Phase 1 Bioavailability Study of Apixaban Solution Formulation Relative to Apixaban Tablets in Healthy Subjects

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02034565
• Collaborator: Pfizer (Industry)
• Enrollment: 48
• Location: 1
• Arms: 2
• Duration (Days): 28
• Patients Per Site Per Month: 52.2

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the oral bioavailability of Apixaban solution formulation (Treatment B, 10 mg as 25 mL x 0.4 mg/mL) relative to Apixaban tablets (Treatment A, 10 mg as 2 x 5 mg tablets) in healthy subjects.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: Apixaban	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Study of Bioavailability of Apixaban Solution Formulation Relative to Apixaban Tablets in Healthy Subjects
• Study Start Date: Feb 1, 2010
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: Mar 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment A: Apixaban tablet Apixaban Film coated Tablet Single dose 10 mg orally	Drug: Apixaban; Other Names: BMS - 562247
Experimental: Treatment B: Apixaban oral solution Apixaban Solution Single dose 10 mg orally	Drug: Apixaban; Other Names: BMS - 562247

Outcome Measures

Primary Outcome Measures

1. Adjusted Geometric Mean of the Maximum Observed Plasma Concentration (Cmax) of Apixaban [Pre-dose and 0.25, 0.50, 1, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 60, 72 hours post-dose per intervention]

   Serial blood samples for pharmacokinetic analysis were collected at selected times up to 72 hours after each dose. Maximum observed plasma concentration (Cmax) is measured in nanograms per milliliter (ng/mL)

2. Adjusted Geometric Mean of the Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero Extrapolated to Infinite Time AUC(INF) of Apixaban [Pre-dose and 0.25, 0.50, 1, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 60, 72 hours post-dose per intervention]

   Serial blood samples for pharmacokinetic analysis were collected at selected times up to 72 hours after each dose. AUC(INF) is measured in nanogram hours per milliliter (ng*h/mL)

3. Adjusted Geometric Mean of the Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] of Apixaban [Pre-dose and 0.25, 0.50, 1, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 60, 72 hours post-dose per intervention]

   Serial blood samples for pharmacokinetic analysis were collected at selected times up to 72 hours after each dose. AUC(0-T) is measured in nanogram hours per milliliter (ng*h/mL)

Secondary Outcome Measures

1. Number of Participants With Serious Adverse Events (SAEs), Treatment-Related Adverse Events (AEs), Deaths or Discontinuation of Study Drug Due to AEs [Day 1 to 30 days after last dose of study drug]

   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. Treatment-related=having certain, probable, possible or missing relationship to study drug. Death=during the study and up to 28 days past study discontinuation. The select AEs were determined using the Medical Dictionary for Regulatory Activities (MedDRA, v13).

2. Number of Participants With Marked Laboratory Abnormalities [Pre-study screen (Day -1) to Day 8 or day of study discharge]

   Clinical laboratory tests were performed pre-study and at selected times throughout the study. Marked laboratory abnormalities were defined as laboratory assessments meeting the following investigator-specified criteria: Leukocytes < 0.9* lower limits of normal (LLN), absolute neutrophils + bands <= 1.500 10*3 cells/microliter, white blood cells (WBC) urine value >= 2+. These laboratory abnormalities were not considered clinically significant and therefore not adverse events.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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 or relevant trauma (e.g., history of chronic hypertension, bacterial endocarditis, hemorrhagic stroke, motor vehicle accident resulting in significant head trauma or internal injuries)

• History or evidence of abnormal bleeding or coagulation disorder (e.g., easy bruising or gingival bleeding, prolonged bleeding after dental extraction, postpartum, or after trauma, wounds or surgery)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mds Pharma Services	Neptune	New Jersey	United States	07753

Sponsors and Collaborators

• Bristol-Myers Squibb
• Pfizer

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• BMS clinical trial educational resource

Publications

None provided.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT02034565
• Other Study ID Numbers: CV185-029
• First Posted: Jan 13, 2014
• Last Update Posted: Aug 22, 2016
• Last Verified: Jul 1, 2016

• Additional relevant MeSH terms: Apixaban

Study Results

Participant Flow

Pre-assignment Detail	48 participants were enrolled; 14 were randomized and treated. Reasons for non-randomization include 23 no longer met study criteria, 4 withdrew consent, 6 due to study being full, and 1 completed an alternate treatment. 13 participants completed the study.

