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A Prospective Multi-dose Study of Apixaban in Subjects With Nephrotic Syndrome

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ClinicalTrials.gov Identifier: NCT04278729
Recruitment Status : Recruiting
First Posted : February 20, 2020
Last Update Posted : August 25, 2021
Sponsor:
Collaborator:
American College of Clinical Pharmacy
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

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).

Condition or disease Intervention/treatment Phase
Nephrotic Syndrome Membranous Nephropathy Drug: Apixaban 5 MG Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Prospective Multi-dose Study of Apixaban in Subjects With Nephrotic Syndrome
Actual Study Start Date : April 14, 2021
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : June 2022


Arm Intervention/treatment
Experimental: Nephrotic Syndrome Arm
Patients diagnosed with Nephrotic syndrome will be in this arm.
Drug: Apixaban 5 MG
1 - 5 mg tablet taken orally twice a day
Other Name: Eliquis

Experimental: Healthy Arm
Healthy volunteers will be in this arm.
Drug: Apixaban 5 MG
1 - 5 mg tablet taken orally twice a day
Other Name: Eliquis




Primary Outcome Measures :
  1. Steady-state Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Apixaban [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8 ]
    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 :
  1. Initial Dose Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Apixaban [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose ]
    AUC (0-12) is the area under the curve from time 0 to 12 hour after the initial dose

  2. Steady state Elimination of Half-Life of Apixaban [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8 ]
    Mean terminal phase plasma t½ of apixaban at steady-state

  3. Initial dose Elimination of Half-Life of Apixaban [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose ]
    Mean terminal phase plasma t½ of apixaban after initial dose

  4. Steady-state Maximum Observed Plasma Concentration of Apixaban [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8 ]
    Maximum observed drug concentration in plasma after administration (Cmax) of apixaban at steady-state

  5. Initial dose Maximum Observed Plasma Concentration of Apixaban [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose ]
    Maximum observed drug concentration in plasma after administration (Cmax) of apixaban after initial dose

  6. Steady state Plasma Clearance as a Function of Bioavailability of Apixaban [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8 ]
    CL/F of apixaban of apixaban at steady-state

  7. Initial dose Plasma Clearance (CL) as a Function of Bioavailability (F) of Apixaban [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose ]
    CL/F of apixaban of apixaban after initial dose

  8. Initial Thrombin Generation Assay (TGA) [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose ]
    Initial apixaban TGA concentrations. Thrombin generation assay is used to investigate hypo- or hypercoagulability.

  9. Steady state Thrombin Generation Assay (TGA) [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8 ]
    Steady state apixaban TGA concentrations. Thrombin generation assay is used to investigate hypo- or hypercoagulability.

  10. Initial dose Anti-Xa activity [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose ]
    Initial apixaban dose Anti-Xa activity. Anti-Xa activity will be used to measure plasma apixaban levels.

  11. Steady state Anti-Xa activity [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8 ]
    Steady state apixaban dose Anti-Xa activity. Anti-Xa activity will be used to measure plasma apixaban levels.

  12. Initial dose Activated Partial Thromboplastin Time (aPTT) [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose ]
    Initial apixaban dose aPTT. The activated partial thromboplastin time (aPTT) will be used to characterize the coagulation of the blood.

  13. Steady state Activated Partial Thromboplastin Time (aPTT) [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8 ]
    Steady state apixaban dose aPTT. The activated partial thromboplastin time (aPTT) will be used to characterize the coagulation of the blood.

  14. Initial dose International Normalised Ratio (INR) [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose ]
    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.

  15. Steady state International Normalised Ratio (INR) [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8 ]
    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.

  16. Initial dose Prothrombin time (PT) [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose ]
    Initial apixaban dose PT. Prothrombin is defined as time taken by the blood to clot in the participants.

  17. Steady state Prothrombin time (PT) [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8 ]
    Steady state apixaban dose PT. Prothrombin is defined as time taken by the blood to clot in the participants.

  18. Total Adverse Events (AE) [ Time Frame: From screening to Day 10 after initial study drug administration ]
    Number of subjects experiencing AEs, bleeding-related AEs, serious adverse events (SAEs), or discontinuations due to AEs


Other Outcome Measures:
  1. Pharmacogenetics and AUC0-12 [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8 ]
    Associations between germline variants within genes that encode proteins that are central to apixaban metabolism and transport and AUC0-12

  2. Pharmacogenetics and CL/F [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8 ]
    Associations between germline variants within genes that encode proteins that are central to apixaban metabolism and transport and CL/F

  3. Pharmacogenetics and t1/2 [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8 ]
    Associations between germline variants within genes that encode proteins that are central to apixaban metabolism and transport and t1/2

  4. Pharmacogenetics and anti-Xa [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8 ]
    Associations between germline variants within genes that encode proteins that are central to apixaban metabolism and transport and anti-Xa

  5. Pharmacogenetics and thrombin generation [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8 ]
    Associations between germline variants within genes that encode proteins that are central to apixaban metabolism and transport and thrombin generation

  6. Pharmacogenetics and Cmax [ Time Frame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8 ]
    Associations between germline variants within genes that encode proteins that are central to apixaban metabolism and transport and Cmax

  7. Baseline Quantitative D-Dimer [ Time Frame: Baseline at hour 0 ]
    Quantitative D-Dimer levels at baseline before first dose of apixaban

  8. Quantitative D-Dimer at steady-state [ Time Frame: Day 8 at hour 8 ]
    Quantitative D-Dimer levels at steady-state apixaban



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 79 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04278729


Contacts
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Contact: Anna DeVane, PharmD 9108745807 sdevane@unc.edu

Locations
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United States, North Carolina
University of North Carolina at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27517
Contact: Anna DeVane, PharmD    910-874-5807    sdevane@unc.edu   
Principal Investigator: Daniel Crona, PharmD, PhD         
Sponsors and Collaborators
University of North Carolina, Chapel Hill
American College of Clinical Pharmacy
Investigators
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Principal Investigator: Daniel Crona, PharmD, PhD University of North Carolina, Chapel Hill
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Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT04278729    
Other Study ID Numbers: 18-2233
First Posted: February 20, 2020    Key Record Dates
Last Update Posted: August 25, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Nephrotic Syndrome
Nephrosis
Glomerulonephritis, Membranous
Syndrome
Disease
Pathologic Processes
Kidney Diseases
Urologic Diseases
Glomerulonephritis
Nephritis
Autoimmune Diseases
Immune System Diseases
Apixaban
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants