Trial synopsis 1275.1 DS DR - Boehringer Ingelheim · Synopsis No.: Name of finished product: Not...

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

EudraCT No.:

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Name of active ingredient: Empagliflozin (BI 10773) / linagliptin (BI 1356)

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Report date: 20 DEC 2013

Trial No. / U No.: 1275.1 / U13-2755-01

Dates of trial: 31 AUG 2011 – 10 SEP 2013

Date of revision: Not applicable

Proprietary confidential information © 2013 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.

No. of subjects:

planned: Entered: 665 patients (metformin), 665 patients (treatment naïve)

actual: Enrolled (overall): 2504 patients Entered (overall): 1363 patients PATIENT POPULATION WITH METFORMIN BACKGROUND: Entered: 686 patients FDC empagliflozin 25 mg/linagliptin 5 mg: entered: 137 treated: 137 analysed (for primary endpoint): 134 FDC empagliflozin 10 mg/linagliptin 5 mg: entered: 136 treated: 136 analysed (for primary endpoint): 135 Empagliflozin 25 mg: entered: 141 treated: 141 analysed (for primary endpoint): 140 Empagliflozin 10 mg: entered: 140 treated: 140 analysed (for primary endpoint): 137 Linagliptin 5 mg: entered: 132 treated: 132 analysed (for primary endpoint): 128 TREATMENT NAÏVE PATIENT POPULATION: Entered: 677 patients FDC empagliflozin 25 mg/linagliptin 5 mg: entered: 137 treated: 137 analysed (for primary endpoint): 134 FDC empagliflozin 10 mg/linagliptin 5 mg: entered: 136 treated: 136 analysed (for primary endpoint): 135 Empagliflozin 25 mg: entered: 135 treated: 135 analysed (for primary endpoint): 133 Empagliflozin 10 mg: entered: 134 treated: 134 analysed (for primary endpoint): 132 Linagliptin 5 mg: entered: 135 treated: 135 analysed (for primary endpoint): 133

Diagnosis and main criteria for inclusion:

Patients aged ≥18 years with confirmed diagnosis of type 2 diabetes mellitus with insufficient glycaemic control, i.e. HbA1c ≥7.0% and ≤10.5% (≥53.0 mmol/mol and ≤91.3 mmol/mol); treatment naïve or pre-treated with metformin, unchanged for 12 weeks prior to randomisation; and body mass index (BMI) ≤45 kg/m2

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Test product: Empagliflozin/linagliptin FDC tablets

dose: 25 mg/5 mg q.d. and 10 mg/5 mg q.d.

mode of admin.: Oral

batch nos.: FDC empagliflozin 25 mg/linagliptin 5 mg: B101005414; B101005415; 104287A; 108247

Placebo matching FDC empagliflozin 25 mg /linagliptin 5 mg: B101005366; B101005367; B111004201; B111004202

FDC empagliflozin 10 mg/linagliptin 5 mg: B101005412; B101005413; 104286A; 108244

Placebo matching FDC empagliflozin 10 mg /linagliptin 5 mg: B101005364; B101005365; B111004134

Reference therapy 1: Empagliflozin tablets

dose: 25 mg q.d. and 10 mg q.d.


batch nos.: Empagliflozin 25 mg: 003532B; 103698

Placebo matching empagliflozin 25 mg: 88684; 96239; 93388

Empagliflozin 10 mg: 4897; 103697

Placebo matching empagliflozin 10 mg: 88608; 96180; 93262

Reference therapy 2: Linagliptin tablets

dose: 5 mg q.d.


batch nos.: Linagliptin 5 mg: 4000427; 4000690

Placebo matching linagliptin 5 mg: 4000428; 4000429; 4000550; 4000829

Duration of treatment:

Two-week single-blinded placebo run-in period followed by a 52-week double-blinded treatment period and a 4-week follow-up period

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Criteria for evaluation:

Efficacy: The primary endpoint was the change from baseline in HbA1c (%) after 24 weeks of treatment. Key secondary endpoints were the change from baseline after 24 weeks of treatment in fasting plasma glucose (FPG) and in body weight (comparison of the FDCs with linagliptin), and the occurrence of the treat-to-target efficacy response measured as HbA1c <7.0% (<53.0 mmol/mol) after 24 weeks of treatment. Further exploratory efficacy endpoints were defined as the occurrence of treat-to-target efficacy response, measured as HbA1c <7.0% (<53.0 mmol/mol) after 52 weeks and <6.5% (<47.5 mmol/mol) after 24 and 52 weeks of treatment; the occurrence of a relative efficacy response measured as HbA1c lowering by at least 0.5% (5.5 mmol/mol) after 24 and 52 weeks of treatment; change from baseline in HbA1c and FPG by visit over time; change from baseline in HbA1c and FPG after 52 weeks of treatment; change from baseline in body weight after 24 weeks of treatment (comparison of the FDCs with empagliflozin); change from baseline in body weight after 52 weeks of treatment and at follow-up (Week 56); change from baseline in waist circumference after 24 and 52 weeks of treatment and at follow-up (Week 56); change from baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) after 24 and 52 weeks of treatment; use of rescue therapy; and patient-reported outcome measures. Endpoints based on biomarkers (for treatment naïve patients only) were defined as the change from baseline in fasting plasma insulin (FPI) and in HOMA indices, HOMA-IR (homeostasis model assessment – insulin resistance) and HOMA-IS (homeostasis model assessment – insulin secretion) after 24 weeks of treatment. Empagliflozin and linagliptin trough plasma concentrations were determined for Visits 4, 5, and 7.

Safety: Adverse events (AEs); adverse events of special interest (AESIs) including hypoglycaemic events, urinary tract infection (UTI), genital infection, AEs related to volume depletion, malignancy, and protocol-specified significant adverse events hepatic injury, decreased renal function, hypersensitivity reactions, skin reactions, and pancreatitis; cardiovascular events (Clinical Event Committee adjudication); changes from baseline in clinical laboratory values and pulse rate

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Statistical methods:

Statistical analyses were performed separately for patients on metformin background and for the treatment naïve patients as these were considered two independent patientpopulations. A hierarchical testing procedure for superiority at alpha =0.05 (two-sided) was defined for each population separately. The primary endpoint was analysed using an analysis of covariance (ANCOVA) applied on the full analysis set (FAS) with randomised treatment, renal function, and geographical region as fixed classification effects and HbA1c baseline as a linear covariate. Missing data was imputed using the last observation carried forward (LOCF) approach. Following a request from health authority, which recommended not using the LOCF approach for primary analysis after completion of the 24-week analysis, mixed model repeated measures (MMRM) approach was considered as an alternative to LOCF. Both, the primary endpoint (HbA1c) and key secondary endpoint of FPG analysed at Week 24 based on the MMRM model using the FAS (OC) were presented for both patient populations in this trial. The primary endpoint was tested first for the high dose FDC compared with the respective monotherapies, each tested at alpha =0.05. If successful, tests of the low dose FDC compared with its individual components followed. Sensitivity analyses of the primary endpoint were performed by ANCOVA modelling using different analysis sets, with missing data imputed using multiple imputation, and using a restricted maximum likelihood (REML)-based MMRM approach. If analysis of the primary endpoint was successful, the key secondary endpoint FPG was analysed following the same testing procedure as for HbA1c using ANCOVA modelling. Body weight as a key secondary endpoint was then tested for the high dose FDC vs. linagliptin 5 mg followed by the low dose FDC vs. linagliptin 5 mg, using ANCOVA modelling. The treat-to-target endpoint (HbA1c <7%) was the last key secondary endpoint and tested using logistic regression with missing data imputed as failure in the sequence: high dose FDC vs. linagliptin 5 mg, low dose FDC vs. linagliptin 5 mg, high dose FDC vs. empagliflozin 25 mg, and low dose FDC vs. empagliflozin 10 mg. Key categories used for subgroup analyses of primary and key secondary endpoints were age, baseline HbA1c, geographical region, sex, andrenal impairment. For further exploratory efficacy endpoints descriptive statistics were generated. Blood pressure and waist circumference were analysed by ANCOVA modelling. Other treat-to-target endpoints and use of rescue medication were analysed using

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logistic regression. Time to first use of rescue medication was analysed by Kaplan-Meier survival probability estimates and compared using a log-rank test. Safety analysis was performed using descriptive statistics. For UTI and genital infection AESIs, Kaplan-Meier time to event analyses were performed. Lipid parameters were additionally analysed using ANCOVA modelling.

SUMMARY – CONCLUSIONS:

Efficacy results:

PATIENT POPULATION WITH METFORMIN BACKGROUND:

Week 24

The study population which was on a stable background of metformin included 1179 enrolled patients from 188 centres in 22 countries in Asia, Europe, Latin America, and North America. A total of 686 patients were randomised in a 1:1:1:1:1 ratio and treated. Of those, 58 patients (8.5%) prematurely discontinued study medication until the data cut-off at Week 24, with the main reason for discontinuation being the occurrence of adverse events for 17 patients (2.5%), followed by 15 patients who were lost to follow-up (2.2%); proportions of patients discontinuing due to these reasons were similar in the treatment groups.

