trial synopsis 1245.15 ds co - boehringer ingelheim€¦ · abcd clinical ... • for an...

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

ABCD

Synopsis No.:

Name of finished product:

Not applicable

Name of active ingredient:

BI 10773

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Report date: 23 AUG 2010

Trial No. / U No.: 1245.15 / U10-2326-01

Date of trial: 15 APR 2009 – 26 OCT 2009

Date of revision (if applicable):Not applicable

Proprietary confidential information © 2010 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: 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

Coordinating Investigator:

MD

Japan

Trial sites: Multicentre trial, cf. Appendix 16.1.4.

Publication (reference): Data of this trial have not been published.

Clinical phase: II

Objectives: To evaluate pharmacodynamics, pharmacokinetics, safety, and tolerability of once daily oral administration of BI 10773 (1 mg, 5 mg, 10 mg, and 25 mg) administered for 28 days in Japanese patients with type 2 diabetes mellitus (T2DM).

Methodology: Randomised, double-blind, placebo-controlled, multicentre, parallel comparison study with multiple oral doses for 28 days

No. of patients:

planned: To be entered: 80 patients

actual: Enrolled: 196 patients, entered: 100 patients Treatment with BI 10773 1 mg:

entered: 19, treated: 19, analysed (for primary endpoint): 19 Treatment with BI 10773 5 mg:



entered: 19, treated: 19, analysed (for primary endpoint): 19 Treatment with placebo:

entered: 21, treated: 21, analysed (for primary endpoint): 21

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Diagnosis and main criteria for inclusion:

Japanese patients with T2DM Haemoglobin A1c (HbA1c) at screening (Visit 1):

For patients treated with one other oral antidiabetic drug: ≥6.5% and ≤9.0% For patients not treated with any antidiabetic drug: ≥7.0% and ≤10.0%

Age: ≥20 and ≤70 years Body mass index (BMI): ≥18.0 and ≤40.0 kg/m2

Test product: BI 10773

dose: 1 mg, 5 mg, 10 mg, and 25 mg

mode of admin.: Once daily oral administration with about 150 mL of water in a fasting condition

batch no.: BI 10773 1 mg tablets: B073000780 BI 10773 5 mg tablets: B073000791 BI 10773 25 mg tablets: B073000869

Reference therapy: Placebo

dose: Not applicable

mode of admin.: Once daily oral administration with about 150 mL of water in a fasting condition

batch no.: B073000702

Duration of treatment: 28 days

Criteria for evaluation:

Efficacy / clinical pharmacology:

Primary endpoints: urinary glucose excretion (UGE), fasting plasma glucose (FPG), an eight-point glucose profile Secondary endpoints: HbA1c, fructosamine, 1,5-anhydroglucitol, fasting insulin, plasma glucose profile (in a meal tolerance test [MTT]), glucagon profile (in an MTT), and insulin profile (in an MTT)

Pharmacokinetics: Cmax, tmax, t1/2, λz, C24,1, AUCτ,1, AUC0-tz, AUC0-∞, Aet1-t2, fet1-t2, CLR,0-24, CL/F, Vz/F, MRTpo, Cmax,ss, Cmin,ss, Cpre,N, C24,ss, tmax,ss, t1/2,ss, λz,ss, AUCτ,ss, MRTpo,ss, CL/F,ss, Vz/F,ss, Aet1-t2,ss, fet1-t2,ss, CLR,ss, Cavg, peak−trough fluctuation (PTF), linearity index (LI), RA,Cmax, and RA,AUC

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Safety: Adverse events, clinical laboratory tests (haematology, clinical chemistry, urinalysis, and hormones associated with glucose metabolism), blood glucose, vital signs (blood pressure and pulse rate), micturition frequency (patient’s diary), tolerability, physical examination, and 12-lead electrocardiogram (ECG)

Statistical methods: Descriptive statistics for pharmacodynamic, pharmacokinetic, safety endpoints, and tolerability were calculated. The changes from baseline of pharmacodynamic variables were compared by treatment in an exploratory way by using an approach of analysis of covariance (ANCOVA). Dose proportionality with BI 10773 was explored by using a power model. For the attainment of steady state, the trough concentrations of BI 10773 were analysed with a linear mixed model with “patient” as a random effect and “time” as a repeated effect.

