Homozygous Familial Hypercholesterolemia
Conditions
Keywords
HoFH
Brief summary
The primary objective of the study is to demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by evinacumab intravenously (IV) in comparison to placebo after 24 weeks in patients with homozygous familial hypercholesterolemia (HoFH). The secondary objectives of the study are to evaluate the effect of evinacumab IV on other lipid parameters, evaluate the effect of evinacumab on LDL-C goal attainment, assess the effect of evinacumab on eligibility for apheresis (using German and US apheresis criteria), evaluate the safety and tolerability of evinacumab in patients with HoFH, assess the pharmacokinetics (PK) of evinacumab in patients with HoFH and evaluate the potential development of anti-evinacumab antibodies.
Interventions
DRUGevinacumab
IV administration of evinacumab
DRUGPlacebo
IV administration of placebo
Sponsors
Regeneron Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Diagnosis of functional HoFH 2. If undergoing LDL apheresis, must have initiated LDL apheresis at least 3 months prior to screening and must have been on a stable weekly or every other week schedule and/or stable settings for at least 8 weeks 3. Willing to consistently maintain his/her usual low fat or heart-healthy diet for the duration of the study Key
Exclusion criteria
1. LDL-C level \<70 mg/dL (1.81 mmol/L) at the screening visit 2. Background medical Lipid Modifying Therapy (LMT) (if applicable) that has not been stable before the screening visit 3. Lipid-apheresis schedule /apheresis settings (if applicable) that have not been stable for at least 8 weeks before the screening visit 4. Use of nutraceuticals or over-the-counter therapies known to affect lipids, at a dose/amount that has not been stable for at least 4 weeks prior to the screening visit 5. Presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins 6. Newly diagnosed (within 3 months prior to randomization visit) diabetes mellitus or poorly controlled (HbA1c \>9%) diabetes 7. History of a MI, unstable angina leading to hospitalization, coronary artery bypass graft surgery, percutaneous coronary intervention, uncontrolled cardiac arrhythmia, carotid surgery or stenting, stroke, transient ischemic attack, valve replacement surgery, carotid revascularization, endovascular procedure or surgical intervention for peripheral vascular disease within 3 months prior to the screening visit 8. Pregnant or breastfeeding women 9. Sexually active women of child bearing potential (WOCBP), who are unwilling to practice a highly effective birth control method prior to the initial dose, during the study, and for 24 weeks after the last dose of study drug 10. Men who are sexually active with women of child bearing potential (WOCBP) and are unwilling to consistently use condoms during the study drug treatment period and for 24 weeks after the last dose of study drug regardless of vasectomy status Note: Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 24 (Intent-to-Treat [ITT] Estimand) | Week 24 | Percent change was calculated as 100x(calculated LDL-C value at Week 24 - calculated LDL-C value at baseline)/calculated LDL-C value at baseline. The baseline LDL-C value was the last calculated LDL-C value obtained before the first dose of double-blind-study drug. The calculated LDL-C at week 24 was the LDL-C value obtained within the week 24 efficacy analysis window, regardless of adherence to treatment and subsequent therapies (intent-to-treat \[ITT\] estimand). The ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 24 (ITT Estimand) | Week 24 | Percent change from baseline in non-HDL-C at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group). |
| Percent Change in Total Cholesterol (TC) From Baseline to Week 24 (ITT Estimand) | Week 24 | Percent change in TC from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group). |
| Percentage of Participants With ≥30% Reduction in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24 (ITT Estimand) | At Week 24 | Percentage of participants who achieved reduction in calculated LDL-C ≥30% at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group). |
