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| ID | Type | Description | Link |
|---|---|---|---|
| 2010-019624-31 | EudraCT Number | EudraCT |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Reference 1 | Active Comparator | administration of BI 10773 once daily for 5 days (20 patients) |
|
| Reference 2 | Active Comparator | administration of hydrochlorothiazide (HTC) once daily for 4 days (10 patients) |
|
| Reference 3 | Active Comparator | administration of torasemide (TOR) once daily for 4 days (10 patients) |
|
| Test 1 | Experimental | administration of BI 10773 + HTC once daily for 5 days (10 patients) |
|
| Test 2 | Experimental | administration of BI 10773 + TOR once daily for 5 days (10 patients) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| BI 10773 | Drug | multiple oral doses |
| |
| hydrochlorothiazide |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | 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 | 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 | 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 | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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). | 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 |
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Inclusion criteria:
1. male and female patients of type 2 diabetes
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| Name | Affiliation | Role |
|---|---|---|
| Boehringer Ingelheim | Boehringer Ingelheim | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| 1245.42.1 Boehringer Ingelheim Investigational Site | Neuss | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27692976 | Derived | Heise T, Jordan J, Wanner C, Heer M, Macha S, Mattheus M, Lund SS, Woerle HJ, Broedl UC. Pharmacodynamic Effects of Single and Multiple Doses of Empagliflozin in Patients With Type 2 Diabetes. Clin Ther. 2016 Oct;38(10):2265-2276. doi: 10.1016/j.clinthera.2016.09.001. Epub 2016 Sep 28. | |
| 27666126 | Derived | Heise T, Jordan J, Wanner C, Heer M, Macha S, Mattheus M, Lund SS, Woerle HJ, Broedl UC. Acute Pharmacodynamic Effects of Empagliflozin With and Without Diuretic Agents in Patients With Type 2 Diabetes Mellitus. Clin Ther. 2016 Oct;38(10):2248-2264.e5. doi: 10.1016/j.clinthera.2016.08.008. Epub 2016 Sep 22. |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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). |
| FG002 | 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. |
| FG003 | 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). |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Treated set (TS) that includes all patients who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | 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 | Posted | Mean | Standard Error | ml/min | 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 |
From first drug administration until up to 14 days after the last drug administration, up to 35 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Empagliflozin (Empa) | Empagliflozin (Empa) 25 mg administered once daily for 5 days |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Atrial tachycardia | Cardiac disorders | MEDDRA 15.0 | Systematic Assessment |
Additional secondary endpoints were listed in the original protocol. Those endpoints are of exploratory nature only and were not considered relevant for trial conclusions. For more information see tab "Full Text Review", section "More Information"
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Boehringer Ingelheim Call Center | Boehringer Ingelheim Pharmaceuticals | 1-800-243-0127 | clintriage.rdg@boehringer-ingelheim.com |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| C570240 | empagliflozin |
| D006852 | Hydrochlorothiazide |
| D000077786 | Torsemide |
| ID | Term |
|---|---|
| D002740 | Chlorothiazide |
| D001581 | Benzothiadiazines |
| D013449 | Sulfonamides |
| D013450 | Sulfones |
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| Drug |
multiple oral doses |
|
| torasemide | Drug | multiple oral doses |
|
| BI 10773 | Drug | multiple oral doses |
|
| torasemide | Drug | multiple oral doses |
|
| BI 10773 | Drug | multiple oral doses |
|
| hydrochlorothiazide | Drug | multiple oral doses |
|
| 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 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 | 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 | 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 | 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 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 | 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 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT |
| 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 | 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 |
| 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. | Baseline and day 5 |
| 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. | One day before the drug administration, then day 4 after the first drug administration |
| 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 | Day 3, 2 and 1 before the first drug administration |
| Maximum Measured Concentration of Empa in Plasma (Cmax, ss) | Maximum measured concentration of Empa in plasma (Cmax, ss) at steady state | 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 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). | 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) | Maximum measured concentration of HCT in plasma (Cmax, ss) at steady state | 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 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). | 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 TOR in Plasma (Cmax, ss) | Maximum measured concentration of Empa in plasma (Cmax, ss) at steady state | 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 |
| 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. | From first drug administration until up to 14 days after the last drug administration, up to 35 days |
| 25636696 | Derived | Heise T, Mattheus M, Woerle HJ, Broedl UC, Macha S. Assessing pharmacokinetic interactions between the sodium glucose cotransporter 2 inhibitor empagliflozin and hydrochlorothiazide or torasemide in patients with type 2 diabetes mellitus: a randomized, open-label, crossover study. Clin Ther. 2015 Apr 1;37(4):793-803. doi: 10.1016/j.clinthera.2014.12.018. Epub 2015 Jan 28. |
| not treated |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| ID | Title | Description |
|---|---|---|
| OG000 | Empagliflozin (Empa) | Empagliflozin (Empa) 25 mg administered once daily for 5 days |
| OG001 | Hydrochlorothiazide (HCT) | Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days |
| OG002 | Torasemide (TOR) | Torasemide (TOR) 5 mg administered once daily for 4 days |
| OG003 | Empa+ HCT | Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days |
| OG004 | Empa + TOR | Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days |
|
|
| 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 | PD analysis set completers | Posted | Mean | Standard Error | mmol/day | 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 |
