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

Sponsor
Amgen (Industry)
Overall Status
Completed
CT.gov ID
NCT02275156
Collaborator
(none)
18
Enrollment
1
Location
1
Arm
4
Actual Duration (Months)
4.5
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Biological: Evolocumab
 Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
18 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date :
Aug 19, 2014
Actual Primary Completion Date :
Dec 19, 2014
Actual Study Completion Date :
Dec 19, 2014

Arms and Interventions

Arm Intervention/Treatment
Experimental: Evolocumab

Participants received a single 140 mg dose of evolocumab subcutaneously on Day 1.

Biological: Evolocumab
Administered by subcutaneous injection
Other Names:
  • AMG 145
  • Repatha

    		•

    Outcome Measures

    Primary Outcome Measures

    1. 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.

    2. 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

    1. 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.

    2. 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.

    3. 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.

    4. 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.

    5. 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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 70 Years
    Sexes Eligible for Study:
    All
    Accepts 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 exclusion criteria may apply.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Research Site Denver Colorado United States 80230

    Sponsors and Collaborators

    • Amgen

    Investigators

    • Study Director: MD, Amgen

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT02275156
    Other Study ID Numbers:
    • 20140213
    First Posted:
    Oct 27, 2014
    Last Update Posted:
    Nov 29, 2018
    Last Verified:
    Nov 1, 2018
    Keywords provided by Amgen
    Subjects with normal renal function or severe renal impairment (RI) or end stage renal disease (ESRD) receiving hemodialysis
    Additional relevant MeSH terms:
    Kidney Diseases
    Kidney Failure, Chronic
    Renal Insufficiency
    Dyslipidemias
    Hyperlipidemias
    Evolocumab

    Study Results

    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.
    Pre-assignment Detail
    Arm/Group Title Normal Renal Function Severe Renal Impairment End Stage Renal Disease
    Arm/Group Description 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. 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. Participants with end-stage renal disease (ESRD) requiring hemodialysis received a single 140 mg dose of evolocumab subcutaneously on Day 1.
    Period Title: Overall Study
    STARTED 6 6 6
    COMPLETED 6 6 6
    NOT COMPLETED 0 0 0

    Baseline Characteristics

    Arm/Group Title Normal Renal Function Severe Renal Impairment End Stage Renal Disease Total
    Arm/Group Description 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. 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. Participants with end-stage renal disease (ESRD) requiring hemodialysis received a single 140 mg dose of evolocumab subcutaneously on Day 1. Total of all reporting groups
    Overall Participants 6 6 6 18
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    51.2
    (9.9)
    63.3
    (7.8)
    57.0
    (8.1)
    57.2
    (9.6)
    Sex: Female, Male (Count of Participants)
    Female
    2
    33.3%
    2
    33.3%
    3
    50%
    7
    38.9%
    Male
    4
    66.7%
    4
    66.7%
    3
    50%
    11
    61.1%
    Race/Ethnicity, Customized (participants) [Number]
    Black (or African American)
    1
    16.7%
    1
    16.7%
    4
    66.7%
    6
    33.3%
    White
    5
    83.3%
    5
    83.3%
    2
    33.3%
    12
    66.7%

    Outcome Measures

    1. Primary Outcome
    Title Maximum Observed Serum Concentration (Cmax) of Evolocumab
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) analysis set (all participants for whom at least 1 PK parameter could be adequately estimated)
    Arm/Group Title Normal Renal Function Severe Renal Impairment End Stage Renal Disease
    Arm/Group Description 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. 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. Participants with end-stage renal disease (ESRD) requiring hemodialysis received a single 140 mg dose of evolocumab subcutaneously on Day 1.
    Measure Participants 6 6 6
    Mean (Standard Deviation) [μg/mL]
    21.3
    (9.00)
    15.1
    (8.86)
    11.7
    (7.20)
    2. Primary Outcome
    Title Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) for Evolocumab
    Description
    Time Frame Predose and 4 hours, 2, 3, 4, 6, 8, 11, 15, 22, 29, 43, 50 and 57 days postdose

    Outcome Measure Data

    Analysis Population Description
    PK analysis set
    Arm/Group Title Normal Renal Function Severe Renal Impairment End Stage Renal Disease
    Arm/Group Description 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. 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. Participants with end-stage renal disease (ESRD) requiring hemodialysis received a single 140 mg dose of evolocumab subcutaneously on Day 1.
    Measure Participants 6 6 6
    Mean (Standard Deviation) [day*μg/mL]
    185
    (92.5)
    141
    (109)
    102
    (80.1)
    3. Secondary Outcome
    Title Number of Participants With Adverse Events
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set (all participants who received at least 1 dose of study drug)
    Arm/Group Title Normal Renal Function Severe Renal Impairment End Stage Renal Disease
    Arm/Group Description 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. 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. Participants with end-stage renal disease (ESRD) requiring hemodialysis received a single 140 mg dose of evolocumab subcutaneously on Day 1.
    Measure Participants 6 6 6
    Any adverse event
    1
    16.7%
    1
    16.7%
    2
    33.3%
    Grade ≥ 2
    1
    16.7%
    1
    16.7%
    0
    0%
    Grade ≥ 3
    0
    0%
    1
    16.7%
    0
    0%
    Grade ≥ 4
    0
    0%
    0
    0%
    0
    0%
    Serious adverse events
    0
    0%
    1
    16.7%
    0
    0%
    Leading to discontinuation of study drug
    0
    0%
    0
    0%
    0
    0%
    Leading to discontinuation from study
    0
    0%
    0
    0%
    0
    0%
    Fatal adverse events
    0
    0%
    0
    0%
    0
    0%
    Treatment-related adverse events
    0
    0%
    0
    0%
    0
    0%
    4. Secondary Outcome
    Title Number of Participants With Clinically Relevant Vital Sign or Clinical Laboratory Changes
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set
    Arm/Group Title Normal Renal Function Severe Renal Impairment End Stage Renal Disease
    Arm/Group Description 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. 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. Participants with end-stage renal disease (ESRD) requiring hemodialysis received a single 140 mg dose of evolocumab subcutaneously on Day 1.
    Measure Participants 6 6 6
    Number [participants]
    0
    0%
    0
    0%
    0
    0%
    5. Secondary Outcome
    Title Number of Participants With Anti-evolocumab Antibodies
    Description Blood samples were tested using an electrochemiluminescence-based bridging immunoassay to detect antibodies capable of binding to evolocumab.
    Time Frame 57 days

