Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Empagliflozin in Chinese Female and Male Patients With Type 2 Diabetes Mellitus

• ClinicalTrials.gov Identifier: NCT01316341
• Recruitment Status: Completed
• First Posted: March 16, 2011
• Results First Posted: June 17, 2014
• Last Update Posted: June 17, 2014
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

Study Description

Brief Summary:

the pharmacokinetics, pharmacodynamics and safety and tolerability of single and multiple oral doses of BI 10773 at low dose once daily (q.d.) and high dose q.d. administered to Chinese female and male patients with type 2 diabetes will be investigated.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 2	Drug: BI10773; Drug: Placebo	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: Pharmacokinetics and Pharmacodynamics of BI 10773 After Single and Multiple Oral Dose of 10 mg and 25 mg BI 10773 in Chinese Male and Female Type 2 Diabetic Patients
• Study Start Date: March 2011
• Actual Primary Completion Date: January 2012

Arms and Interventions

Arm	Intervention/treatment
Experimental: BI10773 low dose Per Os(p.o.); patient to receive a tablet containing low dose BI10773 Per Os(p.o.) plus one placebo	Drug: Placebo; patient to receive two placebos; Drug: BI10773; patient to receive a tablet containing low dose BI10773 p.o. plus one placebo
Placebo Comparator: Placebo; patient to receive two placebos	Drug: Placebo; patient to receive two placebos
Experimental: BI10773 high dose Per Os(p.o.); patient to receive a tablet containing high dose BI10773 Per Os(p.o.) plus one placebo	Drug: BI10773; patient to receive a tablet containing high dose BI10773 p.o. plus one placebo; Drug: Placebo; patient to receive two placebos

Outcome Measures

Primary Outcome Measures :

1. Maximum Measured Concentration (Cmax) [ Time Frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration ]
   Maximum measured concentration of the analyte in plasma after the first dose on day 1.
2. Time to Maximum Measured Concentration (Tmax) [ Time Frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration ]
   Time from dosing to the maximum measured concentration of the analyte in plasma, after the first dose on day 1.
3. Area Under the Curve 0 to Infinity (AUC0-∞) After Single Dosing [ Time Frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration ]
   Area under the concentration-time curve of empagliflozin (empa) in plasma over the time interval from 0 extrapolated to infinity, after the first dose on day 1
4. Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz) [ Time Frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration ]
   Area under the concentration-time curve of empagliflozin (empa) in plasma over the time interval from 0 to the time of the last quantifiable data point, after the first dose on day 1.
5. Terminal Rate Constant (λz) [ Time Frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration ]
   Terminal Rate Constant in Plasma (λz), after the first dose on day 1
6. Terminal Half-life (t1/2) [ Time Frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration ]
   Terminal half-life of empagliflozin (empa) in plasma after the first dose on day 1
7. Mean Residence Time (MRTpo) [ Time Frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration ]
   Mean residence time of empagliflozin (empa) in the body after the first dose on day 1.
8. Apparent Clearance of Empagliflozin After Extravascular Administration (CL/F) [ Time Frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration ]
   Apparent clearance of empagliflozin (empa) in plasma after extravascular administration, after the first dose on day 1.
9. Apparent Volume of Distribution During the Terminal Phase λz (Vz/F) [ Time Frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration ]
   Apparent volume of distribution during the terminal phase λz, after the first dose on day 1.
10. Amount of Empagliflozin Eliminated in Urine in the Time Interval 0 Hours to 24 Hours (Ae 0-24) [ Time Frame: Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration ]
    Amount of empagliflozin (empa) eliminated in urine in the time interval 0 hours to 24 hours, after the first dose on day 1.
11. Fraction of Empagliflozin Excreted Unchanged in Urine in the Time Interval 0 Hours to 24 Hours (fe 0-24). [ Time Frame: Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration ]
    Fraction of empagliflozin (empa) excreted unchanged in urine in the time interval 0 hours to 24 hours, after the first dose on day 1.
12. Renal Clearance After Extravascular Administration (CL R,0-48) [ Time Frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration ]
    Renal clearance of empagliflozin (empa) in plasma after extravascular administration, after the first dose on day 1.
13. Maximum Measured Concentration Over a Uniform Dosing Interval (Cmax,ss) [ Time Frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9 ]
    Maximum measured concentration of empagliflozin (empa) in plasma at steady state over a uniform dosing interval.
14. Time From Last Dosing to Maximum Measured Concentration Over a Uniform Dosing Interval at Steady State (Tmax,ss) [ Time Frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9 ]
    Time from last dosing to maximum measured concentration of empagliflozin (empa) in plasma over a uniform dosing interval at steady state, after multiple dosing.
15. Area Under the Concentration-time Curve in Plasma at Steady State Over a Uniform Dosing Interval (AUCτ,ss) [ Time Frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9 ]
    Area under the concentration-time curve of empagliflozin (empa) in plasma at steady state over a uniform dosing interval, after multiple dosing
16. Terminal Rate Constant in Plasma at Steady State (λz,ss) [ Time Frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9 ]
    Terminal rate constant in plasma at steady state, after multiple dosing.
17. Terminal Half-life in Plasma at Steady State (t1/2,ss) [ Time Frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9 ]
    Terminal half-life of empagliflozin (empa) in plasma at steady state, after multiple dosing.
18. Mean Residence Time at Steady State (MRTpo,ss) [ Time Frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9 ]
    Mean residence time of empagliflozin (empa) in the body at steady state after multiple oral administrations
19. Apparent Clearance of Empagliflozin After Extravascular Administration (CL/Fss) [ Time Frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9 ]
    Apparent clearance of empagliflozin (empa) in the plasma at steady state following multiple oral dose administration.
20. Apparent Volume of Distribution During the Terminal Phase λz (Vz/Fss) [ Time Frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9 ]
    Apparent volume of distribution during the terminal phase λz at steady state following oral administration after multiple dosing
21. Amount of Analyte Eliminated in Urine at Steady State in Time Interval 0 Hours to 24 Hours (Ae 0-24,ss) [ Time Frame: Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration ]
    Amount of empagliflozin (empa) eliminated in urine at steady state in the time interval 0 hours to 24 hours, after multiple dosing.
22. Fraction of Empagliflozin Excreted Unchanged in Urine at Steady State in the Time Interval 0 Hours to 24 Hours (fe 0-24,ss) [ Time Frame: Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration ]
    Fraction of empagliflozin (empa) excreted unchanged in urine at steady state in the time interval 0 hours to 24 hours, after multiple dosing.
23. Renal Clearance at Steady State (CL R,ss) [ Time Frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9 ]
    Renal clearance of empagliflozin (empa) in plasma after extravascular administration, after multiple dosing.
24. Accumulation Ratio Based on AUC (R A,AUC) [ Time Frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, and16h after drug administration on days 1 and 9 ]
    Accumulation ratio of empagliflozin (empa) based on AUC, after multiple dosing
25. Accumulation Ratio Based on Cmax (R A,Cmax) [ Time Frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, and16h after drug administration between days 5 and 9 ]
    Accumulation ratio of empagliflozin (empa) based on Cmax, after multiple dosing
26. Predose Plasma Concentration Before Planned Dose x (Cpre,x) [ Time Frame: 5 minutes before drug administration ]

