Trial Outcomes & Findings for 4 Week Treatment With Three Oral Doses of BI 10773 in Patients With Type 2 Diabetes (NCT NCT00558571)

NCT ID: NCT00558571

Last Updated: 2014-08-07

Results Overview

number of subjects with investigator-defined drug-related adverse events.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

78 participants

Primary outcome timeframe

from drug administration up to 6 weeks

Results posted on

2014-08-07

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Oral administration in the fasted state once daily	10mg Empagliflozin Oral administration in the fasted state once daily.	25mg Empagliflozin Oral administration in the fasted state once daily.	100mg Empagliflozin Oral administration in the fasted state once daily.
Overall Study STARTED	16	16	16	30
Overall Study COMPLETED	16	16	16	30
Overall Study NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

4 Week Treatment With Three Oral Doses of BI 10773 in Patients With Type 2 Diabetes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	100mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.	Total n=78 Participants Total of all reporting groups
Age, Continuous	57.7 years STANDARD_DEVIATION 10.4 • n=99 Participants	56.8 years STANDARD_DEVIATION 8.7 • n=107 Participants	56.1 years STANDARD_DEVIATION 8.5 • n=206 Participants	56.5 years STANDARD_DEVIATION 8.2 • n=7 Participants	56.7 years STANDARD_DEVIATION 8.7 • n=31 Participants
Sex: Female, Male Female	1 Participants n=99 Participants	3 Participants n=107 Participants	4 Participants n=206 Participants	3 Participants n=7 Participants	11 Participants n=31 Participants
Sex: Female, Male Male	15 Participants n=99 Participants	13 Participants n=107 Participants	12 Participants n=206 Participants	27 Participants n=7 Participants	67 Participants n=31 Participants

PRIMARY outcome

Timeframe: from drug administration up to 6 weeks

Population: treated set: comprised all 78 patients who received at least one dose of study medication

number of subjects with investigator-defined drug-related adverse events.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	100mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.
Number of Subjects With Drug Related Adverse Events	7 participants	3 participants	4 participants	14 participants

PRIMARY outcome

Timeframe: from drug administration up to 6 weeks

Population: treated set

Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as Adverse Events.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	100mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG Lipase increased	0 participants	0 participants	1 participants	2 participants
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG Blood triglycerides increased	0 participants	1 participants	0 participants	0 participants
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG Blood creatine phosphokinase increased	0 participants	0 participants	0 participants	1 participants
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG Ventricular extrasystoles	0 participants	1 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 24:00 hours(h) after drug administration on day 1 and 28

Population: Pharmacokinetic (PK) analysis set: comprised all 62 patients who received Empagliflozin and had evaluable PK parameter data.

maximum concentration of the analyte in plasma after first dose (Cmax, Day 1 ) and at steady state over a uniform dosing interval (Cmax,ss, Day 28).

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.	100mg Empagliflozin oral administration in the fasted state once daily.
Cmax of Empagliflozin Cmax	309 nmol/L Geometric Coefficient of Variation 45.2	722 nmol/L Geometric Coefficient of Variation 20	2630 nmol/L Geometric Coefficient of Variation 25.8	—
Cmax of Empagliflozin Cmax,ss	259 nmol/L Geometric Coefficient of Variation 24.8	687 nmol/L Geometric Coefficient of Variation 18.4	2390 nmol/L Geometric Coefficient of Variation 28.1	—

SECONDARY outcome

Timeframe: 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 24:00 h after drug administration on day 1 and 28

Population: PK analysis set

time from last dosing to maximum concentration of the analyte in plasma after first dose (Day 1), denoted by tmax; and at steady state (Day 28), denoted by tmax,ss.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.	100mg Empagliflozin oral administration in the fasted state once daily.
Tmax of Empagliflozin tmax	1.50 hours Full Range 29.8 • Interval 1.0 to 2.5	1.50 hours Full Range 28.7 • Interval 0.75 to 2.0	1.50 hours Full Range 30.9 • Interval 0.75 to 3.0	—
Tmax of Empagliflozin tmax,ss	1.50 hours Full Range 13 • Interval 0.98 to 4.0	1.50 hours Full Range 14.9 • Interval 0.75 to 3.02	1.50 hours Full Range 18.7 • Interval 0.75 to 6.0	—

