Hyperlipidemia, Mixed Dyslipidemia
Conditions
Keywords
Subjects with normal renal function or severe renal impairment (RI) or end stage renal disease (ESRD) receiving hemodialysis
Brief summary
The primary objective of this study was to evaluate the pharmacokinetics of evolocumab after a single 140 mg subcutaneous (SC) dose in aduts with normal renal function or severe renal impairment or end-stage renal disease (ESRD) receiving hemodialysis.
Interventions
BIOLOGICALEvolocumab
Administered by subcutaneous injection
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Body mass index (BMI) of ≥ 18 and ≤ 35 kg/m² at screening. * Subjects will have low-density lipoprotein cholesterol (LDL-C) of 70-190 mg/dL (inclusive) and on statin therapy. * Other inclusion criteria may apply.
Exclusion criteria
* Subject with current or prior history of statin intolerance * Subject has previously received Evolocumab (AMG 145) or any other investigational therapy directed against PCSK9 * Known substance abuse (eg, alcohol, licit or illicit drugs) within 12 months of day -1 * Testing positive for alcohol and/or drugs-of-abuse at screening, day -1, or day 1 (alcohol only) * History of hypersensitivity or allergic reaction to mammalian-derived drug preparations * Known sensitivity to any of the active substances or their excipients to be administered during dosing, eg, carboxymethylcellulose * Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Serum Concentration (Cmax) of Evolocumab | Predose and 4 hours, 2, 3, 4, 6, 8, 11, 15, 22, 29, 43, 50 and 57 days postdose | Serum concentrations of evolocumab were measured by a validated enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) of the assay was 800 ng/mL. |
| Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) for Evolocumab | Predose and 4 hours, 2, 3, 4, 6, 8, 11, 15, 22, 29, 43, 50 and 57 days postdose | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Anti-evolocumab Antibodies | 57 days | Blood samples were tested using an electrochemiluminescence-based bridging immunoassay to detect antibodies capable of binding to evolocumab. |
| Number of Participants With Adverse Events | From the first dose of study drug up until Day 57 | The severity of each adverse event was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4. A serious adverse event is defined as an adverse event that meets at least 1 of the following serious criteria: * fatal; * life threatening (places the participant at immediate risk of death); * requires in patient hospitalization or prolongation of existing hospitalization; * results in persistent or significant disability/incapacity; * congenital anomaly/birth defect; * other medically important serious event. The investigator assessed whether each adverse event was possibly related to the study drug. |
| Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Baseline and 4 hours, 2, 3, 4, 6, 8, 11, 15, 22, 29, 43, 50 and 57 days postdose | Serum PCSK9 concentrations were determined using a qualified ELISA. The LLOQ of the assay was 15 ng/mL. Log-transformed baseline PCSK9 was included in the model as a covariate and participant as a random effect. |
| Area Under the Effect Curve From Baseline to Day 57 (AUECday1-57) for Low-density Lipoprotein Cholesterol (LDL-C) | 4 hours, 2, 3, 4, 6, 8, 11, 15, 22, 29, 43, 50 and 57 days postdose | The derived log-transformed AUECday1-57 for direct LDL-C was analyzed using a mixed-effect analysis of variance model. Log-transformed baseline LDL-C was the covariate. |
| Number of Participants With Clinically Relevant Vital Sign or Clinical Laboratory Changes | 57 days | The investigator reviewed vital signs and laboratory test results and determined whether an abnormal value in an individual participant represented a clinically significant change from the participant's baseline values. |
Countries
United States
Participant flow
Recruitment details
Eighteen participants were enrolled at 1 center in the United States. The first participant enrolled on 19 August 2014 and the last participant enrolled on 28 October 2014.
Participants by arm
| Arm | Count |
|---|---|
| Normal Renal Function Participants with normal renal function (defined as an estimated glomerular filtration rate \[eGFR\] ≥ 90 mL/min/1.73 m²) received a single 140 mg dose of evolocumab subcutaneously on Day 1. | 6 |
| Severe Renal Impairment Participants with severe renal impairment (defined as eGFR 15 to 29 mL/min/1.73 m²) received a single 140 mg dose of evolocumab subcutaneously on Day 1. | 6 |
| End Stage Renal Disease Participants with end-stage renal disease (ESRD) requiring hemodialysis received a single 140 mg dose of evolocumab subcutaneously on Day 1. | 6 |
| Total | 18 |
Baseline characteristics
| Characteristic | Normal Renal Function | Severe Renal Impairment | End Stage Renal Disease | Total |
|---|---|---|---|---|
| Age, Continuous | 51.2 years STANDARD_DEVIATION 9.9 | 63.3 years STANDARD_DEVIATION 7.8 | 57.0 years STANDARD_DEVIATION 8.1 | 57.2 years STANDARD_DEVIATION 9.6 |
| Race/Ethnicity, Customized Black (or African American) | 1 participants | 1 participants | 4 participants | 6 participants |
| Race/Ethnicity, Customized White | 5 participants | 5 participants | 2 participants | 12 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 3 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 6 | 1 / 6 | 2 / 6 | 4 / 18 |
| serious Total, serious adverse events | 0 / 6 | 1 / 6 | 0 / 6 | 1 / 18 |
Outcome results
Primary
Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) for Evolocumab
Time frame: Predose and 4 hours, 2, 3, 4, 6, 8, 11, 15, 22, 29, 43, 50 and 57 days postdose
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) for Evolocumab | 185 day*μg/mL | Standard Deviation 92.5 |
| Severe Renal Impairment | Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) for Evolocumab | 141 day*μg/mL | Standard Deviation 109 |
| End Stage Renal Disease | Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) for Evolocumab | 102 day*μg/mL | Standard Deviation 80.1 |
Primary
Maximum Observed Serum Concentration (Cmax) of Evolocumab
Serum concentrations of evolocumab were measured by a validated enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) of the assay was 800 ng/mL.
