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

Study Overview
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Brief Summary
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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).

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

Conditions
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Nephrotic Syndrome, Membranous Nephropathy

Intervention / Treatment
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* Drug: Apixaban 5 MG


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nephrotic Syndrome Arm<br>Patients diagnosed with Nephrotic syndrome will be in this arm. | Drug: Apixaban 5 MG<br>* 1 - 5 mg tablet taken orally twice a day<br>* Other names: Eliquis;|
| Experimental: Healthy Arm<br>Healthy volunteers will be in this arm. | Drug: Apixaban 5 MG<br>* 1 - 5 mg tablet taken orally twice a day<br>* Other names: Eliquis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose | 
| Steady state Elimination of Half-Life of Apixaban | Mean terminal phase plasma t½ of apixaban at steady-state | Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8 | 
| Initial dose Elimination of Half-Life of Apixaban | Mean terminal phase plasma t½ of apixaban after initial dose | Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose | 
| Steady-state Maximum Observed Plasma Concentration of Apixaban | Maximum observed drug concentration in plasma after administration (Cmax) of apixaban at steady-state | Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8 | 
| Initial dose Maximum Observed Plasma Concentration of Apixaban | Maximum observed drug concentration in plasma after administration (Cmax) of apixaban after initial dose | Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose | 
| Steady state Plasma Clearance as a Function of Bioavailability of Apixaban | CL/F of apixaban of apixaban at steady-state | Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8 | 
| Initial dose Plasma Clearance (CL) as a Function of Bioavailability (F) of Apixaban | CL/F of apixaban of apixaban after initial dose | Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose | 
| Initial Thrombin Generation Assay (TGA) | Initial apixaban TGA concentrations. Thrombin generation assay is used to investigate hypo- or hypercoagulability. | Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose | 
| Steady state Thrombin Generation Assay (TGA) | Steady state apixaban TGA concentrations. Thrombin generation assay is used to investigate hypo- or hypercoagulability. | Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8 | 
| Initial dose Anti-Xa activity | Initial apixaban dose Anti-Xa activity. Anti-Xa activity will be used to measure plasma apixaban levels. | Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose | 
| Steady state Anti-Xa activity | Steady state apixaban dose Anti-Xa activity. Anti-Xa activity will be used to measure plasma apixaban levels. | Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8 | 
| 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. | Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose | 
| 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. | Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8 | 
| 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. | Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose | 
| 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. | Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8 | 
| Initial dose Prothrombin time (PT) | Initial apixaban dose PT. Prothrombin is defined as time taken by the blood to clot in the participants. | Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose | 
| Steady state Prothrombin time (PT) | Steady state apixaban dose PT. Prothrombin is defined as time taken by the blood to clot in the participants. | Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8 | 
| Total Adverse Events (AE) | Number of subjects experiencing AEs, bleeding-related AEs, serious adverse events (SAEs), or discontinuations due to AEs | From screening to Day 10 after initial study drug administration |