SECONDARY outcome

Timeframe: 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 24:00 h after drug administration on day 1 and 28

Population: PK analysis set

terminal half-life of the analyte in plasma after first dose (Day 1), denoted by t1/2; and at steady state (Day 28), denoted by t1/2,ss.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.	100mg Empagliflozin oral administration in the fasted state once daily.
t1/2 of Empagliflozin t1/2	8.69 hours Geometric Coefficient of Variation 12.90	8.16 hours Geometric Coefficient of Variation 14.50	8.53 hours Geometric Coefficient of Variation 18.50	—
t1/2 of Empagliflozin t1/2,ss	12.20 hours Geometric Coefficient of Variation 41.40	12.70 hours Geometric Coefficient of Variation 32.70	15.00 hours Geometric Coefficient of Variation 44.30	—

SECONDARY outcome

Timeframe: 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 24:00 h after drug administration on day 1

Population: PK analysis set

Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) and over a uniform dosing interval τ at steady state (AUCτ,ss)

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.	100mg Empagliflozin oral administration in the fasted state once daily.
AUC0-∞ of Empagliflozin AUC0-∞	1740 nmol*h/L Geometric Coefficient of Variation 16.4	4340 nmol*h/L Geometric Coefficient of Variation 23.1	18000 nmol*h/L Geometric Coefficient of Variation 24.3	—
AUC0-∞ of Empagliflozin AUCτ,ss	1870 nmol*h/L Geometric Coefficient of Variation 15.9	4740 nmol*h/L Geometric Coefficient of Variation 21.2	18700 nmol*h/L Geometric Coefficient of Variation 25.2	—

SECONDARY outcome

Timeframe: 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 24:00 h after drug administration on day 1 and 28

Population: PK analysis set

apparent clearance of the analyte in plasma after first dose (CL/F) and at steady state (CL/F,ss)

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.	100mg Empagliflozin oral administration in the fasted state once daily.
CL/F of Empaglifozin CL/F	218 mL/min Geometric Coefficient of Variation 15.3	223 mL/min Geometric Coefficient of Variation 21.2	215 mL/min Geometric Coefficient of Variation 20.8	—
CL/F of Empaglifozin CL/F,ss	202 mL/min Geometric Coefficient of Variation 15.9	203 mL/min Geometric Coefficient of Variation 21.4	208 mL/min Geometric Coefficient of Variation 22	—

SECONDARY outcome

Timeframe: 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 24:00 h after drug administration on day 1 and 28

Population: PK analysis set for patients who have fe data at day 1 and day 28

Fraction of analyte eliminated in urine from time point 0 to 24h after first dose (fe0-24) and at steady state (fe0-24,ss)

Outcome measures

Outcome measures
Measure	Placebo n=15 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.	100mg Empagliflozin oral administration in the fasted state once daily.
fe0-24 of Empagliflozin fe0-24 (N=14,16,30)	12.5 percentage of Empagliflozin Geometric Coefficient of Variation 24	13.3 percentage of Empagliflozin Geometric Coefficient of Variation 24.5	13.7 percentage of Empagliflozin Geometric Coefficient of Variation 34.1	—
fe0-24 of Empagliflozin fe0-24,ss	18.3 percentage of Empagliflozin Geometric Coefficient of Variation 25	17.8 percentage of Empagliflozin Geometric Coefficient of Variation 17.8	17.5 percentage of Empagliflozin Geometric Coefficient of Variation 28.3	—

SECONDARY outcome

Timeframe: 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 after drug administration on day 1 and 28