SUMMARY – CONCLUSIONS:

Efficacy / clinical pharmacology results:

Pharmacodynamics • For FPG, differences in decreases from baseline to Day 28 between the BI

10773 groups and the placebo group were statistically significant and the decreases were dose-dependent up to 10 mg of BI 10773. The decreases were similar between the BI 10773 10 mg group and the BI 10773 25 mg group.

• For an eight-point glucose profile, differences in decreases from baseline to Days 1 and 27 between the BI 10773 groups and the placebo group were statistically significant and the decreases were dose-dependent.

• For UGE, differences in increases from baseline to Days 1, 27, and 28 between the BI 10773 groups and the placebo group were statistically significant. The increases were larger in the BI 10773 groups than the placebo group. The increases were maintained between Day 1 and Day 27 at all doses of BI 10773.

• After the first and multiple drug administrations, the rates of UGE increased with increasing dose up to 10 mg. The rates were similar between the BI 10773 10 mg group and the BI 10773 25 mg group.

• For plasma glucose (AUEC1-5), differences in decreases from baseline to Day 28 between the BI 10773 groups and the placebo group were statistically significant and the decreases were dose-dependent up to 10 mg of BI 10773. The extents of decrease were similar between the BI 10773 10 mg group and the BI 10773 25 mg group.

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Efficacy / clinical pharmacology results: (continued):

• For HbA1c, differences in decreases from baseline to Day 28 between the BI 10773 5 mg, 10 mg, or 25 mg group and the placebo group were statistically significant and the decreases were dose-dependent up to 10 mg of BI 10773. The decreases were similar between the BI 10773 10 mg group and the BI 10773 25 mg group.

• For 1,5-anhydroglucitol, differences in decreases from baseline to Day 28 between the BI 10773 groups and the placebo group were statistically significant.

• For fructosamine, differences in decreases from baseline to Day 28 between the BI 10773 groups and the placebo group were not statistically significant. However, the decreases from baseline were larger in the BI 10773 10 mg and 25 mg groups than in the placebo group.

• For insulin AUEC1-5 and Epre, differences in decreases from baseline to Day 28 between the BI 10773 10 mg or 25 mg group and the placebo group were statistically significant. The decreases were larger in the BI 10773 groups than the placebo group. The decreases in Epre were similar between the BI 10773 10 mg group and the BI 10773 25 mg group. There was no dose-dependency in Emax of insulin.

• There was no dose-dependency in AUEC1-5 and Emax for glucagon.

Pharmacokinetics • BI 10773 was rapidly absorbed after oral administration, reaching a peak at

approximately 1.5 to 2 hours after drug administration. 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 after multiple drug administration ranged from 13.2 hours to 18.0 hours.

• Increases in BI 10773 exposure (AUC and Cmax) were proportional to dose from 1 mg to 25 mg of BI 10773 once daily.

• Oral clearance (CL/F) was moderate and not apparently different between values after the first drug administration and those after multiple drug administration (150 to 162 mL/min [except for the BI 10773 5 mg group, in which an outlier was noted] on Day 1 and 135 to 149 mL/min on Day 28).

• In urine, 21.4% to 22.3% of the administered dose was excreted unchanged after multiple drug administration.

• The mean LI ranged from 1.08 to 1.32. Accumulation amounted to 4% to 51% in terms of AUC and Cmax after multiple drug administration.

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Safety results:

Adverse events In this trial, 25 (25.0%) of 100 patients experienced an adverse event. Adverse events were more frequent in the BI 10773 groups (23 [29.1%] of 79 patients) than in the placebo group (2 [9.5%] of 21 patients). There was no dose-dependency in frequency of adverse events. Among the adverse events, the investigator considered adverse events in 10 (10.0%) patients related to the investigational products. The proportion of patients having experienced a drug-related adverse event (according to the investigator’s judgement) was slightly higher in the BI 10773 groups (9 [11.4%] of 79 patients) than in the placebo group (1 [4.8%] of 21 patients). All adverse events were mild or moderate in intensity and all the patients recovered from the adverse events. Overall, BI 10773 was well tolerated by all patients according to the assessment of tolerability by the investigator. No death occurred in the trial. Overall, 1 patient in the BI 10773 1 mg group reported one serious adverse event of drug-unrelated transient ischaemic attack and 1 patient in the placebo group reported one other significant adverse event (according to the definition given in ICH E3) of drug-unrelated hyperglycaemia that led the patient premature discontinuation. Symptomatic hypoglycaemia occurred in 1 patient each in the BI 10773 1 mg and the BI 10773 10 mg groups after the meal for the MTT on Day 28: blood glucose levels were within the range of 3.0 to 3.9 mmol/L in the patient in the BI 10773 1 mg group and >3.9 mmol/L in the patient in the BI 10773 10 mg group. Both events were of mild intensity. Both patients did not require assistance for the adverse events and recovered from the adverse events without treatment within the day. The investigator considered that the events might be due to low-calorie intake from the standardised breakfast (200 kcal) on the day of an MTT after the patients had fasted for at least 10 hours, but also considered that the temporal relationship between the events and the drug administration implicated the investigational product as a cause. Therefore, the investigator identified the events as drug-related. As an adverse event of special interest related to a sodium glucose cotransporter (SGLT)-2 inhibitor, five adverse events were experienced in the BI 10773 groups: cystitis in 1 patient in the BI 10773 25 mg group, hypoglycaemia in 1 patient each in the BI 10773 1 mg and 10 mg groups, nocturia in 1 patient in the BI 10773 10 mg group, and pollakiuria in 1 patient in the BI 10773 25 mg group.

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Safety results (continued):

All events were mild in intensity. No genital tract infections occurred.

Laboratory test results No major differences were noted in the frequency of patients with possible clinically significant abnormalities between the BI 10773 groups and the placebo group. No major differences were noted in changes from baseline between the BI 10773 groups and the placebo group for laboratory test results other than gamma-glutamyltransferase (GGT) and triglyceride; and the changes in GGT and triglyceride were not considerable.

Vital signs, physical findings, and other observations related to safety Systolic blood pressure decreased from baseline to Day 29 in all treatment groups. Differences in decreases between the BI 10773 25 mg group and the placebo group were statistically significant: the difference vs. placebo was -7.3 mmHg (ANCOVA: p=0.0029), with the largest degree among the BI 10773 groups. Diastolic blood pressure decreased from baseline (Day 1) to Day 29 in treatment groups except the BI 10773 10 mg group. However, differences in decrease between the BI 10773 groups and the placebo group were not statistically significant. Urine volumes increased dose-dependently on Day 1. But no major differences were seen between the BI 10773 groups and the placebo group on Day 28. Urine volumes were greater than liquid intakes in the BI 10773 5 mg, 10 mg, and 25 mg groups on Day 1, whereas a urine volume was comparable to liquid intake in the placebo group. But no major differences were seen between the BI 10773 groups and the placebo group on Day 28.

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Conclusions: Administration of BI 10773 resulted in statistically significant treatment effects over placebo on all primary endpoints as well as most of the secondary endpoints. The effects were consistently greatest at BI 10773 10 mg and 25 mg for most of the parameters. Increases in BI 10773 exposure were proportional to dose from 1 mg to 25 mg of BI 10773 once daily. The amount of the parent drug excreted in urine ranged from 21.4% to 22.3% of the administered dose after multiple oral drug administration at the steady state. In this trial, 25 (25.0%) of 100 patients experienced an adverse event. Patients having experienced an adverse event were more frequent in the BI 10773 groups than in the placebo group. However, no trend was observed between the frequency of the patients with adverse events and dose. Overall, BI 10773 was well tolerated by all patients according to the assessment of tolerability by the investigator. No clinically relevant findings were noted in laboratory test values, vital signs, physical findings, or other observation related to safety.

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Boehringer Ingelheim BI trial number 1245.15 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 primary and 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

Fasting Plasma Glucose (FPG) change from baseline to Day 28 (primary endpoint)

Table 15.5.1.1.1: 2

8 Point Glucose change from baseline to Day 27 (primary endpoint)

Table 15.5.1.1.2: 6

Urine Glucose Excretion (UGE) change from baseline to Day 28 (primary endpoint)

Table 15.5.1.1.3: 5

Plasma Glucose [AUEC1−5] change from baseline to Day 28 in a MTT (secondary endpoint)

Table 15.5.1.2.1: 2

HbA1c change from baseline to Day 28 (secondary endpoint) Table 15.5.1.2.2: 2

1,5−anhydroglucitol change from baseline to Day 28 (secondary endpoint)