| Percentage of Participants With ≥50% Reduction in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24 (ITT Estimand) | At Week 24 | Percentage of participants who achieved reduction in calculated LDL-C ≥ 50% at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group). |
| Absolute Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 24 (ITT Estimand) | Week 24 | Absolute change in calculated LDL-C from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group). |
| Percentage of Participants Who Met United States (US) Apheresis Eligibility Criteria at Week 24 (ITT Estimand) | At Week 24 | US apheresis eligibility criteria included participants who had inadequate response to diet and LMTs after 6 months of treatment and with functional Homozygous familial hypercholesterolemia (HoFH) or Heterozygous familial hypercholesterolemia (HeFH) (with 0-1 risk factor) with LDL-C ≥ 300 mg/dL (7.77 mmol/L). Percentage of participants who met US apheresis eligibility criteria at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group). |
| Percentage of Participants With Low-Density Lipoprotein Cholesterol (LDL-C) <100 Milligrams Per Deciliter (mg/dL) (2.59 Millimoles Per Liter [mmol/L]) at Week 24 (ITT Estimand) | At Week 24 | Percentage of participants with LDL-C value \<100 mg/dL (2.59 mmol/L) in the DBTP at Week 24 was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analysed according to the treatment group allocated by randomization (i.e., as randomized participant group). |
| Percent Change in Apolipoprotein B (Apo B) From Baseline to Week 24 (ITT Estimand) | Week 24 | Percent change in Apo B from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group). |
| Percentage of Participants With Calculated Low-Density Lipoprotein Cholesterol (LDL-C) <70 mg/dL (1.81 mmol/L) at Week 24 (ITT Estimand) | At Week 24 | Percentage of participants with LDL-C \<70 mg/dL (1.81 mmol/L) at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group). |
| Percent Change in Fasting Triglycerides (TG) From Baseline to Week 24 (ITT Estimand) | Week 24 | Percent change from baseline in TG at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group). |
| Percent Change in Lipoprotein A (Lp[a]) From Baseline to Week 24 (ITT Estimand) | Week 24 | Percent change in Lp(a) from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group). |
| Absolute Change in Apolipoprotein B (Apo B) From Baseline to Week 24 (ITT Estimand) | Week 24 | Absolute change in Apo B from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group). |
| Absolute Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 24 (ITT Estimand) | Week 24 | Absolute change in non-HDL-C from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group). |
| Absolute Change in Total Cholesterol (TC) From Baseline to Week 24 (ITT Estimand) | Week 24 | Absolute change in TC from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group). |
| Percent Change in Apolipoprotein CIII (Apo CIII) From Baseline to Week 24 (ITT Estimand) | Week 24 | Percent change in Apo CIII from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group). |
| Percentage of Participants Who Met European Union (EU) Apheresis Eligibility Criteria at Week 24 (ITT Estimand) | At Week 24 | EU apheresis eligibility criteria included participants who had inadequate response to diet and Lipid modifying therapies (LMTs) after 3 months of treatment, Primary prevention: Participants with Familial hypercholesterolemia (FH) with LDL-C \>160 mg/dL (4.2 mmol/L) and Cardiovascular (CV) events in close relatives. Secondary prevention: Participants with progressive CV events with LDL-C \> 120 to 130 mg/dL (3.1-3.4 mmol/L). Percentage of participants who met EU apheresis eligibility criteria at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group). |
Countries
Australia, Austria, Canada, France, Greece, Italy, Japan, Netherlands, South Africa, Ukraine, United States
Participant flow
Recruitment details
This study was conducted at 30 centers that enrolled participants in 11 countries in Europe, Asia, North America, and Australia. Randomization was stratified by apheresis treatment status and by region (Japan, Rest of the World \[ROW\]).
Pre-assignment details
A total of 75 participants were screened and 65 participants randomized. There were 10 participants that were considered screen failures.
