Trial Outcomes & Findings for Pharmacodynamics and Pharmacokinetics of Empagliflozin and Torasemide in Patients With Type 2 Diabetes (NCT NCT01276288)
NCT ID: NCT01276288
Last Updated: 2014-09-03
Results Overview
Change in serum concentration of ALP from baseline, where baseline was defined as the measurement obtained before first drug administration in the first period The mean change from baseline was evaluated as: Empa: day 6- baseline, HCT: day 5-baseline, TOR: day 5-baseline, Empa+ HCT: day 10- baseline, Empa+ TOR: day 10- baseline, The mean for the Empa arm represent combined adjusted means of all four sequences that is Empa administered before or after the administration of either TOR, HCT and their combination with Empa
COMPLETED
PHASE1
23 participants
baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT
2014-09-03
Participant Flow
This was a randomised, open-label, 2- way cross-over study. All patients received empagliflozin (EMPA). After 7days washout period, half of patients received hydrochlorothiazide (HCT), other half torasemide (TOR) on its own or with EMPA. Then HCT or TOR and its combination with EMPA were administered first, followed by EMPA after 7 days washout.
Participant milestones
| Measure |
Empa / Empa+HCT
Patients received 25mg empagliflozin (Empa) orally in a form of a film-coated tablet once daily following an overnight fast of at least 10 hours (h). Following a wash-out period of seven days, 25mg hydrochlorothiazide (HCT) in a form of a film-coated tablet was administered orally once daily in combination with 25mg Empa.
|
Empa+HCT/ Empa
Patients received 25mg hydrochlorothiazide (HCT) in a form of a film-coated tablet orally once daily in combination with 25mg Empa. Following a wash-out period of seven days 25 mg Empa was administered in a form of a film-coated tablet orally once daily following an overnight fast of at least 10 hours (h).
|
Empa/ Empa+ TOR
Patients received 25mg Empa in a form of a film-coated tablet orally once daily following an overnight fast of at least 10 hours (h). Following a wash-out period of seven days, 5 mg torasemide (TOR) in combination with 25mg Empa was administered.
|
Empa+TOR/ Empa
Patients received 5mg torasemide (TOR) in combination with 25mg Empa. Following a wash-out period of seven days, 25 mg Empa was administered in a form of a film-coated tablet orally once daily following an overnight fast of at least 10 hours (h).
|
|---|---|---|---|---|
|
Overall Study
STARTED
|
7
|
6
|
5
|
5
|
|
Overall Study
Received EMPA
|
6
|
5
|
5
|
5
|
|
Overall Study
Received EMPA+HCT
|
5
|
5
|
0
|
0
|
|
Overall Study
Received EMPA+TOR
|
0
|
0
|
5
|
5
|
|
Overall Study
COMPLETED
|
5
|
5
|
5
|
5
|
|
Overall Study
NOT COMPLETED
|
2
|
1
|
0
|
0
|
Reasons for withdrawal
| Measure |
Empa / Empa+HCT
Patients received 25mg empagliflozin (Empa) orally in a form of a film-coated tablet once daily following an overnight fast of at least 10 hours (h). Following a wash-out period of seven days, 25mg hydrochlorothiazide (HCT) in a form of a film-coated tablet was administered orally once daily in combination with 25mg Empa.
|
Empa+HCT/ Empa
Patients received 25mg hydrochlorothiazide (HCT) in a form of a film-coated tablet orally once daily in combination with 25mg Empa. Following a wash-out period of seven days 25 mg Empa was administered in a form of a film-coated tablet orally once daily following an overnight fast of at least 10 hours (h).
|
Empa/ Empa+ TOR
Patients received 25mg Empa in a form of a film-coated tablet orally once daily following an overnight fast of at least 10 hours (h). Following a wash-out period of seven days, 5 mg torasemide (TOR) in combination with 25mg Empa was administered.
|
Empa+TOR/ Empa
Patients received 5mg torasemide (TOR) in combination with 25mg Empa. Following a wash-out period of seven days, 25 mg Empa was administered in a form of a film-coated tablet orally once daily following an overnight fast of at least 10 hours (h).
|
|---|---|---|---|---|
|
Overall Study
Adverse Event
|
1
|
1
|
0
|
0
|
|
Overall Study
not treated
|
1
|
0
|
0
|
0
|
Baseline Characteristics
Pharmacodynamics and Pharmacokinetics of Empagliflozin and Torasemide in Patients With Type 2 Diabetes
Baseline characteristics by cohort
| Measure |
Overall Patients
n=22 Participants
A randomised, open-label, multiple-dose, 2- way cross-over study. All patients received 25 mg empagliflozin in a form of a film-coated tablet orally once daily following an overnight fast of at least 10 hours (h) (days 1 to 5). Following a wash-out period of seven days, half of the patients received 25 mg hydrochlorothiazide (HCT) either on its own in a form of a film-coated tablet orally once daily (days 1 to 4) or in combination with 25 mg empagliflozin ( days 5 to 9), while the other half of the patients received 5 mg torasemide (TOR) either on its own (days 1 to 4) or in combination with the 25 mg empagliflozin ( days 5 to 9). This sequence was then reversed so that the HCT or TOR and its combination with 25 mg empagliflozin were administered first in a same manner as stated above, followed by 25 mg empagliflozin after seven days wash out period.
