Trial Outcomes & Findings for Demonstration of Bioequivalence of Empagliflozin and Metformin Given in One Tablet Compared to the Intake of Single Tablets (NCT NCT01672788)
NCT ID: NCT01672788
Last Updated: 2015-08-31
Results Overview
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
COMPLETED
PHASE1
36 participants
1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
2015-08-31
Participant Flow
This was an open-label, randomized, 4-way crossover trial. 36 patients were randomised to one of 4 treatment sequences and treated. Each treatment period consisted of a single dose of medication followed by 72 hours of pharmacokinetic sampling, with a washout of at least 7 days between treatment periods.
Participant milestones
| Measure |
T1 / R1 / T2 / R2
Patients received the 4 treatments in the following order:
* Empa 12.5mg Fixed-dose: Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin (T1)
* Empa 12.5mg Free Dose: Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet) (R1)
* Empa 5mg Fixed-dose: Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin (T2)
* Empa 5mg Free Dose: Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet) (R2)
|
R1 / T1 / R2 / T2
Patients received the 4 treatments in the following order:
* Empa 12.5mg Free Dose: Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet) (R1)
* Empa 12.5mg Fixed-dose: Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin (T1)
* Empa 5mg Free Dose: Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet) (R2)
* Empa 5mg Fixed-dose: Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin (T2)
|
T2 / R2 / T1 / R1
Patients received the 4 treatments in the following order:
* Empa 5mg Fixed-dose: Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin (T2)
* Empa 5mg Free Dose: Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet) (R2)
* Empa 12.5mg Fixed-dose: Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin (T1)
* Empa 12.5mg Free Dose: Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet) (R1)
|
R2 / T2 / R1 / T1
Patients received the 4 treatments in the following order:
* Empa 5mg Free Dose: Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet) (R2)
* Empa 5mg Fixed-dose: Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin (T2)
* Empa 12.5mg Free Dose: Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet) (R1)
* Empa 12.5mg Fixed-dose: Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin (T1)
|
|---|---|---|---|---|
|
Treatment Period 1 (3 Days)
STARTED
|
9
|
9
|
9
|
9
|
|
Treatment Period 1 (3 Days)
COMPLETED
|
9
|
9
|
9
|
9
|
|
Treatment Period 1 (3 Days)
NOT COMPLETED
|
0
|
0
|
0
|
0
|
|
Washout Period 1 (7 Days)
STARTED
|
9
|
9
|
9
|
9
|
|
Washout Period 1 (7 Days)
COMPLETED
|
9
|
9
|
9
|
9
|
|
Washout Period 1 (7 Days)
NOT COMPLETED
|
0
|
0
|
0
|
0
|
|
Treatment Period 2 (3 Days)
STARTED
|
9
|
9
|
9
|
9
|
|
Treatment Period 2 (3 Days)
COMPLETED
|
9
|
9
|
9
|
9
|
|
Treatment Period 2 (3 Days)
NOT COMPLETED
|
0
|
0
|
0
|
0
|
|
Washout Period 2 (7 Days)
STARTED
|
9
|
9
|
9
|
9
|
|
Washout Period 2 (7 Days)
COMPLETED
|
9
|
9
|
9
|
8
|
|
Washout Period 2 (7 Days)
NOT COMPLETED
|
0
|
0
|
0
|
1
|
|
Treatment Period 3 (3 Days)
STARTED
|
9
|
9
|
9
|
8
|
|
Treatment Period 3 (3 Days)
COMPLETED
|
9
|
9
|
9
|
8
|
|
Treatment Period 3 (3 Days)
NOT COMPLETED
|
0
|
0
|
0
|
0
|
|
Washout Period 3 (7 Days)
STARTED
|
9
|
9
|
9
|
8
|
|
Washout Period 3 (7 Days)
COMPLETED
|
9
|
9
|
9
|
8
|
|
Washout Period 3 (7 Days)
NOT COMPLETED
|
0
|
0
|
0
|
0
|
|
Treatment Period 4 (3 Days)
STARTED
|
9
|
9
|
9
|
8
|
|
Treatment Period 4 (3 Days)
COMPLETED
|
9
|
9
|
9
|
8
|
|
Treatment Period 4 (3 Days)
NOT COMPLETED
|
0
|
0
|
0
|
0
|
Reasons for withdrawal
| Measure |
T1 / R1 / T2 / R2
Patients received the 4 treatments in the following order:
* Empa 12.5mg Fixed-dose: Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin (T1)
* Empa 12.5mg Free Dose: Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet) (R1)
* Empa 5mg Fixed-dose: Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin (T2)
* Empa 5mg Free Dose: Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet) (R2)
|
R1 / T1 / R2 / T2
Patients received the 4 treatments in the following order:
* Empa 12.5mg Free Dose: Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet) (R1)
* Empa 12.5mg Fixed-dose: Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin (T1)
* Empa 5mg Free Dose: Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet) (R2)
* Empa 5mg Fixed-dose: Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin (T2)
|
T2 / R2 / T1 / R1
Patients received the 4 treatments in the following order:
* Empa 5mg Fixed-dose: Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin (T2)
* Empa 5mg Free Dose: Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet) (R2)