The demographic and baseline characteristics were comparable between the treatment groups. Overall, 53.7% of patients were male, 73.9% were White, 43.9% of patients had normal renal function (estimated glomerular filtration rate [eGFR] ≥90 ml/min/1.73m²), 53.4% had mild renal impairment (eGFR ≥60 to <90 mL/min/1.73m²). Mean (SD) baseline HbA1c was 7.98 (0.85)%, weight was 86.20 (18.69) kg, BMI was 30.98 (5.45) kg/m2, age was 56.2 (10.2) years, FPG was 157.9 (34.3) mg/dL, SBP was 130.1 (14.3) mmHg, and DBP was 79.1 (8.9) mmHg. Most patients had been diagnosed with diabetes for between 1 year and 5 years (35.6%); 32.5% of patients had been diagnosed for between 5 years and 10 years, 22.7% of patients had been diagnosed for more than 10 years, and 9.2% of patients had been diagnosed for 1 year or less. Overall compliance was between 80% and 120% for 97.3% of patients in the treatment groups.

Primary endpoint

Superiority of both FDC doses over the respective empagliflozin dose and over linagliptin 5 mg treatment was demonstrated for the change of HbA1c after 24 weeks of treatment with p<0.0001. A summary of the treatment difference in HbA1c

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Efficacy results: (continued)

adjusted mean change from baseline based on the ANCOVA model using FAS (LOCF) is included in Table 2: 1 below. Reductions in HbA1c from baseline were clinically meaningful in all treatment groups; adjusted mean changes (SE) were -1.19 (0.06)% in the high dose FDC group, -1.08 (0.06)% in the low dose FDC group, -0.62 (0.06)% in the empagliflozin 25 mg group, -0.66 (0.06)% in the empagliflozin 10 mg group, and -0.70 (0.06)% in the linagliptin 5 mg group. Sensitivity analyses confirmed the superiority of both FDC doses over their respective monotherapies. Following a request from health authority, which recommended not using the LOCF approach for primary analysis after completion of the 24-week analysis, MMRM approach was considered as an alternative to LOCF. The primary endpoint analysed at Week 24 based on MMRM model using the FAS (OC) is presented in Table 2:1 below. Reductions in HbA1c from baseline were clinically meaningful in all treatment groups; adjusted mean changes (SE) were -1.20 (0.06)% in the high dose FDC group, -1.09 (0.06)% in the low dose FDC group, -0.64 (0.06)% in the empagliflozin 25 mg group, -0.68 (0.06)% in the empagliflozin 10 mg group, and -0.71 (0.07)% in the linagliptin 5 mg group. The results from this analysis were consistent with the primary analysis performed for the FAS (LOCF) using an ANCOVA model.

Table 2: 1 Comparison of FDCs versus monotherapy for the primary endpoint at Week 24 - (metformin) Comparison vs. monotherapy at Week 24, (95% CI)

FDC empagliflozin 25 mg/linagliptin 5 mg


HbA1c adjusted mean change (%) ANCOVA, FAS (LOCF)

vs. empagliflozin 25 mg or 10 mg -0.58 (-0.75,-0.41)1 -0.42 (-0.59,-0.25)1 vs. linagliptin 5 mg -0.50 (-0.67,-0.32)1 -0.39 (-0.56,-0.21)1

HbA1c adjusted mean change (%) MMRM, FAS (OC)

vs. empagliflozin 25 mg or 10 mg -0.56 (-0.74,-0.39)1 -0.41 (-0.58,-0.23)1 vs. linagliptin 5 mg -0.49 (-0.67,-0.31)1 -0.37 (-0.55,-0.20)1

1 p<0.0001

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Key secondary endpoints

Superiority of both FDC doses over their respective monotherapies was demonstrated for the change of FPG from baseline after 24 weeks of treatment. Both FDCs were also superior to linagliptin 5 mg treatment in the change of body weight after 24 weeks. The proportion of patients achieving HbA1c <7.0% after 24 weeks and the associated odds ratios confirmed the superiority of the FDCs to their respective monotherapies. The proportion of patients attaining HbA1c <7.0% after 24 weeks of treatment among patients with baseline HbA1c of ≥7.0%, was 61.8% in the FDC empagliflozin 25 mg/linagliptin 5 mg group, 57.8% in the FDC empagliflozin 10 mg/linagliptin 5 mg group, 32.6% in the empagliflozin 25 mg group, 28.0% in the empagliflozin 10 mg group, and 36.1% in the linagliptin 5 mg group. The results for the analyses of key secondary endpoints are included in Table 2: 2 below. Following a request from health authority, which recommended not using the LOCF approach for primary analysis after completion of the 24-week analysis, MMRM approach was considered as an alternative to LOCF. The key secondary endpoint of FPG analysed at Week 24 based on the MMRM model using the FAS (OC) is presented in Table 2:2 below. The results from this analysis were consistent with the analysis performed for the FAS (LOCF) using an ANCOVA model.

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Table 2: 2 Comparison of FDCs versus monotherapy for the key secondary endpoints at Week 24, - (metformin) Comparison vs. monotherapy at Week 24, (95% CI)



FPG adjusted mean change (mg/dL) ANCOVA, FAS (LOCF)

vs. empagliflozin 25 mg or 10 mg -16.43 (-23.37, -9.48)3 -11.34 (-18.31, -4.37)1 vs. linagliptin 5 mg -22.20 (-29.30,-15.10)3 -19.12 (-26.21,-12.03)3

FPG adjusted mean change (mg/dL)MMRM, FAS (OC)

vs. empagliflozin 25 mg or 10 mg -15.22 (-21.77,-8.66)3 -11.58 (-18.13, -5.02)2 vs. linagliptin 5 mg -22.74 (-29.43,-16.06)3 -19.96 (-26.61,-13.31)3

Body weight adjusted mean change (kg)

vs. linagliptin 5 mg -2.30 (-3.15,-1.44)3 -1.91 (-2.77,-1.05)3 HbA1c response (<7%), odds ratio FAS (NCF)

vs. empagliflozin 25 mg or 10 mg 4.191 (2.319, 7.573)3 4.500 (2.474, 8.184)3 vs. linagliptin 5 mg 3.495 (1.920, 6.363)3 2.795 (1.562, 5.001)2

1 p<0.01 2 p<0.001 3 p<0.0001 NCF= Non-completers considered failure

Further exploratory efficacy endpoints

A higher proportion of patients treated with the FDC empagliflozin 25 mg/linagliptin 5 mg and the FDC empagliflozin 10 mg/linagliptin 5 mg compared with empagliflozin 25 mg or 10 mg and linagliptin 5 mg reached target HbA1c levels of <6.5% or had an HbA1c reduction of at least 0.5% after 24 weeks of treatment. In addition, clinically meaningful reductions in blood pressure were noted for both FDC doses; relevant differences were demonstrated to the linagliptin 5 mg group. Reductions in waist circumference in the FDC and empagliflozin treatment groups were consistent with reduction in body weight after 24 weeks of treatment. The proportions of patients who required the use of rescue medication during treatment was low in all groups.

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Week 52

Of the total 686 randomised and treated patients, 85 patients (12.4%) prematurely discontinued study medication during the 52 weeks of treatment period, with two main reasons for discontinuations: lost to follow-up observed in 24 patients (3.5%) and the occurrence of adverse events for 23 patients (3.4%); proportions of patients discontinuing due to these reasons were similar in the treatment groups.


The further exploratory endpoints: change from baseline in HbA1c, FPG, body weight and HbA1c response (<7%) after 52 weeks of treatment are presented in Table 2: 3. The results from this analysis were consistent with the primary analysis performed after 24 weeks treatment. After 52-weeks of treatment, the results for key secondary endpoints using the ANCOVA model were consistent with those observed using MMRM model. Both FDCs showed sustained improvements in HbA1c and FPG from baseline over 52 weeks.

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Table 2: 3 Comparison of FDCs versus monotherapy for further exploratory endpoints at Week 52, MMRM - FAS (OC) - (metformin) Comparison vs. monotherapy at Week 52, (95% CI)



HbA1c adjusted mean change (%) vs. empagliflozin 25 mg or 10 mg -0.52 (-0.73,-0.31)4 -0.34 (-0.55,-0.14)2 vs. linagliptin 5 mg -0.77 (-0.98,-0.55)4 -0.60 (-0.81,-0.38)4

FPG adjusted mean change (mg/dL) vs. empagliflozin 25 mg or 10 mg -17.58 (-24.86, -10.29)4 -6.95 (-14.22, -0.33)5 vs. linagliptin 5 mg -31.56 (-39.15,-23.97)4 -22.32 (-29.86,-14.77)4

Body weight adjusted mean change (kg) vs. linagliptin 5 mg -3.19 (-4.24,-2.15)4 -2.75 (-3.79,-1.71)4

HbA1c response (<7%), odds ratio FAS (NCF)


1 p<0.05 2 p<0.01 3 p<0.001 4 p<0.0001 5 p>0.05

The results from further exploratory endpoints: HbA1c response of <6.5% or HbA1c reduction of at least 0.5% at Week 52, change from baseline in blood pressure and waist circumference, and use of rescue medication show sustained results throughout the 52-week treatment period.