|
|
|
| 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 | PD analysis set completers | Posted | Mean | Standard Error | nM BCE/ mMC | 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 |
|
|
|
| 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 | PD analysis set completers | Posted | Mean | Standard Error | mOsm/Kg | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT |
|
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| 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 | PD analysis set completers | Posted | Mean | Standard Error | mmol/L | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT |
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| 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 | PD analysis set completers | Posted | Mean | Standard Error | umol/L | baseline and then day 5 for Empa, day 4 for TOR and HCT, day 9 for Empa+TOR and Empa+HCT |
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| 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 | PD analysis set completers | Posted | Mean | Standard Error | U/L | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT |
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| 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 | PD analysis set completers | Posted | Mean | Standard Error | pg/mL | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT |
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| 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 | PD analysis set completers | Posted | Mean | Standard Error | nmol/L | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT |
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| 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 | PD analysis set completers | Posted | Mean | Standard Error | RU/mL | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT |
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| 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 | PD analysis set completers | Posted | Mean | Standard Error | mmol/L | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT |
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| 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 | PD analysis set completers | Posted | Mean | Standard Error | pH | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT |
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| 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 | PD analysis set completers | Posted | Mean | Standard Error | mOsm/kg | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT |
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| 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 | PD analysis set completers | Posted | Mean | Standard Error | mmol/ L | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT |
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| 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 | PD analysis set completers | Posted | Mean | Standard Error | pH | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT |
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| 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 | PD analysis set completers | Posted | Mean | Standard Error | kg | baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT |
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| 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 | PD analysis set completers | Posted | Mean | Standard Error | g/day | 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 |
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| 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. | PD analysis set completers | Posted | Mean | Standard Error | voids per day | Baseline and day 5 |
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| 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. | PD analysis set completers | Posted | Mean | Standard Error | action potentials per min | One day before the drug administration, then day 4 after the first drug administration |
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| 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). | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | nmol*h/L | 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 |
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| Secondary | Maximum Measured Concentration of Empa in Plasma (Cmax, ss) | Maximum measured concentration of Empa in plasma (Cmax, ss) at steady state | PK set | Posted | Geometric Mean | Geometric Coefficient of Variation | nmol/L | 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 |
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| 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). | PK set | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*h/mL | 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 |
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| Secondary | Maximum Measured Concentration of HCT in Plasma (Cmax, ss) | Maximum measured concentration of HCT in plasma (Cmax, ss) at steady state | PK set | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 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 |
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| 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). | PK set | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*h/mL | 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 |
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| Secondary | Maximum Measured Concentration of TOR in Plasma (Cmax, ss) | Maximum measured concentration of Empa in plasma (Cmax, ss) at steady state | PK set | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 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 |
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| 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 | PD analysis set completers | Posted | Mean | Standard Error | mmol/day | Day 3, 2 and 1 before the first drug administration |
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| 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. | Treated set | Posted | Number | participants | From first drug administration until up to 14 days after the last drug administration, up to 35 days |
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| 0 |
| 21 |
| 1 |
| 21 |
| EG001 | Hydrochlorothiazide (HCT) | Hydrochlorothiazide (HCT) 25 mg administered once daily for 4 days | 0 | 11 | 1 | 11 |
| EG002 | Torasemide (TOR) | Torasemide (TOR) 5 mg administered once daily for 4 days | 0 | 10 | 0 | 10 |
| EG003 | Empa+ HCT | Empagliflozin (Empa) 25 mg + Hydrochlorothiazide (HCT) 25 mg administered once daily for 5 days | 0 | 10 | 4 | 10 |
| EG004 | Empa + TOR | Empagliflozin (Empa) 25 mg + Torasemide (TOR) 5 mg administered once daily for 5 days | 0 | 10 | 6 | 10 |
| Thirst | General disorders | MEDDRA 15.0 | Systematic Assessment |
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| Muscle spasms | Musculoskeletal and connective tissue disorders | MEDDRA 15.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MEDDRA 15.0 | Systematic Assessment |
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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.
