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The purpose of this study is to determine whether the bioavailability of apixaban crushed tablets suspended in water or mixed with applesauce is similar to the bioavailability of apixaban whole tablets administered orally.
This study will investigate the bioavailability of apixaban administered as crushed tablets suspended in water and as crushed tablets mixed with applesauce compared with that of whole tablets. The study results may allow enhancement of the apixaban label to include alternative methods of apixaban administration, which may be of benefit to patients who have difficulty swallowing.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Apixaban, 10 mg (whole tablets) | Experimental | Participants received a single dose of apixaban, 10 mg, given orally as 2 5-mg whole commercial tablets (reference) |
|
| Apixaban, 10 mg (crushed and suspended in water) | Experimental | Participants received a single dose of apixaban, 10 mg, given by mouth as 2 5-mg whole commercial tablets crushed and suspended in 30 mL of water |
|
| Apixaban, 10 mg (crushed and mixed with applesauce) | Experimental | Participants received a single dose of 10 mg, given by mouth as 2 5-mg apixaban commercial tablets crushed and mixed with 30 g of applesauce |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Apixaban | Drug |
|
| Measure | Description | Time Frame |
|---|---|---|
| Adjusted Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Apixaban | Maximum observed plasma concentration (Cmax) measured in nanograms per milliliter (ng/mL) | Days 1, 5, and 9 predose and 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 60 and 72 hours post dose |
| Adjusted Geometric Mean of Area Under the Plasma Concentration-time Curve (AUC) From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Apixaban | Area Under the Plasma Concentration-time Curve (AUC) From Time of Zero Extrapolated to Infinite Time (INF) [AUC (INF)] is measured as nanograms multiplied by hours per milliliter (ng*h/mL) | Days 1, 5, and 9 predose and 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 60, and 72 hours post dose |
| Adjusted Geometric Mean of Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] of Apixaban | Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to the Last Quantifiable Concentration [AUC (0-T)] is measured as nanograms multiplied by hours per milliliter (ng*h/mL) | Days 1, 5, and 9 predose and 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 60, and 72 hours post dose |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Serious Adverse Events, Death, or Discontinuation Due to Adverse Events by Study Completion | Adverse Event (AE) = any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Serious Adverse Event (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. |
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com
Inclusion Criteria:
Exclusion Criteria:
Any significant acute or chronic medical illness
History of significant head injury within the last 2 years, including individuals with base of skull fractures
Any major surgery within 4 weeks of study drug administration or anticipated within 2 weeks after completion of the study
Any gastrointestinal (GI) surgery or GI disease that could impact absorption of study drug
History of Gilbert's Syndrome
Inability to tolerate oral medication
Inability to be venipunctured and/or tolerate venous access
Use of tobacco- or nicotine-containing products (including, but not limited to, cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum) within 6 months prior to study drug administration
Any laboratory test results outside of the range of normal, confirmed by repeat results of:
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| Name | Affiliation | Role |
|---|---|---|
| Bristol-Myers Squibb | Bristol-Myers Squibb | Study Director |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27292282 | Derived | Song Y, Chang M, Suzuki A, Frost RJ, Kelly A, LaCreta F, Frost C. Evaluation of Crushed Tablet for Oral Administration and the Effect of Food on Apixaban Pharmacokinetics in Healthy Adults. Clin Ther. 2016 Jul;38(7):1674-1685.e1. doi: 10.1016/j.clinthera.2016.05.004. Epub 2016 Jun 10. |
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69 participants enrolled, 33 participants randomized. 36 participants were enrolled but not randomized. Reasons for non-randomization include 30 participants no longer met study criteria, 4 participants withdrew consent, 2 participants were not needed for the study.
