trial synopsis 1245.4 ds co - boehringer ingelheim...the synopsis may include approved and...

abcd Clinical Study Synopsis for Public Disclosure This clinical study synopsis is provided in line with Boehringer Ingelheim’s Policy on Transparency and Publication of Clinical Study Data. The synopsis ‐ which is part of the clinical study report ‐ had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may include approved and non‐approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities. A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug. More current information regarding a drug is available in the approved labeling information which may vary from country to country.. Additional information on this study and the drug concerned may be provided upon request based on Boehringer Ingelheim’s Policy on Transparency and Publication of Clinical Study Data. The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission of Boehringer Ingelheim.

Name of company: Boehringer Ingelheim

Tabulated Trial Report

Name of finished product:

Not applicable

EudraCT No.:

2007-002685-36

Name of active ingredient:

BI 10773

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Synopsis No.:

Report date: 23 SEP 2009

Trial No. / U No.: 1245.4 / U09-1970-01

Dates of trial: 14 JAN 2008 – 30 APR 2008

Date of revision: Not applicable

Proprietary confidential information © 2009 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.

This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

Title of trial: Safety, tolerability, pharmacokinetics and pharmacodynamics of 4 weeks treatment with three oral doses of BI 10773 as tablets in female and male patients with type 2 diabetes

Coordinating Investigator:

MD

Trial sites: Germany

Germany

Germany

Publication: Data of this study have not been published.

Clinical phase: I

Objectives: To investigate safety, tolerability, pharmacokinetics and pharmacodynamics of BI 10773 for 28 days

Methodology: Randomised, double-blind within dose group, placebo-controlled, multiple doses in patients with type 2 diabetes

No. of subjects:

planned: entered: 80

actual: entered: 78

Treated Analysed for primary endpoint

Placebo 16 16

BI 10773 10 mg q.d. 16 16

BI 10773 25 mg q.d. 16 16

BI 10773 100 mg q.d 30 30

Total 78 78

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Diagnosis and main criteria for inclusion:

Male and postmenopausal or hysterectomised female patients with type 2 diabetes mellitus, age 18 to 70 years inclusive, body mass index 18.5 to 40 kg/m2 inclusive

Test product: BI 10773 as tablets

dose: 10 mg q.d., 25 mg q.d., 100 mg q.d

mode of admin.: Oral administration with 240 mL water in the fasted state

batch no.: 5 mg BI 10773: B063000365

25 mg BI 10773: B063000368

100 mg BI 10773: B063000369

Reference therapy: Matching placebo as tablets

dose: Not applicable

mode of admin.: Oral administration with 240 mL water in the fasted state

batch no.: 5 mg BI 10773: B063000329

25 mg BI 10773: B063000330

100 mg BI 10773: B063000331

Duration of treatment: 28 days of once daily dosing at each dose level (after 14 days wash-out of previous therapy)

Criteria for evaluation:

Safety: Adverse events (AEs), vital signs (blood pressure, pulse rate), 12-lead electrocardiogram (ECG), clinical laboratory tests, physical examination, liquid balance and micturition diary, and global tolerability

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Pharmacokinetics: Pharmacokinetic (PK) parameters

After the first dose: Cmax, tmax, λz, t1/2, C24,1, AUCτ,1, AUC0-tz, AUC0-∞, Aet1-t2, fet1-t2, CLR, CL/F, Vz/F, MRTpo

After the last dose: Cmax,ss, Cmin,ss, C24,N, C24,ss, Cavg, tmax,ss, t1/2,ss, λz,ss, AUCτ,ss, MRTpo,ss, CL/F,ss, Vz/F,ss, Aet1-t2,ss, fe t1-t2,ss, CLR,ss, peak-trough fluctuation (PTF), linearity index, accumulation ratios RA,Cmax and RA,AUC, and additional parameters as appropriate

Pharmacodynamic (PD) parameters

Fasting plasma glucose (FPG), 8-point mean daily glucose (MDG), urinary glucose excretion (UGE), glucose AUEC after oral glucose tolerance test (OGTT), fasting insulin, insulin and glucagon profiles

Efficacy biomarkers

HbA1c, fructosamine, 1,5-anhydroglucitol

Statistical methods: Descriptive statistics for safety and PK endpoints were calculated.

