Estimation Study to Assess the Effect of Severe Renal Impairment and End-stage Renal Disease Hemodialysis on the Pharmacokinetics of Evolocumab

Study Overview
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Brief Summary
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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.

Official Title
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Phase 1, Open-label, Single-dose Study of Evolocumab (AMG 145) Administered Subcutaneously to Subjects With Normal Renal Function or Severe Renal Impairment or End Stage Renal Disease Receiving Hemodialysis

Conditions
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Hyperlipidemia, Mixed Dyslipidemia

Intervention / Treatment
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* Biological: Evolocumab


Participation Criteria
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Eligibility Criteria
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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 exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Evolocumab<br>Participants received a single 140 mg dose of evolocumab subcutaneously on Day 1. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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: 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. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Subjects with normal renal function or severe renal impairment (RI) or end stage renal disease (ESRD) receiving hemodialysis