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| ID | Title | Description |
|---|---|---|
| FG000 | Treatment A Then Treatment B Then Treatment C | Treatment A = Apixaban, 10 mg (Whole Tablets); Participants received a single dose of apixaban, 10 mg, given orally as two 5-mg whole commercial tablets. Treatment B = Apixaban, 10 mg (Crushed and Suspended in Water); Participants received a single dose of apixaban, 10 mg, given by mouth as two 5-mg whole commercial tablets crushed and suspended in 30 mL of water. Treatment C = Apixaban, 10 mg (Crushed and Mixed With Applesauce); Participants received a single dose of 10 mg, given by mouth as two 5-mg apixaban commercial tablets crushed and mixed with 30 g of applesauce This was a 3-period, 3-treatment crossover study. Each participant received (orally) a single-dose of apixaban 10 mg (two 5-mg tablets) crushed and suspended in 30 mL water and a single-dose of apixaban 10 mg (two 5-mg tablets) crushed and mixed with 30 g applesauce according to a randomization schedule. Each participant underwent a washout of at least 4 days before receiving the next scheduled treatment. |
| FG001 | Treatment A Then Treatment C Then Treatment B | Treatment A = Apixaban, 10 mg (Whole Tablets); Participants received a single dose of apixaban, 10 mg, given orally as two 5-mg whole commercial tablets. Treatment B = Apixaban, 10 mg (Crushed and Suspended in Water); Participants received a single dose of apixaban, 10 mg, given by mouth as two 5-mg whole commercial tablets crushed and suspended in 30 mL of water. Treatment C = Apixaban, 10 mg (Crushed and Mixed With Applesauce); Participants received a single dose of 10 mg, given by mouth as two 5-mg apixaban commercial tablets crushed and mixed with 30 g of applesauce This was a 3-period, 3-treatment crossover study. Each participant received (orally) a single-dose of apixaban 10 mg (two 5-mg tablets) crushed and suspended in 30 mL water and a single-dose of apixaban 10 mg (two 5-mg tablets) crushed and mixed with 30 g applesauce according to a randomization schedule. Each participant underwent a washout of at least 4 days before receiving the next scheduled treatment. |
| FG002 | Treatment B Then Treatment C Then Treatment A | Treatment A = Apixaban, 10 mg (Whole Tablets); Participants received a single dose of apixaban, 10 mg, given orally as two 5-mg whole commercial tablets. Treatment B = Apixaban, 10 mg (Crushed and Suspended in Water); Participants received a single dose of apixaban, 10 mg, given by mouth as two 5-mg whole commercial tablets crushed and suspended in 30 mL of water. Treatment C = Apixaban, 10 mg (Crushed and Mixed With Applesauce); Participants received a single dose of 10 mg, given by mouth as two 5-mg apixaban commercial tablets crushed and mixed with 30 g of applesauce This was a 3-period, 3-treatment crossover study. Each participant received (orally) a single-dose of apixaban 10 mg (two 5-mg tablets) crushed and suspended in 30 mL water and a single-dose of apixaban 10 mg (two 5-mg tablets) crushed and mixed with 30 g applesauce according to a randomization schedule. Each participant underwent a washout of at least 4 days before receiving the next scheduled treatment. |
| FG003 | Treatment B Then Treatment A Then Treatment C | Treatment A = Apixaban, 10 mg (Whole Tablets); Participants received a single dose of apixaban, 10 mg, given orally as two 5-mg whole commercial tablets. Treatment B = Apixaban, 10 mg (Crushed and Suspended in Water); Participants received a single dose of apixaban, 10 mg, given by mouth as two 5-mg whole commercial tablets crushed and suspended in 30 mL of water. Treatment C = Apixaban, 10 mg (Crushed and Mixed With Applesauce); Participants received a single dose of 10 mg, given by mouth as two 5-mg apixaban commercial tablets crushed and mixed with 30 g of applesauce This was a 3-period, 3-treatment crossover study. Each participant received (orally) a single-dose of apixaban 10 mg (two 5-mg tablets) crushed and suspended in 30 mL water and a single-dose of apixaban 10 mg (two 5-mg tablets) crushed and mixed with 30 g applesauce according to a randomization schedule. Each participant underwent a washout of at least 4 days before receiving the next scheduled treatment. |
