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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Evolocumab | Experimental | Participants received a single 140 mg dose of evolocumab subcutaneously on Day 1. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Evolocumab | Biological | Administered by subcutaneous injection |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Predose and 4 hours, 2, 3, 4, 6, 8, 11, 15, 22, 29, 43, 50 and 57 days postdose |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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:
The investigator assessed whether each adverse event was possibly related to the study drug. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| MD | Amgen | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | Denver | Colorado | 80230 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29353350 | Background | Kasichayanula S, Grover A, Emery MG, Gibbs MA, Somaratne R, Wasserman SM, Gibbs JP. Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor. Clin Pharmacokinet. 2018 Jul;57(7):769-779. doi: 10.1007/s40262-017-0620-7. | |
| 30676701 | Background | Lee E, Gibbs JP, Emery MG, Block G, Wasserman SM, Hamilton L, Kasichayanula S, Hanafin P, Somaratne R, Egbuna O. Influence of Renal Function on Evolocumab Exposure, Pharmacodynamics, and Safety. Clin Pharmacol Drug Dev. 2019 Apr;8(3):281-289. doi: 10.1002/cpdd.650. Epub 2019 Jan 24. |
| Label | URL |
|---|---|
| AmgenTrials clinical trials website | View source |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| FG002 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Severe Renal Impairment |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Pharmacokinetic (PK) analysis set (all participants for whom at least 1 PK parameter could be adequately estimated) | Posted | Mean | Standard Deviation | μg/mL | Predose and 4 hours, 2, 3, 4, 6, 8, 11, 15, 22, 29, 43, 50 and 57 days postdose |
|
From the first dose of study drug up until Day 57
Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Summary of Adverse Events includes only those subjects who received at least one dose of investigational product.
ESRD = End stage renal disease requiring dialysis.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Evolocumab 140 mg - 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hyperkalaemia | Metabolism and nutrition disorders | MedDRA 17.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain | Gastrointestinal disorders | MedDRA 17.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Amgen Inc. | 866-572-6436 |
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| ID | Term |
|---|---|
| D006949 | Hyperlipidemias |
| D051437 | Renal Insufficiency |
| D007676 | Kidney Failure, Chronic |
| ID | Term |
|---|---|
| D050171 | Dyslipidemias |
| D052439 | Lipid Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| C577155 | evolocumab |
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| From the first dose of study drug up until Day 57 |
| 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. | 57 days |
| 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. | 57 days |
| 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. | 4 hours, 2, 3, 4, 6, 8, 11, 15, 22, 29, 43, 50 and 57 days postdose |
| 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. | Baseline and 4 hours, 2, 3, 4, 6, 8, 11, 15, 22, 29, 43, 50 and 57 days postdose |
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. |
| BG002 | 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. |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | participants |
|
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. |
| OG002 | 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. |
|
|
| Primary | Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) for Evolocumab | PK analysis set | Posted | Mean | Standard Deviation | day*μg/mL | Predose and 4 hours, 2, 3, 4, 6, 8, 11, 15, 22, 29, 43, 50 and 57 days postdose |
|
|
|
| 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:
The investigator assessed whether each adverse event was possibly related to the study drug. | Safety analysis set (all participants who received at least 1 dose of study drug) | Posted | Number | participants | From the first dose of study drug up until Day 57 |
|
|
|
| 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. | Safety analysis set | Posted | Number | participants | 57 days |
|
|
|
| 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. | Safety analysis set | Posted | Number | participants | 57 days |
|
|
|
| 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. | Safety analysis set | Posted | Geometric Mean | 95% Confidence Interval | mg/dL*day | 4 hours, 2, 3, 4, 6, 8, 11, 15, 22, 29, 43, 50 and 57 days postdose |
|
|
|
| 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. | Safety analysis set | Posted | Geometric Mean | 95% Confidence Interval | percent change | Baseline and 4 hours, 2, 3, 4, 6, 8, 11, 15, 22, 29, 43, 50 and 57 days postdose |
|
|
|
| 0 |
| 6 |
| 1 |
| 6 |
| EG001 | Evolocumab 140 mg - Severe RI | 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. | 1 | 6 | 1 | 6 |
| EG002 | Evolocumab 140 mg - ESRD Requiring Hemodialysis | Participants with end-stage renal disease (ESRD) requiring hemodialysis received a single 140 mg dose of evolocumab subcutaneously on Day 1. | 0 | 6 | 2 | 6 |
| EG003 | Evolocumab 140 mg - Total | Participants received a single 140 mg dose of evolocumab subcutaneously on Day 1. | 1 | 18 | 4 | 18 |
| Vomiting | Gastrointestinal disorders | MedDRA 17.1 | Systematic Assessment |
|
| Tooth infection | Infections and infestations | MedDRA 17.1 | Systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | MedDRA 17.1 | Systematic Assessment |
|
| Upper-airway cough syndrome | Respiratory, thoracic and mediastinal disorders | MedDRA 17.1 | Systematic Assessment |
|
| Dermatitis | Skin and subcutaneous tissue disorders | MedDRA 17.1 | Systematic Assessment |
|
The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D051436 | Renal Insufficiency, Chronic |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| Title | Measurements |
|---|---|
|
| Grade ≥ 3 |
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| Grade ≥ 4 |
|
| Serious adverse events |
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| Leading to discontinuation of study drug |
|
| Leading to discontinuation from study |
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| Fatal adverse events |
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| Treatment-related adverse events |
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| Day 3 |
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| Day 4 |
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| Day 6 |
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| Day 8 |
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| Day 11 |
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| Day 15 |
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| Day 22 |
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| Day 29 |
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| Day 43 |
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| Day 50 |
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| Day 57 |
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