Participants by arm
| Arm | Count |
|---|---|
| Placebo IV Q4W Participants received IV infusion of placebo matched to evinacumab every 4 weeks (Q4W) from day 1 to week 20 in the double-blind treatment period (DBTP). All participants who completed the double-blind treatment period received IV infusion of evinacumab at a dose of 15 mg/kg Q4W from week 24 to week 44 in the open-label treatment period (OLTP). | 22 |
| Evinacumab 15 mg/kg IV Q4W Participants received IV infusion of evinacumab at a dose of 15 mg/kg Q4W from day 1 to week 20 in the double-blind treatment period (DBTP). All participants who completed the double-blind treatment period received IV infusion of evinacumab at a dose of 15 mg/kg Q4W from week 24 to week 44 in the open-label treatment period (OLTP). | 43 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-blind Treatment Period (DBTP) | Withdrawal by Subject | 1 | 0 | 0 | 0 |
| Open-label Treatment Period (OLTP) | Noncompliance with protocol by the participant | 0 | 0 | 1 | 0 |
| Open-label Treatment Period (OLTP) | Pregnancy | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo IV Q4W | Evinacumab 15 mg/kg IV Q4W | Total |
|---|---|---|---|
| Age, Continuous | 36.7 Years STANDARD_DEVIATION 11.52 | 44.3 Years STANDARD_DEVIATION 16.78 | 41.7 Years STANDARD_DEVIATION 15.54 |
| Age, Customized ≥12 years to <18 years of age | 1 Participants | 1 Participants | 2 Participants |
| Age, Customized ≥18 years to <45 years of age | 16 Participants | 23 Participants | 39 Participants |
| Age, Customized ≥45 years to <65 years of age | 5 Participants | 11 Participants | 16 Participants |
| Age, Customized ≥65 years to <75 years of age | 0 Participants | 7 Participants | 7 Participants |
| Age, Customized ≥75 years of age | 0 Participants | 1 Participants | 1 Participants |
| Apolipoprotein B (Apo B) | 175.9 mg/dL STANDARD_DEVIATION 98.76 | 169.1 mg/dL STANDARD_DEVIATION 82.75 | 171.4 mg/dL STANDARD_DEVIATION 87.78 |
| Apolipoprotein CIII (Apo CIII) | 9.7 mg/dL STANDARD_DEVIATION 5.23 | 9.2 mg/dL STANDARD_DEVIATION 4 | 9.39 mg/dL STANDARD_DEVIATION 4.42 |
| Calculated Low-density Lipoprotein Cholesterol (LDL-C) | 246.5 Milligrams per Deciliter (mg/dL) STANDARD_DEVIATION 153.71 | 259.5 Milligrams per Deciliter (mg/dL) STANDARD_DEVIATION 172.4 | 255.1 Milligrams per Deciliter (mg/dL) STANDARD_DEVIATION 165.21 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 38 Participants | 58 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 5 Participants |
| Fasting Triglycerides (TG) | 144.1 mg/dL STANDARD_DEVIATION 144.54 | 113.1 mg/dL STANDARD_DEVIATION 68.39 | 123.6 mg/dL STANDARD_DEVIATION 100.71 |
| Lipoprotein A (Lp[a]) | 103.4 Nanomoles per Liter (nmol/L) STANDARD_DEVIATION 109.43 | 111.3 Nanomoles per Liter (nmol/L) STANDARD_DEVIATION 114.4 | 108.7 Nanomoles per Liter (nmol/L) STANDARD_DEVIATION 111.95 |
| Non-high-density Lipoprotein Cholesterol (non-HDL-C) | 269.9 mg/dL STANDARD_DEVIATION 157.81 | 281.9 mg/dL STANDARD_DEVIATION 172.61 | 277.8 mg/dL STANDARD_DEVIATION 166.6 |
| Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race Asian | 4 Participants | 6 Participants | 10 Participants |
| Race Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race Other | 1 Participants | 2 Participants | 3 Participants |
| Race White | 17 Participants | 31 Participants | 48 Participants |
| Sex: Female, Male Female | 11 Participants | 24 Participants | 35 Participants |
| Sex: Female, Male Male | 11 Participants | 19 Participants | 30 Participants |
| Total Cholesterol (TC) | 315.9 mg/dL STANDARD_DEVIATION 150.44 | 325.6 mg/dL STANDARD_DEVIATION 170.76 | 322.3 mg/dL STANDARD_DEVIATION 163.05 |
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 / 21 | 0 / 44 | 0 / 20 | 0 / 44 |
| other Total, other adverse events | 13 / 21 | 20 / 44 | 12 / 20 | 19 / 44 |
| serious Total, serious adverse events | 0 / 21 | 2 / 44 | 0 / 20 | 7 / 44 |
Outcome results
Primary
Percent Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 24 (Intent-to-Treat [ITT] Estimand)
Percent change was calculated as 100x(calculated LDL-C value at Week 24 - calculated LDL-C value at baseline)/calculated LDL-C value at baseline. The baseline LDL-C value was the last calculated LDL-C value obtained before the first dose of double-blind-study drug. The calculated LDL-C at week 24 was the LDL-C value obtained within the week 24 efficacy analysis window, regardless of adherence to treatment and subsequent therapies (intent-to-treat \[ITT\] estimand). The ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group).