| FG004 | Treatment C Then Treatment A Then Treatment B | Treatment A = Apixaban, 10 mg (Whole Tablets); Participants received a single dose of apixaban, 10 mg, given orally as two 5-mg whole commercial tablets. Treatment B = Apixaban, 10 mg (Crushed and Suspended in Water); Participants received a single dose of apixaban, 10 mg, given by mouth as two 5-mg whole commercial tablets crushed and suspended in 30 mL of water. Treatment C = Apixaban, 10 mg (Crushed and Mixed With Applesauce); Participants received a single dose of 10 mg, given by mouth as two 5-mg apixaban commercial tablets crushed and mixed with 30 g of applesauce This was a 3-period, 3-treatment crossover study. Each participant received (orally) a single-dose of apixaban 10 mg (two 5-mg tablets) crushed and suspended in 30 mL water and a single-dose of apixaban 10 mg (two 5-mg tablets) crushed and mixed with 30 g applesauce according to a randomization schedule. Each participant underwent a washout of at least 4 days before receiving the next scheduled treatment. |
| FG005 | Treatment C Then Treatment B Then Treatment A | Treatment A = Apixaban, 10 mg (Whole Tablets); Participants received a single dose of apixaban, 10 mg, given orally as two 5-mg whole commercial tablets. Treatment B = Apixaban, 10 mg (Crushed and Suspended in Water); Participants received a single dose of apixaban, 10 mg, given by mouth as two 5-mg whole commercial tablets crushed and suspended in 30 mL of water. Treatment C = Apixaban, 10 mg (Crushed and Mixed With Applesauce); Participants received a single dose of 10 mg, given by mouth as two 5-mg apixaban commercial tablets crushed and mixed with 30 g of applesauce This was a 3-period, 3-treatment crossover study. Each participant received (orally) a single-dose of apixaban 10 mg (two 5-mg tablets) crushed and suspended in 30 mL water and a single-dose of apixaban 10 mg (two 5-mg tablets) crushed and mixed with 30 g applesauce according to a randomization schedule. Each participant underwent a washout of at least 4 days before receiving the next scheduled treatment. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
All randomized participants
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| ID | Title | Description |
|---|---|---|
| BG000 | Apixaban, 10 mg (Whole Tablets) | This was a 3-period, 3-treatment crossover study. Each participant received (orally) a single-dose of apixaban 10 mg (two 5-mg tablets) crushed and suspended in 30 mL water and a single-dose of apixaban 10 mg (two 5-mg tablets) crushed and mixed with 30 g applesauce according to a randomization schedule. Each participant underwent a washout of at least 4 days before receiving the next scheduled treatment. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Adjusted Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Apixaban | Maximum observed plasma concentration (Cmax) measured in nanograms per milliliter (ng/mL) | All evaluable pharmacokinetic (PK) participants who were treated with apixaban | Posted | Geometric Mean | 90% Confidence Interval | ng/mL | Days 1, 5, and 9 predose and 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 60 and 72 hours post dose |
|
Day 1 to May 2014; approximately 6 weeks F
Study initiated: March 2014; Study Completion: May 2014
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Apixaban, 10 mg (Whole Tablets) | Participants received a single dose of apixaban, 10 mg, given orally as two 5-mg whole commercial tablets. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Bristol-Myers Squibb Study Director | Bristol-Myers Squibb | Clinical.Trials@bms.com |
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| ID | Term |
|---|---|
| D013927 | Thrombosis |
| ID | Term |
|---|---|
| D016769 | Embolism and Thrombosis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| C522181 | apixaban |
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| Randomization to May 2014; approximately 6 weeks |
| Time of Maximum Observed Plasma Concentration (Tmax) of Apixaban | Time of maximum observed plasma concentration (Tmax) measured in hours (h) | Days 1, 5 and 9 pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12 24, 36, 48, 60 and 72 hrs post dose |
| Terminal Plasma Half-life (T-HALF) of Apixaban | Terminal plasma half-life (T-HALF) was derived from plasma concentration versus time data. T-HALF was the time required for one half of the total amount of administered drug to be eliminated from the body. | Days 1, 5 and 9 pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12 24, 36, 48, 60 and 72 hrs post dose |