For attainment of steady state, trough concentrations of BI 10773 were analysed by a mixed linear model with ‘time’ as a repeated effect.

Dose proportionality was explored for PK endpoints Cmax and AUCτ,1 after the first dose and for Cmax,ss and AUCτ,ss after the last dose using a power model.

The changes from baseline in FPG, MDG, UGE, glucose AUEC0-5 after OGTT, HbA1c, fructosamine, 1,5-anhydroglucitol, insulin, and glucagon were compared by treatment in an exploratory way using an analysis of covariance (ANCOVA) approach.

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SUMMARY – CONCLUSIONS:

Safety results: Overall, 48 of 78 patients (61.5%) experienced at least one AE during the course of this study. The frequency of patients with treatment emergent AEs (47 in total) was similar in the active treatment groups and the placebo group – eight patients (50.0%) with 10 mg BI 10773, nine patients (56.3%) with 25 mg BI 10773, and 20 patients (66.7%) with 100 mg BI 10773, compared with ten patients (62.5%) with placebo. The most frequently reported treatment emergent AEs were pollakiuria (eight patients), nasopharyngitis and constipation (seven patients each), and headache (six patients). Most AEs were considered mild to moderate in intensity. One patient experienced a severe elevation of blood creatine kinase related to strength training. No patients experienced serious AEs, other significant AEs (according to ICH E3), or AEs leading to discontinuation of study treatment.

The investigator considered AEs in 28 patients (35.9%) possibly related to the study medication. The frequencies of patients with investigator-defined drug-related AEs in the active treatment groups were similar to or lower than that of the placebo group – three patients (18.8%) in the 10 mg BI 10773 group, four patients (25.0%) in the 25 mg BI 10773 group, and 14 patients (46.7%) in the 100 mg BI 10773 group, compared with seven patients (43.8%) in the placebo group. The investigator was blinded to whether a patient received placebo or active treatment but was not blinded to the dose level being investigated.

Due to the nature of the investigational product, AEs related to metabolism, nutrition, renal, urinary, and genital disorders (described below) were of special interest.

Mild hypoglycaemia was reported in two patients (6.7%) treated with 100 mg BI 10773 and one patient (6.3%) treated with placebo. All episodes of hypoglycaemia were probably related to prolonged fasting due to OGTT scheduled on that study day. Polydipsia was reported in one patient (3.3%) treated with 100 mg BI 10773.

The frequency of patients with pollakiuria was slightly higher with BI 10773 (10 and 25 mg, two patients each, 12.5%; 100 mg, three patients, 10.0%) than with placebo (one patient, 6.3%). Polyuria was reported in one patient (6.3%) treated with 10 mg BI 10773. Dysuria was reported in one patient (3.3%) treated with 100 mg BI 10773.

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Balanitis and genital pruritis were reported in one patient (6.3%) each. Both patients with genital disorders were in the 25 mg BI 10773 dose group.

No findings of vital signs, 12-lead ECG, weight and waist circumference, liquid intake, micturition frequency or urine volumes were clinically significant. The investigator assessed global tolerability as ‘good’ in 71 patients (91.0%) and ‘satisfactory’ in one patient (6.3%) each in the placebo and 10 and 25 mg BI 10773 groups and four patients (13.3%) in the 100 mg BI 10773 group.

Pharmacokinetic results:

The pharmacokinetics of BI 10773 were similar after administration of a single dose on Day 1 and multiple doses at steady-state on Day 28. BI 10773 was rapidly absorbed after oral administration, reaching peak levels at approximately 1.5 h after dosing. Plasma concentration-time profiles showed a biphasic decline, i.e. a rapid distribution phase and a slower elimination phase. The mean terminal elimination half-life at steady-state ranged from 13.2 to 16.5 h. Increases in BI 10773 exposure (AUC and Cmax) were proportional with dose from 10 to 100 mg BI 10773 q.d.. Oral clearance was moderate (215 to 223 mL/min on Day 1 and 202 to 208 mL/min on Day 28). The amount of parent excreted unchanged in the urine ranged from 17.5% to 18.3% of the administered dose at steady-state. The similarities in single-dose and steady-state parameters suggest linear pharmacokinetics with respect to time. The mean linearity index ranged from 1.04 to 1.10. Consistent with the half-life, up to 22% accumulation was observed at steady-state.

