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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01276288
First received: January 12, 2011
Last updated: August 5, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Diabetes Mellitus, Type 2
Drug: BI 10773
Drug: hydrochlorothiazide
Drug: torasemide
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Investigation of Pharmacodynamic and Pharmacokinetic Interactions Between 25 mg BI 10773 and 25 mg Hydrochlorothiazide or 5 mg Torasemide Under Steady State Conditions in Patients With Type 2 Diabetes Mellitus in an Open-label, Randomised, Cross-over Trial

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Change in Clearance of Sodium, Potassium, Creatinine, Magnesium, Chloride,Calcium, Phosphate and Uric Acid From Baseline [ 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 ] [ Designated as safety issue: No ]

    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 [ 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 ] [ Designated as safety issue: No ]

    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 [ 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 ] [ Designated as safety issue: No ]

    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 [ Time Frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT ] [ Designated as safety issue: No ]

    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 [ Time Frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT ] [ Designated as safety issue: No ]

    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 [ Time Frame: baseline and then day 5 for Empa, day 4 for TOR and HCT, day 9 for Empa+TOR and Empa+HCT ] [ Designated as safety issue: No ]

    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 [ Time Frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT ] [ Designated as safety issue: No ]

    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 [ Time Frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT ] [ Designated as safety issue: No ]

    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 [ Time Frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT ] [ Designated as safety issue: No ]

    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 [ Time Frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT ] [ Designated as safety issue: No ]

    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 [ Time Frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT ] [ Designated as safety issue: No ]

    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 [ Time Frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT ] [ Designated as safety issue: No ]

    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


  • Change in Urine Osmolality From Baseline [ Time Frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT ] [ Designated as safety issue: No ]

    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 [ Time Frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT ] [ Designated as safety issue: No ]

    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 [ Time Frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT ] [ Designated as safety issue: No ]

    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 [ Time Frame: baseline and then day 6 for Empa, day 5 for TOR and HCT, day 10 for Empa+TOR and Empa+HCT ] [ Designated as safety issue: No ]

    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 [ 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 ] [ Designated as safety issue: No ]

    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 [ Time Frame: Baseline and day 5 ] [ Designated as safety issue: No ]
    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 [ Time Frame: One day before the drug administration, then day 4 after the first drug administration ] [ Designated as safety issue: No ]
    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.

  • Urinary Sodium Excretion Over 24-hour run-in Periods [ Time Frame: Day 3, 2 and 1 before the first drug administration ] [ Designated as safety issue: No ]
    Urinary sodium excretion over 24-hour run-in periods to assess the harmonisation of electrolytes after intake of a standardised diet


Secondary Outcome Measures:
  • Area Under the Concentration-time Curve of Empa in Plasma (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 ] [ Designated as safety issue: No ]
    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) [ 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 ] [ Designated as safety issue: No ]
    Maximum measured concentration of Empa in plasma (Cmax, ss) at steady state

  • Area Under the Concentration-time Curve of HCT in Plasma (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 ] [ Designated as safety issue: No ]
    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) [ 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 ] [ Designated as safety issue: No ]
    Maximum measured concentration of HCT in plasma (Cmax, ss) at steady state

  • Area Under the Concentration-time Curve of TOR in Plasma (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 ] [ Designated as safety issue: No ]
    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) [ 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 ] [ Designated as safety issue: No ]
    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 [ Time Frame: From first drug administration until up to 14 days after the last drug administration, up to 35 days ] [ Designated as safety issue: No ]

    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.



Enrollment: 23
Study Start Date: January 2011
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Reference 1
administration of BI 10773 once daily for 5 days (20 patients)
Drug: BI 10773
multiple oral doses
Active Comparator: Reference 2
administration of hydrochlorothiazide (HTC) once daily for 4 days (10 patients)
Drug: hydrochlorothiazide
multiple oral doses
Active Comparator: Reference 3
administration of torasemide (TOR) once daily for 4 days (10 patients)
Drug: torasemide
multiple oral doses
Experimental: Test 1
administration of BI 10773 + HTC once daily for 5 days (10 patients)
Drug: hydrochlorothiazide
multiple oral doses
Drug: BI 10773
multiple oral doses
Experimental: Test 2
administration of BI 10773 + TOR once daily for 5 days (10 patients)
Drug: BI 10773
multiple oral doses
Drug: torasemide
multiple oral doses

  Eligibility

Ages Eligible for Study:   20 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

1. male and female patients of type 2 diabetes

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01276288

Locations
Germany
1245.42.1 Boehringer Ingelheim Investigational Site
Neuss, Germany
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
No publications provided

Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01276288     History of Changes
Other Study ID Numbers: 1245.42, 2010-019624-31
Study First Received: January 12, 2011
Results First Received: May 16, 2014
Last Updated: August 5, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices
United States: Food and Drug Administration

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Hydrochlorothiazide
Torsemide
Antihypertensive Agents
Cardiovascular Agents
Diuretics
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Natriuretic Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sodium Chloride Symporter Inhibitors
Sodium Potassium Chloride Symporter Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 22, 2014