Table 15.5.1.2.3: 3

Fasting insulin change from baseline to Day 28 (secondary endpoint)

Table 15.5.1.2.5: 6

Fructosamine change from baseline to Day 28 (secondary endpoint)

Table 15.5.1.2.4: 3

Insulin [AUEC1−5] change from baseline to Day 28 in a MTT (secondary endpoint)

Table 15.5.1.2.1: 5

Glucagon [AUEC1−5] change from baseline to Day 28 in a MTT (secondary endpoint)

Table 15.5.1.2.7: 2

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Table 15.5.1.1.1: 2 ANCOVA results for change from baseline in fasting plasma glucose (mg/dL) adjusted for baseline − FAS

Day qualifier=Day 28

Difference to placebo

Least square Least square 95% CI 95% CI Treatment N mean SE mean SE (Lower) (Upper) P−value

Placebo 20 −15.436 2.860 1 mg BI 10773 19 −28.116 2.965 −12.680 4.155 −20.936 −4.424 0.0030 5 mg BI 10773 20 −35.355 2.865 −19.920 4.025 −27.919 −11.921 <.0001 10 mg BI 10773 18 −41.643 3.009 −26.208 4.168 −34.490 −17.925 <.0001 25 mg BI 10773 17 −42.670 3.089 −27.235 4.202 −35.586 −18.884 <.0001

Source data: Appendix 16.1.9.3, Statdoc 1.1.1.1 sa\fpg.sas 16FEB2010

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Table 15.5.1.1.2: 6 ANCOVA results for change from baseline in 8 point glucose (mg/dL) on Day 27 adjusted for baseline − FAS



Placebo 20 −17.381 3.932 1 mg BI 10773 19 −35.263 4.121 −17.883 5.861 −29.529 −6.236 0.0030 5 mg BI 10773 20 −39.867 3.903 −22.487 5.445 −33.308 −11.665 <.0001 10 mg BI 10773 18 −43.646 4.113 −26.265 5.785 −37.762 −14.768 <.0001 25 mg BI 10773 17 −45.721 4.187 −28.340 5.699 −39.665 −17.015 <.0001

Source data: Appendix 16.1.9.3, Statdoc 1.1.2.5 sa\eightgl.sas 16FEB2010

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Table 15.5.1.1.3: 5 ANCOVA results for change from baseline in urine glucose excretion (mg) on Day 28 adjusted for baseline − FAS



Placebo 20 599.763 4497.460 1 mg BI 10773 19 43428.245 4598.593 42828.482 6487.174 29936.586 55720.378 <.0001 5 mg BI 10773 20 81564.440 4460.086 80964.677 6303.820 68437.160 93492.194 <.0001 10 mg BI 10773 18 89189.527 4704.967 88589.764 6544.604 75583.738 101595.790 <.0001 25 mg BI 10773 17 86220.111 4828.541 85620.348 6610.091 72484.181 98756.515 <.0001

Source data: Appendix 16.1.9.3, Statdoc 1.1.3.3 sa\uge.sas 16FEB2010

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Table 15.5.1.2.1: 2 ANCOVA results for change from baseline in baseline−corrected AUEC1−5 (hr*mg/dL) with MTT on Day 28 adjusted for baseline − FAS



Placebo 20 −19.800 6.911 1 mg BI 10773 19 −64.324 7.124 −44.524 10.020 −64.437 −24.611 <.0001 5 mg BI 10773 20 −49.813 6.966 −30.013 9.707 −49.303 −10.723 0.0027 10 mg BI 10773 18 −45.824 7.284 −26.024 10.115 −46.126 −5.922 0.0118 25 mg BI 10773 17 −46.624 7.443 −26.823 10.177 −47.048 −6.599 0.0099

Source data: Appendix 16.1.9.3, Statdoc 1.2.1.1 sa\mtt.sas 04MAR2010

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Table 15.5.1.2.2: 2 ANCOVA results for change from baseline in HbA1c (%) on Day 28 adjusted for baseline − FAS



Placebo 20 −0.420 0.089 1 mg BI 10773 19 −0.659 0.093 −0.239 0.130 −0.498 0.020 0.0705 5 mg BI 10773 20 −0.717 0.090 −0.296 0.125 −0.545 −0.047 0.0203 10 mg BI 10773 18 −0.849 0.094 −0.429 0.130 −0.687 −0.170 0.0014 25 mg BI 10773 17 −0.815 0.096 −0.395 0.131 −0.654 −0.135 0.0033