TREATMENT NAÏVE PATIENT POPULATION:

Week 24

The treatment naïve study population included 1325 enrolled patients from 201 centres in 22 countries in Asia, Europe, Latin America, and North America. A total of 677 patients were randomised in a 1:1:1:1:1 ratio and treated. Of those, 63 patients (9.3%) prematurely discontinued study medication until the data cut-off at Week 24, with the main reason for discontinuation being the occurrence of adverse events for

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20 patients (3.0%), with proportions of patients discontinuing due to this reason ranging from 1.5% in the linagliptin 5 mg group to 5.1% in the FDC empagliflozin 25 mg/ linagliptin 5 mg group.

The demographic and baseline characteristics were comparable between the treatment groups. Overall, 53.8% of patients were male, 74.8% were White, 43.5% of patients had normal renal function (eGFR ≥90 mL/min/1.73m2), 54.0% had mild renal impairment (eGFR 60 to <90 mL/min/1.73m2). Mean (SD) baseline HbA1c was 8.02 (0.96)%, weight was 87.85 (20.13) kg, BMI was 31.58 (5.60) kg/m2, age was 54.6 (10.2) years, FPG was 156.5 (37.7) mg/dL, SBP was 128.3 (14.7) mmHg, and DBP was 78.5 (8.8) mmHg,. Most patients had been diagnosed with type 2 diabetes for between 1 year and 5 years (39.7%) or for 1 year or less (34.3%); 18.0% of patients had been diagnosed for between 5 years and 10 years, and 7.9% of patients had been diagnosed for more than 10 years.

Overall compliance was between 80% and 120% for 98.1% of patients in the treatment groups.

Primary endpoint

The first step of the hierarchical testing procedure demonstrated that the FDC empagliflozin 25 mg/linagliptin 5 mg is superior to linagliptin 5 mg treatment (p<0.0001), but there was no statistically significant difference between the FDC empagliflozin 25 mg/linagliptin 5 mg and empagliflozin 25 mg. Hence, all further analyses were considered exploratory with differences termed statistically relevant if p<0.05. Between the FDC empagliflozin 10 mg/linagliptin 5 mg and empagliflozin 10 mg and linagliptin 5 mg statistically relevant differences were noted (p<0.0001). A summary of the treatment difference in HbA1c adjusted mean change from baseline based on ANCOVA model for FAS (LOCF) is included in Table 2: 4 below. Reductions in HbA1c from baseline were clinically meaningful in all treatment groups; adjusted mean changes (SE) were -1.08 (0.07)% in the high dose FDC group, -1.24 (0.07)% in the low dose FDC group, -0.95 (0.07)% in the empagliflozin 25 mg group, -0.83 (0.07)% in the empagliflozin 10 mg group, and -0.67 (0.07)% in the linagliptin 5 mg group. Sensitivity analyses confirmed the results from the main analysis.

Following a request from health authority, which recommended not using the LOCF approach for primary analysis after completion of the 24-week analysis, MMRM approach was considered as an alternative to LOCF. The primary endpoint analysed

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at Week 24 based on the MMRM model using the FAS (OC) is presented in Table 2:4 below. Reductions in HbA1c from baseline were clinically meaningful in all treatment groups; adjusted mean changes (SE) were -1.07 (0.07)% in the high dose FDC group, -1.26 (0.07)% in the low dose FDC group, -0.95 (0.07)% in the empagliflozin 25 mg group, -0.84 (0.07)% in the empagliflozin 10 mg group, and -0.69 (0.07)% in the linagliptin 5 mg group. The results from this analysis were consistent with the primary analysis performed for the FAS (LOCF) using an ANCOVA model.

Table 2: 4 Comparison of FDCs versus monotherapy for the primary endpoint at Week 24 - (treatment naïve) Comparison vs. monotherapy at Week 24, (95% CI)



HbA1c adjusted mean change (%) ANCOVA, FAS (LOCF)

vs. empagliflozin 25 mg or 10 mg -0.14 (-0.33, 0.06)1 -0.41 (-0.61, -0.21)3 vs. linagliptin 5 mg -0.41 (-0.61, -0.22)3 -0.57 (-0.76, -0.37)3

HbA1c adjusted mean change (%) MMRM, FAS (OC)

vs. empagliflozin 25 mg or 10 mg -0.12 (-0.32, 0.08)1 -0.41 (-0.62,-0.21)3 vs. linagliptin 5 mg -0.38 (-0.58,-0.18)2 -0.57 (-0.77,-0.36)3

1 p>0.05 2 p<0.001 3 p<0.0001

Key secondary endpoints

For the adjusted mean changes in FPG from baseline after 24 weeks of treatment for the FAS (LOCF) based on ANCOVA model, there were statistically relevant differences between the FDCs and linagliptin 5 mg treatment; there were no statistically relevant differences between the FDCs and the respective empagliflozin groups. For the change of body weight, there were statistically relevant differences for the adjusted mean changes from baseline at Week 24 between the FDCs and the linagliptin 5 mg group. Furthermore, the proportion of patients achieving HbA1c <7.0% after 24 weeks and the associated odds ratios demonstrated a statistically relevant difference of the FDCs to their respective monotherapies. The proportion of patients attaining HbA1c <7.0% after 24 weeks of treatment among patients with

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baseline HbA1c of ≥7.0%, was 55.4% in the FDC empagliflozin 25 mg/linagliptin 5 mg group, 62.3% in the FDC empagliflozin 10 mg/linagliptin 5 mg group, 41.5% in the empagliflozin 25 mg group, 38.8% in the empagliflozin 10 mg group, and 32.3% in the linagliptin 5 mg group. The results for the analyses of key secondary endpoints are included in Table 2: 5 below. Following a request from health authority, which recommended not using the LOCF approach for primary analysis after completion of the 24-week analysis, MMRM approach was considered as an alternative to LOCF. The key secondary endpoint of FPG analysed at Week 24 based on the MMRM model using the FAS (OC) is also presented in Table 2: 5 below. The results from this analysis were consistent with the analysis performed for the FAS (LOCF) using an ANCOVA model.

Table 2: 5 Comparison of FDCs versus monotherapy for the key secondary endpoints at Week 24, - (treatment naïve) Comparison vs. monotherapy at Week 24, (95% CI)



FPG adjusted mean change (mg/dL) ANCOVA, FAS (LOCF)

vs. empagliflozin 25 mg or 10 mg 1 -5.31 (-12.74, 2.11)5 -5.82 (-13.25, 1.61)5 vs. linagliptin 5 mg 1 -23.63 (-31.06,-16.21)4 -22.29 (-29.71,-14.88)4

FPG adjusted mean change (mg/dL) MMRM, FAS (OC)

vs. empagliflozin 25 mg or 10 mg 1 -5.30 (-11.95, 1.35)5 -3.02 (-9.67, 3.64)5 vs. linagliptin 5 mg 1 -22.03 (-28.76, -15.30)4 -19.78 (-26.51, -13.05)4

Body weight adjusted mean change (kg) vs. linagliptin 5 mg 1 -1.22 (-2.23, -0.21)2 -1.96 (-2.97, -0.95)3


vs. empagliflozin 25 mg or 10 mg 1 1.893 (1.095, 3.274)2 2.961 (1.697, 5.169)3 vs. linagliptin 5 mg 1 3.065 (1.768, 5.314)4 4.303 (2.462, 7.522)4

1 Exploratory/Non-confirmatory analysis 2 p<0.05 3 p<0.001 4 p<0.0001 5 p>0.05

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Further exploratory efficacy endpoints The analyses of absolute efficacy response (HbA1c levels of <6.5%) and relative efficacy response (≥0.5% reduction in HbA1c) relative to baseline after 24 weeks of treatment, showed that greater proportions of patients in the FDC empagliflozin 10 mg/linagliptin 5 mg group than in the individual monotherapy arms (empagliflozin 10 mg and linagliptin 5 mg) attained HbA1c <6.5% at Week 24. No meaningful difference between the FDC empagliflozin 25 mg/linagliptin 5 mg group and the empagliflozin 25 mg group and only a small difference to the linagliptin 5 mg group was noted. Clinically meaningful reductions in SBP were noted for both FDC doses; meaningful differences were demonstrated to the linagliptin 5 mg group. The changes from baseline in DBP after 24 weeks were small in all treatment groups. Consistent with the reduction in weight, waist circumference decreased for the FDC groups and the empagliflozin groups; for the linagliptin 5 mg group the change in waist circumference was small after 24 weeks. Overall, very few patients were reported with rescue medication, with a slightly higher proportion in the linagliptin 5 mg group.

Week 52

Of the total 677 randomised and treated patients, 107 patients (15.8%) prematurely discontinued study medication, with the most common reason for discontinuation being the occurrence of adverse events for 31 patients (4.6%), with proportions of patients discontinuing due to this reason ranging from 1.5% in the linagliptin 5 mg group to 6.6% in the FDC empagliflozin 25 mg/ linagliptin 5 mg group.


