Diabetes Mellitus, Type 2
Conditions
Brief summary
The primary objective of the study is to investigate the effect of BI 10773, hydrochlorothiazide and torasemide on changes in serum and urine electrolytes. Furthermore the pharmacodynamic and pharmacokinetic interactions between BI 10773 and diuretics should be assessed.
Interventions
DRUGtorasemide
multiple oral doses
DRUGhydrochlorothiazide
multiple oral doses
DRUGBI 10773
multiple oral doses
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1\. male and female patients of type 2 diabetes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Urinary Sodium Excretion Over 24-hour run-in Periods | Day 3, 2 and 1 before the first drug administration | Urinary sodium excretion over 24-hour run-in periods to assess the harmonisation of electrolytes after intake of a standardised diet |
| Change in Urine Osmolality From Baseline | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT | 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 |
| Changes in Bicarbonate Concentrations of Calcium, Bicarbonate Ions and Base Excess in Capillary or Arterialised Blood From Baseline | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT | 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 |
| Change in pH in Capillary or Arterialised Blood From Baseline | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT | 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 |
| Change in Body Weight From Baseline | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT | 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 |
| Change in Urinary Weight From Baseline | 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+HCT | 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 |
| The Change in Micturition Frequency From the Baseline | Baseline and day 5 | 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. |
| The Change in Total Muscle Sympathetic Nerve Activity (MSNA) From Off- Treatment | One day before the drug administration, then day 4 after the first drug administration | 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. |
| Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | 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+HCT | 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 |
| Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | 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+HCT | 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 |
| Change in Urinary Excretion in a 24-hour Period of N-terminal Telopeptide (NTx) From Baseline | 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+HCT | 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 |
| Change in Serum Osmolality From Baseline | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT | 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 |
| Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT | 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 |
| Change in Serum Concentration of Creatinine and Uric Acid From Baseline | baseline and then day 5 for Empa, day 4 for TOR and HCT, day 9 for Empa+TOR and Empa+HCT | 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 |
| Change in Serum Concentration of Alkaline Phosphatase (ALP) From Baseline | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT | 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 |
| Change in Serum Concentration of Renin, Intact Parathyroid Hormone (iPTH) and 1,25-dihydroxyvitamin D From Baseline | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT | 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 |
| Change in Serum Concentration of Aldosterone From Baseline | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT | 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 |
| Change in Serum Concentration of Fibroblast Growth Factor-23 (FGF- 23) From Baseline | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT | 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 |
| Change in Urea Concentration in Urine | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT | 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 |
| Change in Urine pH From Baseline | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Measured Concentration of Empa in Plasma (Cmax, ss) | 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 diuretic | Maximum measured concentration of Empa in plasma (Cmax, ss) at steady state |
| Area Under the Concentration-time Curve of HCT in Plasma (AUCτ,ss) | 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 HCT | Area under the concentration-time curve of HCT in plasma at steady state over a uniform dosing interval τ (AUCτ,ss). |
| Maximum Measured Concentration of HCT in Plasma (Cmax, ss) | 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 HCT | Maximum measured concentration of HCT in plasma (Cmax, ss) at steady state |
| Area Under the Concentration-time Curve of TOR in Plasma (AUCτ,ss) | 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 TOR | Area under the concentration-time curve of TOR in plasma at steady state over a uniform dosing interval τ (AUCτ,ss). |
| Maximum Measured Concentration of TOR in Plasma (Cmax, ss) | 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 TOR | Maximum measured concentration of Empa in plasma (Cmax, ss) at steady state |
| 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 | From first drug administration until up to 14 days after the last drug administration, up to 35 days | 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. |
| Area Under the Concentration-time Curve of Empa in Plasma (AUCτ,ss) | 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 diuretic | Area under the concentration-time curve of Empa in plasma at steady state over a uniform dosing interval τ (AUCτ,ss). |
Countries
Germany
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Overall Patients 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. | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 | 0 |
| Overall Study | not treated | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Overall Patients |
