Hyperlipidemia
Conditions
Keywords
AMG145, Multiple Dose, Statin, Ascending
Brief summary
The purpose of the study is to evaluate the safety and tolerability of multiple doses of evolocumab when given as an add-on to stable statin therapy.
Detailed description
Participants receiving low-to-moderate-dose statins were randomized in a 1:3 ratio to receive subcutaneous placebo or evolocumab and enrolled sequentially into one of 5 dose-escalation cohorts: 1. Evolocumab 14 mg/placebo once weekly (QW) × 6 doses 2. Evolocumab 35 mg/placebo once weekly (QW) × 6 doses 3. Evolocumab 140 mg/placebo every 2 weeks (Q2W) × 3 doses 4. Evolocumab 280 mg/placebo every 2 weeks (Q2W) × 3 doses 5. Evolocumab 420 mg/placebo every 4 weeks (Q2W) × 2 doses. Participants receiving high-dose statins were randomized 1:3 to receive subcutaneous placebo or evolocumab 140 mg every 2 weeks × 3 doses (Cohort 6). Participants diagnosed with familial hypercholesterolemia (HeFH) were randomized 1:2 to receive subcutaneous placebo or evolocumab 140 mg every 2 weeks × 3 doses (Cohort 7).
Interventions
BIOLOGICALEvolocumab
Administered by subcutaneous injection
BIOLOGICALPlacebo
Administered by subcutaneous injection
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Men and women ages 18 to 70 years (inclusive) at the time of screening with hyperlipidemia * Body mass index (BMI) ≥18 and ≤ 35 kg/m\^2 at the time of screening * Low-density lipoprotein cholesterol (LDL-C) level of 70-220 mg/dL (inclusive) at screening as measured by direct assay * For Cohorts 1-5: On a stable dose of rosuvastatin (Crestor) \< 40 mg/day, atorvastatin (Lipitor) \< 80 mg/day, or simvastatin (Zocor) 20-80 mg/day for ≥ 1 month prior to enrollment and expected to remain on this dose for the remainder of the study * For Cohort 6: On a stable dose of rosuvastatin (Crestor) 40 mg/day or atorvastatin (Lipitor) 80 mg/day for ≥ 1 month prior to enrollment and expected to remain on this dose for the remainder of the study * For Cohort 7: Diagnosis of heterozygous familial hypercholesterolemia, based on a score of ≥ 9 points using the World health Organization (WHO) criteria
Exclusion criteria
* Diagnosis of homozygous familial hypercholesterolemia * History of heart failure, coronary artery bypass graft, or cardiac arrhythmia * History of acute coronary syndrome (e.g. myocardial infarction, hospitalization for unstable angina) or percutaneous coronary intervention, within 12 months prior to enrollment * Planned cardiac surgery or revascularization * Known aortic, peripheral vascular or cerebrovascular disease (including history of stroke or transient ischemic attack) * Diabetes mellitus with any of the following: 1. known microvascular or macrovascular disease 2. HbA1c \> 8.0% at screening 3. use of any hypoglycemic medication other than metformin * Uncontrolled hypertension (systolic blood pressure ≥ 150 or diastolic blood pressure ≥ 90 mmHg) either on or off therapy at screening or at baseline
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | From the first dose of study drug until Day 85 | The relationship of each adverse event to the investigational product was assessed by the investigator. A serious adverse event (SAE) is defined as an adverse event that * is fatal * is life threatening (places the subject at immediate risk of death) * requires in-patient hospitalization or prolongation of existing hospitalization * results in persistent or significant disability/incapacity * is a congenital anomaly/birth defect * other significant medical hazard. |
| Number of Participants With Anti-Evolocumab Antibodies | From the first dose of study drug until Day 85 | Serum samples were analyzed by an electrochemiluminescence (ECL)-based immunoassay for anti-evolocumab binding antibodies. Positive samples were subsequently tested in a receptor-ligand binding bioassay for anti-evolocumab neutralizing antibodies |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Evolocumab | Day 1, predose and Days 4, 8, 15, 22, 29, 36, 40, 43, 50, 57, 64, 71, 78, and 85 | Serum concentrations of evolocumab were measured by a validated enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 800 ng/mL. |
| Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Evolocumab | Day 29 predose (last dose for Cohorts 3-7) and Days 36 (predose for Cohorts 1 and 2), 40, 43, 50, 57, 64, 71, 78, and 85 | Area under the unbound evolocumab serum concentration-time curve from time of last dose to time of last quantifiable concentration following the last dose of evolocumab. |
| Percent Change From Baseline to End of the Dosing Interval in LDL-C | Baseline and Day 43 for QW and Q2W groups or Day 57 for Q4W group | — |
| Percent Change From Baseline to End of the Dosing Interval in PCSK9 | Baseline and Day 43 for QW and Q2W groups or Day 57 for Q4W group | Serum PCSK9 concentrations were determined by using a qualified enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 15 ng/mL. |
Participant flow
Recruitment details
This study enrolled hypercholesterolemic adults receiving stable statin therapy (7 cohorts: 5 on low-to-moderate-dose statins, 1 on high-dose statin therapy, and 1 with heterozygous familial hypercholesterolemia (HeFH) (score ≥9, World Health Organization criteria). First patient enrolled 28 June 2010. Last patient enrolled 24 June 2011.
