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This Study Tests Whether Taking the Medicines Empagliflozin, Linagliptin, and Metformin Together in 1 Pill is the Same as Taking Them in Separate Pills. The Study is Done in Healthy Men and Women and Measures the Amount of Each Medicine in the Blood

Bioequivalence of a Fixed Dose Combination Tablet of Empagliflozin/Linagliptin/Metformin Extended Release Compared to the Free Combination of Empagliflozin, Linagliptin, and Metformin Extended Release Tablets Following Oral Administration in Healthy Male and Female Subjects (an Open-label, Randomised, Single-dose, Two-period, Two-sequence Crossover Study)

Status
Completed
Phases
Phase 1
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT03259490
Enrollment
30
Registered
2017-08-23
Start date
2017-08-31
Completion date
2017-11-13
Last updated
2020-03-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Healthy

Brief summary

To establish the bioequivalence of one fixed dose combination (FDC) tablet of empagliflozin/linagliptin/metformin extended release (XR) versus the free combination of empagliflozin tablet, linagliptin tablet, and metformin XR tablets administered as a single dose under fed conditions

Interventions

DRUGEmpagliflozin/linagliptin/metformin HCl

Once daily

DRUGEmpagliflozin

Once daily

DRUGLinagliptin

Once daily

DRUGMetformin HCl

Once daily

Sponsors

Eli Lilly and Company
CollaboratorINDUSTRY
Boehringer Ingelheim
Lead SponsorINDUSTRY

Study design

Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes

Inclusion criteria

* Healthy male or female subjects according to the assessment of the investigator, 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.) * 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 Good Clinical Practice (GCP) and local legislation * Female subjects of childbearing potential willing to use adequate contraception. * Further inclusion criteria apply

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 beats per minute (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 * 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

Design outcomes

Primary

MeasureTime frameDescription
Cmax for Linagliptin in PlasmaPharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post doseCmax for linagliptin in plasma.
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) for LinagliptinPharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post doseArea under the concentration-time curve of the analyte in plasma over the time interval from 0 to 72 hours (AUC0-72) for Linagliptin
Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax)Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post doseMaximum measured concentration of the empagliflozin in plasma (Cmax)
Cmax for Metformin in PlasmaPharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post doseCmax for metformin in plasma.
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) for EmpagliflozinPharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post doseArea under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) for empagliflozin. Plasma concentrations and/or parameters of a subject were to be considered as non-evaluable,if for example: * The subject experienced emesis that occurred at or before 2 times median tmax of the respective treatment (median tmax was to be determined excluding the subjects experiencing emesis) * A predose concentration was \>5% Cmax value of that subject * Missing samples/concentration data at important phases of pharmacokinetic (PK) disposition curve. Pharmacokinetic parameter set (PKS): This subject set included all subjects in the treated set (TS) who provided at least one primary or secondary PK parameter that was not excluded according to the description above. Thus, a subject was to be included in the PKS even if he/she contributed only one PK parameter value for one period to the statistical assessment.
AUC0-tz for Metformin.Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post doseAUC0-tz for metformin.

Secondary

MeasureTime frameDescription
AUC(0-∞) for MetforminPharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post doseAUC(0-∞) for Metformin
AUC(0-∞) for LinagliptinPharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post doseAUC(0-∞) for Linagliptin
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Empagliflozin (AUC(0-∞)Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post doseArea under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Empagliflozin (AUC(0-∞)

Countries

Germany

Participant flow

Recruitment details

It was planned to include healthy male and female subjects in this randomised, open label study. They were recruited from the volunteers' pool of the study site.

Pre-assignment details

This trial was a two-way crossover study. All subjects received the 2 treatments in randomised order.

Participants by arm

ArmCount
Test/ Reference (TR)
Subjects were orally administered a single dose of 25 milligram (mg) empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 millilitre (mL) of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered the free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast.
15
Reference/ Test (RT)
Subjects were orally administered the free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered a single dose of 25 milligram (mg) empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 millilitre (mL) of water after a high-fat, high-calorie breakfast.
15
Total30

Withdrawals & dropouts

PeriodReasonFG000FG001
Period 1Withdrawal by Subject01
Period 2Protocol Violation10

Baseline characteristics

CharacteristicReference/ Test (RT)TotalTest/ Reference (TR)
Age, Continuous43.5 years
STANDARD_DEVIATION 8
40.3 years
STANDARD_DEVIATION 10.7
37.1 years
STANDARD_DEVIATION 12.2
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Asian
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Black or African American
0 Participants0 Participants0 Participants
Race (NIH/OMB)
More than one race
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Unknown or Not Reported
0 Participants0 Participants0 Participants
Race (NIH/OMB)
White
15 Participants30 Participants15 Participants
Sex: Female, Male
Female
8 Participants13 Participants5 Participants
Sex: Female, Male
Male
7 Participants17 Participants10 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
0 / 290 / 29
other
Total, other adverse events
11 / 296 / 29
serious
Total, serious adverse events
0 / 290 / 29

Outcome results

Primary

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

Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 72 hours (AUC0-72) for Linagliptin

Time frame: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose

Population: PKS

ArmMeasureValue (GEOMETRIC_MEAN)Dispersion
Empagliflozin/Linagliptin/Metformin FDC (Test)Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) for Linagliptin238.84 nmol*h/LStandard Error 1.04
Empagliflozin/Linagliptin/Metformin FC (Reference)Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) for Linagliptin238.11 nmol*h/LStandard Error 1.04
Comparison: The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.95% CI: [96.65, 104.1]ANOVA
Primary

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

Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) for empagliflozin. Plasma concentrations and/or parameters of a subject were to be considered as non-evaluable,if for example: * The subject experienced emesis that occurred at or before 2 times median tmax of the respective treatment (median tmax was to be determined excluding the subjects experiencing emesis) * A predose concentration was \>5% Cmax value of that subject * Missing samples/concentration data at important phases of pharmacokinetic (PK) disposition curve. Pharmacokinetic parameter set (PKS): This subject set included all subjects in the treated set (TS) who provided at least one primary or secondary PK parameter that was not excluded according to the description above. Thus, a subject was to be included in the PKS even if he/she contributed only one PK parameter value for one period to the statistical assessment.