* Empa 12.5mg Fixed-dose: Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin (T1)
* Empa 12.5mg Free Dose: Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet) (R1)
|
R2 / T2 / R1 / T1
Patients received the 4 treatments in the following order:
* Empa 5mg Free Dose: Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet) (R2)
* Empa 5mg Fixed-dose: Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin (T2)
* Empa 12.5mg Free Dose: Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet) (R1)
* Empa 12.5mg Fixed-dose: Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin (T1)
|
|---|---|---|---|---|
|
Washout Period 2 (7 Days)
Adverse Event
|
0
|
0
|
0
|
1
|
Baseline Characteristics
Demonstration of Bioequivalence of Empagliflozin and Metformin Given in One Tablet Compared to the Intake of Single Tablets
Baseline characteristics by cohort
| Measure |
Overall Study
n=36 Participants
Total number of patients randomised and treated in the study. This was an open-label, randomized, 4-way crossover trial. 36 patients were randomised to one of 4 treatment sequences and treated. Each treatment period consisted of a single dose of medication followed by 72hours of pharmacokinetic sampling, with a washout of at least 7 days between treatment periods.
|
|---|---|
|
Age, Continuous
|
33.6 years
STANDARD_DEVIATION 9.2 • n=93 Participants
|
|
Sex: Female, Male
Female
|
14 Participants
n=93 Participants
|
|
Sex: Female, Male
Male
|
22 Participants
n=93 Participants
|
PRIMARY outcome
Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administrationPopulation: Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Outcome measures
| Measure |
Empa 12.5mg Fixed-dose
n=34 Participants
Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin
|
Empa 12.5mg Free Dose
n=34 Participants
Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)
|
Empa 5mg Fixed-dose
n=35 Participants
Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin
|
Empa 5mg Free Dose
n=33 Participants
Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)
|
|---|---|---|---|---|
|
Empa: Area Under the Curve 0 to Infinity (AUC0-∞)
|
2560 nmol*h/L
Geometric Coefficient of Variation 25.5
|
2530 nmol*h/L
Geometric Coefficient of Variation 29.5
|
986 nmol*h/L
Geometric Coefficient of Variation 26.9
|
968 nmol*h/L
Geometric Coefficient of Variation 23.9
|
PRIMARY outcome
Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administrationPopulation: Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Outcome measures
| Measure |
Empa 12.5mg Fixed-dose
n=34 Participants
Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin
|
Empa 12.5mg Free Dose
n=34 Participants
Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)
|
Empa 5mg Fixed-dose
n=35 Participants
Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin
|
Empa 5mg Free Dose
n=33 Participants
Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)
|
|---|---|---|---|---|
|
Metformin: Area Under the Curve 0 to Infinity (AUC0-∞)
|
8640 ng*h/mL
Geometric Coefficient of Variation 18.0
|
8450 ng*h/mL
Geometric Coefficient of Variation 24.4
|
8520 ng*h/mL
Geometric Coefficient of Variation 23.8
|
8560 ng*h/mL
Geometric Coefficient of Variation 25.8
|
PRIMARY outcome
Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administrationPopulation: Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications
Maximum measured concentration of the analyte in plasma, per period. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Outcome measures
| Measure |
Empa 12.5mg Fixed-dose
n=34 Participants
Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin
|
Empa 12.5mg Free Dose
n=34 Participants
Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)
|
Empa 5mg Fixed-dose
n=35 Participants
Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin
|
Empa 5mg Free Dose
n=33 Participants
Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)
|
|---|---|---|---|---|
|
Empa: Maximum Measured Concentration (Cmax)
|
266 nmol/L
Geometric Coefficient of Variation 20.3
|
258 nmol/L
Geometric Coefficient of Variation 21.3
|
103 nmol/L
Geometric Coefficient of Variation 22.1
|
101 nmol/L
Geometric Coefficient of Variation 24.4
|
PRIMARY outcome
Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administrationPopulation: Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications
Maximum measured concentration of the analyte in plasma, per period. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Outcome measures
| Measure |
Empa 12.5mg Fixed-dose
n=34 Participants
Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin
|
Empa 12.5mg Free Dose
n=34 Participants
Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)
|
Empa 5mg Fixed-dose
n=35 Participants
Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin
|