Time frame: Predose and 4 hours, 2, 3, 4, 6, 8, 11, 15, 22, 29, 43, 50 and 57 days postdose
Population: Pharmacokinetic (PK) analysis set (all participants for whom at least 1 PK parameter could be adequately estimated)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Maximum Observed Serum Concentration (Cmax) of Evolocumab | 21.3 μg/mL | Standard Deviation 9 |
| Severe Renal Impairment | Maximum Observed Serum Concentration (Cmax) of Evolocumab | 15.1 μg/mL | Standard Deviation 8.86 |
| End Stage Renal Disease | Maximum Observed Serum Concentration (Cmax) of Evolocumab | 11.7 μg/mL | Standard Deviation 7.2 |
Secondary
Area Under the Effect Curve From Baseline to Day 57 (AUECday1-57) for Low-density Lipoprotein Cholesterol (LDL-C)
The derived log-transformed AUECday1-57 for direct LDL-C was analyzed using a mixed-effect analysis of variance model. Log-transformed baseline LDL-C was the covariate.
Time frame: 4 hours, 2, 3, 4, 6, 8, 11, 15, 22, 29, 43, 50 and 57 days postdose
Population: Safety analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Normal Renal Function | Area Under the Effect Curve From Baseline to Day 57 (AUECday1-57) for Low-density Lipoprotein Cholesterol (LDL-C) | 4438.6 mg/dL*day |
| Severe Renal Impairment | Area Under the Effect Curve From Baseline to Day 57 (AUECday1-57) for Low-density Lipoprotein Cholesterol (LDL-C) | 4087.5 mg/dL*day |
| End Stage Renal Disease | Area Under the Effect Curve From Baseline to Day 57 (AUECday1-57) for Low-density Lipoprotein Cholesterol (LDL-C) | 4620.2 mg/dL*day |
Secondary
Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)
Serum PCSK9 concentrations were determined using a qualified ELISA. The LLOQ of the assay was 15 ng/mL. Log-transformed baseline PCSK9 was included in the model as a covariate and participant as a random effect.
Time frame: Baseline and 4 hours, 2, 3, 4, 6, 8, 11, 15, 22, 29, 43, 50 and 57 days postdose
Population: Safety analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Normal Renal Function | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 50 | -2.88 percent change |
| Normal Renal Function | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 22 | -65.84 percent change |
| Normal Renal Function | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 8 | -96.67 percent change |
| Normal Renal Function | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 3 | -96.67 percent change |
| Normal Renal Function | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 15 | -90.42 percent change |
| Normal Renal Function | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 11 | -96.67 percent change |
| Normal Renal Function | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 1, Hour 4 | -91.69 percent change |
| Normal Renal Function | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 2 | -96.67 percent change |
| Normal Renal Function | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 43 | -24.93 percent change |
| Normal Renal Function | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 4 | -96.67 percent change |
| Normal Renal Function | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 57 | -1.46 percent change |
| Normal Renal Function | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 29 | -49.12 percent change |
| Normal Renal Function | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 6 | -96.67 percent change |
| Severe Renal Impairment | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 11 | -95.96 percent change |
| Severe Renal Impairment | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 1, Hour 4 | -79.20 percent change |
| Severe Renal Impairment | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 2 | -95.87 percent change |
| Severe Renal Impairment | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 3 | -96.33 percent change |
| Severe Renal Impairment | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 4 | -96.33 percent change |
| Severe Renal Impairment | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 6 | -96.33 percent change |
| Severe Renal Impairment | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 8 | -96.33 percent change |
| Severe Renal Impairment | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 15 | -86.41 percent change |
| Severe Renal Impairment | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 22 | -57.92 percent change |
| Severe Renal Impairment | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 29 | -53.66 percent change |
| Severe Renal Impairment | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 43 | -36.30 percent change |
| Severe Renal Impairment | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 50 | -26.57 percent change |
| Severe Renal Impairment | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 57 | -14.49 percent change |
| End Stage Renal Disease | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 22 | -60.33 percent change |
| End Stage Renal Disease | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 4 | -96.53 percent change |
| End Stage Renal Disease | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 50 | -37.04 percent change |
| End Stage Renal Disease | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 29 | -51.88 percent change |
| End Stage Renal Disease | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 3 | -95.58 percent change |
| End Stage Renal Disease | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 1, Hour 4 | -72.95 percent change |
| End Stage Renal Disease | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 43 | -42.44 percent change |
| End Stage Renal Disease | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 11 | -94.69 percent change |
| End Stage Renal Disease | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 8 | -95.01 percent change |
| End Stage Renal Disease | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 2 | -94.41 percent change |
| End Stage Renal Disease | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 15 | -82.97 percent change |
| End Stage Renal Disease | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 6 | -95.39 percent change |
| End Stage Renal Disease | Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) | Day 57 | -37.74 percent change |
Secondary
Number of Participants With Adverse Events
The severity of each adverse event was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4. A serious adverse event is defined as an adverse event that meets at least 1 of the following serious criteria: * fatal; * life threatening (places the participant at immediate risk of death); * requires in patient hospitalization or prolongation of existing hospitalization; * results in persistent or significant disability/incapacity; * congenital anomaly/birth defect; * other medically important serious event. The investigator assessed whether each adverse event was possibly related to the study drug.
