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Pharmacokinetics of Apixaban in Nephrotic Syndrome

Primary Purpose

Nephrotic Syndrome, Proteinuria

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
apixaban
Sponsored by
University of North Carolina, Chapel Hill
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Nephrotic Syndrome focused on measuring Apixaban, Pharmacokinetics, Pharmacodynamics

Eligibility Criteria

18 Years - 79 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers
  • Inclusion Criteria:

    • Study subjects:

      • Between 18 and 79 years old
      • Confirmed diagnosis of Nephrotic Syndrome, with at least one of the following:

        • 1. Nephrotic-range proteinuria, defined as >3.5 g/24 hours or UPC >3.5 (confirmed within 1 month prior to scheduled study visit)
        • 2. Hypoalbuminemia, defined as <3 g/dL (confirmed within 1 month prior to scheduled study visit)
    • Control subjects:

      • Between 18 and 79 years old
      • Normal albumin levels (≥3.5 mg/dL)
      • No proteinuria (UPC <0.15)
  • Exclusion criteria:

    • Age <18 or ≥ 80 years old
    • SCr ≥ 1.5 AND weight ≤ 60kg (these subjects would receive a reduce dose of apixaban, per drug labeling)
    • On dialysis
    • Baseline prolonged PT/INR, PTT (as defined by greater than the upper limit of normal)

      • INR will be used as the primary lab value to evaluate bleeding risk (e.g. a patient presenting with an INR within normal limits, but prolonged PT or PTT, will not meet this exclusion criterion and will still be eligible for the study)
      • Reference Ranges

        • INR: >1.4
        • PT: >13.3 sec
        • aPTT: >37.7 sec
    • Platelets <100
    • History of GI bleed
    • History of intracranial bleed
    • History of stroke
    • Use of (but not limited to) the following medications within the past 14 days:

      • Inducers of CYP3A4 (e.g. rifampin, carbamazepine, phenytoin, St. John's wort, etc.)
      • Strong inhibitors of CYP3A4 (e.g. ketoconazole, ritonavir, clarithromycin, etc.)
      • Antiplatelet and/ or anticoagulant agents: heparin, aspirin* (see below), clopidogrel, prasugrel, NSAIDs, warfarin, rivaroxaban, dabigatran, edoxaban
      • Selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitors (SNRI)
    • Pregnancy/breastfeeding
    • Liver disease with impaired synthetic function (INR >1.4, total bilirubin >1.2)
    • Congestive heart failure

Special consideration for patients on aspirin: for patients on chronic low-dose aspirin therapy, we will allow a 7 day wash out period. This will only be allowed for patients who are taking aspirin as primary prophylaxis or for unclear indications. Patients who are on aspirin therapy for following indications will be excluded: primary prophylaxis of stroke due to atrial fibrillation, secondary prevention of stroke or myocardial infarction, history of coronary artery disease or peripheral vascular disease. For patients who meet the potential criteria for the 7-day wash out, their medical history will be reviewed by one of the clinician investigators to ensure that it is safe and appropriate to hold the agent.

Those subjects taking aspirin for the following reasons will be excluded:

  • Primary stroke prevention from atrial fibrillation
  • Secondary prevention due to prior stroke, heart attack or cardiac stent
  • Existing heart disease or peripheral vascular disease.

Sites / Locations

  • University of North Carolina at Chapel Hill

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Other

Arm Label

Nephrotic syndrome

Non-nephrotic syndrome

Arm Description

Subjects with nephrotic syndrome will receive a single dose of apixaban 10 mg and will subsequently have blood drawn at 0, 0.5, 1, 3, 4, 6, 8, 24 hours after drug administration.

Subjects without nephrotic syndrome will receive a single dose of apixaban 10 mg and will subsequently have blood drawn at 0, 0.5, 1, 3, 4, 6, 8, 24 hours after drug administration.