Time frame: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose

Population: PKS

ArmMeasureValue (GEOMETRIC_MEAN)Dispersion
Empagliflozin/Linagliptin/Metformin FDC (Test)Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) for Empagliflozin5656.07 nanomoles*hours/ litres (nmol*h/L)Standard Error 1.04
Empagliflozin/Linagliptin/Metformin FC (Reference)Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) for Empagliflozin5488.31 nanomoles*hours/ litres (nmol*h/L)Standard Error 1.04
Comparison: The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.95% CI: [100.36, 105.83]ANOVA
Primary

AUC0-tz for Metformin.

AUC0-tz for metformin.

Time frame: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose

Population: PKS

ArmMeasureValue (GEOMETRIC_MEAN)Dispersion
Empagliflozin/Linagliptin/Metformin FDC (Test)AUC0-tz for Metformin.12455.82 nanogram*hours/ millilitres (ng*h/mL)Standard Error 1.05
Empagliflozin/Linagliptin/Metformin FC (Reference)AUC0-tz for Metformin.12412.57 nanogram*hours/ millilitres (ng*h/mL)Standard Error 1.05
Comparison: The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.95% CI: [96.11, 104.77]ANOVA
Primary

Cmax for Linagliptin in Plasma

Cmax for linagliptin in plasma.

Time frame: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose

Population: PKS

ArmMeasureValue (GEOMETRIC_MEAN)Dispersion
Empagliflozin/Linagliptin/Metformin FDC (Test)Cmax for Linagliptin in Plasma5.69 nmol/LStandard Error 1.04
Empagliflozin/Linagliptin/Metformin FC (Reference)Cmax for Linagliptin in Plasma5.86 nmol/LStandard Error 1.04
Comparison: The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.95% CI: [92.63, 101.93]ANOVA
Primary

Cmax for Metformin in Plasma

Cmax for metformin in plasma.

Time frame: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose

Population: PKS

ArmMeasureValue (GEOMETRIC_MEAN)Dispersion
Empagliflozin/Linagliptin/Metformin FDC (Test)Cmax for Metformin in Plasma1237.16 ng/mLStandard Error 1.04
Empagliflozin/Linagliptin/Metformin FC (Reference)Cmax for Metformin in Plasma1147.88 ng/mLStandard Error 1.04
Comparison: The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.95% CI: [102.52, 113.31]ANOVA
Primary

Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax)

Maximum measured concentration of the empagliflozin in plasma (Cmax)

Time frame: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose

Population: PKS

ArmMeasureValue (GEOMETRIC_MEAN)Dispersion
Empagliflozin/Linagliptin/Metformin FDC (Test)Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax)540.01 nmol/LStandard Error 1.04
Empagliflozin/Linagliptin/Metformin FC (Reference)Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax)540.26 nmol/LStandard Error 1.04
Comparison: The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.95% CI: [94.52, 105.7]ANOVA
Secondary

Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Empagliflozin (AUC(0-∞)

Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Empagliflozin (AUC(0-∞)

Time frame: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose

Population: PKS

ArmMeasureValue (GEOMETRIC_MEAN)Dispersion
Empagliflozin/Linagliptin/Metformin FDC (Test)Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Empagliflozin (AUC(0-∞)5727.20 nmol*h/LStandard Error 1.04
Empagliflozin/Linagliptin/Metformin FC (Reference)Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Empagliflozin (AUC(0-∞)5554.37 nmol*h/LStandard Error 1.04
Comparison: The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.95% CI: [100.38, 105.92]ANOVA
Secondary

AUC(0-∞) for Linagliptin

AUC(0-∞) for Linagliptin

Time frame: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose

Population: PKS

ArmMeasureValue (GEOMETRIC_MEAN)Dispersion
Empagliflozin/Linagliptin/Metformin FDC (Test)AUC(0-∞) for Linagliptin384.27 nmol*h/LStandard Error 1.05
Empagliflozin/Linagliptin/Metformin FC (Reference)AUC(0-∞) for Linagliptin394.95 nmol*h/LStandard Error 1.05
Comparison: The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.95% CI: [91.65, 103.29]ANOVA
Secondary

AUC(0-∞) for Metformin

AUC(0-∞) for Metformin

Time frame: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose

Population: PKS

ArmMeasureValue (GEOMETRIC_MEAN)Dispersion
Empagliflozin/Linagliptin/Metformin FDC (Test)AUC(0-∞) for Metformin12745.62 ng*h/mLStandard Error 1.05
Empagliflozin/Linagliptin/Metformin FC (Reference)AUC(0-∞) for Metformin12724.27 ng*h/mLStandard Error 1.05
Comparison: The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.95% CI: [95.68, 104.86]ANOVA

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026