|
|---|---|
|
Age, Continuous
|
54.0 years
STANDARD_DEVIATION 8.1 • n=99 Participants
|
|
Sex: Female, Male
Female
|
7 Participants
n=99 Participants
|
|
Sex: Female, Male
Male
|
15 Participants
n=99 Participants
|
PRIMARY outcome
Timeframe: 24 hour sampling interval at baseline and then day 5 for Empa, day 4 for TOR and HCT, day 9 for Empa+TOR and Empa+HCTPopulation: Pharmacodynamic (PD) analysis set completers includes all evaluable patients of the treated set who provide a baseline and at least one on-treatment observation for at least one primary (PD) endpoint under any treatment without important protocol violations relevant to the evaluation of PD and who continued the trial as planned
Change in clearance of sodium, potassium, creatinine, magnesium, chloride,calcium, phosphate and uric acid from baseline, where baseline is defined as the value obtained from the last 24-h collection period before the first drug administration in the first treatment period. The mean change from baseline was evaluated as: Empa: day 5- baseline, HCT: day 4-baseline, TOR: day 4-baseline, Empa+ HCT: day 9- baseline, Empa+ TOR: day 9- baseline, The means for the Empa arm represent combined adjusted means of all four sequences that is Empa administered before or after the administration of either TOR, HCT and their combination with Empa
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline
Uric Acid
|
6.377 ml/min
Standard Error 1.100
|
-0.476 ml/min
Standard Error 0.637
|
-1.310 ml/min
Standard Error 0.924
|
5.065 ml/min
Standard Error 1.376
|
4.359 ml/min
Standard Error 1.533
|
—
|
|
Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline
Creatinine
|
3.167 ml/min
Standard Error 4.306
|
-7.034 ml/min
Standard Error 5.494
|
-4.250 ml/min
Standard Error 6.574
|
-10.126 ml/min
Standard Error 7.989
|
-11.768 ml/min
Standard Error 7.135
|
—
|
|
Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline
Sodium
|
-0.031 ml/min
Standard Error 0.038
|
-0.055 ml/min
Standard Error 0.044
|
-0.071 ml/min
Standard Error 0.083
|
0.143 ml/min
Standard Error 0.036
|
-0.004 ml/min
Standard Error 0.088
|
—
|
|
Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline
Chloride
|
-0.129 ml/min
Standard Error 0.042
|
-0.058 ml/min
Standard Error 0.056
|
-0.157 ml/min
Standard Error 0.064
|
0.114 ml/min
Standard Error 0.044
|
-0.117 ml/min
Standard Error 0.088
|
—
|
|
Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline
Potassium
|
2.040 ml/min
Standard Error 0.492
|
2.205 ml/min
Standard Error 0.539
|
-0.518 ml/min
Standard Error 0.585
|
4.125 ml/min
Standard Error 0.634
|
2.324 ml/min
Standard Error 0.832
|
—
|
|
Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline
Magnesium
|
0.398 ml/min
Standard Error 0.171
|
1.826 ml/min
Standard Error 0.288
|
1.148 ml/min
Standard Error 0.206
|
1.115 ml/min
Standard Error 0.181
|
0.209 ml/min
Standard Error 0.227
|
—
|
|
Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline
Calcium
|
-0.326 ml/min
Standard Error 0.087
|
-0.299 ml/min
Standard Error 0.094
|
-0.065 ml/min
Standard Error 0.108
|
-0.407 ml/min
Standard Error 0.102
|
-0.174 ml/min
Standard Error 0.105
|
—
|
|
Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline
Phosphate
|
5.275 ml/min
Standard Error 0.842
|
4.633 ml/min
Standard Error 1.342
|
4.368 ml/min
Standard Error 1.342
|
2.795 ml/min
Standard Error 1.382
|
2.359 ml/min
Standard Error 1.379
|
—
|
PRIMARY outcome
Timeframe: 24 hour sampling interval at baseline and then day 5 for Empa, day 4 for TOR and HCT, day 9 for Empa+TOR and Empa+HCTPopulation: PD analysis set completers
Change in urinary excretion in a 24-hour period of sodium, potassium, magnesium, chloride, calcium, phosphate, creatinine, uric acid, glucose from baseline, where baseline was defined as the value obtained from the last 24-hour (h) collection period before the first drug administration in the first treatment period. This applies also to sodium excretion in urine, which is additionally obtained one day before the drug administration before the second period. The mean change from baseline was evaluated as: Empa: day 5- baseline, HCT: day 4-baseline, TOR: day 4-baseline, Empa+ HCT: day 9- baseline, Empa+ TOR: day 9- baseline, The means for the Empa arm represent combined adjusted means of all four sequences that is Empa administered before or after the administration of either TOR, HCT and their combination with Empa
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline
Sodium
|
-4.300 mmol/day
Standard Error 7.777
|
-11.700 mmol/day
Standard Error 8.495
|
-13.700 mmol/day
Standard Error 16.445
|
28.900 mmol/day
Standard Error 7.512
|
1.200 mmol/day
Standard Error 17.068
|
—
|
|
Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline
Chloride
|
-16.300 mmol/day
Standard Error 6.363
|
-12.300 mmol/day
Standard Error 7.939
|
-22.000 mmol/day
Standard Error 9.421
|
11.400 mmol/day
Standard Error 6.092
|
-14.600 mmol/day
Standard Error 12.120
|
—
|
|
Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline
Potassium
|
10.370 mmol/day
Standard Error 3.171
|