Arm/Group Title	Treatment A, Then Treatment B	Treatment B, Then Treatment A
Arm/Group Description	Each participant was given two interventions, one per period, with a 4 day washout in between periods. Treatment A: Single dose apixaban film-coated tablet, 10 milligrams (mg) via 2 x 5 mg tablets, administered orally Treatment B: Single dose apixaban solution, 10 milligrams (mg) via 25 milliliters (mL) x 0.4 mg/mL, administered orally	Each participant was given two interventions, one per period, with a 4 day washout in between periods. Treatment A: Single dose apixaban film-coated tablet, 10 milligrams (mg) via 2 x 5 mg tablets, administered orally Treatment B: Single dose apixaban solution, 10 milligrams (mg) via 25 milliliters (mL) x 0.4 mg/mL, administered orally
Period Title: Overall Study
STARTED	7	7
COMPLETED	6	7
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	All Treatment Groups
Arm/Group Description	All Randomized Participants
Overall Participants	14
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	36
Sex: Female, Male (Count of Participants)
Female	2 14.3%
Male	12 85.7%

Outcome Measures

1. Primary Outcome

Title	Adjusted Geometric Mean of the Maximum Observed Plasma Concentration (Cmax) of Apixaban
Description	Serial blood samples for pharmacokinetic analysis were collected at selected times up to 72 hours after each dose. Maximum observed plasma concentration (Cmax) is measured in nanograms per milliliter (ng/mL)
Time Frame	Pre-dose and 0.25, 0.50, 1, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 60, 72 hours post-dose per intervention

Outcome Measure Data

Analysis Population Description

All treated participants with available pharmacokinetic (pk) data

Arm/Group Title	Treatment A: Apixaban Tablet	Treatment B: Apixaban Oral Solution
Arm/Group Description	Single dose apixaban 10 mg (film-coated tablet) administered orally	Single dose apixaban 10 mg (solution) administered orally
Measure Participants	14	13
Geometric Mean (90% Confidence Interval) [ng/mL]	293.994	287.164

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A: Apixaban Tablet, Treatment B: Apixaban Oral Solution
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Adjusted Geometric Means
	Estimated Value	0.977
	Confidence Interval	(2-Sided) 90%; 0.756 to 1.261
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Adjusted Geometric Mean of the Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero Extrapolated to Infinite Time AUC(INF) of Apixaban
Description	Serial blood samples for pharmacokinetic analysis were collected at selected times up to 72 hours after each dose. AUC(INF) is measured in nanogram hours per milliliter (ng*h/mL)
Time Frame	Pre-dose and 0.25, 0.50, 1, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 60, 72 hours post-dose per intervention

Outcome Measure Data

Analysis Population Description

All treated participants with available pk data

Arm/Group Title	Treatment A: Apixaban Tablet	Treatment B: Apixaban Oral Solution
Arm/Group Description	Single dose apixaban 10 mg (film-coated tablet) administered orally	Single dose apixaban 10 mg (solution) administered orally
Measure Participants	13	13
Geometric Mean (90% Confidence Interval) [ng*h/mL]	2712.477	2848.968

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A: Apixaban Tablet, Treatment B: Apixaban Oral Solution
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	1.050
	Confidence Interval	(2-Sided) 90%; 0.938 to 1.176
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Adjusted Geometric Mean of the Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] of Apixaban
Description	Serial blood samples for pharmacokinetic analysis were collected at selected times up to 72 hours after each dose. AUC(0-T) is measured in nanogram hours per milliliter (ng*h/mL)
Time Frame	Pre-dose and 0.25, 0.50, 1, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 60, 72 hours post-dose per intervention