|---|---|
| Age, Continuous | 54.0 years STANDARD_DEVIATION 8.1 |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 21 | 1 / 11 | 0 / 10 | 4 / 10 | 6 / 10 |
| serious Total, serious adverse events | 0 / 21 | 0 / 11 | 0 / 10 | 0 / 10 | 0 / 10 |
Outcome results
Primary
Change in Body Weight From Baseline
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
Time frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT
Population: PD analysis set completers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | Change in Body Weight From Baseline | -1.365 kg | Standard Error 0.535 |
| Hydrochlorothiazide (HCT) | Change in Body Weight From Baseline | -1.040 kg | Standard Error 0.227 |
| Torasemide (TOR) | Change in Body Weight From Baseline | -0.380 kg | Standard Error 0.149 |
| Empa+ HCT | Change in Body Weight From Baseline | -2.030 kg | Standard Error 0.344 |
| Empa + TOR | Change in Body Weight From Baseline | -1.750 kg | Standard Error 0.328 |
Primary
Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline
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
Time frame: 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+HCT
Population: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Uric Acid | 6.377 ml/min | Standard Error 1.1 |
| Empagliflozin (Empa) | 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 |
| Hydrochlorothiazide (HCT) | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Potassium | 2.205 ml/min | Standard Error 0.539 |
| Hydrochlorothiazide (HCT) | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Phosphate | 4.633 ml/min | Standard Error 1.342 |
| Hydrochlorothiazide (HCT) | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Sodium | -0.055 ml/min | Standard Error 0.044 |
| Hydrochlorothiazide (HCT) | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Magnesium | 1.826 ml/min | Standard Error 0.288 |
| Hydrochlorothiazide (HCT) | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Chloride | -0.058 ml/min | Standard Error 0.056 |
| Hydrochlorothiazide (HCT) | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Creatinine | -7.034 ml/min | Standard Error 5.494 |
| Hydrochlorothiazide (HCT) | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Calcium | -0.299 ml/min | Standard Error 0.094 |
| Hydrochlorothiazide (HCT) | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Uric Acid | -0.476 ml/min | Standard Error 0.637 |
| Torasemide (TOR) | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Uric Acid | -1.310 ml/min | Standard Error 0.924 |
| Torasemide (TOR) | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Creatinine | -4.250 ml/min | Standard Error 6.574 |
| Torasemide (TOR) | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Magnesium | 1.148 ml/min | Standard Error 0.206 |
| Torasemide (TOR) | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Phosphate | 4.368 ml/min | Standard Error 1.342 |
| Torasemide (TOR) | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Potassium | -0.518 ml/min | Standard Error 0.585 |
| Torasemide (TOR) | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Chloride | -0.157 ml/min | Standard Error 0.064 |
| Torasemide (TOR) | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Sodium | -0.071 ml/min | Standard Error 0.083 |
| Torasemide (TOR) | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Calcium | -0.065 ml/min | Standard Error 0.108 |
| Empa+ HCT | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Chloride | 0.114 ml/min | Standard Error 0.044 |
| Empa+ HCT | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Potassium | 4.125 ml/min | Standard Error 0.634 |
| Empa+ HCT | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Magnesium | 1.115 ml/min | Standard Error 0.181 |
| Empa+ HCT | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Calcium | -0.407 ml/min | Standard Error 0.102 |
| Empa+ HCT | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Phosphate | 2.795 ml/min | Standard Error 1.382 |
| Empa+ HCT | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Creatinine | -10.126 ml/min | Standard Error 7.989 |
| Empa+ HCT | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Sodium | 0.143 ml/min | Standard Error 0.036 |
| Empa+ HCT | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Uric Acid | 5.065 ml/min | Standard Error 1.376 |
| Empa + TOR | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Magnesium | 0.209 ml/min | Standard Error 0.227 |
| Empa + TOR | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Creatinine | -11.768 ml/min | Standard Error 7.135 |
| Empa + TOR | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Potassium | 2.324 ml/min | Standard Error 0.832 |
| Empa + TOR | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Uric Acid | 4.359 ml/min | Standard Error 1.533 |
| Empa + TOR | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Sodium | -0.004 ml/min | Standard Error 0.088 |
| Empa + TOR | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Phosphate | 2.359 ml/min | Standard Error 1.379 |
| Empa + TOR | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Chloride | -0.117 ml/min | Standard Error 0.088 |
| Empa + TOR | Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline | Calcium | -0.174 ml/min | Standard Error 0.105 |
Primary
Change in pH in Capillary or Arterialised Blood From Baseline
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
Time frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT
Population: PD analysis set completers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | Change in pH in Capillary or Arterialised Blood From Baseline | -0.006 pH | Standard Error 0.004 |
| Hydrochlorothiazide (HCT) | Change in pH in Capillary or Arterialised Blood From Baseline | 0.003 pH | Standard Error 0.007 |
| Torasemide (TOR) | Change in pH in Capillary or Arterialised Blood From Baseline | -0.002 pH | Standard Error 0.006 |
| Empa+ HCT | Change in pH in Capillary or Arterialised Blood From Baseline | 0.008 pH | Standard Error 0.008 |
