CClinicalTrials.gg
Sign In
CompletedNCT03259490Updated Mar 5, 2020Results posted

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

A Phase 1 interventional study of Empagliflozin/linagliptin/metformin HCl and Empagliflozin in Healthy, sponsored by Boehringer Ingelheim. Completed at 1 site in Germany. Open to participants aged 18 Years to 55 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2020-03-05.

Sponsored by Boehringer Ingelheim · Phase 1, Interventional, and Treatment

Phase
Phase 1
Study type
Interventional
Enrollment
30
Allocation
Randomized
Ages
18 Years to 55 Years
Sex
All
01

Study 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

02

Conditions studied

  • Healthy
03

Who can participate

Ages eligible
18 Years to 55 Years
Sexes eligible
All
Accepts 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

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 exclusion criteria apply
04

Study design

Phase
Phase 1
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Crossover assignment
Masking
None (open label)
Enrollment
30 participants (actual)

Study arms

  • Experimental
    Test Treatment

    High dose empagliflozin/linagliptin/metformin XR fixed dose combination tablet

    Drug: Empagliflozin/linagliptin/metformin HCl

  • Experimental
    Reference Treatment

    Single tablets of empagliflozin + linagliptin + metformin XR

    Drug: Empagliflozin · Drug: Linagliptin · Drug: Metformin HCl

Interventions

  • DrugEmpagliflozin/linagliptin/metformin HCl

    Once daily

    Also known as: TRIJARDY® XR

  • DrugEmpagliflozin

    Once daily

  • DrugLinagliptin

    Once daily

  • DrugMetformin HCl

    Once daily

05

What researchers measure

Primary outcomes

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

Secondary outcomes

  1. 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

  2. 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

  3. 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

06

Results

Posted Feb 21, 2020

Participant flow

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.

Period 1
Participant flow — Period 1
MilestoneTest/ Reference (TR)Reference/ Test (RT)
Started1515
Completed1514
Not completed01
Withdrew: Withdrawal by subject01
Period 2
Participant flow — Period 2
MilestoneTest/ Reference (TR)Reference/ Test (RT)
Started1514
Completed1414
Not completed10
Withdrew: Protocol violation10

Outcome measures

PrimaryArea 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
Reported as:
Geometric mean · nanomoles*hours/ litres (nmol*h/L)
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
nanomoles*hours/ litres (nmol*h/L)Empagliflozin/Linagliptin/Metformin FDC (Test)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 Empagliflozin5656.07 ± 1.045488.31 ± 1.04
Statistical analysis
  • Empagliflozin/Linagliptin/Metformin FDC (Test) vs Empagliflozin/Linagliptin/Metformin FC (Reference) · ANOVA · Adjusted gmean ratio t/r (%): 103.06 · 95% CI 100.36 to 105.83The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)
PrimaryAUC0-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
Reported as:
Geometric mean · nanogram*hours/ millilitres (ng*h/mL)
AUC0-tz for Metformin.
nanogram*hours/ millilitres (ng*h/mL)Empagliflozin/Linagliptin/Metformin FDC (Test)Empagliflozin/Linagliptin/Metformin FC (Reference)
AUC0-tz for Metformin.12455.82 ± 1.0512412.57 ± 1.05
Statistical analysis
  • Empagliflozin/Linagliptin/Metformin FDC (Test) vs Empagliflozin/Linagliptin/Metformin FC (Reference) · ANOVA · Adjusted gmean ratio t/r (%): 100.35 · 95% CI 96.11 to 104.77The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)
PrimaryArea 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
Reported as:
Geometric mean · nmol*h/L
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) for Linagliptin
nmol*h/LEmpagliflozin/Linagliptin/Metformin FDC (Test)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 Linagliptin238.84 ± 1.04238.11 ± 1.04
Statistical analysis
  • Empagliflozin/Linagliptin/Metformin FDC (Test) vs Empagliflozin/Linagliptin/Metformin FC (Reference) · ANOVA · Adjusted gmean ratio t/r (%): 100.31 · 95% CI 96.65 to 104.10The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)
PrimaryMaximum 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
Reported as:
Geometric mean · nmol/L
Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax)
nmol/LEmpagliflozin/Linagliptin/Metformin FDC (Test)Empagliflozin/Linagliptin/Metformin FC (Reference)
Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax)540.01 ± 1.04540.26 ± 1.04
Statistical analysis
  • Empagliflozin/Linagliptin/Metformin FDC (Test) vs Empagliflozin/Linagliptin/Metformin FC (Reference) · ANOVA · Adjusted gmean ratio t/r (%): 99.95 · 95% CI 94.52 to 105.70The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)
PrimaryCmax 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
Reported as:
Geometric mean · ng/mL
Cmax for Metformin in Plasma
ng/mLEmpagliflozin/Linagliptin/Metformin FDC (Test)Empagliflozin/Linagliptin/Metformin FC (Reference)
Cmax for Metformin in Plasma1237.16 ± 1.041147.88 ± 1.04
Statistical analysis
  • Empagliflozin/Linagliptin/Metformin FDC (Test) vs Empagliflozin/Linagliptin/Metformin FC (Reference) · ANOVA · Adjusted gmean ratio t/r (%): 107.78 · 95% CI 102.52 to 113.31The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)
PrimaryCmax 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
Reported as:
Geometric mean · nmol/L
Cmax for Linagliptin in Plasma
nmol/LEmpagliflozin/Linagliptin/Metformin FDC (Test)Empagliflozin/Linagliptin/Metformin FC (Reference)
Cmax for Linagliptin in Plasma5.69 ± 1.045.86 ± 1.04
Statistical analysis
  • Empagliflozin/Linagliptin/Metformin FDC (Test) vs Empagliflozin/Linagliptin/Metformin FC (Reference) · ANOVA · Adjusted gmean ratio t/r (%): 97.17 · 95% CI 92.63 to 101.93The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)
SecondaryArea 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
Reported as:
Geometric mean · nmol*h/L
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Empagliflozin (AUC(0-∞)
nmol*h/LEmpagliflozin/Linagliptin/Metformin FDC (Test)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-∞)5727.20 ± 1.045554.37 ± 1.04
Statistical analysis
  • Empagliflozin/Linagliptin/Metformin FDC (Test) vs Empagliflozin/Linagliptin/Metformin FC (Reference) · ANOVA · Adjusted gmean ratio t/r (%): 103.11 · 95% CI 100.38 to 105.92The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)
SecondaryAUC(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
Reported as:
Geometric mean · ng*h/mL
AUC(0-∞) for Metformin
ng*h/mLEmpagliflozin/Linagliptin/Metformin FDC (Test)Empagliflozin/Linagliptin/Metformin FC (Reference)
AUC(0-∞) for Metformin12745.62 ± 1.0512724.27 ± 1.05
Statistical analysis
  • Empagliflozin/Linagliptin/Metformin FDC (Test) vs Empagliflozin/Linagliptin/Metformin FC (Reference) · ANOVA · Adjusted gmean ratio t/r (%): 100.17 · 95% CI 95.68 to 104.86The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)
SecondaryAUC(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
Reported as:
Geometric mean · nmol*h/L
AUC(0-∞) for Linagliptin
nmol*h/LEmpagliflozin/Linagliptin/Metformin FDC (Test)Empagliflozin/Linagliptin/Metformin FC (Reference)
AUC(0-∞) for Linagliptin384.27 ± 1.05394.95 ± 1.05
Statistical analysis
  • Empagliflozin/Linagliptin/Metformin FDC (Test) vs Empagliflozin/Linagliptin/Metformin FC (Reference) · ANOVA · Adjusted gmean ratio t/r (%): 97.30 · 95% CI 91.65 to 103.29The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)