The further exploratory endpoints: change from baseline in HbA1c, FPG, body weight, and HbA1c response (<7%) after 52 weeks of treatment are presented in Table 2: 6 below. The results from this analysis were consistent with the primary analysis performed after 24 weeks treatment. The results from further exploratory endpoints: HbA1c response of <6.5% or HbA1c reduction of at least 0.5%, change from baseline in blood pressure and waist circumference, and use of rescue medication show sustained results throughout the 52-week treatment period. Both FDCs showed sustained improvements in HbA1c and FPG from baseline over 52 weeks.

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Table 2: 6 Comparison of FDCs versus monotherapy for further exploratory endpoints at Week 52 – MMRM- FAS (OC) - (treatment naïve) Comparison vs. monotherapy at Week 52, (95% CI)



HbA1c adjusted mean change (%) vs. empagliflozin 25 mg or 10 mg -0.16 (-0.41, 0.08)5 -0.38 (-0.63,-0.13)2 vs. linagliptin 5 mg -0.67 (-0.93,-0.42)4 -0.74 (-0.99,-0.49)4

FPG adjusted mean change (mg/dL) vs. empagliflozin 25 mg or 10 mg -4.53 (−12.60, 3.54)5 -6.43 (-14.68, 1.81)5 vs. linagliptin 5 mg -26.86 (-35.23,-18.49)4 -24.31 (-32.70,-15.92)4

Body weight adjusted mean change (kg) vs. linagliptin 5 mg -2.17 (-3.38,-0.95)2 -1.54 (-2.75,-0.32)1



1 p<0.05 2 p<0.01 3 p<0.001 4 p<0.0001 5 p>0.05

Biomarkers –Pharmacodynamic Results (Only for Treatment Naïve Population):

Biomarkers were assessed only in the treatment-naïve population and following observations were noted after 24 weeks of treatment: for FPI, reductions from baseline were noted in the FDCs and in the empagliflozin groups while an increase from baseline was noted for the linagliptin 5 mg group; for HOMA-IR, reductions from baseline were noted in all treatment groups; and for HOMA-IS, increases from baseline were noted for all treatment groups.

Safety results:

PATIENT POPULATION WITH METFORMIN BACKGROUND: All 686 patients who were treated with study medication in this patient population were included in the safety analysis. The mean (SD) exposure to randomised study medication during the 52-week treatment period was 338.3 (83.5) days in the

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Safety results: (continued)

FDC empagliflozin 25 mg/linagliptin 5 mg group, 349.7 (60.5) days in the FDC empagliflozin 10 mg/linagliptin 5 mg group, 343.5 (72.3) days in the empagliflozin 25 mg group, 329.6 (94.2) days in the empagliflozin 10 mg group, and 333.0 (90.5) days in the linagliptin 5 mg group.

At Week 52, 71.5% of patients in the FDC empagliflozin 25 mg/linagliptin 5 mg group, 69.1% of patients in the FDC empagliflozin 10 mg/linagliptin 5 mg group, 73.0% of patients in the empagliflozin 25 mg group, 68.6% of patients in the empagliflozin 10 mg group, and 68.9% of patients in the linagliptin 5 mg group were reported with at least 1 adverse event on treatment.

The highest frequency of adverse events at Week 52 was reported for the Medical Dictionary for Drug Regulatory Activities (MedDRA) system organ class 'infections and infestations' with similar frequencies in all treatment groups (FDC empagliflozin 25 mg/linagliptin 5 mg: 36.5%, FDC empagliflozin 10 mg/linagliptin 5 mg: 39.7%, empagliflozin 25 mg: 34.8%, empagliflozin 10 mg: 40.0%, and linagliptin 5 mg: 40.9%). The AE reported with the highest frequency at the preferred term level was UTI (FDC empagliflozin 25 mg /linagliptin 5 mg: 8.8%, FDC empagliflozin 10 mg/linagliptin 5 mg: 8.8%, empagliflozin 25 mg: 12.1%, empagliflozin 10 mg: 9.3%, and linagliptin 5 mg: 11.4%). Generally, most adverse events were of mild or moderate intensity; severe adverse events were reported for 11 patients (8.0%) in the FDC empagliflozin 25 mg/linagliptin 5 mg group, 9 patients (6.6%) in the FDC empagliflozin 10 mg/linagliptin 5 mg group, 4 patients (2.8%) in the empagliflozin 25 mg group, 7 patients (5.0%) in the empagliflozin 10 mg group, and 8 patients (6.1%) in the linagliptin 5 mg group.

At Week 52, adverse events leading to treatment discontinuation were reported for 3 patients (2.2%) in the FDC empagliflozin 25 mg/linagliptin 5 mg group, 2 patients (1.5%) in the FDC empagliflozin 10 mg/linagliptin 5 mg group, 4 patients (2.8%) in the empagliflozin 25 mg group, 9 patients (6.4%) in the empagliflozin 10 mg group, and 4 patients (3.0%) in the linagliptin 5 mg group.

At Week 52, adverse events assessed as drug-related by the investigator were reported for 18 patients (13.1%) in the FDC empagliflozin 25 mg/linagliptin 5 mg group, 23 patients (16.9%) in the FDC empagliflozin 10 mg/linagliptin 5 mg group, 26 patients (18.4%) in the empagliflozin 25 mg group, 26 patients (18.6%) in the empagliflozin 10 mg group, and 15 patients (11.4%) in the linagliptin 5 mg group.

Serious adverse events at Week 52 were reported for 6 patients (4.4%) in the

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FDC empagliflozin 25 mg/linagliptin 5 mg group, 9 patients (6.6%) in the FDC empagliflozin 10 mg/linagliptin 5 mg group, 10 patients (7.1%) in the empagliflozin 25 mg group, 6 patients (4.3%) in the empagliflozin 10 mg group, and 8 patients (6.1%) in the linagliptin 5 mg group. Two cases of deaths were reported in the metformin population, for 1 patient in the FDC empagliflozin 10 mg/ linagliptin 5 mg group and 1 patient in the empagliflozin 10 mg group.

At Week 52, 1 patient in the FDC empagliflozin 25 mg/linagliptin 5 mg, 2 patients in the FDC empagliflozin 10 mg/ linagliptin 5 mg group, 1 patient in the empagliflozin 25 mg, 1 patient in the empagliflozin 10 mg group, and 1 patient in the linagliptin 5 mg group were reported with 4-MACE (major adverse cardiovascular event).

The proportion of patients with confirmed hypoglycaemic events at Week 52 was: 5 patients (3.6%) in the FDC empagliflozin 25 mg/linagliptin 5 mg group, 3 patients (2.2%) in the FDC empagliflozin 10 mg/linagliptin 5 mg group, 5 patients (3.5%) in the empagliflozin 25 mg group, 2 patients (1.4%) in the empagliflozin 10 mg group, and 3 patients (2.3%) in the linagliptin 5 mg group. No severe hypoglycaemic events were reported at Week 52 in this population.

AEs related to UTIs were reported for similar proportions in the FDC groups and the respective empagliflozin groups, and slightly higher proportions in the linagliptin 5 mg group. The proportion of female patients reporting UTIs was generally higher than for male patients, with no meaningful differences between the treatment groups.

The frequency of genital infections reported was low in both FDC treatment groups, the empagliflozin 10 mg group, and the linagliptin 5 mg group. The proportion was slightly higher in the empagliflozin 25 mg group. In the FDC empagliflozin 10 mg/linagliptin 5 mg and the empagliflozin 25 mg groups, the proportion of female patients was higher than the proportion of male patients reported with genital infections. In the other treatment groups, no meaningful difference between male and female patients was noted.

Renal and hepatic adverse events were rare. Changes in markers of renal function (creatinine and eGFR) during the treatment phase were generally small and similar in the randomised treatment groups. No lab constellation recorded for this patient population was consistent with potential Hy´s law for any patient.

Patients with AEs related to volume depletion were rare.

At Week 52, none of the patients in this population were reported with adverse

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events of pancreatic neoplasms, thyroid neoplasms, or cutaneous skin lesions. One patient in the linagliptin 5 mg group was reported with chronic pancreatitis. Adverse events related to malignancies at Week 52 were reported for 3 patients (2.2%) in the FDC empagliflozin 25 mg/linagliptin 5 mg (basal cell cancer, breast cancer, renal cancer), 1 patient (0.7%) in the FDC empagliflozin 10 mg/linagliptin 5 mg group (gastrointestinal carcinoma), 2 patients (1.4%) in the empagliflozin 25 mg group (basal cell carcinoma, metastases to peritoneum, ovarian cancer), 2 patients (1.4%) in the empagliflozin 10 mg group (adenoid cystic carcinoma, lung neoplasm, non-small cell lung cancer metastatic), and 2 patients (1.5%) in the linagliptin 5 mg group (prostatic specific antigen increase, squamous cell carcinoma).

The overall frequency of hypersensitivity reactions was low. At Week 52, 1 patient each in the FDC empagliflozin 25 mg/ linagliptin 5mg and linagliptin 5 mg groups was reported with angioedema, and 1 patient in the FDC empagliflozin 10 mg/linagliptin 5 mg group was reported with urticaria. No patient in the empagliflozin groups were reported with hypersensitivity reactions.

