trial synopsis 1218.23 ds co - boehringer ingelheim...voglibose in the proportions of patients who...

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:

Name of active ingredient: Linagliptin, BI 1356

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Disclosure Synopsis 07 JUL 2014

Trial No. / U No.: 1218.23 / U10-1466-01

Date of trial: 01 APR 2008 – 14 JAN 2010

Date of revision (if applicable):

Proprietary confidential information 2014 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 double-blind phase III study to evaluate the efficacy of BI 1356 5 mg and 10 mg vs. placebo for 12 weeks and vs. voglibose 0.6 mg for 26 weeks in patients with type 2 diabetes mellitus and insufficient glycaemic control, followed by an extension study to 52 weeks to evaluate long-term safety

Principal/Coordinating Investigator:

MD, PhD

Japan

Trial sites: Multi-centre trial, cf. Appendix 16.1.4

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

Clinical phase: III

Objectives: Study of the efficacy and safety of BI 1356 (linagliptin) in patients with type 2 diabetes mellitus

Methodology: Randomised, double-blind, placebo-controlled, voglibose-referenced, parallel-group comparison

No. of subjects: planned: actual:

To be enrolled, 750 patients; to be entered, 441 patients. Enrolled, 700 patients; entered, 561 patients. Treatment starting with linagliptin 5 mg: entered, 159; treated, 159; analysed (for primary endpoint), 159 for 12-week treatment and 159 for 26-week treatment. Treatment starting with linagliptin 10 mg: entered, 160; treated, 160; analysed (for primary endpoint), 157 for 12-week treatment and 157 for 26-week treatment. Treatment starting with placebo: entered, 80; treated, 80; analysed (for primary endpoint), 80 for 12-week treatment. Treatment starting with voglibose: entered, 162; treated, 162; analysed (for primary endpoint), 162 for 26-week treatment.

Diagnosis and main criteria for inclusion:

Patients with type 2 diabetes mellitus, age ≥20 and ≤80, body mass index ≤40 kg/m2 Japanese patients with insufficient glycaemic control despite being treated with diet and/or exercise only or with oral antidiabetic drugs

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Test product: Linagliptin

dose: 5 mg/day, 10 mg/day (once daily)

mode of admin.: Oral

batch no.: B071001960

Reference therapy: Placebo

dose: Not applicable


batch no.: B071003943, 575992 for linagliptin YBH-1, YBH-2 for voglibose

Reference therapy: Voglibose

dose: 0.6 mg/day (0.2 mg given three times daily)


batch no.: YBH-1

Duration of treatment: Observation phase: Placebo run-in period for 2 weeks with/without a 2-week wash-out period Double-blind treatment phase: 1st stage for 12 weeks and 2nd stage for 14 weeks Extension treatment phase for 26 weeks

Criteria for evaluation:

Efficacy / clinical pharmacology:

Primary endpoint: Change in haemoglobin A1c (HbA1c) from baseline

Safety: Incidence and intensity of adverse events (AEs), physical examination, electrocardiograms, change from baseline in laboratory parameters

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Statistical methods: To evaluate efficacy, analysis of covariance (ANCOVA) for HbA1c with placebo after 12-week treatment and ANCOVA for HbA1c with voglibose as an active control after 26-week treatment were performed by using “treatment” and “previous antidiabetic therapy” as a fixed effect and baseline values in the observation phase as a covariate. Descriptive statistics for safety analyses, plasma drug concentration, pharmacodynamic parameters, and biomarkers were calculated.

SUMMARY – CONCLUSIONS:

Efficacy / clinical pharmacology results:

Efficacy Primary endpoint: The primary endpoint was a change from baseline in HbA1c for linagliptin 5 mg and linagliptin 10 mg compared with placebo at Week 12 and that compared with voglibose at Week 26. For 12-week treatment

Primary analysis for the 12-week treatment was performed by using the closed testing procedure for the full analysis set for the analysis of 12-week treatment (FAS12) with last observed carried forward (LOCF). Adjusted mean changes from baseline in HbA1c at Week 12 were -0.24% for linagliptin 5 mg, -0.25% for linagliptin 10 mg, and 0.63% for placebo. The differences of adjusted mean changes from baseline in HbA1c at Week 12 were -0.87% (95% confidence interval [CI]: -1.04, -0.70) (ANCOVA: p<0.0001) between linagliptin 5 mg and placebo, and -0.88% (95% CI: -1.05, -0.71) (ANCOVA: p<0.0001) between linagliptin 10 mg and placebo. Both linagliptin 5 mg and linagliptin 10 mg showed statistically significant decreases compared with placebo. For 26-week treatment

