Bioequivalence of a Fixed Dose Combination Tablet of Empa... | NCT02758171

NCT02758171

ID	Type	Description	Link
2015-004234-98	EudraCT Number

Status Module

Sponsor/Collaborators Module

Name	Class
Eli Lilly and Company	INDUSTRY

Oversight Module

No data available

No data is available for this block.

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Empagliflozin+Linagliptin FDC	Experimental	One tablet fix dose combination (FDC)	Drug: Empagliflozin Drug: Linagliptin
Empagliflozin+Linagliptin single tablets	Active Comparator		Drug: Empagliflozin Drug: Linagliptin

Name	Type	Description	Arm Group Labels	Other Names
Empagliflozin	Drug		Empagliflozin+Linagliptin FDC Empagliflozin+Linagliptin single tablets
Linagliptin

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
AUC0-tz (Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point)	This outcome measure presents area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 to the last quantifiable data point. Time frame description: The time -1:00 hour (h) was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for AUC0-tz (area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 to the last quantifiable data point).	1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.
AUC0-72 (Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours)	This outcome measure presents area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 to 72 hours. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for AUC0-72 (area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 to 72 hours).	1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.
Cmax (Maximum Measured Concentration of Empagliflozin Analyte in Plasma)	This outcome measure presents maximum measured concentration of Empagliflozin analyte in plasma. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for Cmax (maximum measured concentration of Empagliflozin analyte in plasma).	1:00 [hour (h): minute] before drug administration and 0:20h, 0:40h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h, and 72:00h after drug administration.

Secondary Outcomes

Measure	Description	Time Frame
AUC0-infinity (Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity)	This outcome measure presents area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 extrapolated to infinity. Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for AUC0-infinity (area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 extrapolated to infinity).

Eligibility Module

Eligibility Criteria

Inclusion criteria:

Healthy male or female subjects according to the investigators 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 of 18 to 55 years (incl.)
Body Mass Index (BMI) of 18.5 to 29.9 kg/m2 (incl.)
Signed and dated written informed consent prior to admission to the study in accordance with GCP (Good Clinical Practice) and local legislation
Male subjects, or female subjects who meet any of the following criteria starting from at least 30 days before the first administration of trial medication and until 30 days after trial completion:
Use of adequate contraception, e.g. any of the following methods plus condom: implants, injectables, combined oral or vaginal contraceptives, intrauterine device
Sexually abstinent
A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment)
Surgically sterilised (including hysterectomy)
Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous levels of FSH (Follicle Stimulating Hormone) above 40 U/L and estradiol below 30 ng/L is confirmatory)

Exclusion criteria:

Any finding in the medical examination (including Blood Pressure [BP], Pulse Rate [PR] or Electrocardiogram [ECG]) is deviating from normal and judged as clinically relevant by the investigator
Repeated 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
Any laboratory value outside the reference range that the investigator considers to be of clinical relevance
Any evidence of a concomitant disease judged as clinically relevant by the investigator
Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the pharmacokinetics 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
Further exclusion criteria apply

Contacts/Locations Module

Name	Affiliation	Role
Boehringer Ingelheim	Boehringer Ingelheim	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
Humanpharmakologisches Zentrum Biberach		Biberach		88397	Germany

References Module

No data available

No data is available for this block.

IPD Sharing Statement Module

No data available

No data is available for this block.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	FDC/Empagliflozin+Linagliptin	The subjects were administered one FDC (Fixed-Dose Combination) film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin orally with 240 mL of water after an overnight fast of at least 10 hours (h), as a single dose in the fasted state on Day 1 of Test treatment (T) in period 1, followed by one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) administered orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R) in period 2. A wash-out period of at least 35 days was set following the drug administration in each period.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

No data available

No data is available for this block.

Intervention Browse Module

Masking Info

Treated Set (TS): This subject set included all subjects from the Randomised Set (RS) [ included all randomised subjects, whether treated or not] who were documented to have received at least 1 dose of study drug.

Arm/Group Information

ID	Title	Description
BG000	FDC/Empagliflozin+Linagliptin	The subjects were administered one FDC (Fixed-Dose Combination) film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin orally with 240 mL of water after an overnight fast of at least 10 hours (h), as a single dose in the fasted state on Day 1 of Test treatment (T) in period 1, followed by one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) administered orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R) in period 2. A wash-out period of at least 35 days was set following the drug administration in each period.
BG001	Empagliflozin+Linagliptin/FDC	The subjects were administered one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R) in period 1, followed by one FDC film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin administered orally with 240 mL of water after an overnight fast of at least 10 h, as a single dose in the fasted state on Day 1 of Test treatment (T) in period 2. A wash-out period of at least 35 days was set following the drug administration in each period.
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG00028 BG00128 BG00256

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
	OG0002550± 18.0 OG0012510± 19.9

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
OG000 OG001	The statistical model used was an Analysis of Variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: Sequence, subjects within sequences, period, and treatment. The effect subjects within sequences was considered as random, whereas the other effects were considered as fixed.	ANOVA		<0.0001		Adjusted geometric mean (gMean) ratio	101.71	Standard Deviation	5.8	2-Sided	90	99.818	103.644			The ratio [%] calculated as T [FDC (10 mg Empagliflozin and 5 mg Linagliptin)]/R [Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets]. Standard deviation is actually intra-individual geometric coefficient of variation (gCV) [%].