Time frame: From the first dose of study drug up until Day 57
Population: Safety analysis set (all participants who received at least 1 dose of study drug)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Normal Renal Function | Number of Participants With Adverse Events | Any adverse event | 1 participants |
| Normal Renal Function | Number of Participants With Adverse Events | Grade ≥ 4 | 0 participants |
| Normal Renal Function | Number of Participants With Adverse Events | Leading to discontinuation from study | 0 participants |
| Normal Renal Function | Number of Participants With Adverse Events | Grade ≥ 2 | 1 participants |
| Normal Renal Function | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| Normal Renal Function | Number of Participants With Adverse Events | Treatment-related adverse events | 0 participants |
| Normal Renal Function | Number of Participants With Adverse Events | Grade ≥ 3 | 0 participants |
| Normal Renal Function | Number of Participants With Adverse Events | Leading to discontinuation of study drug | 0 participants |
| Normal Renal Function | Number of Participants With Adverse Events | Fatal adverse events | 0 participants |
| Severe Renal Impairment | Number of Participants With Adverse Events | Leading to discontinuation of study drug | 0 participants |
| Severe Renal Impairment | Number of Participants With Adverse Events | Leading to discontinuation from study | 0 participants |
| Severe Renal Impairment | Number of Participants With Adverse Events | Fatal adverse events | 0 participants |
| Severe Renal Impairment | Number of Participants With Adverse Events | Treatment-related adverse events | 0 participants |
| Severe Renal Impairment | Number of Participants With Adverse Events | Grade ≥ 3 | 1 participants |
| Severe Renal Impairment | Number of Participants With Adverse Events | Grade ≥ 4 | 0 participants |
| Severe Renal Impairment | Number of Participants With Adverse Events | Serious adverse events | 1 participants |
| Severe Renal Impairment | Number of Participants With Adverse Events | Grade ≥ 2 | 1 participants |
| Severe Renal Impairment | Number of Participants With Adverse Events | Any adverse event | 1 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events | Treatment-related adverse events | 0 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events | Any adverse event | 2 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events | Grade ≥ 2 | 0 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events | Grade ≥ 3 | 0 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events | Grade ≥ 4 | 0 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events | Leading to discontinuation of study drug | 0 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events | Leading to discontinuation from study | 0 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events | Fatal adverse events | 0 participants |
Secondary
Number of Participants With Anti-evolocumab Antibodies
Blood samples were tested using an electrochemiluminescence-based bridging immunoassay to detect antibodies capable of binding to evolocumab.
Time frame: 57 days
Population: Safety analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Normal Renal Function | Number of Participants With Anti-evolocumab Antibodies | 0 participants |
| Severe Renal Impairment | Number of Participants With Anti-evolocumab Antibodies | 0 participants |
| End Stage Renal Disease | Number of Participants With Anti-evolocumab Antibodies | 0 participants |
Secondary
Number of Participants With Clinically Relevant Vital Sign or Clinical Laboratory Changes
The investigator reviewed vital signs and laboratory test results and determined whether an abnormal value in an individual participant represented a clinically significant change from the participant's baseline values.
Time frame: 57 days
Population: Safety analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Normal Renal Function | Number of Participants With Clinically Relevant Vital Sign or Clinical Laboratory Changes | 0 participants |
| Severe Renal Impairment | Number of Participants With Clinically Relevant Vital Sign or Clinical Laboratory Changes | 0 participants |
| End Stage Renal Disease | Number of Participants With Clinically Relevant Vital Sign or Clinical Laboratory Changes | 0 participants |