6.200 mmol/day
Standard Error 3.008
|
-6.990 mmol/day
Standard Error 3.920
|
15.790 mmol/day
Standard Error 2.963
|
8.460 mmol/day
Standard Error 5.288
|
—
|
|
Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline
Magnesium
|
1.190 mmol/day
Standard Error 0.236
|
2.270 mmol/day
Standard Error 0.387
|
1.720 mmol/day
Standard Error 0.263
|
2.030 mmol/day
Standard Error 0.225
|
1.050 mmol/day
Standard Error 0.280
|
—
|
|
Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline
Calcium
|
-1.160 mmol/day
Standard Error 0.281
|
-1.020 mmol/day
Standard Error 0.299
|
-0.430 mmol/day
Standard Error 0.377
|
-1.360 mmol/day
Standard Error 0.294
|
-0.740 mmol/day
Standard Error 0.306
|
—
|
|
Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline
Phosphate
|
9.250 mmol/day
Standard Error 1.198
|
9.000 mmol/day
Standard Error 2.261
|
4.900 mmol/day
Standard Error 1.900
|
8.300 mmol/day
Standard Error 2.103
|
5.000 mmol/day
Standard Error 2.357
|
—
|
|
Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline
Creatinine
|
0.091 mmol/day
Standard Error 0.043
|
-0.078 mmol/day
Standard Error 0.058
|
-0.073 mmol/day
Standard Error 0.045
|
0.022 mmol/day
Standard Error 0.041
|
-0.040 mmol/day
Standard Error 0.068
|
—
|
|
Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline
Uric acid
|
1.641 mmol/day
Standard Error 0.334
|
-0.037 mmol/day
Standard Error 0.251
|
-0.500 mmol/day
Standard Error 0.349
|
1.555 mmol/day
Standard Error 0.327
|
1.244 mmol/day
Standard Error 0.493
|
—
|
|
Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline
Glucose
|
599.449 mmol/day
Standard Error 60.015
|
17.584 mmol/day
Standard Error 8.161
|
17.932 mmol/day
Standard Error 25.477
|
685.233 mmol/day
Standard Error 68.035
|
740.910 mmol/day
Standard Error 54.134
|
—
|
PRIMARY outcome
Timeframe: 24 hour sampling interval at baseline and then day 5 for Empa, day 4 for TOR and HCT, day 9 for Empa+TOR and Empa+HCTPopulation: PD analysis set completers
Change in urinary excretion in a 24-hour period of N-terminal telopeptide (NTx) from baseline, where baseline was defined as the value obtained from the last 24-hour (h) collection period before the first drug administration in the first treatment period. The mean change from baseline was evaluated as: Empa: day 5- baseline, HCT: day 4-baseline, TOR: day 4-baseline, Empa+ HCT: day 9- baseline, Empa+ TOR: day 9- baseline, The means for the Empa arm represent combined adjusted means of all four sequences that is Empa administered before or after the administration of either TOR, HCT and their combination with Empa
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Change in Urinary Excretion in a 24-hour Period of N-terminal Telopeptide (NTx) From Baseline
|
6.010 nM BCE/ mMC
Standard Error 1.334
|
0.730 nM BCE/ mMC
Standard Error 2.704
|
2.030 nM BCE/ mMC
Standard Error 0.723
|
1.380 nM BCE/ mMC
Standard Error 3.429
|
3.900 nM BCE/ mMC
Standard Error 1.424
|
—
|
PRIMARY outcome
Timeframe: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCTPopulation: PD analysis set completers
Changes in serum osmolality from baseline based on a blood sample. Baseline was defined as the measurement obtained before the first drug administration in the first period. The mean change from baseline was evaluated as: Empa: day 6- baseline, HCT: day 5-baseline, TOR: day 5-baseline, Empa+ HCT: day 10- baseline, Empa+ TOR: day 10- baseline, The mean for the Empa arm represent combined adjusted means of all four sequences that is Empa administered before or after the administration of either TOR, HCT and their combination with Empa
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Change in Serum Osmolality From Baseline
|
3.950 mOsm/Kg
Standard Error 3.748
|
-7.500 mOsm/Kg
Standard Error 3.519
|
-5.500 mOsm/Kg
Standard Error 2.915
|
-2.200 mOsm/Kg
Standard Error 3.972
|
10.500 mOsm/Kg
Standard Error 3.625
|
—
|
PRIMARY outcome
Timeframe: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCTPopulation: PD analysis set completers
Change in serum concentration of sodium, potassium, magnesium, calcium, chloride, phosphate, glucose and urea from baseline, where baseline was defined as the measurement obtained before first drug administration in the first period The mean change from baseline was evaluated as: Empa: day 6- baseline, HCT: day 5-baseline, TOR: day 5-baseline, Empa+ HCT: day 10- baseline, Empa+ TOR: day 10- baseline, The means for the Empa arm represent combined adjusted means of all four sequences that is Empa administered before or after the administration of either TOR, HCT and their combination with Empa
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline
Sodium
|
1.500 mmol/L
Standard Error 0.447
|
-0.500 mmol/L
Standard Error 0.401
|
0.200 mmol/L
Standard Error 0.573
|
-0.100 mmol/L
Standard Error 0.433
|
1.600 mmol/L
Standard Error 1.222
|
—
|
|
Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline
Potassium
|
-0.170 mmol/L
Standard Error 0.107
|
-0.470 mmol/L
Standard Error 0.087
|
-0.200 mmol/L
Standard Error 0.087
|
-0.530 mmol/L
Standard Error 0.091