Pre-assignment details
Participants receiving low-to-moderate-dose statins were randomized 1:3 to placebo or evolocumab and sequentially assigned to 1 of 5 dose-escalation cohorts. The high-dose statin and HeFH cohorts were randomized 1:3 and 1:2 respectively to placebo or evolocumab. Placebo participants were pooled for the 5 dose-escalation cohorts.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Cohorts 1-5 Combined: Participants on low-to-moderate dose statin therapy received placebo subcutaneous injections matching active investigational product in volume and frequency. | 10 |
| Evolocumab 14 mg QW × 6 Cohort 1: Participants on low-to-moderate-dose stain therapy received evolocumab 14 mg subcutaneous injection once weekly for 6 weeks. | 6 |
| Evolocumab 35 mg QW × 6 Cohort 2: Participants on low-to-moderate-dose statin therapy received evolocumab 35 mg subcutaneous injection once weekly for 6 weeks. | 6 |
| Evolocumab 140 mg Q2W × 3 Cohort 3: Participants on low-to-moderate-dose statin therapy received evolocumab 140 mg subcutaneous injection every 2 weeks for 6 weeks. | 6 |
| Evolocumab 280 mg Q2W × 3 Cohort 4: Participants on low-to-moderate-dose statin therapy received evolocumab 280 mg subcutaneous injection every 2 weeks for 6 weeks. | 6 |
| Evolocumab 420 mg Q4W × 2 Cohort 5: participants on low-to-moderate-dose statin therapy received evolocumab 420 mg subcutaneous injection every 4 weeks for 8 weeks. | 6 |
| High Dose Statin - Placebo Cohort 6: Participants on high-dose statin therapy received placebo subcutaneous injection every 2 weeks for 6 weeks. | 2 |
| High Dose Statin - Evolocumab 140 mg Q2W × 3 Cohort 6: Participants on high-dose statin therapy received evolocumab 140 mg subcutaneous injection every 2 weeks for 6 weeks. | 9 |
| HeFH - Placebo Cohort 7: Participants diagnosed with HeFH received placebo subcutaneous injection every 2 weeks for 6 weeks. | 2 |
| HeFH - Evolocumab 140 mg Q2W × 3 Cohort 7: Participants diagnosed with HeFH received evolocumab 140 mg subcutaneous injection every 2 weeks for 6 weeks. | 4 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Evolocumab 14 mg QW × 6 | Evolocumab 35 mg QW × 6 | Evolocumab 140 mg Q2W × 3 | Evolocumab 280 mg Q2W × 3 | Evolocumab 420 mg Q4W × 2 | High Dose Statin - Placebo | High Dose Statin - Evolocumab 140 mg Q2W × 3 | HeFH - Placebo | HeFH - Evolocumab 140 mg Q2W × 3 | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 55.8 years STANDARD_DEVIATION 7.5 | 61.3 years STANDARD_DEVIATION 4 | 63.7 years STANDARD_DEVIATION 6.3 | 56.2 years STANDARD_DEVIATION 7.3 | 56.3 years STANDARD_DEVIATION 8.6 | 53.8 years STANDARD_DEVIATION 4.9 | 62.0 years STANDARD_DEVIATION 1.4 | 58.2 years STANDARD_DEVIATION 7.6 | 54.5 years STANDARD_DEVIATION 10.6 | 45.0 years STANDARD_DEVIATION 15.1 | 56.9 years STANDARD_DEVIATION 8.4 |
| Low-Density Lipoprotein Cholesterol (LDL-C) Concentration | 108.9 mg/dL STANDARD_DEVIATION 21.9 | 126.7 mg/dL STANDARD_DEVIATION 22.1 | 106.5 mg/dL STANDARD_DEVIATION 29.4 | 113.7 mg/dL STANDARD_DEVIATION 14.5 | 105.8 mg/dL STANDARD_DEVIATION 17 | 120.3 mg/dL STANDARD_DEVIATION 33 | 99.0 mg/dL STANDARD_DEVIATION 31.1 | 100.2 mg/dL STANDARD_DEVIATION 25.5 | 168.5 mg/dL STANDARD_DEVIATION 57.3 | 134.5 mg/dL STANDARD_DEVIATION 31.1 | 114.1 mg/dL STANDARD_DEVIATION 27.8 |
| Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Concentration | 429.0 ng/mL STANDARD_DEVIATION 93.1 | 491.2 ng/mL STANDARD_DEVIATION 157.9 | 399.8 ng/mL STANDARD_DEVIATION 116.7 | 384.8 ng/mL STANDARD_DEVIATION 88 | 373.7 ng/mL STANDARD_DEVIATION 96 | 459.0 ng/mL STANDARD_DEVIATION 163.4 | 382.5 ng/mL STANDARD_DEVIATION 82.7 | 486.6 ng/mL STANDARD_DEVIATION 214 | 478.5 ng/mL STANDARD_DEVIATION 94 | 396.0 ng/mL STANDARD_DEVIATION 86.4 | 432.0 ng/mL STANDARD_DEVIATION 133.6 |