Mean changes from baseline in differentials (automatic and absolute), enzymes, and plasma proteins were small after 52 weeks of treatment. No changes in electrolytes were observed for any treatment group. Haematocrit increased in the FDC and empagliflozin treatment groups after 52 weeks of treatment; the noted increase in the linagliptin 5 mg group was small.

After 52 weeks, there were no relevant differences in the absolute mean changes from baseline between the FDCs and the respective empagliflozin doses in all analysed parameters. Compared with linagliptin 5 mg treatment, no major differences were noted in mean changes from baseline in all lipid parameters and all groups except for HDL cholesterol, for which an increase vs. linagliptin 5 mg was seen for FDC empagliflozin 25 mg/linagliptin 5 mg.

Overall, no relevant increase in pulse rate was observed for the FDCs and the monotherapy arms; changes over time were small and comparable in all groups.

The overall safety profile of the empagliflozin/linagliptin FDCs after 52 weeks of treatment was similar to the known safety profiles of the individual components in patients with type 2 diabetes and metformin background therapy.

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TREATMENT NAÏVE PATIENT POPULATION: All 677 patients who were treated with study medication in this patient population were included in the safety analysis. The mean (SD) exposure to randomised study medication during the 52-week period was 331.9 (87.7) days in the FDC empagliflozin 25 mg/linagliptin 5 mg group, 335.3 (81.7) days in the FDC empagliflozin 10 mg/linagliptin 5 mg group, 332.9 (85.9) days in the empagliflozin 25 mg group, 332.8 (85.7) days in the empagliflozin 10 mg group, and 332.2 (91.8) days in the linagliptin 5 mg group.

The frequency of patients reported with at least 1 adverse vent on treatment at Week 52 was 75.7% of patients in the FDC empagliflozin 25 mg/linagliptin 5 mg group, 72.8% of patients in the FDC empagliflozin 10 mg/linagliptin 5 mg group, 68.9% of patients in the empagliflozin 25 mg group, 81.5% of patients in the empagliflozin 10 mg group, and 71.9% of patients in the linagliptin 5 mg group.

The highest frequency of adverse events at Week 52 was reported for the MedDRA system organ class 'infections and infestations', with similar frequencies across treatment groups (FDC empagliflozin 25 mg/linagliptin 5 mg: 41.6%, FDC empagliflozin 10 mg/linagliptin 5 mg: 36.8%, empagliflozin 25 mg: 32.6%, empagliflozin 10 mg: 46.7%, and linagliptin 5 mg: 37.0%). The adverse event reported with the highest frequency at the preferred term level was UTI (FDC empagliflozin 25 mg /linagliptin 5 mg: 11.0%, FDC empagliflozin 10 mg/linagliptin 5 mg: 12.5%, empagliflozin 25 mg: 5.9%, empagliflozin 10 mg: 12.6%, and linagliptin 5 mg: 8.9%).

Adverse events were mostly of mild or moderate intensity; severe adverse events were reported at Week 52 for 8 patients (2.9%) in each FDC group, 10 patients (7.4%) in each empagliflozin dose group, and 1 patient (0.7%) in the linagliptin 5 mg group.

A few adverse events leading to premature discontinuation of trial medication were reported at Week 52, for 9 patients (6.6%) in the FDC empagliflozin 25 mg/linagliptin 5 mg group, 8 patients (5.9%) in the FDC empagliflozin 10 mg/linagliptin 5 mg group, 3 patients (2.2%) in the empagliflozin 25 mg group, 6 patients (4.4%) in the empagliflozin 10 mg group, and 2 patients (1.5%) in the linagliptin 5 mg group.

Adverse events (based on actual treatment) assessed as drug-related by the

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investigator were reported at Week 52 for 23 patients (16.9%) in the FDC empagliflozin 25 mg/linagliptin 5 mg group, 14 patients (10.3%) in the FDC empagliflozin 10 mg/linagliptin 5 mg group, 22 patients (16.3%) in the empagliflozin 25 mg group, 16 patients (11.9%) in the empagliflozin 10 mg group, and 17 patients (12.6%) in the linagliptin 5 mg group.

Serious adverse events were reported at Week 52 for 6 patients (4.4%) in the FDC empagliflozin 25 mg/linagliptin 5 mg group, 7 patients (5.1%) in the FDC empagliflozin 10 mg/linagliptin 5 mg group, 9 patients (6.7%) in the empagliflozin 25 mg group, 10 patients (7.4%) in the empagliflozin 10 mg group, and 2 patients (1.5%) in the linagliptin 5 mg group. Four cases of deaths were reported in the treatment naïve patient population, for 1 patient in the FDC empagliflozin 10 mg/linagliptin 5 mg group, 2 patients in the empagliflozin 25 mg group, and 1 patient in the empagliflozin 10 mg group.

Overall at Week 52, the number of patients reported with 4-MACE was: 4 patients in the FDC empagliflozin 25 mg/linagliptin 5 mg group, 1 patient in the empagliflozin 25 mg group, and 1 patient in the linagliptin 5 mg group.

Confirmed hypoglycaemic events (with a plasma glucose ≤70 mg/dL or requiring assistance) were reported at Week 52 for 1 patient (0.7%) in the empagliflozin 25 mggroup, 4 patients (3.0%) in the empagliflozin 10 mg group and 1 patient (0.7%) in the linagliptin 5 mg group. No confirmed hypoglycaemic events were reported in the FDC groups. No severe hypoglycaemic events were reported.

Adverse events related to UTIs were reported for similar proportions of patients in all treatment groups. The proportion of female patients reporting UTIs was generally higher than for male patients, with no meaningful difference between the treatment groups. The incidence of genital infections reported during the trial was low in all groups. In all treatment groups, except the FDC empagliflozin 25 mg/linagliptin 5 mg group, the proportion of female patients was slightly higher than the proportion of male patients reported with genital infections.

Hepatic adverse events were rare; no renal adverse events were reported. Changes in markers of renal function (creatinine and eGFR) during the treatment phase were generally small and similar in the randomised treatment groups. No lab constellation reported for this patient population was consistent with potential Hy´s law.

Patients with AEs related to volume depletion were rare. None of the patients in this population were reported with adverse event of pancreatic neoplasms, thyroid

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neoplasms, or cutaneous skin lesions. At Week 52, 1 patient in the FDC empagliflozin 25 mg/linagliptin 5 mg was reported with acute pancreatitis. Adverse events related to malignancies were reported for 2 patients in the FDC empagliflozin 25 mg/linagliptin 5 mg group (renal cell carcinoma, prostate cancer) and 1 patient in the FDC empagliflozin 10 mg/linagliptin 5 mg group (lung adenocarcinoma).

The overall frequency of hypersensitivity reactions was low; at Week 52, hypersensitivity reactions were reported for 2 patients (1.5%) in the FDC empagliflozin 25 mg/linagliptin 5 mg group (asthmatic crisis, eyelid oedema), 1 patient (0.7%) in the FDC empagliflozin 10 mg/linagliptin 5 mg group (asthma), 2 patients (1.5%) each in each empagliflozin dose group (25 mg: urticarial and 10 mg: asthma). Throughout the randomised treatment period, no patient was reported with hypersensitivity reactions in the linagliptin 5 mg group.

Mean changes from baseline in differentials (automatic and absolute), enzymes, and plasma proteins were negligible after 52 weeks of randomised treatment. No changes in electrolytes were observed for any treatment group over 52 weeks. Haematocrit increased in the FDC and empagliflozin treatment groups after 52 weeks of treatment; the noted increase in the linagliptin 5 mg group was small.

At Week 52, there were no relevant differences in the absolute mean changes from baseline between the FDCs and the respective empagliflozin doses in all analysed lipid parameters. Compared with linagliptin 5 mg treatment, no major differences were noted in mean changes from baseline in the FDC groups for total cholesterol in the FDC empagliflozin 10 mg/linagliptin 5 mg group and for LDL cholesterol, LDL/HDL cholesterol ratio, triglycerides, and non-HDL cholesterol in both FDC groups. For total cholesterol, the numerical increase was higher in the FDC empagliflozin 25 mg/linagliptin 5 mg treatment group than in the linagliptin 5 mg group. For HDL cholesterol, the numerical increase was higher in both FDC group compared with the linagliptin 5 mg group.

Overall, no relevant increase in pulse rate was observed for the FDC groups or the monotherapy groups; changes over time were small and comparable in all groups.

The overall safety profile of the empagliflozin/linagliptin FDCs after 52 weeks of treatment was similar to the known safety profiles of the individual components in drug-naïve patients with type 2 diabetes.

