Back to resultsA Prospective Multi-dose Study of Apixaban in Subjects With Nephrotic Syndrome
Primary Purpose
Nephrotic Syndrome, Membranous Nephropathy
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Apixaban 5 MG
Sponsored by
About this trial
This is an interventional treatment trial for Nephrotic Syndrome
Eligibility Criteria
Inclusion Criteria:
Study Subjects
- 18-79 years of age
- Confirmed diagnosis of NS, with at least one of the following (confirmed within 1 month prior to scheduled Day 1 Study Visit):
- Nephrotic-range proteinuria, defined as >3.0 g/24 hours
- UPC (ratio of protein to creatinine in random spot urine sample), defined as >3.0
- Hypoalbuminemia, defined as <3.0 g/dL
Control Subjects
- 18-79 years of age
- Normal albumin levels (>3.0 mg/dL)
- No history of chronic kidney disease
Exclusion Criteria:
- Age <18 or ≥80 years old
- Serum Creatinine (SCr) ≥1.5 AND weight ≤60kg (these subjects would receive a reduced apixaban dose, per drug labeling)
- Weight >120 kg OR body mass index (BMI) ≥40 kg/m^2
- Estimated Glomerular Filtration Rate (eGFR) <15 mL/min or on dialysis
- Signs and symptoms of increased risk of bleeding, including but not limited to: frequent nosebleeds, unexplained or worsening bruising, blood in urine or stool
- Unwilling to avoid engaging in activities that may increase the risk of bleeding through body injury or bruising, during the study period (e.g., contact sports)
Baseline prolonged INR, defined as INR >1.4
- If INR is elevated, but PT and aPTT are below the upper limit of normal (13.3 sec and 37.7 sec, respectively), then the subject may be cleared to receive the study drug at the discretion of one of the study physicians.
- Platelets <100 x 109/L
- History of stroke, or a history of gastrointestinal or intracranial bleeds
Use of any prescription medications, over-the-counter (OTC) medications, or herbal products that are strong inhibitors or inducers of CYP3A4 and/or P-gp within 14 days prior to Study Day 1 or anticipated need for such drugs during the study. Examples included:
- Strong 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, non-steroidal anti-inflammatory drugs (NSAIDs), warfarin, rivaroxaban, dabigatran, edoxaban
- Pregnancy or breastfeeding
- Liver disease with impaired synthetic function (INR >1.4, total bilirubin >1.2)
- Evidence of acute kidney disease by the KDIGO criteria (>1.5 x baseline SCr, or >0.3 mg/dL increase in SCr, over past 48 hours
- Unwillingness to forgo drinking alcohol during the study period due to heightened bleeding risk.
Sites / Locations
- University of North Carolina at Chapel Hill
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Nephrotic Syndrome Arm
Healthy Arm
Arm Description
Patients diagnosed with Nephrotic syndrome will be in this arm.
Healthy volunteers will be in this arm.
Outcomes
Primary Outcome Measures
Steady-state Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Apixaban
Area Under the Curve (AUC (0-12)) is the area under the curve from time 0 to 12 hour after apixaban steady state concentration is reached.
Secondary Outcome Measures
Initial Dose Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Apixaban
AUC (0-12) is the area under the curve from time 0 to 12 hour after the initial dose
Steady state Elimination of Half-Life of Apixaban
Mean terminal phase plasma t½ of apixaban at steady-state
Initial dose Elimination of Half-Life of Apixaban
Mean terminal phase plasma t½ of apixaban after initial dose
Steady-state Maximum Observed Plasma Concentration of Apixaban
Maximum observed drug concentration in plasma after administration (Cmax) of apixaban at steady-state
Initial dose Maximum Observed Plasma Concentration of Apixaban
Maximum observed drug concentration in plasma after administration (Cmax) of apixaban after initial dose
Steady state Plasma Clearance as a Function of Bioavailability of Apixaban
CL/F of apixaban of apixaban at steady-state
Initial dose Plasma Clearance (CL) as a Function of Bioavailability (F) of Apixaban
CL/F of apixaban of apixaban after initial dose
Initial Thrombin Generation Assay (TGA)
Initial apixaban TGA concentrations. Thrombin generation assay is used to investigate hypo- or hypercoagulability.
Steady state Thrombin Generation Assay (TGA)
Steady state apixaban TGA concentrations. Thrombin generation assay is used to investigate hypo- or hypercoagulability.
Initial dose Anti-Xa activity
Initial apixaban dose Anti-Xa activity. Anti-Xa activity will be used to measure plasma apixaban levels.
Steady state Anti-Xa activity
Steady state apixaban dose Anti-Xa activity. Anti-Xa activity will be used to measure plasma apixaban levels.
Initial dose Activated Partial Thromboplastin Time (aPTT)
Initial apixaban dose aPTT. The activated partial thromboplastin time (aPTT) will be used to characterize the coagulation of the blood.
Steady state Activated Partial Thromboplastin Time (aPTT)
Steady state apixaban dose aPTT. The activated partial thromboplastin time (aPTT) will be used to characterize the coagulation of the blood.
