Clinical trial NCT04278729: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Nephrotic Syndrome
Membranous Nephropathy
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: American College of Clinical Pharmacy
First posted: 2020-02-20
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


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.

Primary outcomes:
measure: Steady-state Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Apixaban
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8
Secondary outcomes:
measure: Initial Dose Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Apixaban
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose
measure: Steady state Elimination of Half-Life of Apixaban
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8
measure: Initial dose Elimination of Half-Life of Apixaban
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose
measure: Steady-state Maximum Observed Plasma Concentration of Apixaban
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8
measure: Initial dose Maximum Observed Plasma Concentration of Apixaban
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose
measure: Steady state Plasma Clearance as a Function of Bioavailability of Apixaban
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8
measure: Initial dose Plasma Clearance (CL) as a Function of Bioavailability (F) of Apixaban
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose
measure: Initial Thrombin Generation Assay (TGA)
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose
measure: Steady state Thrombin Generation Assay (TGA)
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8
measure: Initial dose Anti-Xa activity
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose
measure: Steady state Anti-Xa activity
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8
measure: Initial dose Activated Partial Thromboplastin Time (aPTT)
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose
measure: Steady state Activated Partial Thromboplastin Time (aPTT)
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8
measure: Initial dose International Normalised Ratio (INR)
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose
measure: Steady state International Normalised Ratio (INR)
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8
measure: Initial dose Prothrombin time (PT)
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose
measure: Steady state Prothrombin time (PT)
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 8
measure: Total Adverse Events (AE)
timeFrame: From screening to Day 10 after initial study drug administration
Other outcomes:
measure: Pharmacogenetics and AUC0-12
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8
measure: Pharmacogenetics and CL/F
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8
measure: Pharmacogenetics and t1/2
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8
measure: Pharmacogenetics and anti-Xa
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8
measure: Pharmacogenetics and thrombin generation
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8
measure: Pharmacogenetics and Cmax
timeFrame: Predose; 1, 2, 3, 4, 6, and 8 hours (hr) postdose approximately on Day 1 & 8
measure: Baseline Quantitative D-Dimer
timeFrame: Baseline at hour 0
measure: Quantitative D-Dimer at steady-state
timeFrame: Day 8 at hour 8
Locations:
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
Study officials:
affiliation: University of North Carolina, Chapel Hill
name: Daniel Crona, PharmD, PhD
role: PRINCIPAL_INVESTIGATOR
References: