Bioavailability Study of Five Tablet Formulations of Dabi... | NCT02710630

NCT02710630

Status Module

Sponsor/Collaborators Module

Oversight Module

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Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

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Arms/Interventions Module

Arm Groups

Label	Type	Intervention Names
Dabigatran etexilate capsule	Active Comparator	Drug: Dabigatran etexilate capsule
Dabigatran etexilate tablet A1	Experimental	Drug: Dabigatran etexilate tablet A1
Dabigatran etexilate tablet B1	Experimental	Drug: Dabigatran etexilate tablet B1
Dabigatran etexilate tablet C1	Experimental	Drug: Dabigatran etexilate tablet C1
Dabigatran etexilate tablet D1	Experimental	Drug: Dabigatran etexilate tablet D1
Dabigatran etexilate tablet E1	Experimental	Drug: Dabigatran etexilate tablet E1

Name	Type	Description	Arm Group Labels	Other Names
Dabigatran etexilate tablet E1	Drug		Dabigatran etexilate tablet E1
Dabigatran etexilate tablet D1

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
AUC0-tz (Area Under the Concentration-time Curve of Free Dabigatran in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point)	This outcome measure presents area under the concentration-time curve of free Dabigatran in plasma over the time interval from 0 to the time of the last quantifiable data point.	1:00 [hour (h): minute] before drug administration and 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h, 48:00h after drug administration.
Cmax (Maximum Concentration of Free Dabigatran)	This outcome measure presents maximum concentration of analyte in plasma (Cmax).	1:00 [hour (h): minute] before drug administration and 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h, 48:00h after drug administration.

Secondary Outcomes

Measure	Description	Time Frame
AUC0-infinity (Area Under the Concentration-time Curve of Free Dabigatran in Plasma Over the Time Interval From 0 Extrapolated to Infinity) (if Applicable)	This outcome measure presents area under the concentration-time curve of free Dabigatran in plasma over the time interval from 0 extrapolated to infinity)(if applicable).	1:00 [hour (h): minute] before drug administration and 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h, 48:00h after drug administration.

Eligibility Module

Eligibility Criteria

Inclusion criteria:

Healthy male subjects according to the investigator's assessment, based on a complete medical history including a physical examination, vital signs (blood pressure [BP], pulse rate [PR]), 12-lead electrocardiogram (ECG), and clinical laboratory tests
Age >=20 and <=35 years old
Body mass index (BMI) >=18.0 and <=25.0 kg/m2
Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice (GCP) and local legislation

Exclusion criteria:

Any finding in the medical examination (including BP, Pulse Rate, or ECG) deviating from normal and judged as clinically relevant by the investigator at screening
Measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 45 to 90 bpm at screening
Any laboratory value outside the reference range that the investigator considers to be of clinical relevance
Any relevant bleeding history considered by the investigator
Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
Surgery of the gastrointestinal tract that could interfere with kinetics of the trial medication (except appendectomy and simple hernia repair)
Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders
Any history or evidence of blood dyscrasia, haemorrhagic diathesis, severe thrombocytopenia, cerebrovascular haemorrhage, bleeding tendencies associated with active ulceration or overt bleeding of gastrointestinal, respiratory or genitourinary tract or any disease or condition with haemorrhagic tendencies
History of relevant orthostatic hypotension, fainting spells, or blackouts
Chronic or relevant acute infections
History of relevant allergy or hypersensitivity (including allergy to the trial medication or its excipients)
Any evidence of a concomitant disease considered as clinically relevant by the investigator
Intake of drugs with a long half-life (more than 24 hours) within 30 days or less than 10 half-lives of the respective drug prior to administration of trial medication
Within 10 days prior to administration of trial medication, use of drugs that might reasonably influence the results of the trial
Intake of medication, which influences the blood clotting, e.g., acetylsalicylic acid, coumarin etc. within 10 days prior to trial medication
Participation in another trial where an investigational drug has been administered within 4 months or 5 half-lives (whichever is greater) prior to planned administration of trial medication
Planned surgeries within four weeks following the end-of study examination
Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
Inability to refrain from smoking during in-house confinement at the trial site
Alcohol abuse (consumption of more than 30 g per day: e.g., 750 mL of beer, 1.5 gous [equivalent to 270 mL] of Sake)
Drug abuse or positive drug screening
Blood donation of more than 100 mL within 30 days prior to administration of trial medication or intended donation during the trial
Intention to perform excessive physical activities within one week prior to administration of trial medication or during the trial
Inability to comply with dietary regimen of trial site
Subject assessed as unsuitable for inclusion by the investigator because of, for instance, being considered not able to understand and comply with study requirements, or having a condition that would not allow safe participation in the study