Initial dose International Normalised Ratio (INR)
Initial apixaban dose INR. INR is defined as the ratio of the participants prothrombin time and the normal mean prothrombin time. The INR will help determine the risk of coagulation.
Steady state International Normalised Ratio (INR)
Steady state apixaban dose INR. INR is defined as the ratio of the participants prothrombin time and the normal mean prothrombin time. The INR will help determine the risk of coagulation.
Initial dose Prothrombin time (PT)
Initial apixaban dose PT. Prothrombin is defined as time taken by the blood to clot in the participants.
Steady state Prothrombin time (PT)
Steady state apixaban dose PT. Prothrombin is defined as time taken by the blood to clot in the participants.
Total Adverse Events (AE)
Number of subjects experiencing AEs, bleeding-related AEs, serious adverse events (SAEs), or discontinuations due to AEs
Full Information
NCT ID
NCT04278729
First Posted
February 18, 2020
Last Updated
September 25, 2023
Sponsor
University of North Carolina, Chapel Hill
Collaborators
American College of Clinical Pharmacy
1. Study Identification
Unique Protocol Identification Number
NCT04278729
Brief Title
A Prospective Multi-dose Study of Apixaban in Subjects With Nephrotic Syndrome
Official Title
A Prospective Multi-dose Study of Apixaban in Subjects With Nephrotic Syndrome
Study Type
Interventional
2. Study Status
Record Verification Date
September 2023
Overall Recruitment Status
Completed
Study Start Date
April 14, 2021 (Actual)
Primary Completion Date
September 22, 2023 (Actual)
Study Completion Date
September 22, 2023 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of North Carolina, Chapel Hill
Collaborators
American College of Clinical Pharmacy
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This phase I study is a single arm, multi-dose study that will evaluate steady-state apixaban pharmacokinetics (PK) and pharmacodynamics (PD) in subjects with Nephrotic Syndrome (NS) vs healthy control subjects. This study will enroll 20 subjects diagnosed with NS and 10 healthy control subjects. Comparing differences in steady-state apixaban PK/PD parameters between subjects with NS and healthy volunteers will be essential to identifying a safe and effective apixaban dose and dose administration schedule for future randomized controlled trials (RCTs).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Nephrotic Syndrome, Membranous Nephropathy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
22 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Nephrotic Syndrome Arm
Arm Type
Experimental
Arm Description
Patients diagnosed with Nephrotic syndrome will be in this arm.
Arm Title
Healthy Arm
Arm Type
Experimental
Arm Description
Healthy volunteers will be in this arm.
Intervention Type
Drug
Intervention Name(s)
Apixaban 5 MG
Other Intervention Name(s)
Eliquis
Intervention Description
1 - 5 mg tablet taken orally twice a day
Primary Outcome Measure Information:
Title
Steady-state Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Apixaban
Description
Area Under the Curve (AUC (0-12)) is the area under the curve from time 0 to 12 hour after apixaban steady state concentration is reached.
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8
Secondary Outcome Measure Information:
Title
Initial Dose Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Apixaban
Description
AUC (0-12) is the area under the curve from time 0 to 12 hour after the initial dose
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose
Title
Steady state Elimination of Half-Life of Apixaban
Description
Mean terminal phase plasma t½ of apixaban at steady-state
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8
Title
Initial dose Elimination of Half-Life of Apixaban
Description
Mean terminal phase plasma t½ of apixaban after initial dose
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose
Title
Steady-state Maximum Observed Plasma Concentration of Apixaban
Description
Maximum observed drug concentration in plasma after administration (Cmax) of apixaban at steady-state
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8
Title
Initial dose Maximum Observed Plasma Concentration of Apixaban
Description
Maximum observed drug concentration in plasma after administration (Cmax) of apixaban after initial dose
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose
Title
Steady state Plasma Clearance as a Function of Bioavailability of Apixaban
Description
CL/F of apixaban of apixaban at steady-state
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8
Title
Initial dose Plasma Clearance (CL) as a Function of Bioavailability (F) of Apixaban
Description
CL/F of apixaban of apixaban after initial dose
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose
Title
Initial Thrombin Generation Assay (TGA)
Description
Initial apixaban TGA concentrations. Thrombin generation assay is used to investigate hypo- or hypercoagulability.
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose
Title
Steady state Thrombin Generation Assay (TGA)
Description
Steady state apixaban TGA concentrations. Thrombin generation assay is used to investigate hypo- or hypercoagulability.
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8
Title
Initial dose Anti-Xa activity
Description
Initial apixaban dose Anti-Xa activity. Anti-Xa activity will be used to measure plasma apixaban levels.
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose
Title
Steady state Anti-Xa activity
Description
Steady state apixaban dose Anti-Xa activity. Anti-Xa activity will be used to measure plasma apixaban levels.
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8
Title
Initial dose Activated Partial Thromboplastin Time (aPTT)
Description
Initial apixaban dose aPTT. The activated partial thromboplastin time (aPTT) will be used to characterize the coagulation of the blood.
