Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Rising Doses of BI 10773 Tablets

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of 4 Multiple Rising Oral Doses (2.5 mg to 100 mg) of BI 10773 Tablets in Male and Female Type 2 Diabetic Patients

To investigate safety, tolerability, pharmacokinetics and pharmacodynamics of BI 10773 with repeat dosing for eight days and the exploration of the pharmacokinetics and pharmacodynamics of BI 10773 after multiple dosing, including dose proportionality and assessment of steady state.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: BI 10773 Placebo; Drug: BI 10773

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Neuss, Germany
    • 1245.2.1 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Male and postmenopausal or hysterectomised 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 thiazolidindiones with at least one agent taken at 50% of its maximum dose or less.
2. Glycosylated haemoglobin A1 (HbA1c) £ 8.5 % at screening.
3. Age >21 and Age <70 years (male and hysterectomised female patients) Age >60 and Age <70 years (postmenopausal female patients)
4. Body Mass Index (BMI) >18.5 and <40 kg/m2
5. Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation

Exclusion criteria:

1. Antidiabetic treatment with insulin or glitazones or with more than one oral hypoglycaemic agent (except if 2 agents and at least one of them not taken at more than 50% of its maximum dose)
2. Fasted blood glucose > 240 mg/dl (>13.3 mmol/L) on two consecutive days during washout.
3. Glycosylated haemoglobin A1 (HbA1c) >8.5% at screening

4. Clinically relevant concomitant diseases other than type 2 diabetes, hyperlipidaemia and medically treated hypertension, such as:

   • Any late stage complication of diabetes (e.g. retinopathy, polyneuropathy, vegetative disorders, diabetic foot)
   • Renal insufficiency (calculated creatinine clearance < 80 ml/min/1.73m²)
   • 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 (Transistoric ischaemic attack)
   • Neurological disorders (such as epilepsy) or psychiatric disorders
   • Acute or relevant chronic infections (e.g. HIV, repeated urogenital infections)
   • Any gastrointestinal, hepatic, respiratory, endocrine or immunological disorder
5. History of relevant allergy/hypersensitivity (including allergy to drug or its excipients)
6. A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms)
7. A history of additional risk factors for TdP (torsade des pointes) (e.g., heart failure, hypokalemia, family history of sudden death before the age of 50)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BI 10773 (dose group 3); multiple doses as tablet	Drug: BI 10773 Placebo; po taken fasting with 240 mL water; Drug: BI 10773; po taken fasting with 240 mL water
Experimental: BI 10773 (dose group 4); multiple doses as tablet	Drug: BI 10773 Placebo; po taken fasting with 240 mL water; Drug: BI 10773; po taken fasting with 240 mL water
Experimental: BI 10773 (dose group 1); multiple doses as tablet	Drug: BI 10773 Placebo; po taken fasting with 240 mL water; Drug: BI 10773; po taken fasting with 240 mL water
Experimental: BI 10773 (dose group 2); multiple doses as tablet	Drug: BI 10773 Placebo; po taken fasting with 240 mL water; Drug: BI 10773; po taken fasting with 240 mL water

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Clinically Relevant Findings in Physical Examination, Vital Signs and Clinical Laboratory Tests	Percentage of participants with clinically relevant findings in physical examination, vital signs and clinical laboratory tests. Relevant findings or worsenings of baseline conditions were reported as Adverse Events (cardiac disorders and investigations).	day 1 to day 21
Percentage of Participants With Clinically Relevant Findings in Electrocardiogram (ECG) Results	Percentage of participants with clinically relevant findings in electrocardiogram (ECG) results	day 1 to day 21
Micturition Frequency	Micturition frequency is reported as change from pre-treatment to day 9 during the day, the night and total. Baseline is the mean of days 8-3 before drug administration.	Baseline and Day 9
Assessment of Tolerability by Investigator	Tolerability will be assessed by the investigator according to the categories good, satisfactory, not satisfactory and bad.	day 21