| Empa + TOR | Change in pH in Capillary or Arterialised Blood From Baseline | -0.005 pH | Standard Error 0.008 |
Primary
Change in Serum Concentration of Aldosterone From Baseline
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
Time frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT
Population: PD analysis set completers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | Change in Serum Concentration of Aldosterone From Baseline | -0.018 nmol/L | Standard Error 0.02 |
| Hydrochlorothiazide (HCT) | Change in Serum Concentration of Aldosterone From Baseline | 0.099 nmol/L | Standard Error 0.056 |
| Torasemide (TOR) | Change in Serum Concentration of Aldosterone From Baseline | 0.023 nmol/L | Standard Error 0.018 |
| Empa+ HCT | Change in Serum Concentration of Aldosterone From Baseline | 0.124 nmol/L | Standard Error 0.068 |
| Empa + TOR | Change in Serum Concentration of Aldosterone From Baseline | 0.123 nmol/L | Standard Error 0.069 |
Primary
Change in Serum Concentration of Alkaline Phosphatase (ALP) From Baseline
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
Time frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT
Population: PD analysis set completers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | Change in Serum Concentration of Alkaline Phosphatase (ALP) From Baseline | 2.750 U/L | Standard Error 0.878 |
| Hydrochlorothiazide (HCT) | Change in Serum Concentration of Alkaline Phosphatase (ALP) From Baseline | 3.000 U/L | Standard Error 1.274 |
| Torasemide (TOR) | Change in Serum Concentration of Alkaline Phosphatase (ALP) From Baseline | 2.400 U/L | Standard Error 0.859 |
| Empa+ HCT | Change in Serum Concentration of Alkaline Phosphatase (ALP) From Baseline | 6.500 U/L | Standard Error 1.515 |
| Empa + TOR | Change in Serum Concentration of Alkaline Phosphatase (ALP) From Baseline | 5.800 U/L | Standard Error 1.788 |
Primary
Change in Serum Concentration of Creatinine and Uric Acid From Baseline
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
Time frame: baseline and then day 5 for Empa, day 4 for TOR and HCT, day 9 for Empa+TOR and Empa+HCT
Population: PD analysis set completers
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Empagliflozin (Empa) | Change in Serum Concentration of Creatinine and Uric Acid From Baseline | Creatinine | 2.175 umol/L | Standard Error 1.585 |
| Empagliflozin (Empa) | Change in Serum Concentration of Creatinine and Uric Acid From Baseline | Uric acid | -64.950 umol/L | Standard Error 24.763 |
| Hydrochlorothiazide (HCT) | Change in Serum Concentration of Creatinine and Uric Acid From Baseline | Creatinine | -0.340 umol/L | Standard Error 1.441 |
| Hydrochlorothiazide (HCT) | Change in Serum Concentration of Creatinine and Uric Acid From Baseline | Uric acid | 24.200 umol/L | Standard Error 9.087 |
| Torasemide (TOR) | Change in Serum Concentration of Creatinine and Uric Acid From Baseline | Creatinine | -2.180 umol/L | Standard Error 1.811 |
| Torasemide (TOR) | Change in Serum Concentration of Creatinine and Uric Acid From Baseline | Uric acid | -4.700 umol/L | Standard Error 9.164 |
| Empa+ HCT | Change in Serum Concentration of Creatinine and Uric Acid From Baseline | Uric acid | -31.000 umol/L | Standard Error 18.582 |
| Empa+ HCT | Change in Serum Concentration of Creatinine and Uric Acid From Baseline | Creatinine | 6.280 umol/L | Standard Error 2.764 |
| Empa + TOR | Change in Serum Concentration of Creatinine and Uric Acid From Baseline | Creatinine | 3.570 umol/L | Standard Error 2.348 |
| Empa + TOR | Change in Serum Concentration of Creatinine and Uric Acid From Baseline | Uric acid | -48.200 umol/L | Standard Error 12.984 |
Primary
Change in Serum Concentration of Fibroblast Growth Factor-23 (FGF- 23) From Baseline
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
Time frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT
Population: PD analysis set completers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | Change in Serum Concentration of Fibroblast Growth Factor-23 (FGF- 23) From Baseline | 50.305 RU/mL | Standard Error 23.759 |
| Hydrochlorothiazide (HCT) | Change in Serum Concentration of Fibroblast Growth Factor-23 (FGF- 23) From Baseline | 29.050 RU/mL | Standard Error 25.952 |
| Torasemide (TOR) | Change in Serum Concentration of Fibroblast Growth Factor-23 (FGF- 23) From Baseline | -0.680 RU/mL | Standard Error 5.465 |
| Empa+ HCT | Change in Serum Concentration of Fibroblast Growth Factor-23 (FGF- 23) From Baseline | 109.860 RU/mL | Standard Error 53.745 |
| Empa + TOR | Change in Serum Concentration of Fibroblast Growth Factor-23 (FGF- 23) From Baseline | 13.820 RU/mL | Standard Error 4.739 |
Primary
Change in Serum Concentration of Renin, Intact Parathyroid Hormone (iPTH) and 1,25-dihydroxyvitamin D From Baseline
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
Time frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT
Population: PD analysis set completers
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Hydrochlorothiazide (HCT) | Change in Serum Concentration of Renin, Intact Parathyroid Hormone (iPTH) and 1,25-dihydroxyvitamin D From Baseline | iPTH | 6.160 pg/mL | Standard Error 1.88 |
| Hydrochlorothiazide (HCT) | Change in Serum Concentration of Renin, Intact Parathyroid Hormone (iPTH) and 1,25-dihydroxyvitamin D From Baseline | Renin | 16.150 pg/mL | Standard Error 8.276 |
| Hydrochlorothiazide (HCT) | Change in Serum Concentration of Renin, Intact Parathyroid Hormone (iPTH) and 1,25-dihydroxyvitamin D From Baseline | 1,25-dihydroxyvitamin D | 1.560 pg/mL | Standard Error 4.029 |
| Torasemide (TOR) | Change in Serum Concentration of Renin, Intact Parathyroid Hormone (iPTH) and 1,25-dihydroxyvitamin D From Baseline | iPTH | 6.910 pg/mL | Standard Error 2.059 |
| Torasemide (TOR) | Change in Serum Concentration of Renin, Intact Parathyroid Hormone (iPTH) and 1,25-dihydroxyvitamin D From Baseline | Renin | 2.550 pg/mL | Standard Error 1.882 |
