrate stratum was statistically significant).p-value: <0.000197.5% CI: [-63.7, -35.8]Mixed Models Analysis
Secondary
Percent Change From Baseline in Measured LDL-C at Week 12: Overall ITT Analysis
Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 24
Population: LDL-C ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Measured LDL-C at Week 12: Overall ITT Analysis | -41.7 Percent change | Standard Error 3.3 |
| Usual Care | Percent Change From Baseline in Measured LDL-C at Week 12: Overall ITT Analysis | -7.0 Percent change | Standard Error 3.6 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint of overall ITT analysis was statistically significant).p-value: <0.000197.5% CI: [-40.8, -28.6]Mixed Models Analysis
Secondary
Percent Change From Baseline in Measured LDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum
Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
Time frame: From Baseline to Week 24
Population: LDL-C ITT population. Here, 'Number of participants analyzed' = participants from intent to prescribe fenofibrate stratum who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Measured LDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | -47.0 Percent change | Standard Error 4.2 |
| Usual Care | Percent Change From Baseline in Measured LDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | 8.7 Percent change | Standard Error 5.8 |
Comparison: A separate hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses for ITT-intent to prescribe fenofibrate stratum. 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.p-value: <0.000197.5% CI: [-71.8, -39.6]Mixed Models Analysis
Secondary
Percent Change From Baseline in Measured Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24: Overall ITT Analysis
Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline data from Week 8 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 LDL-C value on-or off-treatment (LDL-C ITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Measured Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24: Overall ITT Analysis | -43.3 Percent change | Standard Error 3.6 |
| Usual Care | Percent Change From Baseline in Measured Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24: Overall ITT Analysis | -0.3 Percent change | Standard Error 4 |
Comparison: A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses for overall ITT analysis. 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.p-value: <0.000197.5% CI: [-49.7, -36.3]Mixed Models Analysis
Secondary
Percent Change From Baseline in Non-HDL-C at Week 12: ITT- Intent to Prescribe Fenofibrate Stratum
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
Time frame: From Baseline to Week 24
Population: ITT population. Here, 'Number of participants analyzed' = participants from intent to prescribe fenofibrate stratum who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Non-HDL-C at Week 12: ITT- Intent to Prescribe Fenofibrate Stratum | -34.7 Percent change | Standard Error 3.2 |
| Usual Care | Percent Change From Baseline in Non-HDL-C at Week 12: ITT- Intent to Prescribe Fenofibrate Stratum | -7.3 Percent change | Standard Error 4.5 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint of ITT-intent to prescribe fenofibrate stratum was statistically significant).p-value: <0.000197.5% CI: [-40, -14.8]Mixed Models Analysis
Secondary
Percent Change From Baseline in Non-HDL-C at Week 12: Overall ITT Analysis
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 8 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 |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Non-HDL-C at Week 12: Overall ITT Analysis | -35.5 Percent change | Standard Error 2.9 |
| Usual Care | Percent Change From Baseline in Non-HDL-C at Week 12: Overall ITT Analysis | -9.4 Percent change | Standard Error 3.2 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint of overall ITT analysis was statistically significant).p-value: <0.000197.5% CI: [-31.5, -20.7]Mixed Models Analysis
Secondary
Percent Change From Baseline in Total-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate.
Time frame: From Baseline to Week 24
Population: Total-C ITT population. Here, 'Number of participants analyzed' = participants from intent to prescribe fenofibrate stratum who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Total-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | -30.9 Percent change | Standard Error 2.6 |
| Usual Care | Percent Change From Baseline in Total-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum | -5.7 Percent change | Standard Error 3.7 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint of ITT- intent to prescribe fenofibrate stratum was statistically significant).p-value: <0.000197.5% CI: [-35.4, -15.1]Mixed Models Analysis
Secondary
Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 : Overall ITT Analysis
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 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 |
|---|---|---|---|
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 : Overall ITT Analysis | -27.4 Percent change | Standard Error 2.3 |
| Usual Care | Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 : Overall ITT Analysis | -2.8 Percent change | Standard Error 2.5 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint of overall ITT analysis was statistically significant).p-value: <0.000197.5% CI: [-28.8, -20.3]Mixed Models Analysis