| D004700 | Endocrine System Diseases |
| D013457 |
| Sulfur Compounds |
| D009930 | Organic Chemicals |
| D049971 | Thiazides |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D000577 | Amides |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| Chloride |
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| Potassium |
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| Magnesium |
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| Calcium |
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| Phosphate |
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| Creatinine |
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| Uric acid |
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| Glucose |
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| Potassium |
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| Magnesium |
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| Chloride |
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| Calcium |
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| Phosphate |
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| Urea |
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| Glucose |
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| Uric acid |
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| iPTH |
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| 1,25-dihydroxyvitamin D |
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| bicarbonate ions |
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| Base excess |
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No formal testing in a confirmatory sense |
| Only patients in sequences Empa/Empa+TOR were included | ANOVA | Model was adjusted for sequence, period and treatment as fixed effects while subjects within sequences as random effect | 0.0030 | p-value for ratio outside interval 80-125% Ratio calculated as Empa plus TOR divided by Empa | Geometric mean ratio | 107.83 | Standard Deviation | 8.9 | 2-Sided | 90 | 100.14 | 116.11 | Standard deviation is actually the geometric coefficient of variation (gCV) reflecting intra-subject variabilities | Yes | Non-Inferiority or Equivalence | No formal testing in a confirmatory sense |
No formal testing in a confirmatory sense |
| Only patients in sequences Empa/Empa+TOR were included | ANOVA | Model was adjusted for sequence, period and treatment as fixed effects while subjects within sequences as random effect | 0.0086 | p-value for ratio outside interval 80-125% Ratio calculated as Empa+ TOR divided by Empa | Geometric mean ratio | 107.50 | Standard Deviation | 11.3 | 2-Sided | 90 | 97.90 | 118.04 | Standard deviation is actually the geometric coefficient of variation (gCV) reflecting intra-subject variabilities | Yes | Non-Inferiority or Equivalence | No formal testing in a confirmatory sense |
No formal testing in a confirmatory sense |
No formal testing in a confirmatory sense |
No formal testing in a confirmatory sense |
| Only patients in sequences Empa/Empa+TOR were included | ANOVA | Model was adjusted for treatment as fixed effect and subject as random effect | <0.0001 | p-value for ratio outside interval 80-125% Ratio calculated as Empa+ TOR-M1 divided by TOR-M1 | Geometric mean ratio | 104.42 | Standard Deviation | 4.8 | 2-Sided | 90 | 100.39 | 108.62 | Standard deviation is actually the geometric coefficient of variation (gCV) reflecting intra-subject variabilities | Yes | Non-Inferiority or Equivalence | No formal testing in a confirmatory sense |
| Only patients in sequences Empa/Empa+TOR were included | ANOVA | Model was adjusted for treatment as fixed effect and subject as random effect | 0.0005 | p-value for ratio outside interval 80-125% Ratio calculated as Empa+ TOR-M3 divided by TOR-M3 | Geometric mean ratio | 103.19 | Standard Deviation | 8.9 | 2-Sided | 90 | 95.93 | 111.01 | Standard deviation is actually the geometric coefficient of variation (gCV) reflecting intra-subject variabilities | Yes | Non-Inferiority or Equivalence | No formal testing in a confirmatory sense |
No formal testing in a confirmatory sense |
| Only patients in sequences Empa/Empa+TOR were included | ANOVA | Model was adjusted for treatment as fixed effect and subject as random effect | 0.0012 | p-value for ratio outside interval 80-125% Ratio calculated as Empa+ TOR-M1 divided by TOR-M1 | Geometric mean ratio | 102.67 | Standard Deviation | 10.6 | 2-Sided | 90 | 94.13 | 111.97 | Standard deviation is actually the geometric coefficient of variation (gCV) reflecting intra-subject variabilities | Yes | Non-Inferiority or Equivalence | No formal testing in a confirmatory sense |
| Only patients in sequences Empa/Empa+TOR were included | ANOVA | Model was adjusted for treatment as fixed effect and subject as random effect | <0.0001 | p-value for ratio outside interval 80-125% Ratio calculated as Empa+ TOR-M3 divided by TOR-M3 | Geometric mean ratio | 102.42 | Standard Deviation | 5.8 | 2-Sided | 90 | 97.65 | 107.42 | Standard deviation is actually the geometric coefficient of variation (gCV) reflecting intra-subject variabilities | Yes | Non-Inferiority or Equivalence | No formal testing in a confirmatory sense |
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| 1 day before the drug administration |
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