| Torasemide (TOR) | Change in Serum Concentration of Renin, Intact Parathyroid Hormone (iPTH) and 1,25-dihydroxyvitamin D From Baseline | 1,25-dihydroxyvitamin D | 3.530 pg/mL | Standard Error 5.123 |
| Empa+ HCT | Change in Serum Concentration of Renin, Intact Parathyroid Hormone (iPTH) and 1,25-dihydroxyvitamin D From Baseline | Renin | 32.760 pg/mL | Standard Error 16.863 |
| Empa+ HCT | Change in Serum Concentration of Renin, Intact Parathyroid Hormone (iPTH) and 1,25-dihydroxyvitamin D From Baseline | 1,25-dihydroxyvitamin D | -5.060 pg/mL | Standard Error 4.07 |
| Empa+ HCT | Change in Serum Concentration of Renin, Intact Parathyroid Hormone (iPTH) and 1,25-dihydroxyvitamin D From Baseline | iPTH | 9.280 pg/mL | Standard Error 1.619 |
| Empa + TOR | Change in Serum Concentration of Renin, Intact Parathyroid Hormone (iPTH) and 1,25-dihydroxyvitamin D From Baseline | iPTH | 12.190 pg/mL | Standard Error 3.233 |
| Empa + TOR | Change in Serum Concentration of Renin, Intact Parathyroid Hormone (iPTH) and 1,25-dihydroxyvitamin D From Baseline | Renin | 17.050 pg/mL | Standard Error 3.645 |
| Empa + TOR | Change in Serum Concentration of Renin, Intact Parathyroid Hormone (iPTH) and 1,25-dihydroxyvitamin D From Baseline | 1,25-dihydroxyvitamin D | -0.970 pg/mL | Standard Error 4.329 |
Primary
Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline
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
Time frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT
Population: PD analysis set completers
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Glucose | -1.123 mmol/L | Standard Error 0.25 |
| Hydrochlorothiazide (HCT) | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Magnesium | 0.025 mmol/L | Standard Error 0.014 |
| Hydrochlorothiazide (HCT) | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Phosphate | 0.060 mmol/L | Standard Error 0.031 |
| Hydrochlorothiazide (HCT) | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Sodium | -0.500 mmol/L | Standard Error 0.401 |
| Hydrochlorothiazide (HCT) | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Chloride | -2.600 mmol/L | Standard Error 0.521 |
| Hydrochlorothiazide (HCT) | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Potassium | -0.470 mmol/L | Standard Error 0.087 |
| Hydrochlorothiazide (HCT) | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Glucose | 0.849 mmol/L | Standard Error 0.177 |
| Hydrochlorothiazide (HCT) | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Calcium | -0.040 mmol/L | Standard Error 0.034 |
| Hydrochlorothiazide (HCT) | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Urea | 0.650 mmol/L | Standard Error 0.149 |
| Torasemide (TOR) | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Urea | 0.318 mmol/L | Standard Error 0.22 |
| Torasemide (TOR) | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Glucose | 0.527 mmol/L | Standard Error 0.29 |
| Torasemide (TOR) | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Chloride | 1.000 mmol/L | Standard Error 0.775 |
| Torasemide (TOR) | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Phosphate | -0.060 mmol/L | Standard Error 0.034 |
| Torasemide (TOR) | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Magnesium | 0.059 mmol/L | Standard Error 0.01 |
| Torasemide (TOR) | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Potassium | -0.200 mmol/L | Standard Error 0.087 |
| Torasemide (TOR) | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Sodium | 0.200 mmol/L | Standard Error 0.573 |
| Torasemide (TOR) | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Calcium | -0.080 mmol/L | Standard Error 0.02 |
| Empa+ HCT | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Potassium | -0.530 mmol/L | Standard Error 0.091 |
| Empa+ HCT | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Magnesium | 0.130 mmol/L | Standard Error 0.014 |
| Empa+ HCT | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Chloride | -3.200 mmol/L | Standard Error 1.365 |
| Empa+ HCT | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Calcium | -0.010 mmol/L | Standard Error 0.031 |
| Empa+ HCT | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Phosphate | 0.170 mmol/L | Standard Error 0.04 |
| Empa+ HCT | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Glucose | -0.033 mmol/L | Standard Error 0.168 |
| Empa+ HCT | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Sodium | -0.100 mmol/L | Standard Error 0.433 |
| Empa+ HCT | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Urea | 1.504 mmol/L | Standard Error 0.161 |
| Empa + TOR | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Chloride | 2.100 mmol/L | Standard Error 1.65 |
| Empa + TOR | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Glucose | -0.526 mmol/L | Standard Error 0.389 |
| Empa + TOR | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Magnesium | 0.145 mmol/L | Standard Error 0.019 |
| Empa + TOR | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Urea | 2.122 mmol/L | Standard Error 0.429 |
| Empa + TOR | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Sodium | 1.600 mmol/L | Standard Error 1.222 |
| Empa + TOR | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Phosphate | 0.050 mmol/L | Standard Error 0.045 |
| Empa + TOR | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Potassium | -0.360 mmol/L | Standard Error 0.097 |
| Empa + TOR | Change in Serum Concentration of Sodium, Potassium, Magnesium, Calcium, Chloride, Phosphate, Glucose and Urea From Baseline | Calcium | -0.060 mmol/L | Standard Error 0.037 |
Primary
Change in Serum Osmolality From Baseline
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
Time frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT
Population: PD analysis set completers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | Change in Serum Osmolality From Baseline | 3.950 mOsm/Kg | Standard Error 3.748 |
| Hydrochlorothiazide (HCT) | Change in Serum Osmolality From Baseline | -7.500 mOsm/Kg | Standard Error 3.519 |