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Conclusions:

Treatment with the FDCs empagliflozin 25 mg/linagliptin 5 mg and empagliflozin 10 mg/linagliptin 5 mg in patients with metformin background medication led to clinically meaningful reductions in HbA1c with statistically significant differences in comparison with empagliflozin 25 mg or 10 mg and linagliptin 5 mg after 24 weeks of treatment. Statistically significant and clinically meaningful differences were observed with both FDCs for the change from baseline in FPG, body weight (comparison versus linagliptin 5 mg only), and for the treat to target efficacy response (HbA1c <7.0%) after 24 weeks of treatment. In treatment naïve patients, clinically meaningful reductions in HbA1c were noted for treatment with both FDCs. For the change in HbA1c after 24 weeks of treatment, the FDC empagliflozin 25 mg/linagliptin 5 mg was statistically superior to linagliptin 5 mg treatment, but was not to empagliflozin 25 mg treatment; subsequently the confirmatory testing hierarchy was stopped. Treatment with empagliflozin 10 mg/linagliptin 5 mg showed statistically relevant benefit in HbA1c reduction over the respective monotherapies. Comparisons in change from baseline in FPG, body weight, and in the treat-to-target efficacy response (HbA1c <7.0%) after 24 weeks of treatment generally showed a statistically relevant benefit for both FDCs over linagliptin 5 mg treatment. For both FDCs there was a statistically relevant difference in treat-to-target efficacy response (HbA1c <7.0%) to the respective empagliflozin dose after 24 weeks of treatment, but there was no relevant difference to empagliflozin treatment in FPG change from baseline. Overall in this study, sustained improvement in HbA1c and FPG was observed with both FDCs in both populations over 52 weeks. Both FDCs showed clinically relevant improvements in terms of body weight reduction and BP reduction, indicating that the FDCs retained the beneficial aspects previously observed for empagliflozin 25 mg and empagliflozin 10 mg. The proportion of patients reported with any of the analysed adverse events of special interest was low, with similar frequencies in the treatment groups. A few hypoglycaemic events were reported in all treatment arms; no event was severe or required assistance. Changes in laboratory parameters, including markers of renal function, electrolytes, haematology, and lipid parameters were small in all groups, with only minor differences between the FDCs and the monotherapies. Overall in this trial, in all treatment groups, a positive benefit-risk profile for the treatment of patients with type 2 diabetes and insufficient glycaemic control was observed. The overall safety profile of the empagliflozin/linagliptin FDCs was

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Conclusions (continued):

similar to the known safety profiles of the individual components, both in treatment-naïve patients with type 2 diabetes and in patients with type 2 diabetes and metformin background therapy. No new safety issues were identified and the FDCs retained the low risk of hypoglycaemia of the invidual components empagliflozin and linagliptin. Generally, there were clinically relevant improvements in glycaemic parameters with the FDC in comparison with the individual components. Moreover, the beneficial improvements of body weight and blood pressure reductions observed previously in the empagliflozin monotherapy clinical development programme were maintained with both FDCs.

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Boehringer Ingelheim BI trial number 1275-0001 Trial Synopsis - Appendix

Trial Synopsis - Appendix

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

synopsis. They complement patient disposition results and results for key secondary

endpoints of the trial. Note that not all endpoints defined in the trial protocol are presented in

this synopsis, because their numbers were too large to allow meaningful presentation in this

format.

Results for presented in

Patient Disposition*

Patients with metformin pre-treatment at 24 weeks

Treatment naïve patients at 24 weeks

Patients with metformin pre-treatment at 52 weeks

Treatment naïve patients at 52 weeks

Table 15.2.1.1: 1

Table 15.1.1.1: 1

Table 15.5.1.1: 1

Table 15.4.1.1: 1

FPG change from baseline for patients with metformin pre-treatment at 24 weeks

FPG change from baseline for treatment naïve patients at

24 weeks

Table 15.2.2.2.1.1: 1

Table 15.1.2.2.1.1: 1

Body Weight change from baseline for patients with metformin pre-treatment at 24 weeks

Body Weight change from baseline for treatment naïve patients at 24 weeks

Table 15.2.2.2.2.1: 1

Table 15.1.2.2.2.1: 1

HbA1c < 7% for patients with metformin pre-treatment at 24 weeks

HbA1c < 7% for treatment naïve patients at 24 weeks

Table 15.2.2.2.3: 1

Table 15.1.2.2.3: 1 *Data of 49 patients (with metformin pre-treatment) and 12 patients (treatment-naïve) were excluded from all analyses due to serious non-compliance.

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Table 15.2.1.1: 1 Disposition of patients − screened patients set (Metformin)

Empa25/Lina5 Empa10/Lina5 Empa 25mg Empa 10mg Lina 5mg Total N (%) N (%) N (%) N (%) N (%) N (%)

Screened 1179 Started placebo run−in 747 Not entered 493 Entered 137 136 141 140 132 686 Not treated 0 0 0 0 0 0 Treated 137 (100.0) 136 (100.0) 141 (100.0) 140 (100.0) 132 (100.0) 686 (100.0)

Not prematurely discontinued from trial medication 126 ( 92.0) 129 ( 94.9) 131 ( 92.9) 124 ( 88.6) 118 ( 89.4) 628 ( 91.5) Still on treatment 126 ( 92.0) 129 ( 94.9) 131 ( 92.9) 124 ( 88.6) 118 ( 89.4) 628 ( 91.5)Prematurely discontinued from trial medication 11 ( 8.0) 7 ( 5.1) 10 ( 7.1) 16 ( 11.4) 14 ( 10.6) 58 ( 8.5) Adverse event 3 ( 2.2) 3 ( 2.2) 2 ( 1.4) 5 ( 3.6) 4 ( 3.0) 17 ( 2.5) Worsening of disease under study 0 0 0 0 1 ( 0.8) 1 ( 0.1) Worsening of other pre−existing disease 1 ( 0.7) 0 0 1 ( 0.7) 0 2 ( 0.3) Other adverse event 2 ( 1.5) 3 ( 2.2) 2 ( 1.4) 4 ( 2.9) 3 ( 2.3) 14 ( 2.0) Lack of efficacy 0 0 0 0 0 0 Non compliant with protocol 1 ( 0.7) 0 0 2 ( 1.4) 0 3 ( 0.4) Lost to follow−up 1 ( 0.7) 2 ( 1.5) 4 ( 2.8) 4 ( 2.9) 4 ( 3.0) 15 ( 2.2) Patient refusal to continue, not due to AE 3 ( 2.2) 1 ( 0.7) 1 ( 0.7) 3 ( 2.1) 2 ( 1.5) 10 ( 1.5) Other 3 ( 2.2) 1 ( 0.7) 3 ( 2.1) 2 ( 1.4) 4 ( 3.0) 13 ( 1.9)

Not prematurely discontinued from trial 131 ( 95.6) 133 ( 97.8) 136 ( 96.5) 132 ( 94.3) 125 ( 94.7) 657 ( 95.8) Still in the trial 131 ( 95.6) 133 ( 97.8) 136 ( 96.5) 132 ( 94.3) 125 ( 94.7) 657 ( 95.8)Prematurely discontinued from trial 6 ( 4.4) 3 ( 2.2) 5 ( 3.5) 8 ( 5.7) 7 ( 5.3) 29 ( 4.2) Lost to follow−up 1 ( 0.7) 1 ( 0.7) 2 ( 1.4) 4 ( 2.9) 2 ( 1.5) 10 ( 1.5) Consent withdrawn 5 ( 3.6) 1 ( 0.7) 3 ( 2.1) 4 ( 2.9) 5 ( 3.8) 18 ( 2.6) Death 0 1 ( 0.7) 0 0 0 1 ( 0.1)

Disposition shown at 24 weeks.49 patient numbers were excluded for suspected fraudulent activities.

Source data: Appendix 16.2.1, Listing 2.1 s15\distdisp1a001.sas 19JUN2013

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Table 15.1.1.1: 1 Disposition of patients − screened patients set (Drug naive)



Not prematurely discontinued from trial medication 125 ( 91.2) 124 ( 91.2) 121 ( 89.6) 121 ( 90.3) 123 ( 91.1) 614 ( 90.7) Still on treatment 125 ( 91.2) 124 ( 91.2) 121 ( 89.6) 121 ( 90.3) 123 ( 91.1) 614 ( 90.7)Prematurely discontinued from trial medication 12 ( 8.8) 12 ( 8.8) 14 ( 10.4) 13 ( 9.7) 12 ( 8.9) 63 ( 9.3) Adverse event 7 ( 5.1) 4 ( 2.9) 3 ( 2.2) 4 ( 3.0) 2 ( 1.5) 20 ( 3.0) Worsening of disease under study 1 ( 0.7) 0 0 1 ( 0.7) 0 2 ( 0.3) Worsening of other pre−existing disease 1 ( 0.7) 0 0 2 ( 1.5) 0 3 ( 0.4) Other adverse event 5 ( 3.6) 4 ( 2.9) 3 ( 2.2) 1 ( 0.7) 2 ( 1.5) 15 ( 2.2) Lack of efficacy 0 0 0 0 0 0 Non compliant with protocol 1 ( 0.7) 0 1 ( 0.7) 1 ( 0.7) 0 3 ( 0.4) Lost to follow−up 0 2 ( 1.5) 3 ( 2.2) 3 ( 2.2) 5 ( 3.7) 13 ( 1.9) Patient refusal to continue, not due to AE 2 ( 1.5) 2 ( 1.5) 1 ( 0.7) 3 ( 2.2) 2 ( 1.5) 10 ( 1.5) Other 2 ( 1.5) 4 ( 2.9) 6 ( 4.4) 2 ( 1.5) 3 ( 2.2) 17 ( 2.5)

Not prematurely discontinued from trial 131 ( 95.6) 130 ( 95.6) 128 ( 94.8) 128 ( 95.5) 125 ( 92.6) 642 ( 94.8) Still in the trial 131 ( 95.6) 130 ( 95.6) 128 ( 94.8) 128 ( 95.5) 125 ( 92.6) 642 ( 94.8)Prematurely discontinued from trial 6 ( 4.4) 6 ( 4.4) 7 ( 5.2) 6 ( 4.5) 10 ( 7.4) 35 ( 5.2) Lost to follow−up 0 1 ( 0.7) 3 ( 2.2) 3 ( 2.2) 4 ( 3.0) 11 ( 1.6) Consent withdrawn 6 ( 4.4) 5 ( 3.7) 4 ( 3.0) 3 ( 2.2) 6 ( 4.4) 24 ( 3.5) Death 0 0 0 0 0 0

Disposition shown at 24 weeks.12 patient numbers were excluded for suspected fraudulent activities.

