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

Nephrotic Syndrome Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04278729
• Other study ID #: 18-2233
• Status: Completed
• Phase: Phase 1
• Start date: April 14, 2021
• Est. completion date: September 22, 2023

Study information

• Verified date: September 2023
• Source: University of North Carolina, Chapel Hill
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: September 22, 2023
• Est. primary completion date: September 22, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 79 Years

Eligibility

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.

Related Conditions & MeSH terms

• Glomerulonephritis, Membranous
• Membranous Nephropathy
• Nephrosis
• Nephrotic Syndrome
• Syndrome

Intervention

Drug:
• Apixaban 5 MG
1 - 5 mg tablet taken orally twice a day

Locations

Country	Name	City	State
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
University of North Carolina, Chapel Hill	American College of Clinical Pharmacy

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Pharmacogenetics and AUC0-12	Associations between germline variants within genes that encode proteins that are central to apixaban metabolism and transport and AUC0-12	Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8
Other	Pharmacogenetics and CL/F	Associations between germline variants within genes that encode proteins that are central to apixaban metabolism and transport and CL/F	Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8
Other	Pharmacogenetics and t1/2	Associations between germline variants within genes that encode proteins that are central to apixaban metabolism and transport and t1/2	Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8
Other	Pharmacogenetics and anti-Xa	Associations between germline variants within genes that encode proteins that are central to apixaban metabolism and transport and anti-Xa	Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8
Other	Pharmacogenetics and thrombin generation	Associations between germline variants within genes that encode proteins that are central to apixaban metabolism and transport and thrombin generation	Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8
Other	Pharmacogenetics and Cmax	Associations between germline variants within genes that encode proteins that are central to apixaban metabolism and transport and Cmax	Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8
Other	Baseline Quantitative D-Dimer	Quantitative D-Dimer levels at baseline before first dose of apixaban	Baseline at hour 0
Other	Quantitative D-Dimer at steady-state	Quantitative D-Dimer levels at steady-state apixaban	Day 8 at hour 8
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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