Primary analysis for 26-week treatment was performed by using the closed testing procedure for the full analysis set for the analysis of 26-week treatment (FAS26) with LOCF. Adjusted mean changes from baseline in HbA1c at Week 26 were -0.13% for linagliptin 5 mg, -0.19% for linagliptin 10 mg, and 0.19%

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Efficacy / clinical pharmacology results: (continued)

for voglibose. The differences of adjusted mean changes from baseline in HbA1c at Week 26 were -0.32% (95% CI: -0.49, -0.15) (ANCOVA: p=0.0003) between linagliptin 5 mg and voglibose, and -0.39% (95% CI: -0.56, -0.21) (ANCOVA: p<0.0001) between linagliptin 10 mg and voglibose. Both linagliptin 5 mg and linagliptin 10 mg showed statistically significant decreases compared with voglibose. Secondary endpoints: HbA1c endpoints are summarized in the table at the end of this section. For 12-week treatment

Both linagliptin 5 mg and linagliptin 10 mg showed statistically significant differences compared with placebo in the proportions of patients who achieved target HbA1c level of <7.0% and <6.5%, and proportions of patients whose HbA1c levels decreased by at least 0.5% (Fisher’s exact test: p<0.0001 to 0.0038 for linagliptin 5 mg; p<0.0001 for linagliptin 10 mg). The results of fasting plasma glucose (FPG) for 12-week treatment, both linagliptin 5 mg and linagliptin 10 mg showed statistically significant decreases compared with placebo (ANCOVA: p<0.0001). The differences of adjusted mean changes from baseline in dipeptidyl-peptidase IV (DPP-4) inhibition were 79.5% for linagliptin 5 mg and 86.2% for linagliptin 10 mg. For 26-week treatment

Linagliptin 10 mg showed statistically significant differences compared with voglibose in the proportions of patients who achieved target HbA1c level of <7.0% and <6.5%, (Fisher’s exact test: p=0.0181 and p=0.0051). Both linagliptin 5 mg and linagliptin 10 mg showed statistically significant differences compared with voglibose in the proportions of patients whose HbA1c levels decreased by at least 0.5% (Fisher’s exact test: p<0.0001 and p=0.0050). The results of FPG, both linagliptin 5 mg and linagliptin 10 mg showed statistically significant decreases compared with voglibose (ANCOVA: p=0.0239 for linagliptin 5 mg and p=0.0015 for linagliptin 10 mg). The differences of adjusted mean changes from baseline in DPP-4 inhibition were 80.2% for linagliptin 5 mg and 85.5% for linagliptin 10 mg. For 52-week treatment

The HbA1c time profiles between linagliptin 5 mg and linagliptin 10 mg were similar throughout the 52-week treatment.

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Efficacy / clinical pharmacology results: (continued)

HbA1c reduction by linagliptin 5 mg and linagliptin 10 mg seemed to attenuate after 18 weeks in the full analysis set (FAS) with LOCF. However, both linagliptin 5 mg and linagliptin 10 mg showed lasting efficacy in the FAS with observed case (OC). For the patients with linagliptin who switched study medication from voglibose at Week 26, the mean HbA1c values decreased and had been kept under the baseline values at Week 26. Time profiles of FPG and glycosylated albumin were similar to those of HbA1c. On the other hand, DPP-4 inhibition by linagliptin 5 mg and linagliptin 10 mg were stable or slightly increased throughout 52-week treatment.

Efficacy Endpoints

Time Frame

Therapy Number of patients (p value)

HbA1c 12 weeks

Placebo Linagliptin 5 mg (p value: vs. placebo)

Linagliptin 10 mg (p value: vs. placebo)

<7% 8 42 (0.0038) 56 (<0.0001) <6.5% 0 15 (0.0031) 18 (<0.0005) ≥0.5% 7 91 (<0.0001) 94 (<0.0001)

HbA1c 26

weeks Voglibose Linagliptin 5 mg Linagliptin 10 mg

<7% 36 48 (0.1274) 54 (0.0181) <6.5% 7 15 (0.0797) 21 (0.0051) ≥0.5% 61 91 (0.0050) 84 (0.0005)

