Relative Bioavailability of Dabigatran Capsules, Pellets and Oral Solution in Healthy Volunteers

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02044367
• Collaborator: (none)
• Enrollment: 54
• Location: 1
• Arms: 3
• Duration (Months): 3
• Patients Per Site Per Month: 18.3

Study Details

Study Description

Brief Summary

To investigate the relative bioavailability of dabigatran etexilate as pellets on food and of dabigatran etexilate as granules resolved in reconstitution solution, each with dabigatran etexilate as capsule following oral administration. To evaluate acceptability and palatability of Pellets sprinkled on food and Oral Liquid Formulation

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Dabigatran etexilate; Drug: Dabigatran etexilate; Drug: Dabigatran etexilate	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 54 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Relative Bioavailability of Dabigatran After Administration of Different Dosage Forms of Multiple Doses of 150 mg Dabigatran Etexilate (Hard Capsule, Granules Resolved in Reconstitution Solution, Pellets on Food) in Healthy Male Volunteers (an Open-label, Randomised, Multiple-dose, Three Way Crossover Study)
• Study Start Date: Jan 1, 2014
• Actual Primary Completion Date: Apr 1, 2014
• Actual Study Completion Date: Apr 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Test 1 (Treatment A) multiple dose of dabigatran	Drug: Dabigatran etexilate; Pellets (multiple dose of dabigatran)
Experimental: Test 2 (Treatment B) multiple dose of dabigatran	Drug: Dabigatran etexilate; Granules resolved in reconstitution solution (multiple dose of dabigatran)
Experimental: Reference multiple dose of dabigatran	Drug: Dabigatran etexilate; Hard capsule (multiple dose of dabigatran)

Outcome Measures

Primary Outcome Measures

1. Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Total Dabigatran. [47:55, 48:30, 49:00, 49:30, 50:00, 50:30, 51:00, 51:30, 52:00, 54:00, 56:00, 58:00, 60:00 relative to first drug administration]

   Area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval t for total dabigatran.

2. Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Total Dabigatran. [47:55, 48:30, 49:00, 49:30, 50:00, 50:30, 51:00, 51:30, 52:00, 54:00, 56:00, 58:00, 60:00 relative to first drug administration]

   Maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval t for total dabigatran.

Secondary Outcome Measures

1. Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Free Dabigatran. [47:55, 48:30, 49:00, 49:30, 50:00, 50:30, 51:00, 51:30, 52:00, 54:00, 56:00, 58:00, 60:00 relative to first drug administration]

   Area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval t for free dabigatran.

2. Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Free Dabigatran. [47:55, 48:30, 49:00, 49:30, 50:00, 50:30, 51:00, 51:30, 52:00, 54:00, 56:00, 58:00, 60:00 relative to first drug administration]

   Maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval t for free dabigatran.

3. Acceptability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. [once on day 3 (48 hours after first dose)]

   Acceptability question: "Would you accept to take this medication for chronic use?" with 3 possible answers: Yes - No - I am not sure.

4. Palatability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. [once on day 3 (48 hours after first dose)]

   Palatability question: "How do you rank the taste?" with 5 possible answers: Very good - Good - Fair - Acceptable - Not acceptable.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Inclusion criteria:

1. Healthy males according to the investigator's assessment, as based on the following criteria: a complete medical history including a physical examination, vital signs (Blood Pressure, Pulse Rate), 12-lead electrocardiogram, and clinical laboratory tests

2. Age 18 to 55 years (incl.)

3. Body Mass Index 18.5 to 29.9 kg/m2 (incl.)

4. Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation

Exclusion criteria:

1. Any finding in the medical examination (including Blood Pressure, Pulse Rate or electrocardiogram) deviating from normal and judged clinically relevant by the investigator.

2. Repeated measurement of systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg

3. Any laboratory value outside the reference range that the investigator considers to be of clinical relevance

4. Any evidence of a concomitant disease judged clinically relevant by the investigator

5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders

6. Surgery of the gastrointestinal tract that could interfere with kinetics of the study drug

7. Diseases of the central nervous system (such as epilepsy), other neurological disorders or psychiatric disorders

8. Subjects who in the investigator's judgement are perceived as having an increased risk of bleeding, for example because of:

• Hemorrhagic disorders or bleeding diathesis

• Occult blood in faeces or haematuria

• Trauma or surgery within the last month or as long as an excessive risk of bleeding persists after these events, or planned surgery during trial participation

• History of arteriovenous malformation or aneurysm

• History of gastroduodenal ulcer disease or gastrointestinal haemorrhage

• History of intracranial, intraocular, spinal, retroperitoneal, or atraumatic intraarticular bleeding

• Anemia at screening

• Thrombocytopenia (platelet count less than 100/nL)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1160.194.1 Boehringer Ingelheim Investigational Site	Biberach		Germany

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02044367
• Other Study ID Numbers: 1160.194; 2013-002498-23
• First Posted: Jan 24, 2014
• Last Update Posted: May 20, 2015
• Last Verified: May 1, 2015

• Additional relevant MeSH terms: Dabigatran

Study Results

Participant Flow

Arm/Group Title	T1-T2-R	T1-R-T2	T2-T1-R	T2-R-T1	R-T1-T2	R-T2-T1
Arm/Group Description	T1: pellets on food; T2: granules for reconstitution into solution; R: hard capsule. The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.	T1: pellets on food; R: hard capsule; T2: granules for reconstitution into solution. The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.	T2: granules for reconstitution into solution; T1: pellets on food; R: hard capsule. The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.	T2: granules for reconstitution into solution; R: hard capsule; T1: pellets on food. The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.	R: hard capsule; T1: pellets on food; T2: granules for reconstitution into solution. The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.	R: hard capsule; T2: granules for reconstitution into solution; T1: pellets on food. The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.
Period Title: Overall Study
STARTED	9	9	9	9	9	9
COMPLETED	9	9	9	9	9	9
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Overall
Arm/Group Description	A randomised, open-label, 3-way crossover, multiple dose trial consisting of 3 identical treatment periods of 3 days. Study drug (150 mg dabigatran etexilate) was administrated twice daily on Day 1 and Day 2 and once on Day 3. The dosage forms used were: hard capsule, granules resolved in reconstitution solution and pellets on food. Treatment periods were separated by a washout phase of at least 5 days between last drug administration of one treatment and the first drug administration of the next treatment.
Overall Participants	54
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.2 (10.6)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	54 100%

Outcome Measures

1. Primary Outcome

Title	Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Total Dabigatran.
Description	Area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval t for total dabigatran.
Time Frame	47:55, 48:30, 49:00, 49:30, 50:00, 50:30, 51:00, 51:30, 52:00, 54:00, 56:00, 58:00, 60:00 relative to first drug administration

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set (PKS) included all treated subjects that provided at least 1 observation for at least 1 primary or secondary PK endpoint without relevant protocol deviations with respect to the statistical evaluation of PK endpoints.

Arm/Group Title	T1 (Treatment A)	T2 (Treatment B)	R (Reference)
Arm/Group Description	multiple dose of dabigatran (Pellets) The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.	multiple dose of dabigatran (Granules resolved in reconstitution solution) The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.	multiple dose of dabigatran (Hard capsule) The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.
Measure Participants	54	54	53
Geometric Mean (Geometric Coefficient of Variation) [ng∙h/mL]	1220 (34.1)	1160 (27.0)	893 (46.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	T1 (Treatment A), R (Reference)
	Comments	Analysis of variance (ANOVA) on the logarithmic scale was used including effects for 'sequence', 'period' and 'treatment' as fixed effects and 'subjects within sequences' as random effect. CIs were calculated based on the residual error from ANOVA.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The sample size determination was not based on a power calculation, but to assure a precise estimation of the relative bioavailability. For this 3-way crossover trial, a precision (defined by ratio of upper CI limit to adjusted GMR) of at most 1.17 had been considered necessary and sufficient by the project team.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	gMean Ratio T1/R (%)
	Estimated Value	137.01
	Confidence Interval	(2-Sided) 90%; 125.773 to 149.250
	Parameter Dispersion	Type: Standard Deviation; Value: 26.8
	Estimation Comments	The standard deviation is actually the intra-individual geometric coefficient of variation (gCV).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	T2 (Treatment B), R (Reference)
	Comments	Analysis of variance (ANOVA) on the logarithmic scale was used including effects for 'sequence', 'period' and 'treatment' as fixed effects and 'subjects within sequences' as random effect. CIs were calculated based on the residual error from ANOVA.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The sample size determination was not based on a power calculation, but to assure a precise estimation of the relative bioavailability. For this 3-way crossover trial, a precision (defined by ratio of upper CI limit to adjusted GMR) of at most 1.17 had been considered necessary and sufficient by the project team.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	gMean Ratio T2/R (%)
	Estimated Value	130.43
	Confidence Interval	(2-Sided) 90%; 119.628 to 142.200
	Parameter Dispersion	Type: Standard Deviation; Value: 27.1
	Estimation Comments	The standard deviation is actually the intra-individual geometric coefficient of variation (gCV).

2. Primary Outcome

Title	Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Total Dabigatran.
Description	Maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval t for total dabigatran.
Time Frame	47:55, 48:30, 49:00, 49:30, 50:00, 50:30, 51:00, 51:30, 52:00, 54:00, 56:00, 58:00, 60:00 relative to first drug administration

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set (PKS) included all treated subjects that provided at least 1 observation for at least 1 primary or secondary PK endpoint without relevant protocol deviations with respect to the statistical evaluation of PK endpoints.

Arm/Group Title	T1 (Treatment A)	T2 (Treatment B)	R (Reference)
Arm/Group Description	multiple dose of dabigatran (Pellets) The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.	multiple dose of dabigatran (Granules resolved in reconstitution solution) The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.	multiple dose of dabigatran (Hard capsule) The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.
Measure Participants	54	54	53
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	191 (37.4)	184 (27.3)	131 (50.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	T1 (Treatment A), R (Reference)
	Comments	Analysis of variance (ANOVA) on the logarithmic scale was used including effects for 'sequence', 'period' and 'treatment' as fixed effects and 'subjects within sequences' as random effect. CIs were calculated based on the residual error from ANOVA.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The sample size determination was not based on a power calculation, but to assure a precise estimation of the relative bioavailability. For this 3-way crossover trial, a precision (defined by ratio of upper CI limit to adjusted GMR) of at most 1.17 had been considered necessary and sufficient by the project team.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	gMean Ratio T1/R (%)
	Estimated Value	146.16
	Confidence Interval	(2-Sided) 90%; 132.217 to 161.576
	Parameter Dispersion	Type: Standard Deviation; Value: 31.6
	Estimation Comments	The standard deviation is actually the intra-individual geometric coefficient of variation (gCV).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	T2 (Treatment B), R (Reference)
	Comments	Analysis of variance (ANOVA) on the logarithmic scale was used including effects for 'sequence', 'period' and 'treatment' as fixed effects and 'subjects within sequences' as random effect. CIs were calculated based on the residual error from ANOVA.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The sample size determination was not based on a power calculation, but to assure a precise estimation of the relative bioavailability. For this 3-way crossover trial, a precision (defined by ratio of upper CI limit to adjusted GMR) of at most 1.17 had been considered necessary and sufficient by the project team.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	gMean Ratio T2/R (%)
	Estimated Value	141.06
	Confidence Interval	(2-Sided) 90%; 127.644 to 155.876
	Parameter Dispersion	Type: Standard Deviation; Value: 31.5
	Estimation Comments	The standard deviation is actually the intra-individual geometric coefficient of variation (gCV).