Population: PK analysis set

The linearity index is defined as AUC0-τ divided by AUC0-∞ both at steady state.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.	100mg Empagliflozin oral administration in the fasted state once daily.
LI (Linearity Index).	1.09 ratio Geometric Coefficient of Variation 11.1	1.1 ratio Geometric Coefficient of Variation 12.5	1.04 ratio Geometric Coefficient of Variation 9.21	—

SECONDARY outcome

Timeframe: Day -2 and 27: -2 to 0, 0 to 5, 5 to 12 and 12 to 24h; Day -1 and 1: 0 to 5, 5 to 12 and 12 to 24; Day 28: 0 to 5, 5 to 12, 12 to 24, 24 to 36, 36 to 48 and 48 to 72h

Population: PD analysis set

Amount of glucose eliminated in urine over the time interval 0 to 24h on day -2, -1, 1, 27 and 28. (Urinary Glucose Excretion)

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	100mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.
Ae0-24 of Glucose Ae0-24 on day -2 (N=15,16,15,26)	4270 mg Geometric Coefficient of Variation 185	7760 mg Geometric Coefficient of Variation 161	5340 mg Geometric Coefficient of Variation 123	6050 mg Geometric Coefficient of Variation 190
Ae0-24 of Glucose Ae0-24 on day -1 (N=13,15,16,25)	6490 mg Geometric Coefficient of Variation 136	8450 mg Geometric Coefficient of Variation 114	8150 mg Geometric Coefficient of Variation 91	6190 mg Geometric Coefficient of Variation 134
Ae0-24 of Glucose Ae0-24 on day 1 (N=15,15,16,29)	3970 mg Geometric Coefficient of Variation 197	81500 mg Geometric Coefficient of Variation 35.7	95700 mg Geometric Coefficient of Variation 30.4	87000 mg Geometric Coefficient of Variation 36.9
Ae0-24 of Glucose Ae0-24 on day 27 (N=14,13,14,27)	3790 mg Geometric Coefficient of Variation 296	78000 mg Geometric Coefficient of Variation 44.1	82900 mg Geometric Coefficient of Variation 32.9	81300 mg Geometric Coefficient of Variation 50.1
Ae0-24 of Glucose Ae0-24 on day 28 (N=13,13,11,23)	6310 mg Geometric Coefficient of Variation 230	75400 mg Geometric Coefficient of Variation 44.6	83400 mg Geometric Coefficient of Variation 26.4	73900 mg Geometric Coefficient of Variation 61.6

SECONDARY outcome

Timeframe: in the morning of days -1 and 28

Population: PD analysis set

fasting plasma glucose on day -1 (baseline) and change from baseline to day 28

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	100mg Empagliflozin n=29 Participants oral administration in the fasted state once daily.
Fasting Plasma Glucose (FPG) baseline (day -1)	153.87 mg/dL Standard Deviation 40.53	186.18 mg/dL Standard Deviation 92.96	167.49 mg/dL Standard Deviation 39.61	149.92 mg/dL Standard Deviation 31.65
Fasting Plasma Glucose (FPG) change from baseline to day 28 (N=15, 15, 16, 28)	-4.08 mg/dL Standard Deviation 27.08	-43.7 mg/dL Standard Deviation 81.81	-34.22 mg/dL Standard Deviation 26.44	-28.69 mg/dL Standard Deviation 18.25

SECONDARY outcome

Timeframe: 0:00, 2:30, 5:00, 7:00, 10:00, 12:00, 13:30, 24:00 h after drug administration on day -2. 0:05 h before drug administration and 2:30, 5:00, 7:00, 10:00, 12:00, 13:30, 24:00 h after drug administration on day 1, 7, 14, 21 and 27