Primary

AUC0-72 (Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours)

This outcome measure presents area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 to 72 hours.

Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for AUC0-72 (area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 to 72 hours).

Posted

Geometric Mean

Geometric Coefficient of Variation

nmol*h/L

ID	Title	Description
OG000	FDC (10 mg Empagliflozin and 5 mg Linagliptin)	The subjects were administered one FDC film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin orally with 240 mL of water after an overnight fast of at least 10 hours (h), as a single dose in the fasted state on Day 1 of Test treatment (T).
OG001	Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets

Primary

Cmax (Maximum Measured Concentration of Empagliflozin Analyte in Plasma)

This outcome measure presents maximum measured concentration of Empagliflozin analyte in plasma.

Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for Cmax (maximum measured concentration of Empagliflozin analyte in plasma).

Posted

Geometric Mean

Geometric Coefficient of Variation

nmol/L

ID	Title	Description
OG000	FDC (10 mg Empagliflozin and 5 mg Linagliptin)	The subjects were administered one FDC film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin orally with 240 mL of water after an overnight fast of at least 10 hours (h), as a single dose in the fasted state on Day 1 of Test treatment (T).
OG001	Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets	The subjects were administered one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R).

Primary

Cmax (Maximum Measured Concentration of Linagliptin Analyte in Plasma)

This outcome measure presents maximum measured concentration of Linagliptin analyte in plasma.

Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for Cmax (maximum measured concentration of Linagliptin analyte in plasma).

Posted

Geometric Mean

Geometric Coefficient of Variation

nmol/L

ID	Title	Description
OG000	FDC (10 mg Empagliflozin and 5 mg Linagliptin)	The subjects were administered one FDC film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin orally with 240 mL of water after an overnight fast of at least 10 hours (h), as a single dose in the fasted state on Day 1 of Test treatment (T).
OG001	Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets	The subjects were administered one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R).

Secondary

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

This outcome measure presents area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 extrapolated to infinity.

Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for AUC0-infinity (area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 extrapolated to infinity).

Posted

Geometric Mean

Geometric Coefficient of Variation

nmol*h/L

ID	Title	Description
OG000	FDC (10 mg Empagliflozin and 5 mg Linagliptin)	The subjects were administered one FDC film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin orally with 240 mL of water after an overnight fast of at least 10 hours (h), as a single dose in the fasted state on Day 1 of Test treatment (T).
OG001	Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets

Secondary

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

This outcome measure presents area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 extrapolated to infinity.

Time frame description: The time -1:00h was approximate; the procedure was to be performed and completed within 2h before drug administration. PKS including participants with available data for (area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 extrapolated to infinity).

Posted

Geometric Mean

Geometric Coefficient of Variation

nmol*h/L

ID	Title	Description
OG000	FDC (10 mg Empagliflozin and 5 mg Linagliptin)	The subjects were administered one FDC film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin orally with 240 mL of water after an overnight fast of at least 10 hours (h), as a single dose in the fasted state on Day 1 of Test treatment (T).
OG001	Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	FDC (10 mg Empagliflozin and 5 mg Linagliptin)	The subjects were administered one FDC film-coated tablet containing 10 mg Empagliflozin and 5 mg Linagliptin orally with 240 mL of water after an overnight fast of at least 10 hours (h), as a single dose in the fasted state on Day 1 of Test treatment (T).			0	56	8	56
EG001	Empagliflozin (10 mg) + Linagliptin (5 mg) Single Tablets	The subjects were administered one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R).			0	54	7	54

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Headache	Nervous system disorders	MedDRA 19.0	Systematic Assessment		EG0008 affected56 at risk EG0017 affected54 at risk

Title	Organization	Phone	Extension	Email
Boehringer Ingelheim, Call Center	Boehringer Ingelheim	1800-243-0127		clintriage.rdg@boehringer-ingelheim.com

ID	Term
C570240	empagliflozin
D000069476	Linagliptin

ID	Term
D011687	Purines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds
D011799	Quinazolines

The subjects were administered one film-coated tablet containing 10 mg Empagliflozin (reference product 1) in combination with 1 film-coated tablet containing 5 mg Linagliptin (reference product 2) orally with 240 mL of water after an overnight fast of at least 10 h, as single doses in the fasted state on Day 1 of Reference treatment (R).