HbA1c 52

weeks Linagliptin

5 mg Linagliptin

10 mg p value:

5 mg vs. 10 mg <7% 38 29 0.2716 <6.5% 6 10 0.3173 ≥0.5% 62 62 1.0000

Pharmacokinetics

Trough plasma concentrations of linagliptin were stable over 26 weeks after once daily administration of linagliptin. The trough concentration of linagliptin increased less than dose-proportionally when the dose was increased from 5 mg to 10 mg. The effect of covariates was investigated for exploratory purposes. Trough

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Safety results:

plasma concentrations of linagliptin increased to a minor extent with decreasing renal function (estimated glomerular filtration rate [eGFR] and estimated creatinine clearance [eCcr]) by 5-11% increase in the patients with mild renal impairment and 19-21% increase in the patients with moderate renal impairment except for 5 mg eCcr group. There was no clear tendency for co-administration of P-glycoprotein (P-gp) inhibitors or cytochrome P450 (CYP)3A4 inhibitors to increase the trough plasma concentration. However, it should be noted that the number of trough plasma concentration data with co-administration of P-gp inhibitors or CYP3A4 inhibitors was small (N <10). The effect of sex was minor: geometric mean values of trough plasma concentration of linagliptin were approximately 9-16% higher in female patients than in male patients.

For 12-week treatment

During the 12-week treatment period, 89 (56.0%) of the 159 patients with linagliptin 5 mg, 85 (53.1%) of the 160 patients with linagliptin 10 mg, 45 (56.3%) of the 80 patients with placebo experienced an AE. The system organ class (SOC) with the highest frequency of reported AEs by using Medical Dictionary for Regulatory Activities (MedDRA) Version 12.1 was infections and infestations followed by gastrointestinal disorders. AEs for infections and infestations were experienced by 38 (23.9%) of the 159 patients with linagliptin 5 mg, 33 (20.6%) of the 160 patients with linagliptin 10 mg, and 12 (15.0%) of the 80 patients with placebo; and those for gastrointestinal disorders by 29 (18.2%) patients with linagliptin 5 mg, 26 (16.3%) patients with linagliptin 10 mg, and 11 (13.8%) patients with placebo. AEs for skin and subcutaneous tissue disorders, which are of medical concern with DPP-4 inhibitors, were experienced by 13 (8.2%) patients with linagliptin 5 mg, 9 (5.6%) patients with linagliptin 10 mg, and 2 (2.5%) patients with placebo. Overall, the preferred term (PT) level with the highest frequency of reported AEs was nasopharyngitis: 26 (16.4%) patients with linagliptin 5 mg, 20 (12.5%) patients with linagliptin 10 mg, and 10 (12.5%) patients with placebo. The number of patients who experienced AEs of severe intensity was considerably small for linagliptin. The frequency of AEs assessed to be drug-related by the investigator was comparable among all the treatments. In terms of SOC, drug-related AEs were experienced most frequently for gastrointestinal

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Safety results: (continued)

disorders. The proportion of patients who experienced AEs that led to the discontinuation of study medication with linagliptin was a third to a quarter of that with placebo. SAEs were experienced by 6 patients: 1 (0.6%) patient with linagliptin 5 mg, 4 (2.5%) patients with linagliptin 10 mg, and 1 (1.3%) patient with placebo. All the SAEs were considered not related to the investigational product by the investigator. No significant AEs (protocol-specified events) based on standardised MedDRA queries (SMQs) were reported. International Conference on Harmonisation (ICH) E3 defined AEs were experienced by 2 (1.3%) patients with linagliptin 5 mg, 3 (1.9%) patients with linagliptin 10 mg, and 7 (8.8%) patients with placebo. No patients experienced investigator-defined hypoglycaemia, protocol-specified significant AEs, or AEs reported as a cardiac or cerebrovascular event which was confirmed after adjudication by the clinical event committee (CEC). Safety laboratory data revealed no trends of clinical relevance. There was no major imbalance among all the treatments in the proportion of patients with possibly clinically significant laboratory abnormalities reported, with the exception of increased value triglycerides: 12 (7.5%) patients with linagliptin 5 mg, 13 (8.2%) patients with linagliptin 10 mg, and 4 (5.0%) patients with placebo. Only minor shifts in categorised stages were found in renal function (glomerular filtration rate) and in creatinine clearance for all treatments. The proportions of patients with positive changes and those with negative changes were comparable among the three treatments and within the individual treatments. Likewise, no relevant trends were found over time in the mean changes from baseline in systolic and diastolic blood pressures and for pulse rate for all the treatments. For 26-week treatment