Population: PD analysis set

change from baseline in MDG on the days 1, 7, 14, 21 and 27. Baseline is defined as day -2.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	100mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.
Mean Daily Glucose (MDG) Measured in Blood baseline (day -2)	152.06 mg/dL Standard Deviation 41.49	164.83 mg/dL Standard Deviation 43.18	166.26 mg/dL Standard Deviation 35.86	149.43 mg/dL Standard Deviation 34.94
Mean Daily Glucose (MDG) Measured in Blood change from baseline to day 1	2.13 mg/dL Standard Deviation 18.37	-14.69 mg/dL Standard Deviation 15.81	-23.51 mg/dL Standard Deviation 17.26	-23.02 mg/dL Standard Deviation 16.72
Mean Daily Glucose (MDG) Measured in Blood change from baseline to day 7	-2.4 mg/dL Standard Deviation 15.78	-25.45 mg/dL Standard Deviation 23.2	-28.58 mg/dL Standard Deviation 17.6	-21.17 mg/dL Standard Deviation 21.95
Mean Daily Glucose (MDG) Measured in Blood change from baseline to day 14	2.68 mg/dL Standard Deviation 28.05	-26.97 mg/dL Standard Deviation 27.9	-20.43 mg/dL Standard Deviation 24.69	-12.03 mg/dL Standard Deviation 28.51
Mean Daily Glucose (MDG) Measured in Blood change from baseline to day 21	-3.41 mg/dL Standard Deviation 30.46	-26.47 mg/dL Standard Deviation 31.71	-19.68 mg/dL Standard Deviation 24.94	-13.93 mg/dL Standard Deviation 24.46
Mean Daily Glucose (MDG) Measured in Blood change from baseline to day 27	-4.69 mg/dL Standard Deviation 32.01	-19.57 mg/dL Standard Deviation 28	-26.37 mg/dL Standard Deviation 18.74	-23.87 mg/dL Standard Deviation 18.44

SECONDARY outcome

Timeframe: 0:00, 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day -1. 0:05 before drug administration and 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day 28.

Population: PD analysis set

change in AUEC0-5 from baseline on day 28. Baseline is defined as day -1.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	100mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.
Insulin AUEC0-5 baseline (day -1)	108.16 µU*h/mL Standard Deviation 70.85	117.34 µU*h/mL Standard Deviation 54.36	102.44 µU*h/mL Standard Deviation 65.8	121.53 µU*h/mL Standard Deviation 101.07
Insulin AUEC0-5 change from baseline to day 28 (N=16, 16, 16, 29)	24.37 µU*h/mL Standard Deviation 99.44	3.24 µU*h/mL Standard Deviation 91.07	3.8 µU*h/mL Standard Deviation 73.66	8.83 µU*h/mL Standard Deviation 67.79

SECONDARY outcome

Timeframe: 0:00, 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day -1. 0:05 before drug administration and 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day 28.

Population: PD analysis set

change in Emax from baseline on day 28. Baseline is defined as day -1

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	100mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.
Insulin Emax (Maximum Measured Effect) baseline (day -1)	50.78 µU/mL Standard Deviation 28.35	48.09 µU/mL Standard Deviation 23.38	46.13 µU/mL Standard Deviation 24.7	53.06 µU/mL Standard Deviation 43.3
Insulin Emax (Maximum Measured Effect) change from baseline to day 28 (N=16, 16, 16, 29)	7.77 µU/mL Standard Deviation 30.73	0.55 µU/mL Standard Deviation 36.94	-0.46 µU/mL Standard Deviation 28.46	2.92 µU/mL Standard Deviation 32.52