Source data: Appendix 16.2.1, Listing 1.1 s15\distdisp1a001.sas 19JUN2013

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Table 15.5.1.1: 1 Disposition of patients − screened patients set (Metformin)



Not prematurely discontinued from trial medication 121 ( 88.3) 124 ( 91.2) 125 ( 88.7) 118 ( 84.3) 113 ( 85.6) 601 ( 87.6)Prematurely discontinued from trial medication 16 ( 11.7) 12 ( 8.8) 16 ( 11.3) 22 ( 15.7) 19 ( 14.4) 85 ( 12.4) Adverse event 3 ( 2.2) 3 ( 2.2) 4 ( 2.8) 9 ( 6.4) 4 ( 3.0) 23 ( 3.4) Worsening of disease under study 0 0 1 ( 0.7) 0 1 ( 0.8) 2 ( 0.3) Worsening of other pre−existing disease 0 0 0 2 ( 1.4) 0 2 ( 0.3) Other adverse event 3 ( 2.2) 3 ( 2.2) 3 ( 2.1) 7 ( 5.0) 3 ( 2.3) 19 ( 2.8) Lack of efficacy 0 1 ( 0.7) 0 0 0 1 ( 0.1) Non compliant with protocol 1 ( 0.7) 0 0 2 ( 1.4) 1 ( 0.8) 4 ( 0.6) Lost to follow−up 3 ( 2.2) 3 ( 2.2) 7 ( 5.0) 4 ( 2.9) 7 ( 5.3) 24 ( 3.5) Patient refusal to continue, not due to AE 5 ( 3.6) 1 ( 0.7) 2 ( 1.4) 4 ( 2.9) 3 ( 2.3) 15 ( 2.2) Other 4 ( 2.9) 4 ( 2.9) 3 ( 2.1) 3 ( 2.1) 4 ( 3.0) 18 ( 2.6)

Not prematurely discontinued from trial 125 ( 91.2) 126 ( 92.6) 128 ( 90.8) 122 ( 87.1) 117 ( 88.6) 618 ( 90.1)Prematurely discontinued from trial 12 ( 8.8) 10 ( 7.4) 13 ( 9.2) 18 ( 12.9) 15 ( 11.4) 68 ( 9.9) Lost to follow−up 3 ( 2.2) 5 ( 3.7) 7 ( 5.0) 5 ( 3.6) 8 ( 6.1) 28 ( 4.1) Consent withdrawn 9 ( 6.6) 4 ( 2.9) 6 ( 4.3) 12 ( 8.6) 7 ( 5.3) 38 ( 5.5) Death 0 1 ( 0.7) 0 1 ( 0.7) 0 2 ( 0.3)

49 patient numbers were excluded for suspected fraudulent activities.

Source data: Appendix 16.2.1, Listing 4.1 s15\distdisp1a001.sas 20NOV2013

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Table 15.4.1.1: 1 Disposition of patients − screened patients set (Drug naive)



Not prematurely discontinued from trial medication 114 ( 83.2) 116 ( 85.3) 114 ( 84.4) 110 ( 82.1) 116 ( 85.9) 570 ( 84.2)Prematurely discontinued from trial medication 23 ( 16.8) 20 ( 14.7) 21 ( 15.6) 24 ( 17.9) 19 ( 14.1) 107 ( 15.8) Adverse event 9 ( 6.6) 8 ( 5.9) 5 ( 3.7) 7 ( 5.2) 2 ( 1.5) 31 ( 4.6) Worsening of disease under study 1 ( 0.7) 0 0 1 ( 0.7) 0 2 ( 0.3) Worsening of other pre−existing disease 1 ( 0.7) 1 ( 0.7) 0 2 ( 1.5) 0 4 ( 0.6) Other adverse event 7 ( 5.1) 7 ( 5.1) 5 ( 3.7) 4 ( 3.0) 2 ( 1.5) 25 ( 3.7) Lack of efficacy 0 0 0 1 ( 0.7) 1 ( 0.7) 2 ( 0.3) Non compliant with protocol 3 ( 2.2) 1 ( 0.7) 1 ( 0.7) 2 ( 1.5) 1 ( 0.7) 8 ( 1.2) Lost to follow−up 5 ( 3.6) 3 ( 2.2) 5 ( 3.7) 6 ( 4.5) 7 ( 5.2) 26 ( 3.8) Patient refusal to continue, not due to AE 2 ( 1.5) 3 ( 2.2) 3 ( 2.2) 5 ( 3.7) 4 ( 3.0) 17 ( 2.5) Other 4 ( 2.9) 5 ( 3.7) 7 ( 5.2) 3 ( 2.2) 4 ( 3.0) 23 ( 3.4)

Not prematurely discontinued from trial 120 ( 87.6) 120 ( 88.2) 112 ( 83.0) 113 ( 84.3) 118 ( 87.4) 583 ( 86.1)Prematurely discontinued from trial 17 ( 12.4) 16 ( 11.8) 23 ( 17.0) 21 ( 15.7) 17 ( 12.6) 94 ( 13.9) Lost to follow−up 5 ( 3.6) 5 ( 3.7) 8 ( 5.9) 7 ( 5.2) 8 ( 5.9) 33 ( 4.9) Consent withdrawn 12 ( 8.8) 10 ( 7.4) 12 ( 8.9) 13 ( 9.7) 9 ( 6.7) 56 ( 8.3) Death 0 1 ( 0.7) 3 ( 2.2) 1 ( 0.7) 0 5 ( 0.7)

12 patient numbers were excluded for suspected fraudulent activities.

Source data: Appendix 16.2.1, Listing 3.1 s15\distdisp1a001.sas 20NOV2013

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Table 15.2.2.2.1.1: 1 FPG (mg/dL) change from baseline ANCOVA results at week 24 − FAS (LOCF) (Metformin)

Visit Description Statistic Empa25/Lina5 Empa10/Lina5 Empa 25mg Empa 10mg Lina 5mg

Number of patients in analysis set 134 135 140 137 128

Number of analysed patients 133 134 139 136 127

Baseline mean (SE) 154.62 ( 2.89) 156.68 ( 2.98) 159.89 ( 3.21) 161.64 ( 2.98) 156.35 ( 2.72)

Week 24 Values at visit Mean (SE) 121.05 ( 2.25) 125.31 ( 2.33) 140.08 ( 4.12) 138.75 ( 2.44) 143.96 ( 2.84) Adjusted* mean (SE) 122.63 ( 2.53) 125.70 ( 2.52) 139.05 ( 2.47) 137.05 ( 2.50) 144.83 ( 2.59)

Change from baseline Mean (SE) −33.57 ( 2.67) −31.37 ( 2.59) −19.81 ( 3.83) −22.89 ( 2.95) −12.39 ( 2.45) Adjusted* mean (SE) −35.25 ( 2.53) −32.18 ( 2.52) −18.83 ( 2.47) −20.84 ( 2.50) −13.05 ( 2.59)

Comparison vs Empa 25mg Adjusted* mean (SE) −16.43 ( 3.54) 95.0% confidence interval (−23.37, −9.48) p−value <0.0001

Comparison vs Empa 10mg Adjusted* mean (SE) −11.34 ( 3.55) 95.0% confidence interval (−18.31, −4.37) p−value 0.0015

Comparison vs Lina 5mg Adjusted* mean (SE) −22.20 ( 3.62) −19.12 ( 3.61) 95.0% confidence interval (−29.30,−15.10) (−26.21,−12.03) p−value <0.0001 <0.0001

* Model for Week 24 includes baseline fasting plasma glucose (p<0.0001), baseline HbA1c (p=0.6082) as linear covariate(s) andbaseline eGFR (MDRD) (p=0.3685), geographical region (p=0.0104), treatment (p<0.0001) as fixed effect(s).