| Race/Ethnicity, Customized Aborigine | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 participants | 0 participants | 0 participants | 1 participants | 0 participants | 3 participants | 0 participants | 2 participants | 0 participants | 0 participants | 7 participants |
| Race/Ethnicity, Customized Japanese | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized White or Caucasian | 9 participants | 6 participants | 6 participants | 4 participants | 6 participants | 3 participants | 2 participants | 7 participants | 2 participants | 2 participants | 47 participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 1 Participants | 3 Participants | 4 Participants | 3 Participants | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 26 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 5 Participants | 3 Participants | 2 Participants | 3 Participants | 1 Participants | 6 Participants | 1 Participants | 4 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 10 | 2 / 6 | 5 / 6 | 4 / 6 | 6 / 6 | 3 / 6 | 1 / 2 | 7 / 9 | 1 / 2 | 1 / 4 |
| serious Total, serious adverse events | 0 / 10 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 2 | 0 / 9 | 0 / 2 | 0 / 4 |
Outcome results
Primary
Number of Participants With Adverse Events
The relationship of each adverse event to the investigational product was assessed by the investigator. A serious adverse event (SAE) is defined as an adverse event that * is fatal * is life threatening (places the subject at immediate risk of death) * requires in-patient hospitalization or prolongation of existing hospitalization * results in persistent or significant disability/incapacity * is a congenital anomaly/birth defect * other significant medical hazard.
Time frame: From the first dose of study drug until Day 85
Population: Safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| Placebo | Number of Participants With Adverse Events | Treatment-related adverse events | 1 participants |
| Placebo | Number of Participants With Adverse Events | Deaths on study | 0 participants |
| Placebo | Number of Participants With Adverse Events | Any adverse event | 7 participants |
| Placebo | Number of Participants With Adverse Events | Discontinuations due to adverse events | 0 participants |
| Evolocumab 14 mg QW × 6 | Number of Participants With Adverse Events | Deaths on study | 0 participants |
| Evolocumab 14 mg QW × 6 | Number of Participants With Adverse Events | Discontinuations due to adverse events | 0 participants |
| Evolocumab 14 mg QW × 6 | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| Evolocumab 14 mg QW × 6 | Number of Participants With Adverse Events | Treatment-related adverse events | 1 participants |
| Evolocumab 14 mg QW × 6 | Number of Participants With Adverse Events | Any adverse event | 2 participants |
| Evolocumab 35 mg QW × 6 | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| Evolocumab 35 mg QW × 6 | Number of Participants With Adverse Events | Treatment-related adverse events | 0 participants |
| Evolocumab 35 mg QW × 6 | Number of Participants With Adverse Events | Discontinuations due to adverse events | 0 participants |
| Evolocumab 35 mg QW × 6 | Number of Participants With Adverse Events | Deaths on study | 0 participants |
| Evolocumab 35 mg QW × 6 | Number of Participants With Adverse Events | Any adverse event | 5 participants |
| Evolocumab 140 mg Q2W × 3 | Number of Participants With Adverse Events | Treatment-related adverse events | 1 participants |
| Evolocumab 140 mg Q2W × 3 | Number of Participants With Adverse Events | Any adverse event | 4 participants |
| Evolocumab 140 mg Q2W × 3 | Number of Participants With Adverse Events | Deaths on study | 0 participants |
| Evolocumab 140 mg Q2W × 3 | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| Evolocumab 140 mg Q2W × 3 | Number of Participants With Adverse Events | Discontinuations due to adverse events | 0 participants |
