trial synopsis 1275.9 dr - boehringer ingelheim€¦ · abcd clinical study synopsis for public...

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

Synopsis

ABCDBI Proprietary Name:

Not applicableEudraCT No.:

2012-002270-31

BI Investigational Product:

Empagliflozin (BI 10773)/linagliptin (BI 1356)

Page:

2 of 11

Report Date:

03 Sep 2015

Trial No. / Doc. No.:

1275.9

c02820144-01

Dates of Trial:

01 Mar 2013 -23 Mar 2015

Date of Revision:

Not applicable

Proprietary confidential information© 2015 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

fixed dose combination (FDC) with lina 5 in the empa 25 and empa 10 treatment groups, respectively. In the placebo treatment group, lina 5 and placebos were administered as separate tablets.

No interim analysis was planned or conducted in this trial.

No. of Patients:

Planned: To be enrolled in the trial: 1110

To enter double-blind treatment (overall): 333

Actual: Enrolled (overall): 1134

Entered lina 5 OL treatment: 606

Randomised to double-blind treatment (overall): 333

FDC empa 25/lina 5:

Entered: 111 Treated: 110 Analysed (for primary endpoint): 110

FDC empa 10/lina 5:


Placebo+lina 5:


Diagnosis: Patients with T2DM

Main Criteria for Inclusion:

Patients aged ≥18 years, with a body mass index ≤45 kg/m2, with a confirmed diagnosis of T2DM, and with insufficient glycaemic control, defined as:

- for entering 16-week OL treatment period: glycated haemoglobin (HbA1c) ≥8.0% and ≤10.5% at screening

- for entering 24-week double-blind treatment period: HbA1c ≥7.0% and ≤10.5% 1 week before the start of double-blind treatment.

Patients had to be treated with metformin at an unchanged dose for at least 12 weeks before start of open-label treatment; ≥1500 mg/d, maximum tolerated dose, or maximum dose as per local label.

Boehringer Ingelheim Clinical Trial ReportBI Trial No.:

Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

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1275.9 c02820144-01Synopsis

Name of company:


Synopsis



2012-002270-31



Page:

3 of 11

Report Date:

03 Sep 2015


1275.9

c02820144-01

Dates of Trial:

01 Mar 2013 -23 Mar 2015

Date of Revision:

Not applicable



BI Investigational Product: FDC (empagliflozin/linagliptin), film-coated tablet

Doses: FDC empa 25/lina 5

FDC empa 10/lina 5

Mode of Admin.: Oral, once daily

Batch No.: FDC empa 25/lina 5: 308325, 108247

FDC empa 10/lina 5: 308324, 108244

BI Investigational Product: Linagliptin, film-coated tablet

Dose: 5 mg (lina 5)


Batch No.: Lina 5: 4000690; 4001581

Comparator Product: Placebos matching FDCs, film-coated tablet

Dose: Not applicable


Batch No.: Placebo matching FDC empa 25/lina 5: B111004201, 118154

Placebo matching FDC empa 10/lina 5: B111004134, 118124

Comparator Product: Placebo matching linagliptin 5 mg, film-coated tablet

Dose: Not applicable


Batch No.: Placebo matching Lina 5: 4000829; 4001579

Duration of Treatment: 16-week open-label period with lina 5 OL

1-week open-label period with lina 5 OL plus placebo matching FDCempa 25/lina 5 plus placebo matching FDC empa 10/lina 5

24-week double-blind double-dummy treatment period with FDC empa 25/lina 5, FDC empa 10/lina 5, or placebo+lina 5

1-week follow-up period



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1275.9 c02820144-01Synopsis

Name of company:


Synopsis



2012-002270-31



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4 of 11

Report Date:

03 Sep 2015


1275.9

c02820144-01

Dates of Trial:

01 Mar 2013 -23 Mar 2015

Date of Revision:

Not applicable



Criteria for Evaluation:

Efficacy: The primary endpoint was the change from baseline in HbA1c (%) after 24 weeks of double-blind trial treatment. Baseline was defined as the last value before the first intake of any randomised, double-blind trial treatment.

Key secondary endpoints were the change from baseline in fasting plasma glucose (FPG) after 24 weeks of double-blind trial treatment and the change from baseline in body weight after 24 weeks of double-blind trial treatment.

In addition, further efficacy endpoints included the proportion of patients with baseline HbA1c ≥7.0% who achieved HbA1c <7.0% after 24 weeks ofdouble-blind trial treatment, the change in mean systolic blood pressure (SBP) and mean diastolic blood pressure (DBP) from baseline after 24 weeks of double-blind trial treatment, and the changes in HbA1c, FPG, and body weight after 16 weeks of open-label treatment.

Safety: The assessment of safety was based on monitoring of adverse events (AEs), protocol-specified AEs of special interest (AESIs; decreased renal function,hepatic injury, skin reactions, hypersensitivity, and pancreatitis), other AESIs (including hypoglycaemia, urinary tract infection, genital infection, and volume depletion), as well as assessment of changes from pre-treatment and baseline in clinical laboratory values and vital signs. Pre-treatment was defined as last measurement before the first administration of open-label medication.