Contacts/Locations Module

Name	Affiliation	Role
Boehringer Ingelheim	Boehringer Ingelheim	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
SOUSEIKAI Sumida Hospital		Tokyo, Sumida-ku		133-0004	Japan

References Module

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IPD Sharing Statement Module

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Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Ref-A1-B1-C1-D1-E1	All subjects were treated with the reference treatment (Ref), Dabigatran Etexilate (BIBR 1048) commercial capsule formulation, 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours in period 1, followed by one of the 5 investigational treatment in the following sequence, i.e., test formulation Dabigatran Etexilate tablet formulations in the sequence Test Formulation A1 (TF-A1) in period 2, followed by Test Formulation B1 (TF-B1) in period 3, followed by Test Formulation C1 (TF-C1) in period 4, followed by Test Formulation D1 (TF-D1) in period 5, followed by Test Formulation E1 (TF-E1) in period 6, 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours. A washout period of at least 4 days was set following the drug administration in each period.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

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Document Section

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Derived Section

Miscellaneous Info Module

Submission Tracking

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Condition Browse Module

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Intervention Browse Module

Masking Info

Treated set (TS): This set included all subjects that were dispensed study drug and were documented to have taken at least one dose of study drug.

Arm/Group Information

ID	Title	Description
BG000	Ref-A1-B1-C1-D1-E1	All subjects were treated with the reference treatment (Ref), Dabigatran Etexilate (BIBR 1048) commercial capsule formulation, 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours in period 1, followed by one of the 5 investigational treatment in the following sequence, i.e., test formulation Dabigatran Etexilate tablet formulations in the sequence Test Formulation A1 (TF-A1) in period 2, followed by Test Formulation B1 (TF-B1) in period 3, followed by Test Formulation C1 (TF-C1) in period 4, followed by Test Formulation D1 (TF-D1) in period 5, followed by Test Formulation E1 (TF-E1) in period 6, 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours. A washout period of at least 4 days was set following the drug administration in each period.
BG001	Ref-B1-C1-D1-E1-A1	All subjects were treated with the reference treatment (Ref), Dabigatran Etexilate (BIBR 1048) commercial capsule formulation, 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours in period 1, followed by one of the 5 investigational treatment in the following sequence, i.e., test formulation Dabigatran Etexilate tablet formulations in the sequence Test Formulation B1 (TF-B1) in period 2, followed by Test Formulation C1 (TF-C1) in period 3, followed by Test Formulation D1 (TF-D1) in period 4, followed by Test Formulation E1 (TF-E1) in period 5, followed by Test Formulation A1 (TF-A1) in period 6, 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours. A washout period of at least 4 days was set following the drug administration in each period.
BG002	Ref-C1-D1-E1-A1-B1	All subjects were treated with the reference treatment (Ref), Dabigatran Etexilate (BIBR 1048) commercial capsule formulation, 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours in period 1, followed by one of the 5 investigational treatment in the following sequence, i.e., test formulation Dabigatran Etexilate tablet formulations in the sequence Test Formulation C1 (TF-C1) in period 2, followed by Test Formulation D1 (TF-D1) in period 3, followed by Test Formulation E1 (TF-E1) in period 4, followed by Test Formulation A1 (TF-A1) in period 5, followed by Test Formulation B1 (TF-B1) in period 6, 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours. A washout period of at least 4 days was set following the drug administration in each period.
BG003	Ref-D1-E1-A1-B1-C1	All subjects were treated with the reference treatment (Ref), Dabigatran Etexilate (BIBR 1048) commercial capsule formulation, 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours in period 1, followed by one of the 5 investigational treatment in the following sequence, i.e., test formulation Dabigatran Etexilate tablet formulations in the sequence Test Formulation D1 (TF-D1) in period 2, followed by Test Formulation E1 (TF-E1) in period 3, followed by Test Formulation A1 (TF-A1) in period 4, followed by Test Formulation B1 (TF-B1) in period 5, followed by Test Formulation C1 (TF-C1) in period 6, 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours. A washout period of at least 4 days was set following the drug administration in each period.
BG004	Ref-E1-A1-B1-C1-D1	All subjects were treated with the reference treatment (Ref), Dabigatran Etexilate (BIBR 1048) commercial capsule formulation, 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours in period 1, followed by one of the 5 investigational treatment in the following sequence, i.e., test formulation Dabigatran Etexilate tablet formulations in the sequence Test Formulation E1 (TF-E1) in period 2, followed by Test Formulation A1 (TF-A1) in period 3, followed by Test Formulation B1 (TF-B1) in period 4, followed by Test Formulation C1 (TF-C1) in period 5, followed by Test Formulation D1 (TF-D1) in period 6, 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours. A washout period of at least 4 days was set following the drug administration in each period.
BG005	Total	Total of all reporting groups