| Torasemide (TOR) | Change in Serum Osmolality From Baseline | -5.500 mOsm/Kg | Standard Error 2.915 |
| Empa+ HCT | Change in Serum Osmolality From Baseline | -2.200 mOsm/Kg | Standard Error 3.972 |
| Empa + TOR | Change in Serum Osmolality From Baseline | 10.500 mOsm/Kg | Standard Error 3.625 |
Primary
Change in Urea Concentration in Urine
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
Time frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT
Population: PD analysis set completers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | Change in Urea Concentration in Urine | -1.515 mmol/L | Standard Error 14.048 |
| Hydrochlorothiazide (HCT) | Change in Urea Concentration in Urine | 67.570 mmol/L | Standard Error 29.271 |
| Torasemide (TOR) | Change in Urea Concentration in Urine | 35.710 mmol/L | Standard Error 34.666 |
| Empa+ HCT | Change in Urea Concentration in Urine | 11.780 mmol/L | Standard Error 9.819 |
| Empa + TOR | Change in Urea Concentration in Urine | 48.690 mmol/L | Standard Error 31.445 |
Primary
Change in Urinary Excretion in a 24-hour Period of N-terminal Telopeptide (NTx) From Baseline
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
Time frame: 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+HCT
Population: PD analysis set completers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | 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 |
| Hydrochlorothiazide (HCT) | Change in Urinary Excretion in a 24-hour Period of N-terminal Telopeptide (NTx) From Baseline | 0.730 nM BCE/ mMC | Standard Error 2.704 |
| Torasemide (TOR) | Change in Urinary Excretion in a 24-hour Period of N-terminal Telopeptide (NTx) From Baseline | 2.030 nM BCE/ mMC | Standard Error 0.723 |
| Empa+ HCT | Change in Urinary Excretion in a 24-hour Period of N-terminal Telopeptide (NTx) From Baseline | 1.380 nM BCE/ mMC | Standard Error 3.429 |
| Empa + TOR | Change in Urinary Excretion in a 24-hour Period of N-terminal Telopeptide (NTx) From Baseline | 3.900 nM BCE/ mMC | Standard Error 1.424 |
Primary
Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline
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
Time frame: 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+HCT
Population: PD analysis set completers
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Hydrochlorothiazide (HCT) | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Creatinine | -0.078 mmol/day | Standard Error 0.058 |
| Hydrochlorothiazide (HCT) | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Phosphate | 9.000 mmol/day | Standard Error 2.261 |
| Hydrochlorothiazide (HCT) | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Magnesium | 2.270 mmol/day | Standard Error 0.387 |
| Hydrochlorothiazide (HCT) | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Calcium | -1.020 mmol/day | Standard Error 0.299 |
| Hydrochlorothiazide (HCT) | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Potassium | 6.200 mmol/day | Standard Error 3.008 |
| Hydrochlorothiazide (HCT) | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Glucose | 17.584 mmol/day | Standard Error 8.161 |
| Hydrochlorothiazide (HCT) | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Chloride | -12.300 mmol/day | Standard Error 7.939 |
| Hydrochlorothiazide (HCT) | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Sodium | -11.700 mmol/day | Standard Error 8.495 |
| Hydrochlorothiazide (HCT) | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Uric acid | -0.037 mmol/day | Standard Error 0.251 |
| Torasemide (TOR) | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Phosphate | 4.900 mmol/day | Standard Error 1.9 |
| Torasemide (TOR) | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Sodium | -13.700 mmol/day | Standard Error 16.445 |
| Torasemide (TOR) | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Chloride | -22.000 mmol/day | Standard Error 9.421 |
| Torasemide (TOR) | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Potassium | -6.990 mmol/day | Standard Error 3.92 |
| Torasemide (TOR) | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Magnesium | 1.720 mmol/day | Standard Error 0.263 |
| Torasemide (TOR) | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Calcium | -0.430 mmol/day | Standard Error 0.377 |
| Torasemide (TOR) | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Creatinine | -0.073 mmol/day | Standard Error 0.045 |
| Torasemide (TOR) | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Uric acid | -0.500 mmol/day | Standard Error 0.349 |
| Torasemide (TOR) | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Glucose | 17.932 mmol/day | Standard Error 25.477 |
| Empa+ HCT | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Magnesium | 2.030 mmol/day | Standard Error 0.225 |
| Empa+ HCT | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Phosphate | 8.300 mmol/day | Standard Error 2.103 |
| Empa+ HCT | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Potassium | 15.790 mmol/day | Standard Error 2.963 |
| Empa+ HCT | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Creatinine | 0.022 mmol/day | Standard Error 0.041 |
| Empa+ HCT | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Chloride | 11.400 mmol/day | Standard Error 6.092 |
| Empa+ HCT | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Glucose | 685.233 mmol/day | Standard Error 68.035 |
| Empa+ HCT | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Uric acid | 1.555 mmol/day | Standard Error 0.327 |
| Empa+ HCT | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Sodium | 28.900 mmol/day | Standard Error 7.512 |
| Empa+ HCT | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Calcium | -1.360 mmol/day | Standard Error 0.294 |
| Empa + TOR | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Sodium | 1.200 mmol/day | Standard Error 17.068 |
| Empa + TOR | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Magnesium | 1.050 mmol/day | Standard Error 0.28 |
| Empa + TOR | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Phosphate | 5.000 mmol/day | Standard Error 2.357 |