Outcome Measure Data

Analysis Population Description

All treated participants with available pk data

Arm/Group Title	Treatment A: Apixaban Tablet	Treatment B: Apixaban Oral Solution
Arm/Group Description	Single dose apixaban 10 mg (film-coated tablet) administered orally	Single dose apixaban 10 mg (solution) administered orally
Measure Participants	13	13
Geometric Mean (90% Confidence Interval) [ng*h/mL]	2668.310	2784.366

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A: Apixaban Tablet, Treatment B: Apixaban Oral Solution
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	1.043
	Confidence Interval	(2-Sided) 90%; 0.933 to 1.167
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of Participants With Serious Adverse Events (SAEs), Treatment-Related Adverse Events (AEs), Deaths or Discontinuation of Study Drug Due to AEs
Description	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. Treatment-related=having certain, probable, possible or missing relationship to study drug. Death=during the study and up to 28 days past study discontinuation. The select AEs were determined using the Medical Dictionary for Regulatory Activities (MedDRA, v13).
Time Frame	Day 1 to 30 days after last dose of study drug

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Arm A: Apixaban Tablet	Arm B: Apixaban Oral Solution
Arm/Group Description	Single dose apixaban 10 mg (film-coated tablet) administered orally	Single dose apixaban 10 mg (solution) administered orally
Measure Participants	14	13
SAE	0 0%	0 NaN
Treatment-Related AE	0 0%	1 NaN
Deaths	0 0%	0 NaN
Treatment-Related Deaths	0 0%	0 NaN
Discontinuation of Study Drug Due to AEs	1 7.1%	0 NaN

5. Secondary Outcome

Title	Number of Participants With Marked Laboratory Abnormalities
Description	Clinical laboratory tests were performed pre-study and at selected times throughout the study. Marked laboratory abnormalities were defined as laboratory assessments meeting the following investigator-specified criteria: Leukocytes < 0.9* lower limits of normal (LLN), absolute neutrophils + bands <= 1.500 10*3 cells/microliter, white blood cells (WBC) urine value >= 2+. These laboratory abnormalities were not considered clinically significant and therefore not adverse events.
Time Frame	Pre-study screen (Day -1) to Day 8 or day of study discharge

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Arm A: Apixaban Tablet	Arm B: Apixaban Oral Solution
Arm/Group Description	Single dose apixaban 10 mg (film-coated tablet) administered orally	Single dose apixaban 10 mg (solution) administered orally
Measure Participants	14	13
Leukocytes, Low	1 7.1%	1 NaN
Absolute Neutrophils + Bands, Low	1 7.1%	1 NaN
WBC, Urine, High	0 0%	1 NaN

Adverse Events

Time Frame	From first dose to last dose plus 30 days
Arm/Group Title	Arm A: Apixaban Tablet		Arm B: Apixaban Oral Solution
Arm/Group Description	Single dose apixaban 10 mg (film-coated tablet) administered orally		Single dose apixaban 10 mg (solution) administered orally
All Cause Mortality
	Arm A: Apixaban Tablet		Arm B: Apixaban Oral Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A: Apixaban Tablet		Arm B: Apixaban Oral Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Arm A: Apixaban Tablet		Arm B: Apixaban Oral Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/14 (28.6%)		2/13 (15.4%)
Gastrointestinal disorders
Constipation	1/14 (7.1%)		0/13 (0%)
Toothache	1/14 (7.1%)		0/13 (0%)
Dyspepsia	1/14 (7.1%)		0/13 (0%)
Eructation	1/14 (7.1%)		0/13 (0%)
General disorders
Vessel puncture site haematoma	1/14 (7.1%)		0/13 (0%)
Fatigue	1/14 (7.1%)		0/13 (0%)
Nervous system disorders
Headache	2/14 (14.3%)		1/13 (7.7%)
Respiratory, thoracic and mediastinal disorders
Throat irritation	0/14 (0%)		1/13 (7.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.