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of the Analyte in Plasma	Maximum concentration of the analyte in plasma (Cmax) after first dose, Maximum, minimum (Cmin) and average (Cavg) concentration of the analyte in plasma at steady-state, Concentration of analyte in plasma at 24 h after administration of the 8th dose (at steady-state) (C24,8)	-0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1.-0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9.
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval (AUC)	AUC0-∞: from 0 extrapolated to infinity after first dose AUCtau,1: over a uniform dosing interval tau after first dose AUCtau,ss: over a uniform dosing interval tau at steady-state AUCs were computed using the linear up/log down algorithm. If an analyte concentration was equal to or higher than the preceding concentration, the linear trapezoidal method was to be used. If the analyte concentration was smaller than the preceding concentration, the logarithmic method was to be used.	-0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1.-0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9.
Time to Maximum Concentration of the Analyte in Plasma	Time from last dosing to maximum concentration of the analyte in plasma (tmax) after first dose and at steady-state	-0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1.-0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9.
Terminal Rate Constant in Plasma	Terminal rate constant in plasma after first dose and at steady-state	-0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1. -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9.
Half-life and Mean Residence Time of the Analyte in Plasma	Terminal half life of the analyte in plasma (t1/2) and mean residence time of the analyte in the body after single oral administration (MRTpo) after first dose and at steady-state.	-0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1. -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9.
Apparent Volume of Distribution During the Terminal Phase	Apparent volume of distribution during the terminal phase (Vz/F) after first dose and at steady state. Apparent volume is defined as CL/F divided by the terminal rate constant in plasma (either after first dose or at steady-state).	-0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1. -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9.
Amount of Analyte Eliminated in Urine	Amount of analyte that is eliminated in urine after first dose and at steady state from the time interval 0 to 24 h (Ae0-24) and 0 to 48 h (Ae0-48)	0-2, 2-4, 4-6, 6-8, 8-12, 12-16, 16-24, 24-36, 36-48 hours (h) after dose on day 1 and 0-2, 2-4, 4-6, 6-8, 8-12, 12-16, 16-24, 24-36, 36-48 and 48-72 hours (h) after dose on day 9
Fraction of Analyte Excreted Unchanged in Urine	Fraction of analyte excreted unchanged in urine in the time interval 0 to 12 h (fe0-12) after first dose and at steady-state. The fraction excreted was calculated by dividing Ae0-12 by the Dose and multiply it with 100. Fraction of analyte excreted unchanged in urine in the time interval 0 to 24 h (fe0-24) after first dose and at steady-state. The fraction excreted was calculated by dividing Ae0-24 by the Dose and multiply it with 100.	0-2, 2-4, 4-6, 6-8, 8-12, 12-16, 16-24, 24-36, 36-48 hours (h) after dose on day 1 and 0-2, 2-4, 4-6, 6-8, 8-12, 12-16, 16-24, 24-36, 36-48 and 48-72 hours (h) after dose on day 9
Apparent and Renal Clearance of the Analyte in Plasma	Apparent clearance of the analyte in plasma (CL/F) after first dose and at steady-state, Renal clearance of the analyte in plasma after extravascular administration (CLR) after first dose and at steady-state. Apparent clearance after first dose is defined as the dose divided by AUC0-∞; apparent clearance at steady-state is defined as the dose divided by AUC0-tau at steady-state. Renal clearance CLR(0-t) is defined as Ae0-t divided by AUC0-t.	-0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1. -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9.
Peak Trough Fluctuation	Peak trough fluctuation (PTF) is defined as the difference between Cmax and Cmin divided by Cavg and multiplied with 100% at steady-state	-0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1. -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9.
Linearity Index	The linearity index is defined as AUC0-tau divided by AUC0-∞ both at steady state.	-0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1. -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9.
Accumulation Ratios	Accumulation ratio based on Cmax (RA,Cmax) and Accumulated ratio based on AUC0-tau (RA,AUC) at steady-state. Accumulation ratio for the respective doses were calculated using below mentioned equations: RA,Cmax = Cmax,ss/Cmax RA,AUC= AUCtau,ss/AUCtau	-0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1. -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9.
Change From Baseline to Day 8 in Urinary Glucose Excretion	Change from baseline to day 8 in urinary glucose excretion. Baseline is defined as Day -2.	-2-0 hours(h) before drug administration and 0-2, 2-4, 4-6, 6-8, 8-12,12-16 and 16-24 h after drug administration on day -2 and day 8
Mean Daily Glucose	Change from baseline to Day 8 in mean daily glucose. Baseline is defined as Day -2.	0:00, 2:00, 5:00, 7:00, 10:00, 12:00,13:30 and 24:00 hours(h) after drug administration on day -2 and -0.05, 2:30, 5:00, 7:00, 10:00, 12.00, 13:30 and 24:00 hours (h) after drug administration on day 8
Fasting Plasma Glucose	Percentage change from baseline to Day 8 in fasting plasma glucose. Baseline is defined as Day -2.	-0:30 (Pre dose samples)
Serum Insulin	Serum insulin measured for on day -2 and day 8 for AUEC0-5 and AUEC0-12. AUEC0-5: The area under the effect concentration-time curve over the time interval 0 to 5. AUEC0-12: The area under the effect concentration-time curve over the time interval 0 to 12.	0.0h, 2h, 5h, 7h, 10h, 12h on day -2 & day 8
Serum Insulin	Serum insulin measured for on day -2 and day 8 for Emax0-5, Emax0-12, Emin0-5 and Emin0-12. Emax: Maximum effect (maximum measured concentration of glucose or insulin in plasma) & Emin: Minimum effect (minimum measured concentration of glucose or insulin in plasma)	0.0h, 2h, 5h, 7h, 10h, 12h on day -2 & day 8

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

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Study record dates

Study Major Dates

• Study Start: July 1, 2007
• Primary Completion (Actual): November 1, 2007
• Study Completion (Actual): November 1, 2007

Study Registration Dates

• First Submitted: August 9, 2013
• First Submitted That Met QC Criteria: August 15, 2013
• First Posted (Estimate): August 16, 2013

Study Record Updates

• Last Update Posted (Estimate): July 4, 2014
• Last Update Submitted That Met QC Criteria: July 3, 2014
• Last Verified: July 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: 1245.2; 2007-000654-32 (EudraCT Number: EudraCT)