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

• ClinicalTrials.gov Identifier: NCT01924767
• Recruitment Status: Completed
• First Posted: August 16, 2013
• Results First Posted: July 4, 2014
• Last Update Posted: July 4, 2014
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 2	Drug: BI 10773 Placebo; Drug: BI 10773	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: July 2007
• Actual Primary Completion Date: November 2007
• Actual Study Completion Date: November 2007

Arms and Interventions

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; po taken fasting with 240 mL water; Drug: BI 10773 Placebo; 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

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Clinically Relevant Findings in Physical Examination, Vital Signs and Clinical Laboratory Tests [ Time Frame: day 1 to day 21 ]
   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).
2. Percentage of Participants With Clinically Relevant Findings in Electrocardiogram (ECG) Results [ Time Frame: day 1 to day 21 ]
   Percentage of participants with clinically relevant findings in electrocardiogram (ECG) results
3. Micturition Frequency [ Time Frame: Baseline and Day 9 ]
   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.
4. Assessment of Tolerability by Investigator [ Time Frame: day 21 ]
   Tolerability will be assessed by the investigator according to the categories good, satisfactory, not satisfactory and bad.

Secondary Outcome Measures :

1. Concentration of the Analyte in Plasma [ Time Frame: -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. ]
   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)
2. Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval (AUC) [ Time Frame: -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. ]
   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.
3. Time to Maximum Concentration of the Analyte in Plasma [ Time Frame: -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 from last dosing to maximum concentration of the analyte in plasma (tmax) after first dose and at steady-state
4. Terminal Rate Constant in Plasma [ Time Frame: -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 after first dose and at steady-state
5. Half-life and Mean Residence Time of the Analyte in Plasma [ Time Frame: -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 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.
6. Apparent Volume of Distribution During the Terminal Phase [ Time Frame: -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 (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).
7. Amount of Analyte Eliminated in Urine [ Time Frame: 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 ]
   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)
8. Fraction of Analyte Excreted Unchanged in Urine [ Time Frame: 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 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.

9. Apparent and Renal Clearance of the Analyte in Plasma [ Time Frame: -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 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.

10. Peak Trough Fluctuation [ Time Frame: -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 (PTF) is defined as the difference between Cmax and Cmin divided by Cavg and multiplied with 100% at steady-state
11. Linearity Index [ Time Frame: -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. ]
    The linearity index is defined as AUC0-tau divided by AUC0-∞ both at steady state.
12. Accumulation Ratios [ Time Frame: -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 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

13. Change From Baseline to Day 8 in Urinary Glucose Excretion [ Time Frame: -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 ]
    Change from baseline to day 8 in urinary glucose excretion. Baseline is defined as Day -2.
14. Mean Daily Glucose [ Time Frame: 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 ]
    Change from baseline to Day 8 in mean daily glucose. Baseline is defined as Day -2.
15. Fasting Plasma Glucose [ Time Frame: -0:30 (Pre dose samples) ]
    Percentage change from baseline to Day 8 in fasting plasma glucose. Baseline is defined as Day -2.
16. Serum Insulin [ Time Frame: 0.0h, 2h, 5h, 7h, 10h, 12h on day -2 & day 8 ]

    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.

17. Serum Insulin [ Time Frame: 0.0h, 2h, 5h, 7h, 10h, 12h on day -2 & day 8 ]

    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)

Eligibility Criteria

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

Criteria

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)

Contacts and Locations

Locations

Germany

1245.2.1 Boehringer Ingelheim Investigational Site

Neuss, Germany

Sponsors and Collaborators

Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim; Boehringer Ingelheim

More Information

Additional Information:

Related Info 

Related Info 

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01924767
• Other Study ID Numbers: 1245.2; 2007-000654-32 ( EudraCT Number: EudraCT )
• First Posted: August 16, 2013
• Results First Posted: July 4, 2014
• Last Update Posted: July 4, 2014
• Last Verified: July 2014

Additional relevant MeSH terms:

Diabetes Mellitus, Type 2; Diabetes Mellitus; 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