SECONDARY outcome

Timeframe: in the morning of days -1( baseline), 1, 7, 14, 21 and 28

Population: PD analysis set

Change from baseline to the days 1, 7, 14, 21 and 28. Baseline is defined as day -1.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	100mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.
Fasting Insulin baseline (day -1) (N=12,12,14,23)	10 µU/mL Standard Deviation 4.37	11.43 µU/mL Standard Deviation 6.23	8.74 µU/mL Standard Deviation 4.13	9.3 µU/mL Standard Deviation 5.14
Fasting Insulin change from baseline to day 1 (N=11,12,14,22)	-1.08 µU/mL Standard Deviation 2.9	-1.56 µU/mL Standard Deviation 3.97	-1.1 µU/mL Standard Deviation 2.29	0.15 µU/mL Standard Deviation 4.51
Fasting Insulin change from baseline to day 7 (N=9,10,9,18)	0.48 µU/mL Standard Deviation 2.56	-2.49 µU/mL Standard Deviation 6.01	-1 µU/mL Standard Deviation 3.36	-0.2 µU/mL Standard Deviation 6.58
Fasting Insulin change from baseline to day 14 (N=12,11,14,22)	2.32 µU/mL Standard Deviation 4.68	-1.16 µU/mL Standard Deviation 4.58	0.18 µU/mL Standard Deviation 2.74	1.37 µU/mL Standard Deviation 4.75
Fasting Insulin change from baseline to day 21 (N=10,11,14,21)	1.84 µU/mL Standard Deviation 4.76	-0.17 µU/mL Standard Deviation 6.35	-1.21 µU/mL Standard Deviation 2.85	1.53 µU/mL Standard Deviation 5.87
Fasting Insulin change from baseline to day 28 (N=11,11,12,20)	-1.2 µU/mL Standard Deviation 1.74	-2.89 µU/mL Standard Deviation 4.68	-1.73 µU/mL Standard Deviation 3.64	-2.1 µU/mL Standard Deviation 4.46

SECONDARY outcome

Timeframe: 0:00, 2:30, 5:00, 7:00, 10:00, 12:00, 24:00 h after drug administration on day -1. 0:05 before drug administration and 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day 28.

Population: PD analysis set

Change from baseline (day -1) in Emax on day 28.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	100mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.
Glucagon Emax (Maximum Measured Effect) baseline (day -1)	80.35 ng/L Standard Deviation 18.01	90.58 ng/L Standard Deviation 19.63	82.75 ng/L Standard Deviation 17.79	86.98 ng/L Standard Deviation 22.51
Glucagon Emax (Maximum Measured Effect) change from baseline to day 28 (N=14, 14, 16, 28)	12.44 ng/L Standard Deviation 28.69	13.69 ng/L Standard Deviation 23.96	7.84 ng/L Standard Deviation 16.66	6.84 ng/L Standard Deviation 21.45

SECONDARY outcome

Timeframe: 0:00, 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day -1. 0:05 before drug administration and 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day 28.

Population: Pharmacodynamic (PD) analysis set: All patients who receive at least one dose of study medication (active drug or placebo) and had some PD data were included in the pharmacodynamic analysis.

Change from baseline (day -1) in AUEC0-5 on day 28.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	100mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.
Glucagon AUEC0-5 baseline (day -1)	290.66 ng*h/L Standard Deviation 74.99	310.76 ng*h/L Standard Deviation 72.1	291.09 ng*h/L Standard Deviation 104.11	303.06 ng*h/L Standard Deviation 75.4
Glucagon AUEC0-5 change from baseline to day 28 (N=14, 14, 16, 28)	9.01 ng*h/L Standard Deviation 81.1	59.69 ng*h/L Standard Deviation 89.52	33.6 ng*h/L Standard Deviation 73.09	40.65 ng*h/L Standard Deviation 75.72

SECONDARY outcome

Timeframe: day -1 (baseline), 14 and 28

Population: PD analysis set

change from baseline to days 14 and 18. Baseline is defined as day -1.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	100mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.
Fructosamine baseline (day -1)	237.27 µmol/L Standard Deviation 33.97	251.88 µmol/L Standard Deviation 39.19	257.88 µmol/L Standard Deviation 53.64	237.07 µmol/L Standard Deviation 41.48
Fructosamine change from baseline to day 14 (N=14, 16, 15, 29)	19.57 µmol/L Standard Deviation 24.67	24.75 µmol/L Standard Deviation 21.55	13.07 µmol/L Standard Deviation 20.83	18.31 µmol/L Standard Deviation 22
Fructosamine change from baseline to day 28 (N=14, 15, 16, 28)	-23.57 µmol/L Standard Deviation 28.67	-24.33 µmol/L Standard Deviation 29.98	-22.06 µmol/L Standard Deviation 32.89	-26.29 µmol/L Standard Deviation 31.04