|
-0.360 mmol/L
Standard Error 0.097
|
—
|
|
Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline
Magnesium
|
0.139 mmol/L
Standard Error 0.011
|
0.025 mmol/L
Standard Error 0.014
|
0.059 mmol/L
Standard Error 0.010
|
0.130 mmol/L
Standard Error 0.014
|
0.145 mmol/L
Standard Error 0.019
|
—
|
|
Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline
Chloride
|
2.050 mmol/L
Standard Error 0.592
|
-2.600 mmol/L
Standard Error 0.521
|
1.000 mmol/L
Standard Error 0.775
|
-3.200 mmol/L
Standard Error 1.365
|
2.100 mmol/L
Standard Error 1.650
|
—
|
|
Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline
Urea
|
0.710 mmol/L
Standard Error 0.153
|
0.650 mmol/L
Standard Error 0.149
|
0.318 mmol/L
Standard Error 0.220
|
1.504 mmol/L
Standard Error 0.161
|
2.122 mmol/L
Standard Error 0.429
|
—
|
|
Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline
Glucose
|
-1.123 mmol/L
Standard Error 0.250
|
0.849 mmol/L
Standard Error 0.177
|
0.527 mmol/L
Standard Error 0.290
|
-0.033 mmol/L
Standard Error 0.168
|
-0.526 mmol/L
Standard Error 0.389
|
—
|
|
Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline
Calcium
|
-0.055 mmol/L
Standard Error 0.023
|
-0.040 mmol/L
Standard Error 0.034
|
-0.080 mmol/L
Standard Error 0.020
|
-0.010 mmol/L
Standard Error 0.031
|
-0.060 mmol/L
Standard Error 0.037
|
—
|
|
Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline
Phosphate
|
0.045 mmol/L
Standard Error 0.031
|
0.060 mmol/L
Standard Error 0.031
|
-0.060 mmol/L
Standard Error 0.034
|
0.170 mmol/L
Standard Error 0.040
|
0.050 mmol/L
Standard Error 0.045
|
—
|
PRIMARY outcome
Timeframe: baseline and then day 5 for Empa, day 4 for TOR and HCT, day 9 for Empa+TOR and Empa+HCTPopulation: PD analysis set completers
Change in serum concentration of Creatinine and Uric acid from baseline, where baseline was defined as the measurement obtained before first drug administration in the first period The mean change from baseline was evaluated as: Empa: day 5- baseline, HCT: day 4-baseline, TOR: day 4-baseline, Empa+ HCT: day 9- baseline, Empa+ TOR: day 9- baseline, The means for the Empa arm represent combined adjusted means of all four sequences that is Empa administered before or after the administration of either TOR, HCT and their combination with Empa
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Change in Serum Concentration of Creatinine and Uric Acid From Baseline
Creatinine
|
2.175 umol/L
Standard Error 1.585
|
-0.340 umol/L
Standard Error 1.441
|
-2.180 umol/L
Standard Error 1.811
|
6.280 umol/L
Standard Error 2.764
|
3.570 umol/L
Standard Error 2.348
|
—
|
|
Change in Serum Concentration of Creatinine and Uric Acid From Baseline
Uric acid
|
-64.950 umol/L
Standard Error 24.763
|
24.200 umol/L
Standard Error 9.087
|
-4.700 umol/L
Standard Error 9.164
|
-31.000 umol/L
Standard Error 18.582
|
-48.200 umol/L
Standard Error 12.984
|
—
|
PRIMARY outcome
Timeframe: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCTPopulation: PD analysis set completers
Change in serum concentration of ALP from baseline, where baseline was defined as the measurement obtained before first drug administration in the first period The mean change from baseline was evaluated as: Empa: day 6- baseline, HCT: day 5-baseline, TOR: day 5-baseline, Empa+ HCT: day 10- baseline, Empa+ TOR: day 10- baseline, The mean for the Empa arm represent combined adjusted means of all four sequences that is Empa administered before or after the administration of either TOR, HCT and their combination with Empa
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Change in Serum Concentration of Alkaline Phosphatase (ALP) From Baseline
|
2.750 U/L
Standard Error 0.878
|
3.000 U/L
Standard Error 1.274
|
2.400 U/L
Standard Error 0.859
|
6.500 U/L
Standard Error 1.515
|
5.800 U/L
Standard Error 1.788
|
—
|
PRIMARY outcome
Timeframe: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCTPopulation: PD analysis set completers
Change in serum concentration of Renin, intact parathyroid hormone (iPTH) and 1,25-dihydroxyvitamin D from baseline , where baseline was defined as the measurement obtained before first drug administration in the first period The mean change from baseline was evaluated as: Empa: day 6- baseline, HCT: day 5-baseline, TOR: day 5-baseline, Empa+ HCT: day 10- baseline, Empa+ TOR: day 10- baseline, The means for the Empa arm represent combined adjusted means of all four sequences that is Empa administered before or after the administration of either TOR, HCT and their combination with Empa
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Change in Serum Concentration of Renin, Intact Parathyroid Hormone (iPTH) and 1,25-dihydroxyvitamin D From Baseline
Renin
|
-0.960 pg/mL
Standard Error 4.155
|
16.150 pg/mL
Standard Error 8.276
|
2.550 pg/mL
Standard Error 1.882
|
32.760 pg/mL
Standard Error 16.863
|
17.050 pg/mL
Standard Error 3.645
|
—
|
|
Change in Serum Concentration of Renin, Intact Parathyroid Hormone (iPTH) and 1,25-dihydroxyvitamin D From Baseline
iPTH
|
8.265 pg/mL
Standard Error 1.593
|