Pharmacodynamic results:

Administration of BI 10773 q.d. led to statistically significant differences from placebo in many PD endpoints. Administration of single oral doses of BI 10773 resulted in statistically significant increases in amount of UGE at all doses compared with placebo. The amounts of UGE were similar in all BI 10773 treatment groups. The increase in UGE was maintained with multiple dosing and not affected by glucose challenge. A concomitant increase in the rate of UGE was observed.

Reductions in MDG of up to 24 mg/dL from baseline were observed after single and multiple doses of BI 10773. Changes in MDG were significantly different from placebo at all doses on Day 1 but only at doses of 25 and 100 mg on Day 27. Administration of multiple oral doses of BI 10773 resulted in reductions in FPG of up to 44 mg/dL on Day 28 and differences from placebo were statistically significant at all doses. Significant reductions were observed in

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uncorrected but not in baseline-corrected plasma glucose AUEC0-5.

Statistically significant treatment effects compared with placebo were not observed in analyses of fasting insulin, fructosamine, or insulin and glucagon PD parameters (AUEC0-5 and Emax). BI 10073 did not result in significant reductions compared with placebo in HbA1c or fructosamine.

Conclusions: BI 10773 was rapidly absorbed following oral administration and showed a biphasic decline. Increases in exposure were approximately proportional with dose from 10 to 100 mg q.d. The mean terminal half-life ranged from 13.2 to 16.5 h. Oral clearance was moderate. The amount of drug excreted unchanged in the urine ranged from 17.5% to 18.3% of the administered dose at steady-state. The similarities in single-dose and steady-state parameters suggest linear pharmacokinetics with respect to time. Consistent with the half-life, up to 22% drug accumulation was observed at steady-state.

Administration of BI 10773 resulted in significant increases from baseline in UGE and reductions from baseline in MDG of up to 24 mg/dL and FPG of up to 44 mg/dL. Treatment differences compared with placebo were statistically significant at all doses. No significant reductions in insulin, glucagon, HbA1c, or fructosamine were observed.

Multiple oral doses of BI 10773 up to doses of 100 mg administered once daily over 28 days were safe and well tolerated in patients with type 2 diabetes. No patients experienced serious AEs, other significant AEs (according to ICH E3), or AEs leading to discontinuation of study treatment. The frequency of patients with AEs and investigator-defined drug-related AEs was similar with BI 10773 and placebo.

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Boehringer Ingelheim BI trial number 1245.4 Trial Synopsis - Appendix

Trial Synopsis - Appendix

The appended tables on the following pages supplement the trial results presented in the Trial

Synopsis. They complement results for secondary endpoints of the trial. Note that not all

secondary endpoints defined in the trial protocol are presented in this synopsis because their

number was too large to allow meaningful presentation in this format.

Results for presented in

Summary of PK parameters by treatment for Day 1 Table 15.6.3: 1

Summary of PK parameters by treatment for Day 28 Table 15.6.3: 2

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Table 15.6.3: 1 Comparison of pharmacokinetic parameters (N, gMean and gCV [%]) of BI 10773 by treatment Day 1

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10 mg 25 mg 100 mg N gMean gCV [%] N gMean gCV [%] N gMean gCV [%]____________________________________________________________________________________________