Outcomes

Primary Outcome Measures

Area under the concentration versus time curve after single dose (AUC) of apixaban

Secondary Outcome Measures

Mean terminal phase plasma half-life (t½)
Apparent oral clearance (CL/F)
Maximum observed drug concentration in plasma after single dose administration (Cmax)
Thrombin Generation Assay
Anti-Xa activity

Full Information

First Posted
November 4, 2015
Last Updated
July 23, 2019
Sponsor
University of North Carolina, Chapel Hill
Collaborators
North Carolina Translational and Clinical Sciences Institute
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1. Study Identification

Unique Protocol Identification Number
NCT02599532
Brief Title
Pharmacokinetics of Apixaban in Nephrotic Syndrome
Official Title
Pharmacokinetics of Apixaban in Nephrotic Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Completed
Study Start Date
April 30, 2017 (Actual)
Primary Completion Date
June 28, 2019 (Actual)
Study Completion Date
June 28, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of North Carolina, Chapel Hill
Collaborators
North Carolina Translational and Clinical Sciences Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This study is to investigate the pharmacokinetics and pharmacodynamics of apixaban in nephrotic syndrome.
Detailed Description
Nephrotic syndrome (NS) is characterized by proteinuria and hypoalbuminemia, and patients with nephrotic syndrome are known to be hypercoaguable with increased incidence of venous thromboembolism necessitating anticoagulation. While classically warfarin has been used as an anticoagulant in NS, newer oral anticoagulants, such as apixaban, are increasingly used to treat venous thromboembolism (VTE) in the general population. It is unknown how hypoalbuminemia and proteinuria affect the pharmacokinetics and pharmacodynamics of apixaban. This will be a parallel arm, single-dose pilot study of the pharmacokinetics of apixaban in adults with nephrotic syndrome. Goal enrollment of twenty subjects with non-diabetic nephropathy who have nephrotic-range proteinuria, defined as >3.5g/24 hours or UPC >3.5 and ten healthy control subjects without nephrotic syndrome. Each subject will be administered a single dose of apixaban 10 mg. Plasma drug concentration level and plasma anti-Xa activity levels will be measured at 0, 0.5, 1, 3, 4, 6, 8, 24 hours after drug administration in order to determine the maximum plasma concentration of apixaban, area under the curve, and half-life of apixaban in the setting of hypoalbuminemia and proteinuria due to nephrotic syndrome. Apixaban levels will be measured via liquid-chromatography spectrometry mass. Additionally, thrombin generation will be measured at 0, 3, 6, and 24 hours.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Nephrotic Syndrome, Proteinuria
Keywords
Apixaban, Pharmacokinetics, Pharmacodynamics