6.160 pg/mL
Standard Error 1.880
|
6.910 pg/mL
Standard Error 2.059
|
9.280 pg/mL
Standard Error 1.619
|
12.190 pg/mL
Standard Error 3.233
|
—
|
|
Change in Serum Concentration of Renin, Intact Parathyroid Hormone (iPTH) and 1,25-dihydroxyvitamin D From Baseline
1,25-dihydroxyvitamin D
|
0.230 pg/mL
Standard Error 3.488
|
1.560 pg/mL
Standard Error 4.029
|
3.530 pg/mL
Standard Error 5.123
|
-5.060 pg/mL
Standard Error 4.070
|
-0.970 pg/mL
Standard Error 4.329
|
—
|
PRIMARY outcome
Timeframe: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCTPopulation: PD analysis set completers
Change in serum concentration of Aldosterone from baseline , where baseline was defined as the measurement obtained before first drug administration in the first period The mean change from baseline was evaluated as: Empa: day 6- baseline, HCT: day 5-baseline, TOR: day 5-baseline, Empa+ HCT: day 10- baseline, Empa+ TOR: day 10- baseline, The mean for the Empa arm represent combined adjusted means of all four sequences that is Empa administered before or after the administration of either TOR, HCT and their combination with Empa
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Change in Serum Concentration of Aldosterone From Baseline
|
-0.018 nmol/L
Standard Error 0.020
|
0.099 nmol/L
Standard Error 0.056
|
0.023 nmol/L
Standard Error 0.018
|
0.124 nmol/L
Standard Error 0.068
|
0.123 nmol/L
Standard Error 0.069
|
—
|
PRIMARY outcome
Timeframe: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCTPopulation: PD analysis set completers
Change in serum concentration of fibroblast growth factor-23 (FGF- 23) from baseline, where baseline was defined as the measurement obtained before first drug administration in the first period The mean change from baseline was evaluated as: Empa: day 6- baseline, HCT: day 5-baseline, TOR: day 5-baseline, Empa+ HCT: day 10- baseline, Empa+ TOR: day 10- baseline, The mean for the Empa arm represent combined adjusted means of all four sequences that is Empa administered before or after the administration of either TOR, HCT and their combination with Empa
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Change in Serum Concentration of Fibroblast Growth Factor-23 (FGF- 23) From Baseline
|
50.305 RU/mL
Standard Error 23.759
|
29.050 RU/mL
Standard Error 25.952
|
-0.680 RU/mL
Standard Error 5.465
|
109.860 RU/mL
Standard Error 53.745
|
13.820 RU/mL
Standard Error 4.739
|
—
|
PRIMARY outcome
Timeframe: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCTPopulation: PD analysis set completers
Change in urea concentration in urine from baseline, where baseline was defined as the measurement obtained before first drug administration in the first period The mean change from baseline was evaluated as: Empa: day 6- baseline, HCT: day 5-baseline, TOR: day 5-baseline, Empa+ HCT: day 10- baseline, Empa+ TOR: day 10- baseline, The mean for the Empa arm represent combined adjusted means of all four sequences that is Empa administered before or after the administration of either TOR, HCT and their combination with Empa
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Change in Urea Concentration in Urine
|
-1.515 mmol/L
Standard Error 14.048
|
67.570 mmol/L
Standard Error 29.271
|
35.710 mmol/L
Standard Error 34.666
|
11.780 mmol/L
Standard Error 9.819
|
48.690 mmol/L
Standard Error 31.445
|
—
|
PRIMARY outcome
Timeframe: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCTPopulation: PD analysis set completers
Change in urine pH from baseline, where baseline was defined as the measurement obtained before first drug administration in the first period The mean change from baseline was evaluated as: Empa: day 6- baseline, HCT: day 5-baseline, TOR: day 5-baseline, Empa+ HCT: day 10- baseline, Empa+ TOR: day 10- baseline, The mean for the Empa arm represent combined adjusted means of all four sequences that is Empa administered before or after the administration of either TOR, HCT and their combination with Empa
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Change in Urine pH From Baseline
|
-0.132 pH
Standard Error 0.161
|
-0.452 pH
Standard Error 0.291
|
-0.147 pH
Standard Error 0.062
|
-0.448 pH
Standard Error 0.259
|
0.130 pH
Standard Error 0.191
|
—
|
PRIMARY outcome
Timeframe: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCTPopulation: PD analysis set completers
Change in urine osmolality from baseline, where baseline was defined as the measurement obtained before first drug administration in the first period The mean change from baseline was evaluated as: Empa: day 6- baseline, HCT: day 5-baseline, TOR: day 5-baseline, Empa+ HCT: day 10- baseline, Empa+ TOR: day 10- baseline, The mean for the Empa arm represent combined adjusted means of all four sequences that is Empa administered before or after the administration of either TOR, HCT and their combination with Empa
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Change in Urine Osmolality From Baseline
|
223.15 mOsm/kg
Standard Error 34.850
|
-3.900 mOsm/kg
Standard Error 43.239
|
-5.800 mOsm/kg