Time frame: Week 24
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo IV Q4W | Percent Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 24 (Intent-to-Treat [ITT] Estimand) | 1.9 Percent Change | Standard Error 6.5 |
| Evinacumab 15 mg/kg IV Q4W | Percent Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 24 (Intent-to-Treat [ITT] Estimand) | -47.1 Percent Change | Standard Error 4.6 |
Comparison: Confidence interval (CI) with p-value was based on-treatment group difference of least squares (LS) means using mixed-effect model repeat measurement (MMRM), randomization strata, treatment/strata/baseline value-by-time point interaction and continuous fixed covariates of baseline calculated LDL-C value.p-value: <0.000195% CI: [-65, -33.1]Mixed-effect Model Repeat Measure (MMRM)
Secondary
Absolute Change in Apolipoprotein B (Apo B) From Baseline to Week 24 (ITT Estimand)
Absolute change in Apo B from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group).
Time frame: Week 24
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo IV Q4W | Absolute Change in Apolipoprotein B (Apo B) From Baseline to Week 24 (ITT Estimand) | -8.0 mg/dL | Standard Error 9.1 |
| Evinacumab 15 mg/kg IV Q4W | Absolute Change in Apolipoprotein B (Apo B) From Baseline to Week 24 (ITT Estimand) | -74.4 mg/dL | Standard Error 6.3 |
Secondary
Absolute Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 24 (ITT Estimand)
Absolute change in calculated LDL-C from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group).
Time frame: Week 24
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo IV Q4W | Absolute Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 24 (ITT Estimand) | -2.6 Milligrams per Deciliter (mg/dL) | Standard Error 17.6 |
| Evinacumab 15 mg/kg IV Q4W | Absolute Change in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 24 (ITT Estimand) | -134.7 Milligrams per Deciliter (mg/dL) | Standard Error 12.4 |
Comparison: A 2-sided hierarchical testing procedure was used for the secondary endpoints in a pre-specified order to control type I error. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. CI with p-value was based on-treatment group difference of LS means using MMRM, randomization strata, treatment/strata/baseline value-by-time point interaction and continuous fixed covariates of baseline calculated LDL-C value.p-value: <0.000195% CI: [-175.3, -88.9]Mixed-effect Model Repeat Measure (MMRM)
Secondary
Absolute Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 24 (ITT Estimand)
Absolute change in non-HDL-C from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group).
Time frame: Week 24
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo IV Q4W | Absolute Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 24 (ITT Estimand) | -0.4 mg/dL | Standard Error 17.4 |
| Evinacumab 15 mg/kg IV Q4W | Absolute Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 24 (ITT Estimand) | -148.0 mg/dL | Standard Error 12.3 |
Secondary
Absolute Change in Total Cholesterol (TC) From Baseline to Week 24 (ITT Estimand)
Absolute change in TC from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group).
Time frame: Week 24
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo IV Q4W | Absolute Change in Total Cholesterol (TC) From Baseline to Week 24 (ITT Estimand) | -0.4 mg/dL | Standard Error 17.2 |
| Evinacumab 15 mg/kg IV Q4W | Absolute Change in Total Cholesterol (TC) From Baseline to Week 24 (ITT Estimand) | -161.6 mg/dL | Standard Error 12.2 |
Secondary
Percentage of Participants Who Met European Union (EU) Apheresis Eligibility Criteria at Week 24 (ITT Estimand)
EU apheresis eligibility criteria included participants who had inadequate response to diet and Lipid modifying therapies (LMTs) after 3 months of treatment, Primary prevention: Participants with Familial hypercholesterolemia (FH) with LDL-C \>160 mg/dL (4.2 mmol/L) and Cardiovascular (CV) events in close relatives. Secondary prevention: Participants with progressive CV events with LDL-C \> 120 to 130 mg/dL (3.1-3.4 mmol/L). Percentage of participants who met EU apheresis eligibility criteria at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group).
Time frame: At Week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo IV Q4W | Percentage of Participants Who Met European Union (EU) Apheresis Eligibility Criteria at Week 24 (ITT Estimand) | 77.3 Percentage of Participants |
| Evinacumab 15 mg/kg IV Q4W | Percentage of Participants Who Met European Union (EU) Apheresis Eligibility Criteria at Week 24 (ITT Estimand) | 32.6 Percentage of Participants |
Comparison: A 2-sided hierarchical testing procedure was used for the secondary endpoints in a pre-specified order to control type I error. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. Combined estimate for odds ratio was obtained by using Rubin's formulae. Logistic regression models stratified the fixed categorical effect of treatment group and the continuous fixed covariate of baseline calculated LDL-C value.p-value: =0.000495% CI: [0, 0.3]Logistic Regression Models Analysis
Secondary
Percentage of Participants Who Met United States (US) Apheresis Eligibility Criteria at Week 24 (ITT Estimand)
US apheresis eligibility criteria included participants who had inadequate response to diet and LMTs after 6 months of treatment and with functional Homozygous familial hypercholesterolemia (HoFH) or Heterozygous familial hypercholesterolemia (HeFH) (with 0-1 risk factor) with LDL-C ≥ 300 mg/dL (7.77 mmol/L). Percentage of participants who met US apheresis eligibility criteria at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group).
Time frame: At Week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo IV Q4W | Percentage of Participants Who Met United States (US) Apheresis Eligibility Criteria at Week 24 (ITT Estimand) | 22.7 Percentage of Participants |
| Evinacumab 15 mg/kg IV Q4W | Percentage of Participants Who Met United States (US) Apheresis Eligibility Criteria at Week 24 (ITT Estimand) | 7.0 Percentage of Participants |
Comparison: A 2-sided hierarchical testing procedure was used for the secondary endpoints in a pre-specified order to control type I error. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. Combined estimate for odds ratio was obtained by using Rubin's formulae. Logistic regression models stratified the fixed categorical effect of treatment group and the continuous fixed covariate of baseline calculated LDL-C value.p-value: =0.084595% CI: [0, 1.3]Logistic Regression Models Analyses
Secondary
Percentage of Participants With ≥30% Reduction in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24 (ITT Estimand)
Percentage of participants who achieved reduction in calculated LDL-C ≥30% at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group).
Time frame: At Week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo IV Q4W | Percentage of Participants With ≥30% Reduction in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24 (ITT Estimand) | 18.2 Percentage of Participants |
| Evinacumab 15 mg/kg IV Q4W | Percentage of Participants With ≥30% Reduction in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24 (ITT Estimand) | 83.7 Percentage of Participants |
Comparison: A 2-sided hierarchical testing procedure was used for secondary endpoints in pre-specified order to control type I error.Testing sequence continued only when previous endpoint was statistically significant at 0.05.Multiple imputation addressed missing data at week 24.Combined estimate for odds ratio obtained by Rubin's formulae.Logistic regression models stratified by randomized strata include fixed categorical effect of treatment group \& continuous fixed covariate of baseline calculated LDL-C.p-value: <0.000195% CI: [5.7, 110.5]Logistic Regression Models Analyses
Secondary
Percentage of Participants With ≥50% Reduction in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24 (ITT Estimand)
Percentage of participants who achieved reduction in calculated LDL-C ≥ 50% at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group).