Empa 5mg Free Dose
n=33 Participants
Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)
|
|---|---|---|---|---|
|
Metformin: Maximum Measured Concentration (Cmax)
|
1080 ng/mL
Geometric Coefficient of Variation 16.4
|
1080 ng/mL
Geometric Coefficient of Variation 19.6
|
1090 ng/mL
Geometric Coefficient of Variation 16.5
|
1100 ng/mL
Geometric Coefficient of Variation 17.5
|
SECONDARY outcome
Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administrationPopulation: Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Outcome measures
| Measure |
Empa 12.5mg Fixed-dose
n=34 Participants
Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin
|
Empa 12.5mg Free Dose
n=34 Participants
Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)
|
Empa 5mg Fixed-dose
n=35 Participants
Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin
|
Empa 5mg Free Dose
n=33 Participants
Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)
|
|---|---|---|---|---|
|
Empa: Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz)
|
2520 nmol*h/L
Geometric Coefficient of Variation 25.1
|
2490 nmol*h/L
Geometric Coefficient of Variation 29.3
|
963 nmol*h/L
Geometric Coefficient of Variation 27.1
|
946 nmol*h/L
Geometric Coefficient of Variation 24.2
|
SECONDARY outcome
Timeframe: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administrationPopulation: Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point. In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Outcome measures
| Measure |
Empa 12.5mg Fixed-dose
n=34 Participants
Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin
|
Empa 12.5mg Free Dose
n=34 Participants
Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)
|
Empa 5mg Fixed-dose
n=35 Participants
Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin
|
Empa 5mg Free Dose
n=33 Participants
Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)
|
|---|---|---|---|---|
|
Metformin: Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz)
|
8370 ng*h/mL
Geometric Coefficient of Variation 18.1
|
8190 ng*h/mL
Geometric Coefficient of Variation 24.1
|
8280 ng*h/mL
Geometric Coefficient of Variation 23.2
|
8320 ng*h/mL
Geometric Coefficient of Variation 25.2
|
Adverse Events
Empa 12.5mg Fixed-dose
Empa 12.5mg Free Dose
Empa 5mg Fixed-dose
Empa 5mg Free Dose
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Empa 12.5mg Fixed-dose
n=35 participants at risk
Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin
|
Empa 12.5mg Free Dose
n=36 participants at risk
Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)
|
Empa 5mg Fixed-dose
n=34 participants at risk
Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin
|
Empa 5mg Free Dose
n=35 participants at risk
Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)
|
|---|---|---|---|---|
|
Gastrointestinal disorders
Diarrhoea
|
22.9%
8/35 • Treatment period and following washout period, up to 35 days
|
22.2%
8/36 • Treatment period and following washout period, up to 35 days
|
14.7%
5/34 • Treatment period and following washout period, up to 35 days
|
20.0%
7/35 • Treatment period and following washout period, up to 35 days
|
|
Gastrointestinal disorders
Nausea
|
8.6%
3/35 • Treatment period and following washout period, up to 35 days
|
2.8%
1/36 • Treatment period and following washout period, up to 35 days
|
0.00%
0/34 • Treatment period and following washout period, up to 35 days
|
2.9%
1/35 • Treatment period and following washout period, up to 35 days
|
|
Gastrointestinal disorders
Vomiting
|
5.7%
2/35 • Treatment period and following washout period, up to 35 days
|
2.8%
1/36 • Treatment period and following washout period, up to 35 days
|
0.00%
0/34 • Treatment period and following washout period, up to 35 days
|
2.9%
1/35 • Treatment period and following washout period, up to 35 days
|
|
Gastrointestinal disorders
Nasopharyngitis
|
8.6%
3/35 • Treatment period and following washout period, up to 35 days
|
5.6%
2/36 • Treatment period and following washout period, up to 35 days
|
11.8%
4/34 • Treatment period and following washout period, up to 35 days
|
0.00%
0/35 • Treatment period and following washout period, up to 35 days
|
|
Nervous system disorders
Headache
|
14.3%
5/35 • Treatment period and following washout period, up to 35 days
|
8.3%
3/36 • Treatment period and following washout period, up to 35 days
|
14.7%
5/34 • Treatment period and following washout period, up to 35 days
|
5.7%
2/35 • Treatment period and following washout period, up to 35 days
|
Additional Information
Boehringer Ingelheim Call Center
Boehringer Ingelheim
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- Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
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Restriction type: OTHER