Standard Error 54.743
|
217.700 mOsm/kg
Standard Error 31.430
|
330.400 mOsm/kg
Standard Error 45.645
|
—
|
PRIMARY outcome
Timeframe: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCTPopulation: PD analysis set completers
Changes in bicarbonate concentrations of calcium, bicarbonate ions and base excess in capillary or arterialised blood from baseline, where baseline was defined as the last measurement before trial drug administration of each treatment period The mean change from baseline was evaluated as: Empa: day 6- baseline, HCT: day 5-baseline, TOR: day 5-baseline, Empa+ HCT: day 10- baseline, Empa+ TOR: day 10- baseline, The means for the Empa arm represent combined adjusted means of all four sequences that is Empa administered before or after the administration of either TOR, HCT and their combination with Empa
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Changes in Bicarbonate Concentrations of Calcium, Bicarbonate Ions and Base Excess in Capillary or Arterialised Blood From Baseline
Bicarbonate concentrations of calcium
|
-1.090 mmol/ L
Standard Error 0.309
|
2.020 mmol/ L
Standard Error 0.397
|
-0.400 mmol/ L
Standard Error 0.450
|
1.860 mmol/ L
Standard Error 0.445
|
-1.590 mmol/ L
Standard Error 0.580
|
—
|
|
Changes in Bicarbonate Concentrations of Calcium, Bicarbonate Ions and Base Excess in Capillary or Arterialised Blood From Baseline
Base excess
|
-1.045 mmol/ L
Standard Error 0.284
|
1.640 mmol/ L
Standard Error 0.325
|
-0.420 mmol/ L
Standard Error 0.386
|
1.720 mmol/ L
Standard Error 0.432
|
-1.450 mmol/ L
Standard Error 0.576
|
—
|
|
Changes in Bicarbonate Concentrations of Calcium, Bicarbonate Ions and Base Excess in Capillary or Arterialised Blood From Baseline
bicarbonate ions
|
-0.049 mmol/ L
Standard Error 0.012
|
-0.043 mmol/ L
Standard Error 0.023
|
-0.041 mmol/ L
Standard Error 0.018
|
-0.053 mmol/ L
Standard Error 0.015
|
-0.049 mmol/ L
Standard Error 0.015
|
—
|
PRIMARY outcome
Timeframe: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCTPopulation: PD analysis set completers
Change in pH in capillary or arterialised blood from baseline, where baseline was defined as the last measurement before trial drug administration of each treatment period The mean change from baseline was evaluated as: Empa: day 6- baseline, HCT: day 5-baseline, TOR: day 5-baseline, Empa+ HCT: day 10- baseline, Empa+ TOR: day 10- baseline, The mean for the Empa arm represent combined adjusted means of all four sequences that is Empa administered before or after the administration of either TOR, HCT and their combination with Empa
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Change in pH in Capillary or Arterialised Blood From Baseline
|
-0.006 pH
Standard Error 0.004
|
0.003 pH
Standard Error 0.007
|
-0.002 pH
Standard Error 0.006
|
0.008 pH
Standard Error 0.008
|
-0.005 pH
Standard Error 0.008
|
—
|
PRIMARY outcome
Timeframe: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCTPopulation: PD analysis set completers
Change in body weight from baseline , where baseline was defined as the last measurement before trial drug administration of each treatment period The mean change from baseline was evaluated as: Empa: day 6- baseline, HCT: day 5-baseline, TOR: day 5-baseline, Empa+ HCT: day 10- baseline, Empa+ TOR: day 10- baseline, The mean for the Empa arm represent combined adjusted means of all four sequences that is Empa administered before or after the administration of either TOR, HCT and their combination with Empa
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Change in Body Weight From Baseline
|
-1.365 kg
Standard Error 0.535
|
-1.040 kg
Standard Error 0.227
|
-0.380 kg
Standard Error 0.149
|
-2.030 kg
Standard Error 0.344
|
-1.750 kg
Standard Error 0.328
|
—
|
PRIMARY outcome
Timeframe: 24 hour sampling interval at baseline and then day 5 for Empa, day 4 for TOR and HCT, day 9 for Empa+TOR and Empa+HCTPopulation: PD analysis set completers
Change from baseline in urinary weight in a 24 hour (h)- collection period, where baseline is the last 24-h collection period before first trial drug administration in each treatment period. The mean change from baseline was evaluated as: Empa: day 5- baseline, HCT: day 4-baseline, TOR: day 4-baseline, Empa+ HCT: day 9- baseline, Empa+ TOR: day 9- baseline, The mean for the Empa arm represent combined adjusted means of all four sequences that is Empa administered before or after the administration of either TOR, HCT and their combination with Empa
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Change in Urinary Weight From Baseline
|
134.700 g/day
Standard Error 95.358
|
-55.300 g/day
Standard Error 67.517
|
-39.000 g/day
Standard Error 106.642
|
429.000 g/day
Standard Error 92.357
|
353.200 g/day
Standard Error 116.293
|
—
|
PRIMARY outcome
Timeframe: Baseline and day 5Population: PD analysis set completers
For this endpoint the change in total micturition frequency from the baseline was only examined for EMPA where baseline was defined as the day before the first drug administration.