7. Study Design

Primary Purpose
Other
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
21 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Nephrotic syndrome
Arm Type
Other
Arm Description
Subjects with nephrotic syndrome will receive a single dose of apixaban 10 mg and will subsequently have blood drawn at 0, 0.5, 1, 3, 4, 6, 8, 24 hours after drug administration.
Arm Title
Non-nephrotic syndrome
Arm Type
Other
Arm Description
Subjects without nephrotic syndrome will receive a single dose of apixaban 10 mg and will subsequently have blood drawn at 0, 0.5, 1, 3, 4, 6, 8, 24 hours after drug administration.
Intervention Type
Drug
Intervention Name(s)
apixaban
Other Intervention Name(s)
Eliquis
Intervention Description
Study subjects will be given a single-dose of apixaban 10 mg.
Primary Outcome Measure Information:
Title
Area under the concentration versus time curve after single dose (AUC) of apixaban
Time Frame
Predose; 0.5, 1, 3, 4, 6, and 8 hours (hr) postdose on Day 1; 24 hours postdose on Day 2
Secondary Outcome Measure Information:
Title
Mean terminal phase plasma half-life (t½)
Time Frame
Predose; 0.5, 1, 3, 4, 6, and 8 hours postdose on Day 1; 24 hours postdose on Day 2
Title
Apparent oral clearance (CL/F)
Time Frame
Predose; 0.5, 1, 3, 4, 6, and 8 hours postdose on Day 1; 24 hours postdose on Day 2
Title
Maximum observed drug concentration in plasma after single dose administration (Cmax)
Time Frame
Predose; 0.5, 1, 3, 4, 6, and 8 hours postdose on Day 1; 24 hours postdose on Day 2
Title
Thrombin Generation Assay
Time Frame
Predose; 3 and 6 hours postdose on Day 1; 24 hours postdose on Day 2
Title
Anti-Xa activity
Time Frame
Predose; 0.5, 1, 3, 4, 6, and 8 hours postdose on Day 1; 24 hours postdose on Day 2
Other Pre-specified Outcome Measures:
Title
Proportion of germline variants in genes involved in apixaban metabolism and clearance
Description
Explore the relationship between variant genes responsible for apixaban metabolism and clearance (CYP3A4/5, CYP1A2, CYP2J2, ABCB1, and ABCG2) and drug exposure as measured by AUC. Genotyping analyses will be performed at conclusion of study and appropriate conventional statistical analyses will be employed to assess all genotype-phenotype associations.
Time Frame
DNA extracted from whole blood specimens will be genotyped at the conclusion of enrollment, approximately 12 months.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
79 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Study subjects: Between 18 and 79 years old Confirmed diagnosis of Nephrotic Syndrome, with at least one of the following: 1. Nephrotic-range proteinuria, defined as >3.5 g/24 hours or UPC >3.5 (confirmed within 1 month prior to scheduled study visit) 2. Hypoalbuminemia, defined as <3 g/dL (confirmed within 1 month prior to scheduled study visit) Control subjects: Between 18 and 79 years old Normal albumin levels (≥3.5 mg/dL) No proteinuria (UPC <0.15) Exclusion criteria: Age <18 or ≥ 80 years old SCr ≥ 1.5 AND weight ≤ 60kg (these subjects would receive a reduce dose of apixaban, per drug labeling) On dialysis Baseline prolonged PT/INR, PTT (as defined by greater than the upper limit of normal) INR will be used as the primary lab value to evaluate bleeding risk (e.g. a patient presenting with an INR within normal limits, but prolonged PT or PTT, will not meet this exclusion criterion and will still be eligible for the study) Reference Ranges INR: >1.4 PT: >13.3 sec aPTT: >37.7 sec Platelets <100 History of GI bleed History of intracranial bleed History of stroke Use of (but not limited to) the following medications within the past 14 days: Inducers of CYP3A4 (e.g. rifampin, carbamazepine, phenytoin, St. John's wort, etc.) Strong inhibitors of CYP3A4 (e.g. ketoconazole, ritonavir, clarithromycin, etc.) Antiplatelet and/ or anticoagulant agents: heparin, aspirin* (see below), clopidogrel, prasugrel, NSAIDs, warfarin, rivaroxaban, dabigatran, edoxaban Selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitors (SNRI) Pregnancy/breastfeeding Liver disease with impaired synthetic function (INR >1.4, total bilirubin >1.2) Congestive heart failure Special consideration for patients on aspirin: for patients on chronic low-dose aspirin therapy, we will allow a 7 day wash out period. This will only be allowed for patients who are taking aspirin as primary prophylaxis or for unclear indications. Patients who are on aspirin therapy for following indications will be excluded: primary prophylaxis of stroke due to atrial fibrillation, secondary prevention of stroke or myocardial infarction, history of coronary artery disease or peripheral vascular disease. For patients who meet the potential criteria for the 7-day wash out, their medical history will be reviewed by one of the clinician investigators to ensure that it is safe and appropriate to hold the agent. Those subjects taking aspirin for the following reasons will be excluded: Primary stroke prevention from atrial fibrillation Secondary prevention due to prior stroke, heart attack or cardiac stent Existing heart disease or peripheral vascular disease.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Daniel Crona, PharmD, PhD
Organizational Affiliation
University of North Carolina, Chapel Hill
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Vimal Derebail, MD, MPH
Organizational Affiliation
University of North Carolina, Chapel Hill
Official's Role
Study Director
Facility Information:
Facility Name
University of North Carolina at Chapel Hill
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States

12. IPD Sharing Statement

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Pharmacokinetics of Apixaban in Nephrotic Syndrome

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