| Relative Bioavailability (Frel) of Apixaban | Frel is calculated using the treatment ratio of AUC(INF) where the denominator is the AUC(INF) of the reference therapy, 10mg of Apixaban (whole tablet). | Days 1, 5 and 9 pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12 24, 36, 48, 60 and 72 hrs post dose |
| Withdrawal by Subject |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Weight | Mean | Standard Deviation | kilograms |
|
| Height | Mean | Standard Deviation | centimeters |
|
| Body Mass Index (BMI) | Mean | Standard Deviation | kilograms per meter^2 |
|
| OG002 | Apixaban, 10 mg (Crushed and Mixed With Applesauce) | Participants received a single dose of 10 mg, given by mouth as two 5-mg apixaban commercial tablets crushed and mixed with 30 g of applesauce |
|
|
|
| Primary | Adjusted Geometric Mean of Area Under the Plasma Concentration-time Curve (AUC) From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Apixaban | Area Under the Plasma Concentration-time Curve (AUC) From Time of Zero Extrapolated to Infinite Time (INF) [AUC (INF)] is measured as nanograms multiplied by hours per milliliter (ng*h/mL) | All evaluable pharmacokinetic (PK) participants who were treated with apixaban | Posted | Geometric Mean | 90% Confidence Interval | ng*h/mL | Days 1, 5, and 9 predose and 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 60, and 72 hours post dose |
|
|
|
|
| Primary | Adjusted Geometric Mean of Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] of Apixaban | Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to the Last Quantifiable Concentration [AUC (0-T)] is measured as nanograms multiplied by hours per milliliter (ng*h/mL) | All evaluable pharmacokinetic (PK) participants who were treated with apixaban | Posted | Geometric Mean | 90% Confidence Interval | ng*h/mL | Days 1, 5, and 9 predose and 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 60, and 72 hours post dose |
|
|
|
|
| Secondary | Number of Participants With Serious Adverse Events, Death, or Discontinuation Due to Adverse Events by Study Completion | Adverse Event (AE) = any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Serious Adverse Event (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. | All randomized and treated participants | Posted | Number | participants | Randomization to May 2014; approximately 6 weeks |
|
|
|
| Secondary | Time of Maximum Observed Plasma Concentration (Tmax) of Apixaban | Time of maximum observed plasma concentration (Tmax) measured in hours (h) | All evaluable pharmacokinetic (PK) participants who were treated with apixaban | Posted | Median | Full Range | hours | Days 1, 5 and 9 pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12 24, 36, 48, 60 and 72 hrs post dose |
|
|
|
| Secondary | Terminal Plasma Half-life (T-HALF) of Apixaban | Terminal plasma half-life (T-HALF) was derived from plasma concentration versus time data. T-HALF was the time required for one half of the total amount of administered drug to be eliminated from the body. | All evaluable pharmacokinetic (PK) participants who were treated with apixaban | Posted | Mean | Standard Deviation | hours | Days 1, 5 and 9 pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12 24, 36, 48, 60 and 72 hrs post dose |
|
|
|
| Secondary | Relative Bioavailability (Frel) of Apixaban | Frel is calculated using the treatment ratio of AUC(INF) where the denominator is the AUC(INF) of the reference therapy, 10mg of Apixaban (whole tablet). | All evaluable pharmacokinetic (PK) participants who were treated with apixaban | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | Days 1, 5 and 9 pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12 24, 36, 48, 60 and 72 hrs post dose |
|
|
|
| 0 |
| 32 |
| 0 |
| 32 |
| EG001 | Apixaban, 10 mg (Crushed and Suspended in Water) | Participants received a single dose of apixaban, 10 mg, given by mouth as two 5-mg whole commercial tablets crushed and suspended in 30 mL of water. | 0 | 33 | 0 | 33 |
| EG002 | Apixaban, 10 mg (Crushed and Mixed With Applesauce) | Participants received a single dose of 10 mg, given by mouth as two 5-mg apixaban commercial tablets crushed and mixed with 30 g of applesauce | 0 | 32 | 0 | 32 |
Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
| Ratio of Adjusted Geometric Means |
| 0.835 |
| 2-Sided |
| 90 |
| 0.797 |
| 0.875 |
| No |
| Superiority or Other |
| Ratio of Adjusted Geometric Means |
| 0.832 |
| 2-Sided |
| 90 |
| 0.794 |
| 0.871 |
| No |
| Superiority or Other |
| Title | Measurements |
|---|---|
|
| Drug-related AEs |
|
| Discontinuation due to AE |
|