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
The Change in Micturition Frequency From the Baseline
|
1.600 voids per day
Standard Error 0.478
|
—
|
—
|
—
|
—
|
—
|
PRIMARY outcome
Timeframe: One day before the drug administration, then day 4 after the first drug administrationPopulation: PD analysis set completers
The change in total Muscle sympathetic nerve activity (MSNA) that represents an area under the curve of all C-fiber action potentials per minute. This endpoint was evaluated only for Empa. For this endpoint a baseline value was not defined. However, the parameters obtained at 2 measurements time points during the trial were compared.
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
The Change in Total Muscle Sympathetic Nerve Activity (MSNA) From Off- Treatment
|
0.241 action potentials per min
Standard Error 0.354
|
—
|
—
|
—
|
—
|
—
|
PRIMARY outcome
Timeframe: Day 3, 2 and 1 before the first drug administrationPopulation: PD analysis set completers
Urinary sodium excretion over 24-hour run-in periods to assess the harmonisation of electrolytes after intake of a standardised diet
Outcome measures
| Measure |
Empagliflozin (Empa)
n=20 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Urinary Sodium Excretion Over 24-hour run-in Periods
3 days before the drug administration
|
198.50 mmol/day
Standard Error 20.30
|
211.10 mmol/day
Standard Error 9.37
|
217.90 mmol/day
Standard Error 27.77
|
—
|
—
|
—
|
|
Urinary Sodium Excretion Over 24-hour run-in Periods
2 days before the drug administration
|
174.35 mmol/day
Standard Error 10.26
|
183.30 mmol/day
Standard Error 13.15
|
178.70 mmol/day
Standard Error 13.00
|
—
|
—
|
—
|
|
Urinary Sodium Excretion Over 24-hour run-in Periods
1 day before the drug administration
|
163.90 mmol/day
Standard Error 8.57
|
170.10 mmol/day
Standard Error 7.58
|
179.10 mmol/day
Standard Error 8.87
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 post-dose on Day 5 with EMPA alone and on Day 9 with EMPA plus diuretic. The Pre-dose values were averaged over Days 1 to 4 with EMPA alone and on Days 7 & 8 with EMPA plus diureticPopulation: Pharmacokinetic (PK) set, including all patients of the treated set who provide at least one observation for at least one secondary PK endpoint of AUC τ,ss or C max,ss for any analyte under any treatment without important protocol violations relevant to the evaluation of PK.
Area under the concentration-time curve of Empa in plasma at steady state over a uniform dosing interval τ (AUCτ,ss).
Outcome measures
| Measure |
Empagliflozin (Empa)
n=21 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Area Under the Concentration-time Curve of Empa in Plasma (AUCτ,ss)
|
4990 nmol*h/L
Geometric Coefficient of Variation 21.1
|
5570 nmol*h/L
Geometric Coefficient of Variation 25.2
|
5260 nmol*h/L
Geometric Coefficient of Variation 19.1
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 post-dose on Day 5 with EMPA alone and on Day 9 with EMPA plus diuretic. The Pre-dose values were averaged over Days 1 to 4 with EMPA alone and on Days 7 & 8 with EMPA plus diureticPopulation: PK set
Maximum measured concentration of Empa in plasma (Cmax, ss) at steady state
Outcome measures
| Measure |
Empagliflozin (Empa)
n=21 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Maximum Measured Concentration of Empa in Plasma (Cmax, ss)
|
939 nmol/L
Geometric Coefficient of Variation 21.4
|
1030 nmol/L
Geometric Coefficient of Variation 31.2
|
949 nmol/L
Geometric Coefficient of Variation 21.9
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 post-dose on Day 4 with HCT alone and on Day 9 with EMPA plus HCT. The Pre-dose values were averaged over Days 1 to 3 with HCT alone and on Days 7 & 8 with EMPA plus HCTPopulation: PK set
Area under the concentration-time curve of HCT in plasma at steady state over a uniform dosing interval τ (AUCτ,ss).