AUC0−5 [nmol*h/L] 16 768 19.9 16 2030 20.5 30 7570 19.8AUC0−12 [nmol*h/L] 16 1240 17.5 16 3180 21.1 30 12500 18.4AUCτ,1 [nmol*h/L] 16 1530 16.2 16 3840 21.5 30 15600 20.2AUC0−tz [nmol*h/L] 16 1530 16.3 16 3840 21.5 30 15600 20.2AUC0−∞ [nmol*h/L] 16 1720 15.9 16 4240 22.0 30 17600 22.5AUC0−∞,norm [nmol*h/L/mg] 16 178 19.9 16 181 18.8 30 167 21.8%AUCtz−∞ [%] 16 10.5 28.9 16 9.02 29.1 30 10.7 37.0C24,1 [nmol/L] 16 14.7 22.1 16 33.4 30.8 30 157 38.6Cmax [nmol/L] 16 291 33.4 16 709 19.9 30 2540 27.3Cmax,norm [nmol/L/mg] 16 29.1 33.4 16 28.4 19.9 30 25.4 27.3t½ [h] 16 8.69 12.9 16 8.16 14.5 30 8.53 18.5λZ [1/h] 16 0.0797 12.9 16 0.0849 14.5 30 0.0813 18.5MRTpo [h] 16 10.0 14.8 16 9.27 13.3 30 10.3 18.2CL/F [mL/min] 16 215 15.9 16 218 22.0 30 210 22.5VZ/F [L] 16 162 19.9 16 154 24.2 30 155 22.7Ae0−24 [nmol] 14 2710 22.7 16 7140 26.8 30 28700 34.5fe0−24 [%] 14 12.2 22.7 16 12.9 26.8 30 12.9 34.5CLR,0−24 [mL/min] 14 29.2 26.2 16 31.0 33.0 30 30.7 41.1

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Source data: Section 15, Table 6.2.1: 1, 6.2.1: 2, 6.2.1: 3 pk\pkover.sas 02MAR2009

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Table 15.6.3: 2 Comparison of pharmacokinetic parameters (N, gMean and gCV [%]) of BI 10773 by treatment Day 28

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10 mg 25 mg 100 mg N gMean gCV [%] N gMean gCV [%] N gMean gCV [%]____________________________________________________________________________________________

AUC0−5,ss [nmol*h/L] 16 855 19.9 16 2210 19.9 30 7980 23.8AUC0−12,ss [nmol*h/L] 16 1470 16.0 16 3730 19.7 30 14200 21.0AUCτ,ss [nmol*h/L] 16 1850 15.8 16 4640 20.8 30 18200 23.6AUCτ,ss,norm [nmol*h/L/mg] 16 185 15.8 16 186 20.8 30 182 23.6Cmax,ss [nmol/L] 16 252 25.7 16 676 18.7 30 2300 27.9Cmax,ss,norm [nmol/L/mg] 16 25.2 25.7 16 27.0 18.7 30 23.0 27.9Cmin,ss [nmol/L] 16 17.3 28.6 16 35.4 56.3 30 186 44.6Cavg [nmol/L] 16 77.1 15.8 16 193 20.8 30 760 23.6t½,ss [h] 16 12.2 41.4 16 12.7 32.7 30 15.0 44.3λZ,ss [1/h] 16 0.0570 41.4 16 0.0546 32.7 30 0.0461 44.3MRTpo,ss [h] 16 11.5 16.0 16 11.2 17.8 30 12.7 21.8CL/F,ss [mL/min] 16 200 15.8 16 199 20.8 30 203 23.6VZ/F,ss [L] 16 210 38.5 16 219 43.3 30 264 46.7PTF [%] 16 303 16.1 16 329 20.5 30 277 25.1LI 16 1.08 11.1 16 1.10 12.4 30 1.04 9.18RA,Cmax 16 0.865 42.4 16 0.954 20.5 30 0.906 25.1RA,AUC0−24 16 1.21 13.0 16 1.21 12.3 30 1.17 11.1Ae0−24,ss [nmol] 15 3930 27.1 16 9730 18.8 30 36900 36.8fe0−24,ss [%] 15 17.7 27.1 16 17.6 18.8 30 16.6 36.8CLR,0−24,ss [mL/min] 15 35.3 32.7 16 34.9 28.1 30 33.7 46.5

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Source data: Section 15, Table 6.2.1: 4, 6.2.1: 5, 6.2.1: 6 pk\pkover.sas 02MAR2009

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trial synopsis 1245.4 ds co - boehringer ingelheim...the synopsis may include approved and...

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