| Evolocumab 280 mg Q2W × 3 | Number of Participants With Adverse Events | Any adverse event | 6 participants |
| Evolocumab 280 mg Q2W × 3 | Number of Participants With Adverse Events | Treatment-related adverse events | 6 participants |
| Evolocumab 280 mg Q2W × 3 | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| Evolocumab 280 mg Q2W × 3 | Number of Participants With Adverse Events | Deaths on study | 0 participants |
| Evolocumab 280 mg Q2W × 3 | Number of Participants With Adverse Events | Discontinuations due to adverse events | 0 participants |
| Evolocumab 420 mg Q4W × 2 | Number of Participants With Adverse Events | Treatment-related adverse events | 0 participants |
| Evolocumab 420 mg Q4W × 2 | Number of Participants With Adverse Events | Any adverse event | 3 participants |
| Evolocumab 420 mg Q4W × 2 | Number of Participants With Adverse Events | Deaths on study | 0 participants |
| Evolocumab 420 mg Q4W × 2 | Number of Participants With Adverse Events | Discontinuations due to adverse events | 0 participants |
| Evolocumab 420 mg Q4W × 2 | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| High Dose Statin - Placebo | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| High Dose Statin - Placebo | Number of Participants With Adverse Events | Treatment-related adverse events | 1 participants |
| High Dose Statin - Placebo | Number of Participants With Adverse Events | Discontinuations due to adverse events | 0 participants |
| High Dose Statin - Placebo | Number of Participants With Adverse Events | Deaths on study | 0 participants |
| High Dose Statin - Placebo | Number of Participants With Adverse Events | Any adverse event | 1 participants |
| High Dose Statin - Evolocumab 140 mg Q2W × 3 | Number of Participants With Adverse Events | Discontinuations due to adverse events | 0 participants |
| High Dose Statin - Evolocumab 140 mg Q2W × 3 | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| High Dose Statin - Evolocumab 140 mg Q2W × 3 | Number of Participants With Adverse Events | Any adverse event | 7 participants |
| High Dose Statin - Evolocumab 140 mg Q2W × 3 | Number of Participants With Adverse Events | Treatment-related adverse events | 2 participants |
| High Dose Statin - Evolocumab 140 mg Q2W × 3 | Number of Participants With Adverse Events | Deaths on study | 0 participants |
| HeFH - Placebo | Number of Participants With Adverse Events | Treatment-related adverse events | 0 participants |
| HeFH - Placebo | Number of Participants With Adverse Events | Deaths on study | 0 participants |
| HeFH - Placebo | Number of Participants With Adverse Events | Discontinuations due to adverse events | 0 participants |
| HeFH - Placebo | Number of Participants With Adverse Events | Any adverse event | 1 participants |
| HeFH - Placebo | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| HeFH - Evolocumab 140 mg Q2W × 3 | Number of Participants With Adverse Events | Discontinuations due to adverse events | 0 participants |
| HeFH - Evolocumab 140 mg Q2W × 3 | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| HeFH - Evolocumab 140 mg Q2W × 3 | Number of Participants With Adverse Events | Deaths on study | 0 participants |
| HeFH - Evolocumab 140 mg Q2W × 3 | Number of Participants With Adverse Events | Treatment-related adverse events | 0 participants |
| HeFH - Evolocumab 140 mg Q2W × 3 | Number of Participants With Adverse Events | Any adverse event | 1 participants |
Primary
Number of Participants With Anti-Evolocumab Antibodies
Serum samples were analyzed by an electrochemiluminescence (ECL)-based immunoassay for anti-evolocumab binding antibodies. Positive samples were subsequently tested in a receptor-ligand binding bioassay for anti-evolocumab neutralizing antibodies
Time frame: From the first dose of study drug until Day 85