    Predose plasma concentration of empagliflozin (empa) before planned dose by day.

    This endpoint in steady state is identical to Cmin,ss.

27. Urinary Glucose Excretion (UGE) Change From Baseline [ Time Frame: Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration ]
    Change from day -1 in urinary glucose excretion in a 24 hour collection period per time point.
28. Fasting Plasma Glucose (FPG) Change From Baseline [ Time Frame: Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration ]
    Fasting Plasma Glucose (FPG) change from baseline between day 1 and day 9.

Secondary Outcome Measures :

1. Clinical Relevant Abnormalities for Protocol-Specified Significant Adverse Events, Hypoglycaemic Events, Vital Signs, Blood Chemistry, Rescue Therapy, Body Weight and Waist Circumference [ Time Frame: Drug administration until end of trial, up to 21 days ]

   Clinically relevant abnormalities for protocol-specified significant adverse events, hypoglycaemic events, vital signs, blood chemistry, use of rescue therapy, change in body weight and change in waist circumference.

   Results shown are for hypoglycaemic events, as this was the only event that occurred for this endpoint.

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

1. Chinese male and female patients with proven diagnosis of type 2 diabetes mellitus treated with diet and exercise only or on a maximum of two oral antidiabetic agents except thiazolidinediones with at least one agent taken at 50% of its maximum dose or less, unchanged for at least 12 weeks before randomization
2. Glycosylated haemoglobin A1(HbA1c)<=8.5% and >=7.0% at screening,age>=21 and age<=70 years (male and female patients),BMI>=19 and <=40 kg/m2
3. Signed and dated written informed consent by date of Visit 1 in accordance with GCP and local legislation.

Exclusion criteria:

1. Patient who did not discontinue the antidiabetic treatment with insulin or glitazones, DPP-IV at least before 12 weeks before randomization
2. Uncontrolled hyperglycaemia with a glucose level >240 mg/dl (>13.3 mmol/L) after an overnight fast at screening visit
3. Clinically relevant concomitant diseases other than type 2 diabetes, hyperlipidaemia and medically treated hypertension, such as:

4 Any late stage complication of diabetes (e.g. retinopathy, polyneuropathy, vegetative disorders, diabetic foot) 5 Renal insufficiency (calculated creatinine clearance < 80 ml/min/1.73m²) 6 Cardiac insufficiency NYHA II-IV, myocardial infarction, other known cardiovascular diseases including hypertension > 160/95mmHg (measured at training visit and each of the timepoints of Day -1), stroke and TIA 7 Neurological disorders (such as epilepsy) or psychiatric disorders 8 Acute or relevant chronic infections (e.g. HIV, repeated urogenital infections) 9 Any gastrointestinal, hepatic, respiratory, endocrine or immunological disorder 10. History of relevant allergy/hypersensitivity (including allergy to drug or its excipients) 11. A marked baseline prolongation of QT/QTc interval (e.g., ECG demonstration of a QTc interval >450 ms ) at screening visit

Contacts and Locations

Locations

China

1245.44.86001 Boehringer Ingelheim Investigational Site

Beijing, China

Sponsors and Collaborators

Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim; Boehringer Ingelheim

More Information

Additional Information:

Related Info 

Related Info 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Zhao X, Cui Y, Zhao S, Lang B, Broedl UC, Salsali A, Pinnetti S, Macha S. Pharmacokinetic and Pharmacodynamic Properties and Tolerability of Single- and multiple-dose Once-daily Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, in Chinese Patients With Type 2 Diabetes Mellitus. Clin Ther. 2015 Jul 1;37(7):1493-502. doi: 10.1016/j.clinthera.2015.05.001. Epub 2015 Jun 19.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01316341
• Other Study ID Numbers: 1245.44
• First Posted: March 16, 2011
• Results First Posted: June 17, 2014
• Last Update Posted: June 17, 2014
• Last Verified: May 2014

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Empagliflozin; Sodium-Glucose Transporter 2 Inhibitors; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Physiological Effects of Drugs