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose
Title
Steady state Activated Partial Thromboplastin Time (aPTT)
Description
Steady state apixaban dose aPTT. The activated partial thromboplastin time (aPTT) will be used to characterize the coagulation of the blood.
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8
Title
Initial dose International Normalised Ratio (INR)
Description
Initial apixaban dose INR. INR is defined as the ratio of the participants prothrombin time and the normal mean prothrombin time. The INR will help determine the risk of coagulation.
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose
Title
Steady state International Normalised Ratio (INR)
Description
Steady state apixaban dose INR. INR is defined as the ratio of the participants prothrombin time and the normal mean prothrombin time. The INR will help determine the risk of coagulation.
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8
Title
Initial dose Prothrombin time (PT)
Description
Initial apixaban dose PT. Prothrombin is defined as time taken by the blood to clot in the participants.
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose
Title
Steady state Prothrombin time (PT)
Description
Steady state apixaban dose PT. Prothrombin is defined as time taken by the blood to clot in the participants.
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8
Title
Total Adverse Events (AE)
Description
Number of subjects experiencing AEs, bleeding-related AEs, serious adverse events (SAEs), or discontinuations due to AEs
Time Frame
From screening to Day 10 after initial study drug administration
Other Pre-specified Outcome Measures:
Title
Pharmacogenetics and AUC0-12
Description
Associations between germline variants within genes that encode proteins that are central to apixaban metabolism and transport and AUC0-12
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8
Title
Pharmacogenetics and CL/F
Description
Associations between germline variants within genes that encode proteins that are central to apixaban metabolism and transport and CL/F
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8
Title
Pharmacogenetics and t1/2
Description
Associations between germline variants within genes that encode proteins that are central to apixaban metabolism and transport and t1/2
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8
Title
Pharmacogenetics and anti-Xa
Description
Associations between germline variants within genes that encode proteins that are central to apixaban metabolism and transport and anti-Xa
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8
Title
Pharmacogenetics and thrombin generation
Description
Associations between germline variants within genes that encode proteins that are central to apixaban metabolism and transport and thrombin generation
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8
Title
Pharmacogenetics and Cmax
Description
Associations between germline variants within genes that encode proteins that are central to apixaban metabolism and transport and Cmax
Time Frame
Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8
Title
Baseline Quantitative D-Dimer
Description
Quantitative D-Dimer levels at baseline before first dose of apixaban
Time Frame
Baseline at hour 0
Title
Quantitative D-Dimer at steady-state
Description
Quantitative D-Dimer levels at steady-state apixaban
Time Frame
Day 8 at hour 8
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
18-79 years of age
Confirmed diagnosis of NS, with at least one of the following (confirmed within 1 month prior to scheduled Day 1 Study Visit):
Nephrotic-range proteinuria, defined as >3.0 g/24 hours
UPC (ratio of protein to creatinine in random spot urine sample), defined as >3.0
Hypoalbuminemia, defined as <3.0 g/dL
Control Subjects
18-79 years of age
Normal albumin levels (>3.0 mg/dL)
No history of chronic kidney disease
Exclusion Criteria:
Age <18 or ≥80 years old
Serum Creatinine (SCr) ≥1.5 AND weight ≤60kg (these subjects would receive a reduced apixaban dose, per drug labeling)
Weight >120 kg OR body mass index (BMI) ≥40 kg/m^2
Estimated Glomerular Filtration Rate (eGFR) <15 mL/min or on dialysis
Signs and symptoms of increased risk of bleeding, including but not limited to: frequent nosebleeds, unexplained or worsening bruising, blood in urine or stool
Unwilling to avoid engaging in activities that may increase the risk of bleeding through body injury or bruising, during the study period (e.g., contact sports)
Baseline prolonged INR, defined as INR >1.4
If INR is elevated, but PT and aPTT are below the upper limit of normal (13.3 sec and 37.7 sec, respectively), then the subject may be cleared to receive the study drug at the discretion of one of the study physicians.
Platelets <100 x 109/L
History of stroke, or a history of gastrointestinal or intracranial bleeds
Use of any prescription medications, over-the-counter (OTC) medications, or herbal products that are strong inhibitors or inducers of CYP3A4 and/or P-gp within 14 days prior to Study Day 1 or anticipated need for such drugs during the study. Examples included:
Strong 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, non-steroidal anti-inflammatory drugs (NSAIDs), warfarin, rivaroxaban, dabigatran, edoxaban
Pregnancy or breastfeeding
Liver disease with impaired synthetic function (INR >1.4, total bilirubin >1.2)
Evidence of acute kidney disease by the KDIGO criteria (>1.5 x baseline SCr, or >0.3 mg/dL increase in SCr, over past 48 hours
Unwillingness to forgo drinking alcohol during the study period due to heightened bleeding risk.
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
Facility Information:
Facility Name
University of North Carolina at Chapel Hill
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27517
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
A Prospective Multi-dose Study of Apixaban in Subjects With Nephrotic Syndrome
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