Source data: Appendix 16.1.9.2, Statdoc 2.6.2.1.8, Appendix 16.2.6, Listing 2.3 s15\fpgtancova1001.sas 19JUN2013

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Table 15.1.2.2.1.1: 1 FPG (mg/dL) change from baseline ANCOVA results at week 24 − FAS (LOCF) (Drug naive)




Baseline mean (SE) 156.10 ( 3.09) 157.18 ( 3.05) 152.83 ( 3.38) 160.27 ( 3.59) 156.03 ( 3.22)

Week 24 Values at visit Mean (SE) 126.66 ( 2.40) 128.73 ( 2.52) 130.47 ( 2.64) 135.92 ( 3.61) 150.30 ( 3.94) Adjusted* mean (SE) 126.92 ( 2.67) 128.26 ( 2.66) 132.24 ( 2.68) 134.08 ( 2.69) 150.56 ( 2.68)

Change from baseline Mean (SE) −29.43 ( 3.16) −28.45 ( 2.78) −22.36 ( 2.98) −24.35 ( 3.28) −5.73 ( 3.68) Adjusted* mean (SE) −29.55 ( 2.67) −28.21 ( 2.66) −24.24 ( 2.68) −22.39 ( 2.69) −5.92 ( 2.68)

Comparison vs Empa 25mg Adjusted* mean (SE) −5.31 ( 3.78) 95.0% confidence interval (−12.74, 2.11) p−value 0.1605

Comparison vs Empa 10mg Adjusted* mean (SE) −5.82 ( 3.78) 95.0% confidence interval (−13.25, 1.61) p−value 0.1246

Comparison vs Lina 5mg Adjusted* mean (SE) −23.63 ( 3.78) −22.29 ( 3.77) 95.0% confidence interval (−31.06,−16.21) (−29.71,−14.88) p−value <0.0001 <0.0001

* Model for Week 24 includes baseline fasting plasma glucose (p<0.0001), baseline HbA1c (p=0.4591) as linear covariate(s) andbaseline eGFR (MDRD) (p=0.7413), geographical region (p=0.1504), treatment (p<0.0001) as fixed effect(s).

Source data: Appendix 16.1.9.2, Statdoc 1.6.2.1.8, Appendix 16.2.6, Listing 1.3 s15\fpgtancova1001.sas 19JUN2013

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Table 15.2.2.2.2.1: 1 Body weight (kg) change from baseline ANCOVA results at week 24 − FAS (LOCF) (Metformin)




Baseline mean (SE) 85.47 (1.76) 86.57 (1.64) 87.68 (1.49) 86.14 (1.55) 85.01 (1.62)

Week 24 Values at visit Mean (SE) 82.48 (1.71) 83.96 (1.62) 84.46 (1.43) 83.62 (1.55) 84.35 (1.61) Adjusted* mean (SE) 83.21 (0.31) 83.60 (0.30) 83.02 (0.30) 83.66 (0.30) 85.50 (0.31)

Change from baseline Mean (SE) −2.99 (0.30) −2.61 (0.27) −3.22 (0.43) −2.51 (0.21) −0.65 (0.30) Adjusted* mean (SE) −2.99 (0.31) −2.60 (0.30) −3.18 (0.30) −2.53 (0.30) −0.69 (0.31)

Comparison vs Empa 25mg Adjusted* mean (SE) 0.19 (0.43) 95.0% confidence interval (−0.65, 1.03) p−value 0.6604

Comparison vs Empa 10mg Adjusted* mean (SE) −0.07 (0.43) 95.0% confidence interval (−0.91, 0.77) p−value 0.8757

Comparison vs Lina 5mg Adjusted* mean (SE) −2.30 (0.44) −1.91 (0.44) 95.0% confidence interval (−3.15,−1.44) (−2.77,−1.05) p−value <0.0001 <0.0001

* Model for Week 24 includes baseline weight (p<0.0001), baseline HbA1c (p=0.1610) as linear covariate(s) andbaseline eGFR (MDRD) (p=0.3685), geographical region (p=0.0162), treatment (p<0.0001) as fixed effect(s).

Source data: Appendix 16.1.9.2, Statdoc 2.6.2.2.9, Appendix 16.2.6, Listing 2.5 s15\vstancova1001.sas 19JUN2013

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Table 15.1.2.2.2.1: 1 Body weight (kg) change from baseline ANCOVA results at week 24 − FAS (LOCF) (Drug naive)




Baseline mean (SE) 87.92 (1.57) 87.30 (1.59) 86.73 (1.71) 87.82 (2.08) 89.51 (1.74)

Week 24 Values at visit Mean (SE) 85.90 (1.56) 84.58 (1.54) 84.61 (1.72) 85.60 (2.02) 88.66 (1.75) Adjusted* mean (SE) 85.85 (0.36) 85.11 (0.36) 85.72 (0.36) 85.58 (0.37) 87.07 (0.36)

Change from baseline Mean (SE) −2.02 (0.28) −2.72 (0.43) −2.12 (0.48) −2.22 (0.35) −0.85 (0.29) Adjusted* mean (SE) −2.00 (0.36) −2.74 (0.36) −2.13 (0.36) −2.27 (0.37) −0.78 (0.36)

Comparison vs Empa 25mg Adjusted* mean (SE) 0.13 (0.51) 95.0% confidence interval (−0.88, 1.14) p−value 0.8010

Comparison vs Empa 10mg Adjusted* mean (SE) −0.47 (0.51) 95.0% confidence interval (−1.48, 0.54) p−value 0.3616

Comparison vs Lina 5mg Adjusted* mean (SE) −1.22 (0.51) −1.96 (0.51) 95.0% confidence interval (−2.23,−0.21) (−2.97,−0.95) p−value 0.0178 0.0001

* Model for Week 24 includes baseline weight (p<0.0001), baseline HbA1c (p=0.0023) as linear covariate(s) andbaseline eGFR (MDRD) (p=0.0316), geographical region (p=0.0134), treatment (p=0.0031) as fixed effect(s).

Source data: Appendix 16.1.9.2, Statdoc 1.6.2.2.9, Appendix 16.2.6, Listing 1.5 s15\vstancova1001.sas 19JUN2013

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Table 15.2.2.2.3: 1 Logistic regression for HbA1c <7% at week 24− FAS (NCF) − patients with HbA1c >= 7% at baseline (Metformin)

Empa25/Lina5 Empa10/Lina5 Empa 25mg Empa 10mg Lina 5mg


Number of analysed patients, N (%) 123 (100.0) 128 (100.0) 132 (100.0) 125 (100.0) 119 (100.0)

Number (%) satisfying HbA1c 76 ( 61.8) 74 ( 57.8) 43 ( 32.6) 35 ( 28.0) 43 ( 36.1)response <7.0% at week 2495.0% Confidence interval [%]* (52.6, 70.4) (48.8, 66.5) (24.7, 41.3) (20.3, 36.7) (27.5, 45.4)

Comparison vs Empa 25mg Odds Ratio ** 4.191 95.0% Confidence interval ** ( 2.319, 7.573) p−value ** <0.0001

Comparison vs Empa 10mg Odds Ratio ** 4.500 95.0% Confidence interval ** ( 2.474, 8.184) p−value ** <0.0001

* Exact 95% CI by Clopper and Pearson.** Logistic regression includes treatment, baseline eGFR (MDRD), geographical region and baseline HbA1c.

Source data: Appendix 16.2.6, Listing 2.1, 2.13 s15\hbatbin2001.sas 19JUN2013

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Table 15.2.2.2.3: 1 Logistic regression for HbA1c <7% at week 24− FAS (NCF) − patients with HbA1c >= 7% at baseline (Metformin)


Comparison vs Lina 5mg Odds Ratio ** 3.495 2.795 95.0% Confidence interval ** ( 1.920, 6.363) ( 1.562, 5.001) p−value ** <0.0001 0.0005



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Table 15.1.2.2.3: 1 Logistic regression for HbA1c <7% at week 24− FAS (NCF) − patients with HbA1c >= 7% at baseline (Drug naive)



Number of analysed patients, N (%) 121 (100.0) 122 (100.0) 118 (100.0) 121 (100.0) 127 (100.0)

Number (%) satisfying HbA1c 67 ( 55.4) 76 ( 62.3) 49 ( 41.5) 47 ( 38.8) 41 ( 32.3)response <7.0% at week 2495.0% Confidence interval [%]* (46.1, 64.4) (53.1, 70.9) (32.5, 51.0) (30.1, 48.1) (24.3, 41.2)

Comparison vs Empa 25mg Odds Ratio ** 1.893 95.0% Confidence interval ** ( 1.095, 3.274) p−value ** 0.0224

Comparison vs Empa 10mg Odds Ratio ** 2.961 95.0% Confidence interval ** ( 1.697, 5.169) p−value ** 0.0001



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Table 15.1.2.2.3: 1 Logistic regression for HbA1c <7% at week 24− FAS (NCF) − patients with HbA1c >= 7% at baseline (Drug naive)


Comparison vs Lina 5mg Odds Ratio ** 3.065 4.303 95.0% Confidence interval ** ( 1.768, 5.314) ( 2.462, 7.522) p−value ** <0.0001 <0.0001



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