3. Secondary Outcome

Title	Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Free Dabigatran.
Description	Area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval t for free dabigatran.
Time Frame	47:55, 48:30, 49:00, 49:30, 50:00, 50:30, 51:00, 51:30, 52:00, 54:00, 56:00, 58:00, 60:00 relative to first drug administration

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set (PKS) included all treated subjects that provided at least 1 observation for at least 1 primary or secondary PK endpoint without relevant protocol deviations with respect to the statistical evaluation of PK endpoints.

Arm/Group Title	T1 (Treatment A)	T2 (Treatment B)	R (Reference)
Arm/Group Description	multiple dose of dabigatran (Pellets) The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.	multiple dose of dabigatran (Granules resolved in reconstitution solution) The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.	multiple dose of dabigatran (Hard capsule) The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.
Measure Participants	54	54	53
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	1000 (35.8)	958 (27.6)	727 (50.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	T1 (Treatment A), R (Reference)
	Comments	Analysis of variance (ANOVA) on the logarithmic scale was used including effects for 'sequence', 'period' and 'treatment' as fixed effects and 'subjects within sequences' as random effect. CIs were calculated based on the residual error from ANOVA.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The sample size determination was not based on a power calculation, but to assure a precise estimation of the relative bioavailability. For this 3-way crossover trial, a precision (defined by ratio of upper CI limit to adjusted GMR) of at most 1.17 had been considered necessary and sufficient by the project team.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	gMean Ratio T1/R (%)
	Estimated Value	137.61
	Confidence Interval	(2-Sided) 90%; 126.418 to 149.797
	Parameter Dispersion	Type: Standard Deviation; Value: 26.5
	Estimation Comments	The standard deviation is actually the intra-individual geometric coefficient of variation (gCV).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	T2 (Treatment B), R (Reference)
	Comments	Analysis of variance (ANOVA) on the logarithmic scale was used including effects for 'sequence', 'period' and 'treatment' as fixed effects and 'subjects within sequences' as random effect. CIs were calculated based on the residual error from ANOVA.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The sample size determination was not based on a power calculation, but to assure a precise estimation of the relative bioavailability. For this 3-way crossover trial, a precision (defined by ratio of upper CI limit to adjusted GMR) of at most 1.17 had been considered necessary and sufficient by the project team.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	gMean Ratio T2/R (%)
	Estimated Value	132.00
	Confidence Interval	(2-Sided) 90%; 120.714 to 144.342
	Parameter Dispersion	Type: Standard Deviation; Value: 28.0
	Estimation Comments	The standard deviation is actually the intra-individual geometric coefficient of variation (gCV).

4. Secondary Outcome

Title	Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Free Dabigatran.
Description	Maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval t for free dabigatran.
Time Frame	47:55, 48:30, 49:00, 49:30, 50:00, 50:30, 51:00, 51:30, 52:00, 54:00, 56:00, 58:00, 60:00 relative to first drug administration

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set (PKS) included all treated subjects that provided at least 1 observation for at least 1 primary or secondary PK endpoint without relevant protocol deviations with respect to the statistical evaluation of PK endpoints.

Arm/Group Title	T1 (Treatment A)	T2 (Treatment B)	R (Reference)
Arm/Group Description	multiple dose of dabigatran (Pellets) The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.	multiple dose of dabigatran (Granules resolved in reconstitution solution) The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.	multiple dose of dabigatran (Hard capsule) The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.
Measure Participants	54	54	53
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	157 (37.9)	154 (27.6)	106 (55.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	T1 (Treatment A), R (Reference)
	Comments	Analysis of variance (ANOVA) on the logarithmic scale was used including effects for 'sequence', 'period' and 'treatment' as fixed effects and 'subjects within sequences' as random effect. CIs were calculated based on the residual error from ANOVA.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The sample size determination was not based on a power calculation, but to assure a precise estimation of the relative bioavailability. For this 3-way crossover trial, a precision (defined by ratio of upper CI limit to adjusted GMR) of at most 1.17 had been considered necessary and sufficient by the project team.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	gMean Ratio T1/R (%)
	Estimated Value	147.80
	Confidence Interval	(2-Sided) 90%; 133.384 to 163.779
	Parameter Dispersion	Type: Standard Deviation; Value: 32.4
	Estimation Comments	The standard deviation is actually the intra-individual geometric coefficient of variation (gCV).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	T2 (Treatment B), R (Reference)
	Comments	Analysis of variance (ANOVA) on the logarithmic scale was used including effects for 'sequence', 'period' and 'treatment' as fixed effects and 'subjects within sequences' as random effect. CIs were calculated based on the residual error from ANOVA.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The sample size determination was not based on a power calculation, but to assure a precise estimation of the relative bioavailability. For this 3-way crossover trial, a precision (defined by ratio of upper CI limit to adjusted GMR) of at most 1.17 had been considered necessary and sufficient by the project team.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	gMean Ratio T2/R (%)
	Estimated Value	144.80
	Confidence Interval	(2-Sided) 90%; 130.853 to 160.242
	Parameter Dispersion	Type: Standard Deviation; Value: 32.0
	Estimation Comments	The standard deviation is actually the intra-individual geometric coefficient of variation (gCV).