| Empa + TOR | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Potassium | 8.460 mmol/day | Standard Error 5.288 |
| Empa + TOR | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Calcium | -0.740 mmol/day | Standard Error 0.306 |
| Empa + TOR | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Glucose | 740.910 mmol/day | Standard Error 54.134 |
| Empa + TOR | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Uric acid | 1.244 mmol/day | Standard Error 0.493 |
| Empa + TOR | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Creatinine | -0.040 mmol/day | Standard Error 0.068 |
| Empa + TOR | Change in Urinary Excretion in a 24-hour Period of Sodium, Potassium, Magnesium, Chloride, Calcium, Phosphate, Creatinine, Uric Acid, Glucose From Baseline | Chloride | -14.600 mmol/day | Standard Error 12.12 |
Primary
Change in Urinary Weight From Baseline
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
Time frame: 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+HCT
Population: PD analysis set completers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | Change in Urinary Weight From Baseline | 134.700 g/day | Standard Error 95.358 |
| Hydrochlorothiazide (HCT) | Change in Urinary Weight From Baseline | -55.300 g/day | Standard Error 67.517 |
| Torasemide (TOR) | Change in Urinary Weight From Baseline | -39.000 g/day | Standard Error 106.642 |
| Empa+ HCT | Change in Urinary Weight From Baseline | 429.000 g/day | Standard Error 92.357 |
| Empa + TOR | Change in Urinary Weight From Baseline | 353.200 g/day | Standard Error 116.293 |
Primary
Change in Urine Osmolality From Baseline
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
Time frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT
Population: PD analysis set completers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | Change in Urine Osmolality From Baseline | 223.15 mOsm/kg | Standard Error 34.85 |
| Hydrochlorothiazide (HCT) | Change in Urine Osmolality From Baseline | -3.900 mOsm/kg | Standard Error 43.239 |
| Torasemide (TOR) | Change in Urine Osmolality From Baseline | -5.800 mOsm/kg | Standard Error 54.743 |
| Empa+ HCT | Change in Urine Osmolality From Baseline | 217.700 mOsm/kg | Standard Error 31.43 |
| Empa + TOR | Change in Urine Osmolality From Baseline | 330.400 mOsm/kg | Standard Error 45.645 |
Primary
Change in Urine pH From Baseline
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
Time frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT
Population: PD analysis set completers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | Change in Urine pH From Baseline | -0.132 pH | Standard Error 0.161 |
| Hydrochlorothiazide (HCT) | Change in Urine pH From Baseline | -0.452 pH | Standard Error 0.291 |
| Torasemide (TOR) | Change in Urine pH From Baseline | -0.147 pH | Standard Error 0.062 |
| Empa+ HCT | Change in Urine pH From Baseline | -0.448 pH | Standard Error 0.259 |
| Empa + TOR | Change in Urine pH From Baseline | 0.130 pH | Standard Error 0.191 |
Primary
Changes in Bicarbonate Concentrations of Calcium, Bicarbonate Ions and Base Excess in Capillary or Arterialised Blood From Baseline
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
Time frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT
Population: PD analysis set completers
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Empagliflozin (Empa) | 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 |
| Hydrochlorothiazide (HCT) | Changes in Bicarbonate Concentrations of Calcium, Bicarbonate Ions and Base Excess in Capillary or Arterialised Blood From Baseline | bicarbonate ions | -0.043 mmol/ L | Standard Error 0.023 |
| Hydrochlorothiazide (HCT) | Changes in Bicarbonate Concentrations of Calcium, Bicarbonate Ions and Base Excess in Capillary or Arterialised Blood From Baseline | Bicarbonate concentrations of calcium | 2.020 mmol/ L | Standard Error 0.397 |
| Hydrochlorothiazide (HCT) | Changes in Bicarbonate Concentrations of Calcium, Bicarbonate Ions and Base Excess in Capillary or Arterialised Blood From Baseline | Base excess | 1.640 mmol/ L | Standard Error 0.325 |
| Torasemide (TOR) | Changes in Bicarbonate Concentrations of Calcium, Bicarbonate Ions and Base Excess in Capillary or Arterialised Blood From Baseline | bicarbonate ions | -0.041 mmol/ L | Standard Error 0.018 |
| Torasemide (TOR) | Changes in Bicarbonate Concentrations of Calcium, Bicarbonate Ions and Base Excess in Capillary or Arterialised Blood From Baseline | Bicarbonate concentrations of calcium | -0.400 mmol/ L | Standard Error 0.45 |
| Torasemide (TOR) | Changes in Bicarbonate Concentrations of Calcium, Bicarbonate Ions and Base Excess in Capillary or Arterialised Blood From Baseline | Base excess | -0.420 mmol/ L | Standard Error 0.386 |
| Empa+ HCT | Changes in Bicarbonate Concentrations of Calcium, Bicarbonate Ions and Base Excess in Capillary or Arterialised Blood From Baseline | Bicarbonate concentrations of calcium | 1.860 mmol/ L | Standard Error 0.445 |
| Empa+ HCT | Changes in Bicarbonate Concentrations of Calcium, Bicarbonate Ions and Base Excess in Capillary or Arterialised Blood From Baseline | Base excess | 1.720 mmol/ L | Standard Error 0.432 |
| Empa+ HCT | Changes in Bicarbonate Concentrations of Calcium, Bicarbonate Ions and Base Excess in Capillary or Arterialised Blood From Baseline | bicarbonate ions | -0.053 mmol/ L | Standard Error 0.015 |
| Empa + TOR | 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 0.015 |
| Empa + TOR | Changes in Bicarbonate Concentrations of Calcium, Bicarbonate Ions and Base Excess in Capillary or Arterialised Blood From Baseline | Bicarbonate concentrations of calcium | -1.590 mmol/ L | Standard Error 0.58 |
| Empa + TOR | Changes in Bicarbonate Concentrations of Calcium, Bicarbonate Ions and Base Excess in Capillary or Arterialised Blood From Baseline | Base excess | -1.450 mmol/ L | Standard Error 0.576 |
Primary
The Change in Micturition Frequency From the Baseline
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.