During the 26-week treatment period, 115 (72.3%) of the 159 patients with linagliptin 5 mg, 124 (77.5%) of the 160 patients with linagliptin 10 mg, and 116 (71.6%) of the 162 patients with voglibose experienced an AE. The SOC with the highest frequency of reported AEs was infections and infestations followed by gastrointestinal disorders. AEs for infections and infestations were experienced by 70 (44.0%) of the 159 patients with linagliptin 5 mg, 58 (36.3%) of the 160 patients with linagliptin 10 mg, and 56 (34.6%) of the 162 patients with voglibose; and those for gastrointestinal disorders by 48 (30.2%) patients with linagliptin 5 mg, 38 (23.8%) patients with linagliptin 10 mg, and 49 (30.2%) with voglibose.

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AEs for skin and subcutaneous tissue disorders, which are of medical concern with DPP-4 inhibitors, were experienced by 22 (13.8%) patients with linagliptin 5 mg, 13 (8.1%) patients with linagliptin 10 mg, and 7 (4.3%) patients with voglibose. Overall, the PT level with the highest frequency of reported AEs was nasopharyngitis: 46 (28.9%) patients with linagliptin 5 mg, 39 (24.4%) patients with linagliptin 10 mg, and 36 (22.2%) patients with voglibose. Among the AEs experienced more by the patients with linagliptin than those with voglibose and more than 5% of patients under either one of the three treatments, those having occurred more than twice as frequently as in the patients with linagliptin than those with voglibose were respiratory, thoracic and mediastinal disorders (9 [5.7%] patients with linagliptin 5 mg, 10 [6.3%] patients with linagliptin 10 mg, and 5 [3.1%] patients with voglibose) and skin and subcutaneouse tissue disorders (22 [13.8%] patients with linagliptin 5 mg, 13 [8.1%] patients with linagliptin 10 mg, and 7 [4.3%] patients with voglibose). The number of patients who experienced AEs of severe intensity was considerably small in linagliptin and voglibose. The frequencies of AEs assessed to be drug-related by the investigator were lower in linagliptin than voglibose. In terms of SOC, drug-related AEs were experienced most frequently for gastrointestinal disorders. The proportion of patients who experienced AEs that led to the discontinuation of study medication with linagliptin was a half from a third of that in voglibose. SAEs were experienced by 20 patients: 5 (3.1%) patients with linagliptin 5 mg, 8 (5.0%) patients with linagliptin 10 mg, and 7 (4.3%) patients with voglibose. Of the 20 patients, 19 patients required hospitalisation. All the SAEs were considered not related to the investigational product by the investigator. No significant AEs (protocol-specified events) based on SMQs were reported. ICH E3 defined AEs were experienced by 2 (1.3%) patients with linagliptin 5 mg, 6 (3.8%) patients with linagliptin 10 mg, and 10 (6.2%) patients with voglibose. Three patients were reported with a cardiac or cerebrovascular event which was confirmed after adjudication by the CEC. One (0.6%) patient with linagliptin 10 mg and 2 (1.2%) patients with voglibose experienced investigator-defined hypoglycaemia, all of which were not a severe hypoglycaemic episode. Safety laboratory data revealed no trends of clinical relevance except for triglycerides. For triglycerides, possibly clinically significant increases were reported for 20 (12.6%) patients with linagliptin 5 mg, 18 (11.3%) patients with

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linagliptin 10 mg, and 21 (13.0%) patients with voglibose. There was no major imbalance among all treatments in the percentages of patients with possibly clinically significant laboratory abnormalities reported, including triglycerides. Only minor shifts in categorised stages were found in renal function (glomerular filtration rate) and in creatinine clearance for all treatments. The proportions of patients with positive changes and those with negative changes were comparable among the three treatments and within the individual treatments. Likewise, no relevant trends were found over time in the mean changes from baseline in systolic and diastolic blood pressures and for pulse rate for all treatments. For 52-week treatment