SECONDARY outcome

Timeframe: in the morning of days -1 and 28

Population: PD analysis set

change from baseline on day 28. Baseline is defined as day -1.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants oral administration in the fasted state once daily.	10mg Empagliflozin n=15 Participants oral administration in the fasted state once daily.	25mg Empagliflozin n=16 Participants oral administration in the fasted state once daily.	100mg Empagliflozin n=30 Participants oral administration in the fasted state once daily.
HbA1c baseline (day -1)	6.89 percentage of hemoglobin Standard Deviation 0.91	7.15 percentage of hemoglobin Standard Deviation 0.67	7.45 percentage of hemoglobin Standard Deviation 0.8	7.1 percentage of hemoglobin Standard Deviation 0.88
HbA1c change from baseline to day 28 (N=13, 13, 15, 28)	-0.18 percentage of hemoglobin Standard Deviation 0.62	-0.27 percentage of hemoglobin Standard Deviation 0.36	-0.22 percentage of hemoglobin Standard Deviation 0.32	-0.36 percentage of hemoglobin Standard Deviation 0.31

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

10mg Empagliflozin

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

25mg Empagliflozin

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

100mg Empagliflozin

Serious events: 0 serious events

Other events: 18 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
Publication restrictions are in place

Restriction type: OTHER

Other adverse events
Measure	Placebo n=16 participants at risk oral administration in the fasted state once daily	10mg Empagliflozin n=16 participants at risk oral administration in the fasted state once daily	25mg Empagliflozin n=16 participants at risk oral administration in the fasted state once daily	100mg Empagliflozin n=30 participants at risk oral administration in the fasted state once daily
Cardiac disorders Ventricular extrasystoles	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Ear and labyrinth disorders Vertigo	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	3.3% 1/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Gastrointestinal disorders Constipation	12.5% 2/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	13.3% 4/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Gastrointestinal disorders Diarrhoea	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	3.3% 1/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Gastrointestinal disorders Flatulence	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	3.3% 1/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Gastrointestinal disorders Toothache	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.7% 2/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
General disorders Fatigue	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
General disorders Pain	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
General disorders Pyrexia	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Infections and infestations Bronchitis	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Infections and infestations Influenza	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Infections and infestations Nasopharyngitis	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	25.0% 4/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.7% 2/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Infections and infestations Sinusitis	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Investigations Blood triglycerides increased	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Investigations Lipase increased	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.7% 2/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Metabolism and nutrition disorders Hypoglycaemia	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.7% 2/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Musculoskeletal and connective tissue disorders Arthritis	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Musculoskeletal and connective tissue disorders Back pain	12.5% 2/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Nervous system disorders Headache	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	18.8% 3/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	3.3% 1/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Renal and urinary disorders Pollakiuria	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	12.5% 2/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	12.5% 2/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	10.0% 3/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Renal and urinary disorders Polyuria	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Reproductive system and breast disorders Balanitis	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Reproductive system and breast disorders Pruritus genital	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Respiratory, thoracic and mediastinal disorders Cough	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Respiratory, thoracic and mediastinal disorders Hiccups	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	3.3% 1/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Vascular disorders Phlebitis	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	6.2% 1/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.
Vascular disorders Thrombophlebitis	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	0.00% 0/16 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.	16.7% 5/30 • From screening (35 to 15 days before treatment administration) until the end of study examination (35 to 41 days after treatment administration) Patients were required to report spontaneously any AEs, including the time of onset, duration and intensity of these events. Each patient could be assessed by the investigator whenever necessary.