Adverse events

Collected over All adverse events (AEs) which occurred through the treatment phase and throughout the residual effect period (REP); up to 50 days. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Empagliflozin/Linagliptin/Metformin FDC (Test)0/29 (0%)0/29 (0%)11/29 (37.9%)
Empagliflozin/Linagliptin/Metformin FC (Reference)0/29 (0%)0/29 (0%)6/29 (20.7%)
Most frequent other events
Most frequent other events
EventEmpagliflozin/Linagliptin/Metformin FDC (Test)Empagliflozin/Linagliptin/Metformin FC (Reference)
HeadacheNervous system disorders8/292/29
NauseaGastrointestinal disorders1/292/29
Oral herpesInfections and infestations2/290/29
Oropharyngeal painRespiratory, thoracic and mediastinal disorders1/292/29

Baseline characteristics

Treated set (TS): This subject set included all subjects who were documented to have received one dose of study drug.

Age, Continuous
Age, Continuous(years)Test/ Reference (TR)Reference/ Test (RT)Total
Mean37.1 ± 12.243.5 ± 8.040.3 ± 10.7
Sex: Female, Male
Sex: Female, Male(Participants)Test/ Reference (TR)Reference/ Test (RT)Total
Female5813
Male10717
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Test/ Reference (TR)Reference/ Test (RT)Total
American Indian or Alaska Native000
Asian000
Native Hawaiian or Other Pacific Islander000
Black or African American000
White151530
More than one race000
Unknown or Not Reported000
07

Study locations

1 site
  • Humanpharmakologisches Zentrum Biberach
    Biberach, 88397, Germany
08

References and documents

Study documents

  • Study protocol · Jun 28, 2017
  • Statistical analysis plan · Dec 8, 2017

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

09

Registry details

Key details

Study ID
NCT03259490
Lead sponsor
Boehringer Ingelheim
Collaborators
Eli Lilly and Company
Responsible party
Sponsor
First posted
Aug 23, 2017
Start date
Aug 31, 2017
Primary completion
Nov 13, 2017
Completion
Nov 13, 2017
Results posted
Feb 21, 2020
Last update
Mar 5, 2020

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in Feb 2020. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Sign in to follow

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies from this sponsor

Boehringer Ingelheim

Start the discussion