During the 52-week treatment period, 204 (76.7%) of the 266 patients with linagliptin 5 mg and 224 (81.8%) of the 274 patients with linagliptin 10 mg experienced an AE. The SOC with the highest frequency of reported AEs was infections and infestations followed by gastrointestinal disorders: AEs for infections and infestations were experienced by 120 (45.1%) of the 266 patients with linagliptin 5 mg and 122 (44.5%) of the 274 patients with linagliptin 10 mg; and those for gastrointestinal disorders by 76 (28.6%) patients with linagliptin 5 mg and 78 (28.5%) patients with linagliptin 10 mg. AEs for skin and subcutaneous tissue disorders, which are of medical concern with DPP-4 inhibitors, were experienced by 37 (13.9%) patients with linagliptin 5 mg and 32 (11.7%) patients with linagliptin 10 mg. Overall, the PT level with the highest frequency of reported AEs was nasopharyngitis: 84 (31.6%) patients with linagliptin 5 mg and 81 (29.6%) patients with linagliptin 10 mg. The number of patients who experienced AEs of severe intensity was considerably small and a dose-dependent trend was not observed. AEs assessed to be drug-related by the investigator were experienced by 27 (10.2%) of the 266 patients with linagliptin 5 mg and 29 (10.6%) of the 274 patients with linagliptin 10 mg. In terms of SOC, drug-related AEs were experienced most frequently for gastrointestinal disorders. AEs that led to the discontinuation of study medication were experienced by 16 (6.0%) patients with linagliptin 5 mg and 16 (5.8%) patients with linagliptin 10 mg. SAEs were experienced by 34 patients: 20 (7.5%) patients with linagliptin 5 mg and 14 (5.1%) patients with linagliptin 10 mg. Of the 34 patients, 33 patients required hospitalisation. All the SAEs

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except one event were considered not related to the investigational product by the investigator. Significant AEs (protocol-specified events) based on SMQs were experienced by 2 (0.8%) patients with linagliptin 5 mg and 3 (1.1%) patients with linagliptn 10 mg. ICH E3 defined AEs were experienced by 11 (4.1%) patients each with linagliptin 5 mg and 12 (4.4%) patients with linagliptin 10 mg. Twelve patients were reported with a cardiac or cerebrovascular event which was confirmed after adjudication by the CEC. One (0.4%) patient each with linagliptin 5 mg and linagliptin 10 mg experienced investigator-defined hypoglycaemia, both of which were not a severe hypoglycaemic episode. Safety laboratory data showed that the mean values of haematological and electrolytes parameters both at baseline and at the end of treatment were within the normal reference range and the mean changes from baseline were small for both treatments. A few patients had possibly clinically significant increases or decreases in haematological and electrolytes parameters. Only minor shifts in categorised stages were noted in renal function (glomerular filtratation rate) and in creatinine clearance for both treatments and the proportions of patients were comparable in both treatments. The proportions of patients with positive changes and those with negative changes were comparable among the two treatments and within the individual treatments.

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Conclusions: Linagliptin showed clinically relevant reduction in HbA1c from baseline to Week 12, in comparison to placebo, and from baseline to Week 26, in comparison to voglibose. Superiority of linagliptin over placebo and voglibose in HbA1c reduction was shown and treatment with linagliptin was well tolerated and assessment of safety did not reveal any trends of clinical relevance for up to 52 weeks of treatment. The incidence of hypoglycaemic events during treatment with linagliptin was considerably low. The safety data were consistent with the reported safety profile of other DPP-4 inhibitors and no new safety concerns were reported. Trough plasma concentrations of linagliptin were stable over 26 weeks after once daily administration of linagliptin, indicating the pharmacokinetics of linagliptin does not change after multiple administration over a long period. The trough concentration of linagliptin increased less than dose-proportionally when the dose was increased from 5 mg to 10 mg. In this trial, linagliptin was more efficacious than both placebo and voglibose, was well tolerated, and no new safety concerns arose. The 5 mg and 10 mg doses of linagliptin showed comparable efficacy over 52 weeks.