5. Secondary Outcome

Title	Acceptability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question.
Description	Acceptability question: "Would you accept to take this medication for chronic use?" with 3 possible answers: Yes - No - I am not sure.
Time Frame	once on day 3 (48 hours after first dose)

Outcome Measure Data

Analysis Population Description

Treated set including all subjects that provided at least 1 observation for at least 1 of the questions for at least 1 of the test products.

Arm/Group Title	T1 (Treatment A)	T2 (Treatment B)
Arm/Group Description	T1: Pellets on food The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for both treatments T1 and T2. All treatments were administered orally with 240 mL of water.	T2: Granules resolved in reconstitution solution The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for both treatments T1 and T2. All treatments were administered orally with 240 mL of water.
Measure Participants	53	53
Yes	37 68.5%	29 NaN
No	9 16.7%	17 NaN
I am not sure	7 13%	7 NaN

6. Secondary Outcome

Title	Palatability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question.
Description	Palatability question: "How do you rank the taste?" with 5 possible answers: Very good - Good - Fair - Acceptable - Not acceptable.
Time Frame	once on day 3 (48 hours after first dose)

Outcome Measure Data

Analysis Population Description

Treated set including all subjects that provided at least 1 observation for at least 1 of the questions for at least 1 of the test products.

Arm/Group Title	T1 (Treatment A)	T2 (Treatment B)
Arm/Group Description	T1: Pellets on food The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for both treatments T1 and T2. All treatments were administered orally with 240 mL of water.	T2: Granules resolved in reconstitution solution The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for both treatments T1 and T2. All treatments were administered orally with 240 mL of water.
Measure Participants	53	53
Very good	2 3.7%	0 NaN
Good	20 37%	15 NaN
Fair	18 33.3%	17 NaN
Acceptable	11 20.4%	14 NaN
Not acceptable	2 3.7%	7 NaN

Adverse Events

Time Frame	First dose of study drug date/time until the end-of-trial examination (last per protocol visit)
Arm/Group Title	T1 (Treatment A)		T2 (Treatment B)		R (Reference)
Arm/Group Description	multiple dose of dabigatran (Pellets). The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.		multiple dose of dabigatran (Granules resolved in reconstitution solution) The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.		multiple dose of dabigatran (Hard capsule) The treatments were 150 mg dabigatran etexilate twice daily on Days 1 and 2 and once after an overnight fast of at least 10 hours on Day 3 for all treatments T1, T2 and R. All treatments were administered orally with 240 mL of water.
All Cause Mortality
	T1 (Treatment A)		T2 (Treatment B)		R (Reference)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	T1 (Treatment A)		T2 (Treatment B)		R (Reference)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/54 (0%)		0/54 (0%)		0/54 (0%)
Other (Not Including Serious) Adverse Events
	T1 (Treatment A)		T2 (Treatment B)		R (Reference)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/54 (3.7%)		3/54 (5.6%)		1/54 (1.9%)
Nervous system disorders
Headache	2/54 (3.7%)		3/54 (5.6%)		1/54 (1.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.