Units	Counts
Participants	BG0007 BG0017 BG0027 BG0037 BG0047 BG00535

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

Years

Title

Denominators

Categories

Title	Measurements
	OG000600± 51.8 OG001714± 42.1 OG002318± 327 OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG001						Ratio [Test/Reference]	119.33	Standard Deviation	40.4	2-Sided	90	101.838	139.834			The adjusted geometric mean (gMean) ratio [%] calculated as Dabigatran Etexilate Tablet: A1/Dabigatran Etexilate Capsule: Ref. Standard deviation is actually intra-individual geometric coefficient of variation (gCV) [%].		Superiority or Other
OG002

Primary

Cmax (Maximum Concentration of Free Dabigatran)

This outcome measure presents maximum concentration of analyte in plasma (Cmax).

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

1:00 [hour (h): minute] before drug administration and 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h, 48:00h after drug administration.

ID	Title	Description
OG000	Dabigatran Etexilate Capsule: Ref	The subjects received Dabigatran Etexilate (Reference) capsule formulation (commercial formulation) 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours.
OG001	Dabigatran Etexilate Tablet: A1	The subjects received Dabigatran Etexilate (Test) tablet formulation (A1), 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours.
OG002	Dabigatran Etexilate Tablet: B1

Secondary

AUC0-infinity (Area Under the Concentration-time Curve of Free Dabigatran in Plasma Over the Time Interval From 0 Extrapolated to Infinity) (if Applicable)

This outcome measure presents area under the concentration-time curve of free Dabigatran in plasma over the time interval from 0 extrapolated to infinity)(if applicable).

The PharmacoKinetic (PK) parameter analysis Set (PKS): Included all subjects of the treated set who provided at least one primary or secondary PK parameter.

PK Set 2 (PKS2): Included all subjects in the PKS who had evaluable PK variable of the reference treatment and at least one of the 5 test treatments.

PKS2 was used for statistical analyses.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng*h/mL

1:00 [hour (h): minute] before drug administration and 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h, 48:00h after drug administration.

ID	Title	Description
OG000	Dabigatran Etexilate Capsule: Ref	The subjects received Dabigatran Etexilate (Reference) capsule formulation (commercial formulation) 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours.
OG001	Dabigatran Etexilate Tablet: A1	The subjects received Dabigatran Etexilate (Test) tablet formulation (A1), 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours.

Secondary

AUC0-tz (Area Under the Concentration-time Curve of Total Dabigatran in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point)

This outcome measure presents area under the concentration-time curve of total Dabigatran in plasma over the time interval from 0 to the time of the last quantifiable data point.

The PharmacoKinetic (PK) parameter analysis Set (PKS): Included all subjects of the treated set who provided at least one primary or secondary PK parameter.

PK Set 2 (PKS2): Included all subjects in the PKS who had evaluable PK variable of the reference treatment and at least one of the 5 test treatments.

PKS2 was used for statistical analyses.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng*h/mL

1:00 [hour (h): minute] before drug administration and 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h, 48:00h after drug administration.