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Boehringer Ingelheim BI trial number 1218.0023 Trial Synopsis - Appendix

Trial Synopsis - Appendix

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

Synopsis. They complement the results for patient disposition and secondary endpoints. 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

Patient Disposition Table 15.1.1: 1

FPG Change from Baseline at 12, 26 and 52 weeks Table 15.2.3: 8 Table 15.2.3: 9 Table 15.2.3: 11

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Pla−L5−L5 Pla−L10−L10 L5−L5−L5 L10−L10−L10 Vog−Vog−L5 Vog−Vog−L10 Total N (%) N (%) N (%) N (%) N (%) N (%) N (%)

Enrolled 700 Started wash−out 276 Started placebo run−in 597 Not randomised 139Randomised 39 41 159 160 81 81 561 Not treated 0 0 0 0 0 0 0Treated * 39 (100.0) 41 (100.0) 159 (100.0) 160 (100.0) 81 (100.0) 81 (100.0) 561 (100.0)Stage I:Not prematurely discontinued trial med. 36 ( 92.3) 38 ( 92.7) 156 ( 98.1) 155 ( 96.9) 79 ( 97.5) 79 ( 97.5) 543 ( 96.8)Stage I:Prematurely discontinued trial med. 3 ( 7.7) 3 ( 7.3) 3 ( 1.9) 5 ( 3.1) 2 ( 2.5) 2 ( 2.5) 18 ( 3.2) Adverse events 3 ( 7.7) 3 ( 7.3) 3 ( 1.9) 3 ( 1.9) 2 ( 2.5) 1 ( 1.2) 15 ( 2.7) AE study dis. worse 2 ( 5.1) 3 ( 7.3) 0 ( 0.0) 1 ( 0.6) 2 ( 2.5) 0 ( 0.0) 8 ( 1.4) AE other dis. worse 0 ( 0.0) 0 ( 0.0) 1 ( 0.6) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2) AE other 1 ( 2.6) 0 ( 0.0) 2 ( 1.3) 2 ( 1.3) 0 ( 0.0) 1 ( 1.2) 6 ( 1.1) Lack of efficacy # 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Non compl. protocol 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Lost to follow−up 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Refused cont. medic. 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 0.6) 0 ( 0.0) 1 ( 1.2) 2 ( 0.4) Other 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 0.6) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2)Stage II:Not prematurely discontinued trial med. 34 ( 87.2) 38 ( 92.7) 153 ( 96.2) 151 ( 94.4) 71 ( 87.7) 76 ( 93.8) 523 ( 93.2)Stage II:Prematurely discontinued trial med. 2 ( 5.1) 0 ( 0.0) 3 ( 1.9) 4 ( 2.5) 8 ( 9.9) 3 ( 3.7) 20 ( 3.6) Adverse events 2 ( 5.1) 0 ( 0.0) 2 ( 1.3) 3 ( 1.9) 7 ( 8.6) 2 ( 2.5) 16 ( 2.9) AE study dis. worse 1 ( 2.6) 0 ( 0.0) 1 ( 0.6) 3 ( 1.9) 3 ( 3.7) 2 ( 2.5) 10 ( 1.8) AE other dis. worse 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) AE other 1 ( 2.6) 0 ( 0.0) 1 ( 0.6) 0 ( 0.0) 4 ( 4.9) 0 ( 0.0) 6 ( 1.1) Lack of efficacy # 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Non compl. protocol 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Lost to follow−up 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) Refused cont. medic. 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 1.2) 1 ( 1.2) 2 ( 0.4) Other 0 ( 0.0) 0 ( 0.0) 1 ( 0.6) 1 ( 0.6) 0 ( 0.0) 0 ( 0.0) 2 ( 0.4)Extension:Not prematurely discontinued trial med. 33 ( 84.6) 36 ( 87.8) 142 ( 89.3) 142 ( 88.8) 68 ( 84.0) 73 ( 90.1) 494 ( 88.1)Extension:Prematurely discontinued trial med. 1 ( 2.6) 2 ( 4.9) 11 ( 6.9) 9 ( 5.6) 3 ( 3.7) 3 ( 3.7) 29 ( 5.2) Adverse events 1 ( 2.6) 2 ( 4.9) 9 ( 5.7) 7 ( 4.4) 1 ( 1.2) 1 ( 1.2) 21 ( 3.7) AE study dis. worse 1 ( 2.6) 0 ( 0.0) 6 ( 3.8) 2 ( 1.3) 0 ( 0.0) 0 ( 0.0) 9 ( 1.6) AE other dis. worse 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) AE other 0 ( 0.0) 2 ( 4.9) 3 ( 1.9) 5 ( 3.1) 1 ( 1.2) 1 ( 1.2) 12 ( 2.1) Lack of efficacy # 0 ( 0.0) 0 ( 0.0) 1 ( 0.6) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2) Non compl. protocol 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 0.6) 0 ( 0.0) 0 ( 0.0) 1 ( 0.2) Lost to follow−up 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)

