Pharmacodynamics and Pharmacokinetics of Empagliflozin and Torasemide in Patients With Type 2 Diabetes

Phase 1

Completed

• Conditions: Diabetes Mellitus, Type 2
• Interventions: Drug: BI 10773; Drug: hydrochlorothiazide; Drug: torasemide

• Registration Number: NCT01276288
• Lead Sponsor: Boehringer Ingelheim

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2011-01
• Study First Submitted: 2011-01-12
• Study First Submitted QC: 2011-01-12
• Study First Posted: 2011-01-13
• Primary Completion: 2011-06
• Results First Submitted: 2014-05-16
• Results First Submitted QC: 2014-07-10
• Status Verified: 2014-08
• Last Update Submitted: 2014-08-05
• Results First Posted: 2014-08-06
• Last Update Posted: 2014-09-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 23

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Reference 1	BI 10773	administration of BI 10773 once daily for 5 days (20 patients)
Reference 2	hydrochlorothiazide	administration of hydrochlorothiazide (HTC) once daily for 4 days (10 patients)
Reference 3	torasemide	administration of torasemide (TOR) once daily for 4 days (10 patients)
Test 1	BI 10773	administration of BI 10773 + HTC once daily for 5 days (10 patients)
Test 2	BI 10773	administration of BI 10773 + TOR once daily for 5 days (10 patients)
Test 2	torasemide	administration of BI 10773 + TOR once daily for 5 days (10 patients)
Test 1	hydrochlorothiazide	administration of BI 10773 + HTC once daily for 5 days (10 patients)

Primary Outcome Measures

Name	Time	Method
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 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
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 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
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 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 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
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 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 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 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 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
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

Secondary Outcome Measures

Name	Time	Method
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).
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.

Trial Locations

Locations (1)

1245.42.1 Boehringer Ingelheim Investigational Site; 🇩🇪 Neuss, Germany