Phase 1 Oral Solution Bioavailability Study of Apixaban When Administered Through a Nasogastric Tube in Healthy Subjects

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the bioavailability of Apixaban solution administered through NGT and washed with Dextrose 5% in water (D5W) or infant formula relative to Apixaban solution administered orally in healthy subjects

Official Title
-----------------
Study of Apixaban Oral Solution Bioavailability When Administered Through a Nasogastric Tube in Healthy Subjects

Conditions
-----------------
Healthy Volunteers

Intervention / Treatment
-----------------
* Drug: Apixaban


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: - Healthy subjects as determined by no clinically significant deviation from normal in medical history, physical examination, ECGs, and clinical laboratory determinations Exclusion Criteria: Any significant acute or chronic medical illness Any history or evidence of abnormal bleeding or coagulation disorders, intracranial hemorrhage, or abnormal bleeding (including heavy menstrual bleeding that has resulted in anemia within the past 1 year) or coagulation disorders in a first degree relative

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Apixaban<br>Single dose Apixaban 5 mg (0.4 mg/mL x 12.5 mL) oral solution via oral syringe | Drug: Apixaban<br> <br> * Other names: BMS-562247;|
| Experimental: Arm B: Apixaban<br>Single dose Apixaban 5 mg (0.4 mg/mL x 12.5 mL) oral solution via nasogastric tube (NGT) immediately followed by 60 mL of D5W via NGT | Drug: Apixaban<br> <br> * Other names: BMS-562247;|
| Experimental: Arm C: Apixaban<br>Single dose Apixaban 5 mg (0.4 mg/mL x 12.5 mL) oral solution via NGT immediately followed by 60 mL of infant formula via NGT | Drug: Apixaban<br> <br> * Other names: BMS-562247;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Geometric Mean Maximum Observed Plasma Concentration (Cmax) of Apixaban | Samples of plasma from participants were obtained at the following times: 0 hour (h) and post dose at 0.25h, 0.50h, 1h, 2h, 3h, 4h, 5h, 6h, 9h, 12h, 24h, 36h, 48h, 60h, and 72h. Apixaban was assayed using a validated Liquid chromatography tandem mass spectrometry (LC-MS/MS) method during the period of known analyte stability. Maximum observed plasma concentration (Cmax) was measured in nanograms per milliliter (ng/mL). | Day 1 (0 h, 0.25h, 0.50h, 1h, 2h, 3h, 4h, 5h, 6h, 9h, 12h, 24h, 36h, 48h, 60h, and 72h post dose) in Periods 1, 2 and 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuation Due to AEs, Death | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. | Day 1 to Day 12 | 
| Median Time of Maximum Observed Plasma Concentration (Tmax) of Apixaban | Samples of plasma from participants were obtained at the following times: 0 hour (h), 0.25h, 0.50h, 1h, 2h, 3h, 4h, 5h, 6h, 9h, 12h, 24h, 36h, 48h, 60h, and 72h, relative to the single dose on Day 1 in each cross over period. Apixaban was assayed using a validated LC-MS/MS method during the period of known analyte stability. Maximum observed plasma concentration (Tmax) was measured in hours (h). | Day 1 (0 h, 0.25h, 0.50h, 1h, 2h, 3h, 4h, 5h, 6h, 9h, 12h, 24h, 36h, 48h, 60h, and 72h post dose) in Periods 1, 2 and 3 | 
| Adjusted Geometric Mean Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of Last Quantifiable Plasma Concentration, AUC(0-T), of Apixaban | Samples of plasma from participants were obtained at the following times: 0 h, 0.25h, 0.50h, 1h, 2h, 3h, 4h, 5h, 6h, 9h, 12h, 24h, 36h, 48h, 60h, and 72h, relative to the single dose on Day 1 in each cross over period. Apixaban was assayed using a validated LC-MS/MS method during the period of known analyte stability. AUC(0-T) was measured in nanograms*hours per milliliter (ng*h/mL). | Day 1 (0 h, 0.25h, 0.50h, 1h, 2h, 3h, 4h, 5h, 6h, 9h, 12h, 24h, 36h, 48h, 60h, and 72h post dose) in Periods 1, 2 and 3 | 
| Adjusted Geometric Mean Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time, AUC(INF), of Apixaban | Samples of plasma from participants were obtained at the following times: 0 h, 0.25h, 0.50h, 1h, 2h, 3h, 4h, 5h, 6h, 9h, 12h, 24h, 36h, 48h, 60h, and 72h, relative to the single dose on Day 1 in each cross over period. Apixaban was assayed using a validated LC-MS/MS method during the period of known analyte stability. AUC(0-INF) was measured in ng*h/mL. | Day 1 (0 h, 0.25h, 0.50h, 1h, 2h, 3h, 4h, 5h, 6h, 9h, 12h, 24h, 36h, 48h, 60h, and 72h post dose) in Periods 1, 2 and 3 | 
| Mean Plasma Elimination Half-Life (T-HALF) of Apixaban | Samples of plasma from participants were obtained at the following times: 0 h, 0.25h, 0.50h, 1h, 2h, 3h, 4h, 5h, 6h, 9h, 12h, 24h, 36h, 48h, 60h, and 72h, relative to the single dose on Day 1 in each cross over period. Apixaban was assayed using a validated LC-MS/MS method during the period of known analyte stability. T-HALF was measured in hours (h). | Day 1 (0 h, 0.25h, 0.50h, 1h, 2h, 3h, 4h, 5h, 6h, 9h, 12h, 24h, 36h, 48h, 60h, and 72h post dose) in Periods 1, 2 and 3 | 
| Number of Participants With Clinically Significant Electrocardiogram, Vital Sign, or Physical Examination Findings | 12-lead electrocardiograms (ECGs) and Vital Signs were performed at Screening, and Day 1 of Periods 1, 2 and 3 (pre-dose and prior to NGT placement, if done). Vital signs and ECGs were also performed on Day 4 of Period 3, prior to discharge from the study. Vital signs included body temperature, respiratory rate, seated blood pressure and heart rate. Blood pressure and heart rate were measured after the participant had been seated quietly for at least 5 minutes. Participants had physical examinations on Period 1, Day 1 (pre-dose) and Day 4 of Period 3, prior to study discharge. | Screening, Day 1 of Periods, 1, 2, and 3, and Day 4 of Period 3 | 
| Number of Participants With Marked Abnormality in Hematology, Chemistry and Urinalysis Laboratory Tests | Participants were required to fast for at least 10 hours prior to the collection of specimens for clinical laboratory tests. Tests were performed at Screening, Day -1, and Day 4 of each period 1 - 3. Leukocyte criteria: Lower limits of normal (LLN), upper limits of normal (ULN), pre-treatment (preRX). Low Leukocytes: if value < 0.9*LLN, or if preRX < LLN then use < 0.85* preRX. High lymphocytes: if value > 7.500 10^3 cells/ µL. Low neutrophils plus bands: if value <= 1.500 10^3 cells/µL. High creatine kinase: if value > 1.5* ULN. Blood in urine: if value >= 2 plus, or if preRX >= 1 plus then use >= 2*preRX. | Screening, Day -1, Day 4 of Periods, 1, 2, and 3 |