Time frame: At Week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo IV Q4W | Percentage of Participants With ≥50% Reduction in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24 (ITT Estimand) | 4.5 Percentage of Participants |
| Evinacumab 15 mg/kg IV Q4W | Percentage of Participants With ≥50% Reduction in Calculated Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24 (ITT Estimand) | 55.8 Percentage of Participants |
Comparison: A 2-sided hierarchical testing procedure was used for secondary endpoints in pre-specified order to control type I error.Testing sequence continued only when previous endpoint was statistically significant at 0.05.Multiple imputation addressed missing data at week 24.Combined estimate for odds ratio obtained by Rubin's formulae.Logistic regression models stratified by randomized strata include fixed categorical effect of treatment group \& continuous fixed covariate of baseline calculated LDL-C.p-value: =0.002895% CI: [3, 195.6]Logistic Regression Models Analyses
Secondary
Percentage of Participants With Calculated Low-Density Lipoprotein Cholesterol (LDL-C) <70 mg/dL (1.81 mmol/L) at Week 24 (ITT Estimand)
Percentage of participants with LDL-C \<70 mg/dL (1.81 mmol/L) at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group).
Time frame: At Week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo IV Q4W | Percentage of Participants With Calculated Low-Density Lipoprotein Cholesterol (LDL-C) <70 mg/dL (1.81 mmol/L) at Week 24 (ITT Estimand) | 4.5 Percentage of Participants |
| Evinacumab 15 mg/kg IV Q4W | Percentage of Participants With Calculated Low-Density Lipoprotein Cholesterol (LDL-C) <70 mg/dL (1.81 mmol/L) at Week 24 (ITT Estimand) | 27.9 Percentage of Participants |
Secondary
Percentage of Participants With Low-Density Lipoprotein Cholesterol (LDL-C) <100 Milligrams Per Deciliter (mg/dL) (2.59 Millimoles Per Liter [mmol/L]) at Week 24 (ITT Estimand)
Percentage of participants with LDL-C value \<100 mg/dL (2.59 mmol/L) in the DBTP at Week 24 was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analysed according to the treatment group allocated by randomization (i.e., as randomized participant group).
Time frame: At Week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo IV Q4W | Percentage of Participants With Low-Density Lipoprotein Cholesterol (LDL-C) <100 Milligrams Per Deciliter (mg/dL) (2.59 Millimoles Per Liter [mmol/L]) at Week 24 (ITT Estimand) | 22.7 Percentage of Participants |
| Evinacumab 15 mg/kg IV Q4W | Percentage of Participants With Low-Density Lipoprotein Cholesterol (LDL-C) <100 Milligrams Per Deciliter (mg/dL) (2.59 Millimoles Per Liter [mmol/L]) at Week 24 (ITT Estimand) | 46.5 Percentage of Participants |
Comparison: A 2-sided hierarchical testing procedure was used for the secondary endpoints in a pre-specified order to control type I error. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. Combined estimate for odds ratio was obtained by using Rubin's formulae. Logistic regression models stratified the fixed categorical effect of treatment group and the continuous fixed covariate of baseline calculated LDL-C value.p-value: =0.020395% CI: [1.3, 24.9]Logistic Regression Models Analyses
Secondary
Percent Change in Apolipoprotein B (Apo B) From Baseline to Week 24 (ITT Estimand)
Percent change in Apo B from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group).
Time frame: Week 24
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo IV Q4W | Percent Change in Apolipoprotein B (Apo B) From Baseline to Week 24 (ITT Estimand) | -4.5 Percent Change | Standard Error 4.8 |
| Evinacumab 15 mg/kg IV Q4W | Percent Change in Apolipoprotein B (Apo B) From Baseline to Week 24 (ITT Estimand) | -41.4 Percent Change | Standard Error 3.3 |
Comparison: A 2-sided hierarchical testing procedure was used for the secondary endpoints in a pre-specified order to control type I error. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. CI with p-value was based on-treatment group difference of LS means using MMRM, randomization strata, treatment/strata/baseline value-by-time point interaction and continuous fixed covariates of baseline calculated Apo B value.p-value: <0.000195% CI: [-48.6, -25.2]Mixed-effect Model Repeat Measure (MMRM)
Secondary
Percent Change in Apolipoprotein CIII (Apo CIII) From Baseline to Week 24 (ITT Estimand)
Percent change in Apo CIII from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group).