Population: Safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Anti-Evolocumab Antibodies | Binding Antibodies | 0 participants |
| Placebo | Number of Participants With Anti-Evolocumab Antibodies | Neutralizing Antibodies | 0 participants |
| Evolocumab 14 mg QW × 6 | Number of Participants With Anti-Evolocumab Antibodies | Neutralizing Antibodies | 0 participants |
| Evolocumab 14 mg QW × 6 | Number of Participants With Anti-Evolocumab Antibodies | Binding Antibodies | 0 participants |
| Evolocumab 35 mg QW × 6 | Number of Participants With Anti-Evolocumab Antibodies | Neutralizing Antibodies | 0 participants |
| Evolocumab 35 mg QW × 6 | Number of Participants With Anti-Evolocumab Antibodies | Binding Antibodies | 0 participants |
| Evolocumab 140 mg Q2W × 3 | Number of Participants With Anti-Evolocumab Antibodies | Neutralizing Antibodies | 0 participants |
| Evolocumab 140 mg Q2W × 3 | Number of Participants With Anti-Evolocumab Antibodies | Binding Antibodies | 1 participants |
| Evolocumab 280 mg Q2W × 3 | Number of Participants With Anti-Evolocumab Antibodies | Binding Antibodies | 0 participants |
| Evolocumab 280 mg Q2W × 3 | Number of Participants With Anti-Evolocumab Antibodies | Neutralizing Antibodies | 0 participants |
| Evolocumab 420 mg Q4W × 2 | Number of Participants With Anti-Evolocumab Antibodies | Neutralizing Antibodies | 0 participants |
| Evolocumab 420 mg Q4W × 2 | Number of Participants With Anti-Evolocumab Antibodies | Binding Antibodies | 0 participants |
| High Dose Statin - Placebo | Number of Participants With Anti-Evolocumab Antibodies | Binding Antibodies | 0 participants |
| High Dose Statin - Placebo | Number of Participants With Anti-Evolocumab Antibodies | Neutralizing Antibodies | 0 participants |
| High Dose Statin - Evolocumab 140 mg Q2W × 3 | Number of Participants With Anti-Evolocumab Antibodies | Binding Antibodies | 0 participants |
| High Dose Statin - Evolocumab 140 mg Q2W × 3 | Number of Participants With Anti-Evolocumab Antibodies | Neutralizing Antibodies | 0 participants |
| HeFH - Placebo | Number of Participants With Anti-Evolocumab Antibodies | Neutralizing Antibodies | 0 participants |
| HeFH - Placebo | Number of Participants With Anti-Evolocumab Antibodies | Binding Antibodies | 0 participants |
| HeFH - Evolocumab 140 mg Q2W × 3 | Number of Participants With Anti-Evolocumab Antibodies | Binding Antibodies | 0 participants |
| HeFH - Evolocumab 140 mg Q2W × 3 | Number of Participants With Anti-Evolocumab Antibodies | Neutralizing Antibodies | 0 participants |
Secondary
Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Evolocumab
Area under the unbound evolocumab serum concentration-time curve from time of last dose to time of last quantifiable concentration following the last dose of evolocumab.
Time frame: Day 29 predose (last dose for Cohorts 3-7) and Days 36 (predose for Cohorts 1 and 2), 40, 43, 50, 57, 64, 71, 78, and 85
Population: Pharmacokinetic analysis set with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Evolocumab 35 mg QW × 6 | Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Evolocumab | 226 day*μg/mL | Standard Deviation 249 |
| Evolocumab 140 mg Q2W × 3 | Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Evolocumab | 1200 day*μg/mL | Standard Deviation 634 |
| Evolocumab 280 mg Q2W × 3 | Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Evolocumab | 903 day*μg/mL | Standard Deviation 280 |
| Evolocumab 420 mg Q4W × 2 | Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Evolocumab | 181 day*μg/mL | Standard Deviation 157 |
| High Dose Statin - Placebo | Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Evolocumab | 165 day*μg/mL | Standard Deviation 69 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Evolocumab
Serum concentrations of evolocumab were measured by a validated enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 800 ng/mL.