Source data: Appendix 16.2.1, Listing 1, 2, 3 stat\disp.sas 29JAN2010

Page BI Trial No.:

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Table 15.1.1: 1 Disposition of patients after randomisation

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Pla−L5−L5 Pla−L10−L10 L5−L5−L5 L10−L10−L10 Vog−Vog−L5 Vog−Vog−L10 Total N (%) N (%) N (%) N (%) N (%) N (%) N (%)

Refused cont. medic. 0 ( 0.0) 0 ( 0.0) 1 ( 0.6) 1 ( 0.6) 1 ( 1.2) 1 ( 1.2) 4 ( 0.7) Other 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 1.2) 1 ( 1.2) 2 ( 0.4) __________________________________________________________________________________________________________________________________

* In all tables ’treated’ refers to treatment with randomised study drug # Includes patients discontinued due to hyperglycaemia

Source data: Appendix 16.2.1, Listing 1, 2, 3 stat\disp.sas 29JAN2010

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Table 15.2.3: 8 Comparison of FPG after 12 weeks between linagliptin and voglibose (LOCF) − FAS26

5mg 10mg Voglibose

Number of patients 159 160 162

Number of patients with baseline and on−treatment results 159 160 162

Baseline Mean (SE) 163.3 ( 2.5) 165.0 ( 2.7) 163.1 ( 2.5)

Week 12 Mean (SE) 148.5 ( 2.4) 148.9 ( 2.4) 160.6 ( 3.0)

Change from baseline Mean (SE) −14.9 ( 1.9) −16.1 ( 1.7) −2.5 ( 2.3) Adjusted* mean (SE) −11.9 ( 2.1) −12.6 ( 2.1) 0.3 ( 2.0)

Comparison vs. Voglibose (diff. Lina − Voglibose) Adjusted* mean (SE) −12.2 ( 2.6) −12.9 ( 2.6) 95% Confidence interval (−17.3, −7.1) (−18.0, −7.9) p−value <.0001 <.0001

* Model includes treatment, baseline FPG and previous anti−diabetic medication

Source data: Appendix 16.1.9.2, Statdoc 6.3.6 stat\fpg.sas 29JAN2010

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Table 15.2.3: 9 Comparison of FPG after 26 weeks between linagliptin and voglibose (LOCF) − FAS26

5mg 10mg Voglibose

Number of patients 159 160 162

Number of patients with baseline and on−treatment results 159 160 162

Baseline Mean (SE) 163.3 ( 2.5) 165.0 ( 2.7) 163.1 ( 2.5)

Week 26 Mean (SE) 154.3 ( 2.8) 152.6 ( 2.7) 161.2 ( 3.2)

Change from baseline Mean (SE) −9.1 ( 2.4) −12.4 ( 1.9) −1.9 ( 2.5) Adjusted* mean (SE) −5.0 ( 2.4) −7.8 ( 2.4) 2.0 ( 2.4)

Comparison vs. Voglibose (diff. Lina − Voglibose) Adjusted* mean (SE) −6.9 ( 3.1) −9.8 ( 3.1) 95% Confidence interval (−13.0, −0.9) (−15.8, −3.8) p−value 0.0239 0.0015


Source data: Appendix 16.1.9.2, Statdoc 6.3.7 stat\fpg.sas 29JAN2010

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Table 15.2.3: 11 Comparison of FPG after 52 weeks between linagliptin 5 mg and 10 mg for the patients who started with linagliptin (LOCF) − FASLI

5mg 10mg

Number of patients 159 160

Number of patients with baseline and on−treatment results 159 160

Baseline Mean (SE) 163.3 ( 2.5) 165.0 ( 2.7)

Week 52 Mean (SE) 156.2 ( 3.0) 154.7 ( 2.9)

Change from baseline Mean (SE) −7.2 ( 2.6) −10.3 ( 2.1) Adjusted* mean (SE) −3.2 ( 2.7) −5.9 ( 2.7)

Comparison vs. 5mg (diff. 10mg − 5mg) Adjusted* mean (SE) −2.7 ( 3.2) 95% Confidence interval ( −8.9, 3.6) p−value 0.4022


Source data: Appendix 16.1.9.2, Statdoc 6.3.8 stat\fpg52.sas 31JAN2010

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trial synopsis 1218.23 ds co - boehringer ingelheim...voglibose in the proportions of patients who...

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