Outcome measures
| Measure |
Empagliflozin (Empa)
n=11 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Area Under the Concentration-time Curve of HCT in Plasma (AUCτ,ss)
|
1040 ng*h/mL
Geometric Coefficient of Variation 17.9
|
1000 ng*h/mL
Geometric Coefficient of Variation 18.7
|
—
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 post-dose on Day 4 with HCT alone and on Day 9 with EMPA plus HCT. The Pre-dose values were averaged over Days 1 to 3 with HCT alone and on Days 7 & 8 with EMPA plus HCTPopulation: PK set
Maximum measured concentration of HCT in plasma (Cmax, ss) at steady state
Outcome measures
| Measure |
Empagliflozin (Empa)
n=11 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Maximum Measured Concentration of HCT in Plasma (Cmax, ss)
|
203 ng/mL
Geometric Coefficient of Variation 31.5
|
205 ng/mL
Geometric Coefficient of Variation 30.3
|
—
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 post-dose on Day 4 with TOR alone and on Day 9 with EMPA plus TOR. The Pre-dose values were averaged over Days 1 to 3 with TOR alone and on Days 7 & 8 with EMPA plus TORPopulation: PK set
Area under the concentration-time curve of TOR in plasma at steady state over a uniform dosing interval τ (AUCτ,ss).
Outcome measures
| Measure |
Empagliflozin (Empa)
n=10 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
n=10 Participants
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Area Under the Concentration-time Curve of TOR in Plasma (AUCτ,ss)
|
1320 ng*h/mL
Geometric Coefficient of Variation 14.0
|
1340 ng*h/mL
Geometric Coefficient of Variation 16.1
|
74.8 ng*h/mL
Geometric Coefficient of Variation 15.9
|
40.5 ng*h/mL
Geometric Coefficient of Variation 23.9
|
78.1 ng*h/mL
Geometric Coefficient of Variation 17.7
|
41.8 ng*h/mL
Geometric Coefficient of Variation 18.2
|
SECONDARY outcome
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 post-dose on Day 4 with TOR alone and on Day 9 with EMPA plus TOR. The Pre-dose values were averaged over Days 1 to 3 with TOR alone and on Days 7 & 8 with EMPA plus TORPopulation: PK set
Maximum measured concentration of Empa in plasma (Cmax, ss) at steady state
Outcome measures
| Measure |
Empagliflozin (Empa)
n=10 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=10 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
n=10 Participants
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Maximum Measured Concentration of TOR in Plasma (Cmax, ss)
|
710 ng/mL
Geometric Coefficient of Variation 19.1
|
741 ng/mL
Geometric Coefficient of Variation 12.9
|
42.6 ng/mL
Geometric Coefficient of Variation 23.0
|
8.58 ng/mL
Geometric Coefficient of Variation 12.3
|
43.8 ng/mL
Geometric Coefficient of Variation 18.0
|
8.79 ng/mL
Geometric Coefficient of Variation 16.8
|
SECONDARY outcome
Timeframe: From first drug administration until up to 14 days after the last drug administration, up to 35 daysPopulation: Treated set
Number of subjects with clinical relevant abnormalities in vital signs (blood pressure, pulse rate), 12-lead resting electrocardiogram (ECG), clinical laboratory tests (haematology, clinical chemistry, urinalysis, and monitoring of fasting plasma glucose), physical examination and assessment of tolerability by the investigator. New abnormal findings were reported as Adverse Events (AE). Only Alanine aminotransferase normal under system organ class investigations was determined as an existing AE.
Outcome measures
| Measure |
Empagliflozin (Empa)
n=21 Participants
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=11 Participants
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 Participants
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 Participants
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 Participants
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
TOR-M3 + Empa
TOR metabolite which pharmacological activity is equal to TOR after TOR undergoes extensive hepatic metabolism in combination with Empa 25 mg
|
|---|---|---|---|---|---|---|
|
Number of Subjects With Clinical Relevant Abnormalities in Vital Signs, Clinical Laboratory Tests, 12-lead Resting Electrocardiogram (ECG), Physical Examination and Assessment of Tolerability by the Investigator
|
1 participants
|
0 participants
|
0 participants
|
0 participants
|
0 participants
|
—
|
Adverse Events
Empagliflozin (Empa)
Hydrochlorothiazide (HCT)
Torasemide (TOR)
Empa+ HCT
Empa + TOR
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Empagliflozin (Empa)
n=21 participants at risk
Empagliflozin (Empa) 25 mg administered once daily for 5 days
|
Hydrochlorothiazide (HCT)
n=11 participants at risk
Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days
|
Torasemide (TOR)
n=10 participants at risk
Torasemide (TOR) 5 mg administered once daily for 4 days
|
Empa+ HCT
n=10 participants at risk
Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days
|
Empa + TOR
n=10 participants at risk
Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days
|
|---|---|---|---|---|---|
|
Cardiac disorders
Atrial tachycardia
|
0.00%
0/21 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
9.1%
1/11 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
0.00%
0/10 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
0.00%
0/10 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
0.00%
0/10 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
|
General disorders
Thirst
|
0.00%
0/21 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
0.00%
0/11 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
0.00%
0/10 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
20.0%
2/10 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
60.0%
6/10 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
|
Musculoskeletal and connective tissue disorders
Muscle spasms
|
0.00%
0/21 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
0.00%
0/11 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
0.00%
0/10 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
10.0%
1/10 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
0.00%
0/10 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
|
Nervous system disorders
Headache
|
4.8%
1/21 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
0.00%
0/11 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
0.00%
0/10 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
10.0%
1/10 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
0.00%
0/10 • From first drug administration until up to 14 days after the last drug administration, up to 35 days
|
Additional Information
Boehringer Ingelheim Call Center
Boehringer Ingelheim Pharmaceuticals
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