ID	Title	Description
OG000	Dabigatran Etexilate Capsule: Ref	The subjects received Dabigatran Etexilate (Reference) capsule formulation (commercial formulation) 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours.
OG001	Dabigatran Etexilate Tablet: A1	The subjects received Dabigatran Etexilate (Test) tablet formulation (A1), 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours.

Secondary

Cmax (Maximum Plasma Concentration of Total Dabigatran)

This outcome measure presents maximum concentration of analyte in plasma (Cmax).

The PharmacoKinetic (PK) parameter analysis Set (PKS): Included all subjects of the treated set who provided at least one primary or secondary PK parameter.

PK Set 2 (PKS2): Included all subjects in the PKS who had evaluable PK variable of the reference treatment and at least one of the 5 test treatments.

PKS2 was used for statistical analyses.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

1:00 [hour (h): minute] before drug administration and 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h, 48:00h after drug administration.

ID	Title	Description
OG000	Dabigatran Etexilate Capsule: Ref	The subjects received Dabigatran Etexilate (Reference) capsule formulation (commercial formulation) 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours.
OG001	Dabigatran Etexilate Tablet: A1	The subjects received Dabigatran Etexilate (Test) tablet formulation (A1), 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours.
OG002	Dabigatran Etexilate Tablet: B1

Secondary

AUC0-infinity (Area Under the Concentration-time Curve of Total Dabigatran in Plasma Over the Time Interval From 0 Extrapolated to Infinity) (if Applicable)

This outcome measure presents area under the concentration-time curve of total Dabigatran in plasma over the time interval from 0 extrapolated to infinity)(if applicable).

The PharmacoKinetic (PK) parameter analysis Set (PKS): Included all subjects of the treated set who provided at least one primary or secondary PK parameter.

PK Set 2 (PKS2): Included all subjects in the PKS who had evaluable PK variable of the reference treatment and at least one of the 5 test treatments.

PKS2 was used for statistical analyses.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng*h/mL

1:00 [hour (h): minute] before drug administration and 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h, 48:00h after drug administration.

ID	Title	Description
OG000	Dabigatran Etexilate Capsule: Ref	The subjects received Dabigatran Etexilate (Reference) capsule formulation (commercial formulation) 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours.
OG001	Dabigatran Etexilate Tablet: A1	The subjects received Dabigatran Etexilate (Test) tablet formulation (A1), 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours.

Arm/Groups

ID	Title	Description	Serious Events (At Risk)	Other Events (At Risk)
EG000	Dabigatran Etexilate Capsule: Ref	The subjects received Dabigatran Etexilate (Reference) capsule formulation (commercial formulation) 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours.	35	35
EG001	Dabigatran Etexilate Tablet: A1	The subjects received Dabigatran Etexilate (Test) tablet formulation (A1), 110 mg orally (one day, single dose) with 200 mL of water after an overnight fast of at least 10 hours.	34	34
EG002	Dabigatran Etexilate Tablet: B1	The subjects received Dabigatran Etexilate (Test) tablet formulation (B1), 110 mg orally (one day single dose) with 200 mL of water after an overnight fast of at least 10 hours.	35	35
EG003	Dabigatran Etexilate Tablet: C1	The subjects received Dabigatran Etexilate (Test) tablet formulation (C1), 110 mg orally (one day single dose) with 200 mL of water after an overnight fast of at least 10 hours.	35	35
EG004	Dabigatran Etexilate Tablet: D1	The subjects received Dabigatran Etexilate (Test) tablet formulation (D1), 110 mg orally (one day single dose) with 200 mL of water after an overnight fast of at least 10 hours.	35	35
EG005	Dabigatran Etexilate Tablet: E1	The subjects received Dabigatran Etexilate (Test) tablet formulation (E1), 110 mg orally (one day single dose) with 200 mL of water after an overnight fast of at least 10 hours.	35	35

ID	Term
D000069604	Dabigatran

Ancestor Terms

ID	Term
D011725	Pyridines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D001562	Benzimidazoles
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring

The subjects received Dabigatran Etexilate (Test) tablet formulation (B1), 110 mg orally (one day single dose) with 200 mL of water after an overnight fast of at least 10 hours.