Source data: Appendix 16.1.9.3, Statdoc 1.2.2.1 sa\hba1c.sas 16FEB2010

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Table 15.5.1.2.3: 3 ANCOVA results for change from baseline in 1,5−anhydroglucitol (ug/mL) on Day 28 adjusted for baseline − FAS



Placebo 20 1.174 0.439 1 mg BI 10773 12 −3.018 0.581 −4.192 0.728 −5.653 −2.731 <.0001 5 mg BI 10773 11 −3.435 0.615 −4.609 0.756 −6.126 −3.091 <.0001 10 mg BI 10773 10 −2.863 0.622 −4.036 0.762 −5.565 −2.508 <.0001 25 mg BI 10773 4 −3.713 0.982 −4.887 1.076 −7.048 −2.726 <.0001

Source data: Appendix 16.1.9.3, Statdoc 1.2.3.2 sa\anhyd.sas 16FEB2010

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Table 15.5.1.2.5: 6 ANCOVA results for change from baseline in fasting insulin (uU/mL) on Day 28 adjusted for baseline − FAS



Placebo 20 −0.387 0.287 1 mg BI 10773 19 −0.866 0.295 −0.480 0.414 −1.302 0.343 0.2498 5 mg BI 10773 20 −0.766 0.287 −0.379 0.408 −1.189 0.430 0.3544 10 mg BI 10773 18 −1.730 0.301 −1.343 0.416 −2.171 −0.516 0.0018 25 mg BI 10773 17 −1.643 0.312 −1.257 0.421 −2.094 −0.419 0.0037

Source data: Appendix 16.1.9.3, Statdoc 1.2.5.5 sa\fastins.sas 16FEB2010

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Table 15.5.1.2.4: 3 ANCOVA results for change from baseline in fructosamine (umol/L) on Day 28 adjusted for baseline − FAS



Placebo 20 −8.436 12.289 1 mg BI 10773 19 4.091 12.663 12.527 17.755 −22.757 47.811 0.4823 5 mg BI 10773 20 −2.453 12.362 5.984 17.313 −28.422 40.390 0.7305 10 mg BI 10773 18 −26.294 12.933 −17.858 17.903 −53.438 17.721 0.3213 25 mg BI 10773 17 −28.275 13.282 −19.838 18.130 −55.869 16.192 0.2768

Source data: Appendix 16.1.9.3, Statdoc 1.2.4.2 sa\fruct.sas 16FEB2010

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Table 15.5.1.2.1: 5 ANCOVA results for change from baseline in uncorrected AUEC1−5 (hr*mg/dL) with MTT on Day 28 adjusted for baseline − FAS



Placebo 20 −81.357 10.481 1 mg BI 10773 19 −176.771 10.924 −95.414 15.388 −125.995 −64.833 <.0001 5 mg BI 10773 20 −190.837 10.554 −109.480 14.670 −138.633 −80.327 <.0001 10 mg BI 10773 18 −212.693 11.023 −131.336 15.354 −161.848 −100.824 <.0001 25 mg BI 10773 17 −217.698 11.247 −136.341 15.357 −166.860 −105.823 <.0001

Source data: Appendix 16.1.9.3, Statdoc 1.2.1.3 sa\mtt.sas 04MAR2010

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Table 15.5.1.2.7: 2 ANCOVA results for change from baseline in glucagon [AUEC1−5 (hr*pg/mL)] with MTT on Day 28 adjusted for baseline − FAS



Placebo 20 −23.452 9.177 1 mg BI 10773 19 −0.785 9.383 22.668 13.152 −3.470 48.805 0.0883 5 mg BI 10773 20 7.124 9.138 30.576 12.941 4.859 56.293 0.0203 10 mg BI 10773 18 −17.478 9.635 5.974 13.289 −20.434 32.382 0.6541 25 mg BI 10773 17 −12.437 9.964 11.015 13.612 −16.036 38.066 0.4206

Source data: Appendix 16.1.9.3, Statdoc 1.2.7.1 sa\glucagon.sas 25FEB2010

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trial synopsis 1245.15 ds co - boehringer ingelheim€¦ · abcd clinical ... • for an...

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