Time frame: Baseline and day 5
Population: PD analysis set completers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | The Change in Micturition Frequency From the Baseline | 1.600 voids per day | Standard Error 0.478 |
Primary
The Change in Total Muscle Sympathetic Nerve Activity (MSNA) From Off- Treatment
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.
Time frame: One day before the drug administration, then day 4 after the first drug administration
Population: PD analysis set completers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | The Change in Total Muscle Sympathetic Nerve Activity (MSNA) From Off- Treatment | 0.241 action potentials per min | Standard Error 0.354 |
Primary
Urinary Sodium Excretion Over 24-hour run-in Periods
Urinary sodium excretion over 24-hour run-in periods to assess the harmonisation of electrolytes after intake of a standardised diet
Time frame: Day 3, 2 and 1 before the first drug administration
Population: PD analysis set completers
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Empagliflozin (Empa) | Urinary Sodium Excretion Over 24-hour run-in Periods | 1 day before the drug administration | 163.90 mmol/day | Standard Error 8.57 |
| Empagliflozin (Empa) | Urinary Sodium Excretion Over 24-hour run-in Periods | 2 days before the drug administration | 174.35 mmol/day | Standard Error 10.26 |
| Empagliflozin (Empa) | Urinary Sodium Excretion Over 24-hour run-in Periods | 3 days before the drug administration | 198.50 mmol/day | Standard Error 20.3 |
| Hydrochlorothiazide (HCT) | Urinary Sodium Excretion Over 24-hour run-in Periods | 1 day before the drug administration | 170.10 mmol/day | Standard Error 7.58 |
| Hydrochlorothiazide (HCT) | Urinary Sodium Excretion Over 24-hour run-in Periods | 3 days before the drug administration | 211.10 mmol/day | Standard Error 9.37 |
| Hydrochlorothiazide (HCT) | Urinary Sodium Excretion Over 24-hour run-in Periods | 2 days before the drug administration | 183.30 mmol/day | Standard Error 13.15 |
| Torasemide (TOR) | Urinary Sodium Excretion Over 24-hour run-in Periods | 1 day before the drug administration | 179.10 mmol/day | Standard Error 8.87 |
| Torasemide (TOR) | Urinary Sodium Excretion Over 24-hour run-in Periods | 2 days before the drug administration | 178.70 mmol/day | Standard Error 13 |
| Torasemide (TOR) | Urinary Sodium Excretion Over 24-hour run-in Periods | 3 days before the drug administration | 217.90 mmol/day | Standard Error 27.77 |
Secondary
Area Under the Concentration-time Curve of Empa in Plasma (AUCτ,ss)
Area under the concentration-time curve of Empa in plasma at steady state over a uniform dosing interval τ (AUCτ,ss).
Time frame: 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 diuretic
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | Area Under the Concentration-time Curve of Empa in Plasma (AUCτ,ss) | 4990 nmol*h/L | Geometric Coefficient of Variation 21.1 |
| Hydrochlorothiazide (HCT) | Area Under the Concentration-time Curve of Empa in Plasma (AUCτ,ss) | 5570 nmol*h/L | Geometric Coefficient of Variation 25.2 |
| Torasemide (TOR) | Area Under the Concentration-time Curve of Empa in Plasma (AUCτ,ss) | 5260 nmol*h/L | Geometric Coefficient of Variation 19.1 |
Comparison: Only patients in sequences Empa/Empa+HCT were includedp-value: 0.009290% CI: [97.11, 118.07]ANOVA
Comparison: Only patients in sequences Empa/Empa+TOR were includedp-value: 0.00390% CI: [100.14, 116.11]ANOVA
Secondary
Area Under the Concentration-time Curve of HCT in Plasma (AUCτ,ss)
Area under the concentration-time curve of HCT in plasma at steady state over a uniform dosing interval τ (AUCτ,ss).
Time frame: 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 HCT
Population: PK set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | Area Under the Concentration-time Curve of HCT in Plasma (AUCτ,ss) | 1040 ng*h/mL | Geometric Coefficient of Variation 17.9 |
| Hydrochlorothiazide (HCT) | Area Under the Concentration-time Curve of HCT in Plasma (AUCτ,ss) | 1000 ng*h/mL | Geometric Coefficient of Variation 18.7 |
Comparison: Only patients in sequences Empa/Empa+HCT were includedp-value: 0.000890% CI: [89.08, 104.05]ANOVA
Secondary
Area Under the Concentration-time Curve of TOR in Plasma (AUCτ,ss)
Area under the concentration-time curve of TOR in plasma at steady state over a uniform dosing interval τ (AUCτ,ss).