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set
    Arm/Group Title Normal Renal Function Severe Renal Impairment End Stage Renal Disease
    Arm/Group Description 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. 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. Participants with end-stage renal disease (ESRD) requiring hemodialysis received a single 140 mg dose of evolocumab subcutaneously on Day 1.
    Measure Participants 6 6 6
    Number [participants]
    0
    0%
    0
    0%
    0
    0%
    6. Secondary Outcome
    Title Area Under the Effect Curve From Baseline to Day 57 (AUECday1-57) for Low-density Lipoprotein Cholesterol (LDL-C)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set
    Arm/Group Title Normal Renal Function Severe Renal Impairment End Stage Renal Disease
    Arm/Group Description 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. 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. Participants with end-stage renal disease (ESRD) requiring hemodialysis received a single 140 mg dose of evolocumab subcutaneously on Day 1.
    Measure Participants 6 6 6
    Geometric Mean (95% Confidence Interval) [mg/dL*day]
    4438.6
    4087.5
    4620.2
    7. Secondary Outcome
    Title Mean Percent Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set
    Arm/Group Title Normal Renal Function Severe Renal Impairment End Stage Renal Disease
    Arm/Group Description 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. 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. Participants with end-stage renal disease (ESRD) requiring hemodialysis received a single 140 mg dose of evolocumab subcutaneously on Day 1.
    Measure Participants 6 6 6
    Day 1, Hour 4
    -91.69
    -79.20
    -72.95
    Day 2
    -96.67
    -95.87
    -94.41
    Day 3
    -96.67
    -96.33
    -95.58
    Day 4
    -96.67
    -96.33
    -96.53
    Day 6
    -96.67
    -96.33
    -95.39
    Day 8
    -96.67
    -96.33
    -95.01
    Day 11
    -96.67
    -95.96
    -94.69
    Day 15
    -90.42
    -86.41
    -82.97
    Day 22
    -65.84
    -57.92
    -60.33
    Day 29
    -49.12
    -53.66
    -51.88
    Day 43
    -24.93
    -36.30
    -42.44
    Day 50
    -2.88
    -26.57
    -37.04
    Day 57
    -1.46
    -14.49
    -37.74

    Adverse Events

    Time Frame From the first dose of study drug up until Day 57
    Adverse Event Reporting Description 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.
    Arm/Group Title Evolocumab 140 mg - Normal Renal Function Evolocumab 140 mg - Severe RI Evolocumab 140 mg - ESRD Requiring Hemodialysis Evolocumab 140 mg - Total
    Arm/Group Description 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. 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. Participants with end-stage renal disease (ESRD) requiring hemodialysis received a single 140 mg dose of evolocumab subcutaneously on Day 1. Participants received a single 140 mg dose of evolocumab subcutaneously on Day 1.
    All Cause Mortality
    Evolocumab 140 mg - Normal Renal Function Evolocumab 140 mg - Severe RI Evolocumab 140 mg - ESRD Requiring Hemodialysis Evolocumab 140 mg - Total
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Evolocumab 140 mg - Normal Renal Function Evolocumab 140 mg - Severe RI Evolocumab 140 mg - ESRD Requiring Hemodialysis Evolocumab 140 mg - Total
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/6 (0%) 1/6 (16.7%) 0/6 (0%) 1/18 (5.6%)
    Metabolism and nutrition disorders
    Hyperkalaemia 0/6 (0%) 1/6 (16.7%) 0/6 (0%) 1/18 (5.6%)
    Other (Not Including Serious) Adverse Events
    Evolocumab 140 mg - Normal Renal Function Evolocumab 140 mg - Severe RI Evolocumab 140 mg - ESRD Requiring Hemodialysis Evolocumab 140 mg - Total
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/6 (16.7%) 1/6 (16.7%) 2/6 (33.3%) 4/18 (22.2%)
    Gastrointestinal disorders
    Abdominal pain 0/6 (0%) 1/6 (16.7%) 0/6 (0%) 1/18 (5.6%)
    Vomiting 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 1/18 (5.6%)
    Infections and infestations
    Tooth infection 1/6 (16.7%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%)
    Injury, poisoning and procedural complications
    Contusion 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 1/18 (5.6%)
    Respiratory, thoracic and mediastinal disorders
    Upper-airway cough syndrome 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 1/18 (5.6%)
    Skin and subcutaneous tissue disorders
    Dermatitis 1/6 (16.7%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    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.

    Results Point of Contact

    Name/Title Study Director
    Organization Amgen Inc.
    Phone 866-572-6436
    Email
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT02275156
    Other Study ID Numbers:
    • 20140213
    First Posted:
    Oct 27, 2014
    Last Update Posted:
    Nov 29, 2018
    Last Verified:
    Nov 1, 2018