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

Phase 1

Completed

• Conditions: Diabetes Mellitus, Type 2
• Interventions: Drug: BI 10773 Placebo; Drug: BI 10773

• Registration Number: NCT01924767
• Lead Sponsor: Boehringer Ingelheim

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2007-07
• Primary Completion: 2007-11
• Study Completion: 2007-11
• Study First Submitted: 2013-08-09
• Study First Submitted QC: 2013-08-15
• Study First Posted: 2013-08-16
• Results First Submitted: 2014-05-16
• Status Verified: 2014-07
• Results First Submitted QC: 2014-07-03
• Last Update Submitted: 2014-07-03
• Results First Posted: 2014-07-04
• Last Update Posted: 2014-07-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 48

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
BI 10773 (dose group 1)	BI 10773	multiple doses as tablet
BI 10773 (dose group 2)	BI 10773	multiple doses as tablet
BI 10773 (dose group 3)	BI 10773 Placebo	multiple doses as tablet
BI 10773 (dose group 3)	BI 10773	multiple doses as tablet
BI 10773 (dose group 4)	BI 10773	multiple doses as tablet
BI 10773 (dose group 4)	BI 10773 Placebo	multiple doses as tablet
BI 10773 (dose group 2)	BI 10773 Placebo	multiple doses as tablet
BI 10773 (dose group 1)	BI 10773 Placebo	multiple doses as tablet

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Terminal Rate Constant in Plasma	-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
Apparent Volume of Distribution During the Terminal Phase	-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).
Apparent and Renal Clearance of the Analyte in Plasma	-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.
Mean Daily Glucose	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.
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval (AUC)	-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.
Time to Maximum Concentration of the Analyte in Plasma	-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
Amount of Analyte Eliminated in Urine	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)
Half-life and Mean Residence Time of the Analyte in Plasma	-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.
Linearity Index	-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.
Fraction of Analyte Excreted Unchanged in Urine	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.
Concentration of the Analyte in Plasma	-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)
Peak Trough Fluctuation	-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
Accumulation Ratios	-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
Change From Baseline to Day 8 in Urinary Glucose Excretion	-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.
Fasting Plasma Glucose	-0:30 (Pre dose samples)	Percentage change from baseline to Day 8 in fasting plasma glucose. Baseline is defined as Day -2.
Serum Insulin	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)

Trial Locations

Locations (1)

1245.2.1 Boehringer Ingelheim Investigational Site; 🇩🇪 Neuss, Germany