Time frame: 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 TOR
Population: PK set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | Area Under the Concentration-time Curve of TOR in Plasma (AUCτ,ss) | 1320 ng*h/mL | Geometric Coefficient of Variation 14 |
| Hydrochlorothiazide (HCT) | Area Under the Concentration-time Curve of TOR in Plasma (AUCτ,ss) | 1340 ng*h/mL | Geometric Coefficient of Variation 16.1 |
| Torasemide (TOR) | Area Under the Concentration-time Curve of TOR in Plasma (AUCτ,ss) | 74.8 ng*h/mL | Geometric Coefficient of Variation 15.9 |
| Empa+ HCT | Area Under the Concentration-time Curve of TOR in Plasma (AUCτ,ss) | 40.5 ng*h/mL | Geometric Coefficient of Variation 23.9 |
| Empa + TOR | Area Under the Concentration-time Curve of TOR in Plasma (AUCτ,ss) | 78.1 ng*h/mL | Geometric Coefficient of Variation 17.7 |
| TOR-M3 + Empa | Area Under the Concentration-time Curve of TOR in Plasma (AUCτ,ss) | 41.8 ng*h/mL | Geometric Coefficient of Variation 18.2 |
Comparison: Only patients in sequences Empa/Empa+TOR were includedp-value: <0.000190% CI: [99.06, 103.88]ANOVA
Comparison: Only patients in sequences Empa/Empa+TOR were includedp-value: <0.000190% CI: [100.39, 108.62]ANOVA
Comparison: Only patients in sequences Empa/Empa+TOR were includedp-value: 0.000590% CI: [95.93, 111.01]ANOVA
Secondary
Maximum Measured Concentration of Empa in Plasma (Cmax, ss)
Maximum measured concentration of Empa in plasma (Cmax, ss) at steady state
Time frame: 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 diuretic
Population: PK set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | Maximum Measured Concentration of Empa in Plasma (Cmax, ss) | 939 nmol/L | Geometric Coefficient of Variation 21.4 |
| Hydrochlorothiazide (HCT) | Maximum Measured Concentration of Empa in Plasma (Cmax, ss) | 1030 nmol/L | Geometric Coefficient of Variation 31.2 |
| Torasemide (TOR) | Maximum Measured Concentration of Empa in Plasma (Cmax, ss) | 949 nmol/L | Geometric Coefficient of Variation 21.9 |
Comparison: Only patients in sequences Empa/Empa+HCT were includedp-value: 0.019990% CI: [88.55, 119.29]ANOVA
Comparison: Only patients in sequences Empa/Empa+TOR were includedp-value: 0.008690% CI: [97.9, 118.04]ANOVA
Secondary
Maximum Measured Concentration of HCT in Plasma (Cmax, ss)
Maximum measured concentration of HCT in plasma (Cmax, ss) at steady state
Time frame: 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 HCT
Population: PK set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | Maximum Measured Concentration of HCT in Plasma (Cmax, ss) | 203 ng/mL | Geometric Coefficient of Variation 31.5 |
| Hydrochlorothiazide (HCT) | Maximum Measured Concentration of HCT in Plasma (Cmax, ss) | 205 ng/mL | Geometric Coefficient of Variation 30.3 |
Comparison: Only patients in sequences Empa/Empa+HCT were includedp-value: 0.011490% CI: [88.63, 116.85]ANOVA
Secondary
Maximum Measured Concentration of TOR in Plasma (Cmax, ss)
Maximum measured concentration of Empa in plasma (Cmax, ss) at steady state
Time frame: 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 TOR
Population: PK set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin (Empa) | Maximum Measured Concentration of TOR in Plasma (Cmax, ss) | 710 ng/mL | Geometric Coefficient of Variation 19.1 |
| Hydrochlorothiazide (HCT) | Maximum Measured Concentration of TOR in Plasma (Cmax, ss) | 741 ng/mL | Geometric Coefficient of Variation 12.9 |
| Torasemide (TOR) | Maximum Measured Concentration of TOR in Plasma (Cmax, ss) | 42.6 ng/mL | Geometric Coefficient of Variation 23 |
| Empa+ HCT | Maximum Measured Concentration of TOR in Plasma (Cmax, ss) | 8.58 ng/mL | Geometric Coefficient of Variation 12.3 |
| Empa + TOR | Maximum Measured Concentration of TOR in Plasma (Cmax, ss) | 43.8 ng/mL | Geometric Coefficient of Variation 18 |
| TOR-M3 + Empa | Maximum Measured Concentration of TOR in Plasma (Cmax, ss) | 8.79 ng/mL | Geometric Coefficient of Variation 16.8 |
Comparison: Only patients in sequences Empa/Empa+TOR were includedp-value: 0.006690% CI: [93.81, 116.25]ANOVA
Comparison: Only patients in sequences Empa/Empa+TOR were includedp-value: 0.001290% CI: [94.13, 111.97]ANOVA
Comparison: Only patients in sequences Empa/Empa+TOR were includedp-value: <0.000190% CI: [97.65, 107.42]ANOVA
Secondary
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
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.
Time frame: From first drug administration until up to 14 days after the last drug administration, up to 35 days
Population: Treated set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Empagliflozin (Empa) | 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 |
| Hydrochlorothiazide (HCT) | 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 | 0 participants |
| Torasemide (TOR) | 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 | 0 participants |
| Empa+ HCT | 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 | 0 participants |
| Empa + TOR | 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 | 0 participants |