Time frame: Week 24
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo IV Q4W | Percent Change in Apolipoprotein CIII (Apo CIII) From Baseline to Week 24 (ITT Estimand) | 5.8 Percent Change | Standard Error 5.5 |
| Evinacumab 15 mg/kg IV Q4W | Percent Change in Apolipoprotein CIII (Apo CIII) From Baseline to Week 24 (ITT Estimand) | -84.1 Percent Change | Standard Error 3.9 |
Secondary
Percent Change in Fasting Triglycerides (TG) From Baseline to Week 24 (ITT Estimand)
Percent change from baseline in TG at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group).
Time frame: Week 24
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo IV Q4W | Percent Change in Fasting Triglycerides (TG) From Baseline to Week 24 (ITT Estimand) | -4.6 Percent Change | Standard Error 7 |
| Evinacumab 15 mg/kg IV Q4W | Percent Change in Fasting Triglycerides (TG) From Baseline to Week 24 (ITT Estimand) | -55.0 Percent Change | Standard Error 3.1 |
Secondary
Percent Change in Lipoprotein A (Lp[a]) From Baseline to Week 24 (ITT Estimand)
Percent change in Lp(a) from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group).
Time frame: Week 24
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo IV Q4W | Percent Change in Lipoprotein A (Lp[a]) From Baseline to Week 24 (ITT Estimand) | -3.6 Percent Change | Standard Error 5.8 |
| Evinacumab 15 mg/kg IV Q4W | Percent Change in Lipoprotein A (Lp[a]) From Baseline to Week 24 (ITT Estimand) | -5.5 Percent Change | Standard Error 4 |
Secondary
Percent Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 24 (ITT Estimand)
Percent change from baseline in non-HDL-C at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group).
Time frame: Week 24
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo IV Q4W | Percent Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 24 (ITT Estimand) | 2.0 Percent Change | Standard Error 5.4 |
| Evinacumab 15 mg/kg IV Q4W | Percent Change in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 24 (ITT Estimand) | -49.7 Percent Change | Standard Error 3.8 |
Comparison: A 2-sided hierarchical testing procedure was used for the secondary endpoints in a pre-specified order to control type I error. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. CI with p-value was based on-treatment group difference of LS means using MMRM, randomization strata, treatment/strata/baseline value-by-time point interaction and continuous fixed covariates of baseline calculated non-HDL-C value.p-value: <0.000195% CI: [-64.8, -38.5]Mixed-effect Model Repeat Measure (MMRM)
Secondary
Percent Change in Total Cholesterol (TC) From Baseline to Week 24 (ITT Estimand)
Percent change in TC from baseline at Week 24 in the DBTP was reported; value obtained regardless of adherence to study treatment and subsequent therapies (ITT estimand). ITT population included all randomized participants who received at least one dose or part of a dose of double-blind study drug. Participants in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as randomized participant group).
Time frame: Week 24
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo IV Q4W | Percent Change in Total Cholesterol (TC) From Baseline to Week 24 (ITT Estimand) | 1.0 Percent Change | Standard Error 4.2 |
| Evinacumab 15 mg/kg IV Q4W | Percent Change in Total Cholesterol (TC) From Baseline to Week 24 (ITT Estimand) | -47.4 Percent Change | Standard Error 3 |
Comparison: A 2-sided hierarchical testing procedure was used for the secondary endpoints in a pre-specified order to control type I error. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. CI with p-value was based on-treatment group difference of LS means using MMRM, randomization strata, treatment/strata/baseline value-by-time point interaction and continuous fixed covariates of baseline calculated TC value.p-value: <0.000195% CI: [-58.7, -38.1]Mixed-effect Model Repeat Measure (MMRM)