4 Weeks Treatment With Empagliflozin (BI 10773) in Japanese Type 2 Diabetic Patients (T2DM)

A Phase II, Randomised, Double-blind, Placebo-controlled, Multiple Dose Study to Evaluate Pharmacodynamics, Pharmacokinetics, Safety, and Tolerability of Once Daily Oral Administration of BI 10773 (1 mg, 5 mg, 10 mg, and 25 mg) for 28 Days in Japanese Patients With Type 2 Diabetes Mellitus

The objective of this trial is to evaluate the pharmacodynamics, pharmacokinetics, safety, and tolerability of once daily oral administration of BI 10773 administered for 28 days in Japanese patients with T2DM.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: BI 10773; Drug: BI 10773; Drug: BI 10773; Drug: Placebo (low dose); Drug: Placebo (middle dose); Drug: Placebo (high dose); Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Hachioji, Tokyo, Japan
    • 1245.15.003 Boehringer Ingelheim Investigational Site
  • Koganei, Tokyo, Japan
    • 1245.15.002 Boehringer Ingelheim Investigational Site
  • Nakano-ku, Tokyo, Japan
    • 1245.15.001 Boehringer Ingelheim Investigational Site
  • Suita, Osaka, Japan
    • 1245.15.005 Boehringer Ingelheim Investigational Site
  • Yokohama, Kanagawa, Japan
    • 1245.15.004 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Japanese male or female patients with T2DM treated with diet and exercise alone or with one hypoglycaemic drug other than glitazones.

2. Hemoglobin A1c (HbA1c) at screening (Visit 1)

   • For patients treated with 1 other oral antidiabetic drug: HbA1c between 6.5% and 9.0%.
   • For patients not treated with any antidiabetic drug: HbA1c between 7.0% and 10.0%.
3. Age between 20 and 70 years
4. Body mass index (BMI) between18.0 and 40.0 kg/m2
5. Signed and dated written informed consent before admission to the trial in accordance with the Good Clinical Practice (GCP) and the local legislation.

Exclusion criteria:

1. Antidiabetic treatment with insulin or glitazones within 3 months before obtaining informed consent or with more than 1 oral hypoglycaemic agent at the time of informed consent
2. Fasted blood glucose of >240 mg/dL (>13.3 mmol/L) or a randomly determined blood glucose level of >400 mg/dL (22.2 mmol/L) on 2 consecutive days during wash-out period.
3. Myocardial infarction, stroke, or transient ischaemic attack within 6 months before informed consent.

4. Clinically relevant concomitant diseases other than T2DM, hyperlipidaemia, and medically treated hypertension before the first administration such as

   • Renal insufficiency (calculated estimated glomerular filtration rate <60)
   • Cardiac insufficiency of New York Heart Association (NYHA) II-IV or other known cardiovascular diseases including hypertension of >160/95 mmHg,
   • Neurological disorders (such as epilepsy) or psychiatric disorders
   • Acute or clinically relevant chronic infections (e.g., human immunodeficiency virus, hepatitis, repeated urogenital infections)
   • Any gastrointestinal, hepatic, respiratory, endocrine, or immunological disorder

5. Patients under treatment with any concomitant medication except for the following drugs at the time of informed consent.:

   • Statins.
   • Antihypertensives (diuretics not allowed)
   • alpha-Blockers for benign prostate hypertrophy
   • Occasional use of acetylsalicylic acid, ibuprofen, or paracetamol
6. Additional inclusion/exclusion criteria apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BI 10773 low dose quaque die (QD); patient to receive a BI 10773 low dose tablet and a placebo tablet once daily	Drug: BI 10773; BI 10773 middle dose tablets once a day; Drug: BI 10773; BI 10773 high dose tablets once a day; Drug: BI 10773; BI 10773 low dose tablets once a day; Drug: Placebo (low dose); Placebo tablets once a day
Experimental: BI 10773 mid-low dose QD; patient to receive a BI 10773 middle dose tablet and a placebo tablet once daily	Drug: BI 10773; BI 10773 middle dose tablets once a day; Drug: BI 10773; BI 10773 high dose tablets once a day; Drug: BI 10773; BI 10773 low dose tablets once a day; Drug: Placebo (middle dose); Placebo tablets once a day
Experimental: BI 10773 mid-high dose QD; patient to receive two tablets of BI 10773 middle dose once daily	Drug: BI 10773; BI 10773 middle dose tablets once a day; Drug: BI 10773; BI 10773 high dose tablets once a day; Drug: BI 10773; BI 10773 low dose tablets once a day
Experimental: BI 10773 high dose QD; patient to receive a BI 10773 high dose tablet and a placebo tablet once daily	Drug: BI 10773; BI 10773 middle dose tablets once a day; Drug: BI 10773; BI 10773 high dose tablets once a day; Drug: BI 10773; BI 10773 low dose tablets once a day; Drug: Placebo (high dose); Placebo tablets once a day
Placebo Comparator: Placebo; patient to receive two tablets of placebo once daily	Drug: Placebo; Placebo tablets once a day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Urine Glucose Excretion	Change from baseline in Urine glucose excretion to 28 days	baseline and 28 days
Change From Baseline in Fasting Plasma Glucose	Change from baseline in Fasting plasma glucose to 28 days	baseline and 28 days
Change From Baseline in 8-point Glucose	Change from baseline in 8-point glucose to 27 days	baseline and 27 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in HbA1c	Change from baseline in HbA1c to 28 days	baseline and 28 days
Change From Baseline in Fructosamine	Change from baseline in Fructosamine to 28 days	baseline and 28 days
Change From Baseline in 1,5-anhydroglucitol	Change from baseline in 1,5-anhydroglucitol to 28 days	baseline and 28 days
Change From Baseline in Fasting Insulin	Change from baseline in Fasting insulin to 28 days	baseline and 28 days
Change From Baseline in the Area Under the Curve of Plasma Glucose Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test)	Change from baseline in the area under the curve of plasma glucose levels until 4 hours after intake of a standardised food (meal tolerance test) to 28 days	baseline and 28 days
Change From Baseline in the Area Under the Curve of Glucagon Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test)	Change from baseline in the area under the curve of glucagon levels until 4 hours after intake of a standardised food (meal tolerance test) to 28 days	baseline and 28 days
Change From Baseline in the Area Under the Curve of Insulin Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test)	Change from baseline in the area under the curve of insulin levels until 4 hours after intake of a standardised food (meal tolerance test) to 28 days	baseline and 28 days
AUCτ,1	Area under the concentration-time curve of the analyte in plasma after administration of the first dose over a uniform dosing interval τ	Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration
AUC0-tz	area under the concentration-time curve of the analyte in plasma over the time interval from 0 to last quantifiable plasma concentration	Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration
AUC0-∞	area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity	Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration
Cmax	maximum measured concentration of the analyte in plasma	Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration
t1/2	terminal half-life of the analyte in plasma	Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration
CL/F	apparent clearance of the analyte in plasma after extravascular administration	Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration
Vz/F	apparent volume of distribution during the terminal phase λz following an extravascular dose	Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration
Ae0-24	amount of the analyte that is eliminated in urine over the time interval 0 to 24	0-5, 5-12, 12-24 hour after first drug administration
fe0-24	fraction of the analyte excreted unchanged in urine from time interval 0 to 24	0-5, 5-12, 12-24 hour after first drug administration
CLR,0-24	renal clearance of the analyte in plasma after extravascular administration - based on 0-24 hours data	Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min, 0-5h, 5-12h, 12-24h after first drug administration
AUCτ,ss	area under the concentration-time curve of the analyte in plasma over a uniform dosing interval τ at steady state	Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h after last drug administration
Cmax,ss	maximum measured concentration of the analyte in plasma at steady state	Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h 48h, 72h after last drug administration
t1/2,ss	terminal half-life of the analyte in plasma at steady state	Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h 48h, 72h after last drug administration
CL/F,ss	apparent clearance of the analyte in plasma after extravascular administration at steady state	Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h 48h, 72h after last drug administration
Vz/F,ss	apparent volume of distribution during the terminal phase λz following an extravascular dose at steady state	Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h 48h, 72h after last drug administration
RA,Cmax	accumulation ratios of the analyte in plasma after 28 doses (once daily) over a uniform dosing interval τ, based on Cmax	Predose, 15min, 30min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration, and predose, 15min, 30min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h after last drug administration
RA,AUC	accumulation ratios of the analyte in plasma after 28 doses (once daily) over a uniform dosing interval τ, based on AUCτ	Predose, 15min, 30min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration, and predose, 15min, 30min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h after last drug administration
Ae0-24,ss	amount of the analyte that is eliminated in urine at steady state over the time interval 0 to 24	0-5, 5-12, 12-24 hour after last drug administration
fe0-24,ss	fraction of the analyte excreted unchanged in urine at steady state from time interval 0 to 24	0-5, 5-12, 12-24 hour after last drug administration
CLR,ss	renal clearance of the analyte at steady state determined over the dosing interval τ	Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 0-5h, 5-12h, 12-24h after last drug administration

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Tuttle KR, Levin A, Nangaku M, Kadowaki T, Agarwal R, Hauske SJ, Elsasser A, Ritter I, Steubl D, Wanner C, Wheeler DC. Safety of Empagliflozin in Patients With Type 2 Diabetes and Chronic Kidney Disease: Pooled Analysis of Placebo-Controlled Clinical Trials. Diabetes Care. 2022 Jun 2;45(6):1445-1452. doi: 10.2337/dc21-2034.
• Riggs MM, Staab A, Seman L, MacGregor TR, Bergsma TT, Gastonguay MR, Macha S. Population pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with type 2 diabetes. J Clin Pharmacol. 2013 Oct;53(10):1028-38. doi: 10.1002/jcph.147. Epub 2013 Aug 13.
• Yasui A, Lee G, Hirase T, Kaneko T, Kaspers S, von Eynatten M, Okamura T. Empagliflozin Induces Transient Diuresis Without Changing Long-Term Overall Fluid Balance in Japanese Patients With Type 2 Diabetes. Diabetes Ther. 2018 Apr;9(2):863-871. doi: 10.1007/s13300-018-0385-5. Epub 2018 Feb 27.
• Kanada S, Koiwai K, Taniguchi A, Sarashina A, Seman L, Woerle HJ. Pharmacokinetics, pharmacodynamics, safety and tolerability of 4 weeks' treatment with empagliflozin in Japanese patients with type 2 diabetes mellitus. J Diabetes Investig. 2013 Nov 27;4(6):613-7. doi: 10.1111/jdi.12110. Epub 2013 Jun 25.

Helpful Links

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Study record dates

Study Major Dates

• Study Start: April 1, 2009
• Primary Completion (Actual): October 1, 2009

Study Registration Dates

• First Submitted: April 20, 2009
• First Submitted That Met QC Criteria: April 20, 2009
• First Posted (Estimate): April 21, 2009

Study Record Updates

• Last Update Posted (Estimate): November 25, 2014
• Last Update Submitted That Met QC Criteria: November 13, 2014
• Last Verified: November 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: 1245.15