Time frame: Day 1, predose and Days 4, 8, 15, 22, 29, 36, 40, 43, 50, 57, 64, 71, 78, and 85
Population: The Pharmacokinetic analysis set consisted of all participants for whom at least 1 pharmacokinetic parameter or endpoint could be adequately estimated. Serum evolocumab concentrations were not detectable in Cohorts 1 and 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Evolocumab 35 mg QW × 6 | Maximum Observed Plasma Concentration (Cmax) of Evolocumab | 20.3 μg/mL | Standard Deviation 13.2 |
| Evolocumab 140 mg Q2W × 3 | Maximum Observed Plasma Concentration (Cmax) of Evolocumab | 62.8 μg/mL | Standard Deviation 22.7 |
| Evolocumab 280 mg Q2W × 3 | Maximum Observed Plasma Concentration (Cmax) of Evolocumab | 63.6 μg/mL | Standard Deviation 11.2 |
| Evolocumab 420 mg Q4W × 2 | Maximum Observed Plasma Concentration (Cmax) of Evolocumab | 16.3 μg/mL | Standard Deviation 10.8 |
| High Dose Statin - Placebo | Maximum Observed Plasma Concentration (Cmax) of Evolocumab | 14.7 μg/mL | Standard Deviation 2.9 |
Secondary
Percent Change From Baseline to End of the Dosing Interval in LDL-C
Time frame: Baseline and Day 43 for QW and Q2W groups or Day 57 for Q4W group
Population: Participants with non-missing data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline to End of the Dosing Interval in LDL-C | 3.14 percent change | Standard Deviation 33.73 |
| Evolocumab 14 mg QW × 6 | Percent Change From Baseline to End of the Dosing Interval in LDL-C | -23.79 percent change | Standard Deviation 21.57 |
| Evolocumab 35 mg QW × 6 | Percent Change From Baseline to End of the Dosing Interval in LDL-C | -51.76 percent change | Standard Deviation 18.29 |
| Evolocumab 140 mg Q2W × 3 | Percent Change From Baseline to End of the Dosing Interval in LDL-C | -69.58 percent change | Standard Deviation 18.13 |
| Evolocumab 280 mg Q2W × 3 | Percent Change From Baseline to End of the Dosing Interval in LDL-C | -74.65 percent change | Standard Deviation 3.47 |
| Evolocumab 420 mg Q4W × 2 | Percent Change From Baseline to End of the Dosing Interval in LDL-C | -62.01 percent change | Standard Deviation 11.43 |
| High Dose Statin - Placebo | Percent Change From Baseline to End of the Dosing Interval in LDL-C | -3.01 percent change | Standard Deviation 3.09 |
| High Dose Statin - Evolocumab 140 mg Q2W × 3 | Percent Change From Baseline to End of the Dosing Interval in LDL-C | -61.82 percent change | Standard Deviation 17.67 |
| HeFH - Placebo | Percent Change From Baseline to End of the Dosing Interval in LDL-C | -4.89 percent change | Standard Deviation 0.82 |
| HeFH - Evolocumab 140 mg Q2W × 3 | Percent Change From Baseline to End of the Dosing Interval in LDL-C | -62.91 percent change | Standard Deviation 16.04 |
Secondary
Percent Change From Baseline to End of the Dosing Interval in PCSK9
Serum PCSK9 concentrations were determined by using a qualified enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 15 ng/mL.
Time frame: Baseline and Day 43 for QW and Q2W groups or Day 57 for Q4W group
Population: Participants with non-missing data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline to End of the Dosing Interval in PCSK9 | 6.00 percent change | Standard Deviation 25.49 |
| Evolocumab 14 mg QW × 6 | Percent Change From Baseline to End of the Dosing Interval in PCSK9 | -42.07 percent change | Standard Deviation 16.99 |
| Evolocumab 35 mg QW × 6 | Percent Change From Baseline to End of the Dosing Interval in PCSK9 | -64.46 percent change | Standard Deviation 3.7 |
| Evolocumab 140 mg Q2W × 3 | Percent Change From Baseline to End of the Dosing Interval in PCSK9 | -70.42 percent change | Standard Deviation 16.05 |
| Evolocumab 280 mg Q2W × 3 | Percent Change From Baseline to End of the Dosing Interval in PCSK9 | -91.49 percent change | Standard Deviation 6.45 |
| Evolocumab 420 mg Q4W × 2 | Percent Change From Baseline to End of the Dosing Interval in PCSK9 | -32.72 percent change | Standard Deviation 29.41 |
| High Dose Statin - Placebo | Percent Change From Baseline to End of the Dosing Interval in PCSK9 | 43.60 percent change | Standard Deviation 51.39 |
| High Dose Statin - Evolocumab 140 mg Q2W × 3 | Percent Change From Baseline to End of the Dosing Interval in PCSK9 | -62.50 percent change | Standard Deviation 18.33 |
| HeFH - Placebo | Percent Change From Baseline to End of the Dosing Interval in PCSK9 | 36.76 percent change | Standard Deviation 12.54 |
| HeFH - Evolocumab 140 mg Q2W × 3 | Percent Change From Baseline to End of the Dosing Interval in PCSK9 | -68.52 percent change | Standard Deviation 10.67 |