Statistical Methods: The primary endpoint was analysed using a restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach on the full analysis set (FAS). The statistical model included ‘HbA1c baseline’ as linear covariate and ‘treatment’, ‘baseline renal function’, ‘region’, ‘visit’, and ‘visit-by-treatment interaction’ as fixed effects. An unstructured covariance structure was used to model the within-patient errors.

Fasting plasma glucose and body weight changes from baseline wereanalysed using a similar model as for the HbA1c primary analysis, whichincluded an additional linear covariate for baseline FPG and baseline body weight, respectively.

The change from baseline in HbA1c after 24 weeks was first analysed for empa 25 vs. placebo, then for empa 10 vs. placebo using a two-sided alpha of 0.05. If both tests for the primary endpoint were successful, the key



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1275.9 c02820144-01Synopsis

Name of company:


Synopsis



2012-002270-31



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Report Date:

03 Sep 2015


1275.9

c02820144-01

Dates of Trial:

01 Mar 2013 -23 Mar 2015

Date of Revision:

Not applicable



secondary endpoints FPG and body weight were tested sequentially using a hierarchical testing procedure.

No confirmatory statistical testing was performed for further efficacy endpoints. Systolic blood pressure and DBP were analysed using a similar MMRM approach as for the primary analysis. The HbA1c responder analysis at 24 weeks was performed by determining the percentage of patients that fulfilled responder criteria by treatment; a non-completers considered failures (NCF) imputation-technique was used to impute missing data. Changes in HbA1c, FPG, and body weight during open-label treatment were presented using descriptive statistics.

Safety analyses using descriptive statistics were done separately for the overall 17-week open-label treatment period (16-week lina 5 OL+1-week placebo add-on) and the 24-week double-blind period with empa 25, empa 10, or placebo. Lipid parameters were additionally analysed using an MMRM approach similar to the primary efficacy analysis.

To reflect the scientific approach of the trial, the treatment groups for double blind trial treatment are denoted empa 25, empa 10 and placebo in the following. Each of the double-blind treatments were administered in addition to lina 5; either as an FDC (empa 25 and empa 10) or as separate tablets (placebo). All double-blind treatments were also given in addition to stable metformin background therapy.

SUMMARY - CONCLUSIONS:

Trial Patients and Compliance with Trial Protocol:

A total of 1134 patients were screened, 606 patients entered the lina 5 OL phase of the trial. A total of 333 patients (55.0% of open-label treated patients) were randomised to double-blind trial treatment in a 1:1:1 ratio to empa 25 (111 patients), empa 10 (112 patients), and placebo (110 patients)treatment.

Overall, 314 patients (94.6% of treated patients) completed the 24-week double-blind treatment period. Eighteen patients (5.4%) prematurely discontinued double-blind treatment; discontinuation rates were 3.6% in the empa 25 group, 8.0% in the empa 10 group, and 4.5% in the placebo group.Discontinuations due to AEs were reported for 2.7% of patients in empa 10 group, and 1.8% of patients in placebo group; no patient in the empa 25 group prematurely discontinued study medication.



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1275.9 c02820144-01Synopsis

Name of company:


Synopsis



2012-002270-31



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Report Date:

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1275.9

c02820144-01

Dates of Trial:

01 Mar 2013 -23 Mar 2015

Date of Revision:

Not applicable



Demographic data at baseline (last observation before start of double-blind treatment) were generally similar across the 3 treatment groups. Overall, 60.2% of the patients were male and 58.4% were White. A total of 33.9% of the patients were from North America, 31.2% from Europe, 21.7% from Asia, and 13.1% from Latin America. The mean (standard deviation [SD]) age was 55.2 (9.7) years; more than 84% of the patients were below 65 years of age and <2% were older than 75 years. At baseline, most of the patients had normal renal function (eGFR ≥90 mL/min/1.73m2) or mild renal impairment (eGFR 60 to <90 mL/min/1.73m2; 49.2% of patients for each category).

Efficacy variables at baseline were generally similar across the treatment groups. Overall, the mean (SD) baseline HbA1c was 7.97 (0.84)%, and the mean (SD) FPG was 9.27 (2.12) mmol/L. The mean (SD) body weight was higher in the empa 10 group (88.41 [20.76]) kg than the empa 25 group (84.38 [19.23]) kg or the placebo group (82.34 [19.77]) kg. The mean (SD)SBP at baseline was 131.0 (1.4) mmHg in the empa 25 group, 130.4 (1.4) mmHg in the empa 10 group, and 130.1 (1.6) mmHg in the placebo group. The mean (SD) DBP at baseline was 79.7 (0.8) mmHg in the empa 25 group, 80.0 (0.8) mmHg in the empa 10 group, and 78.0 (0.8) mmHg in the placebo group.

Mean (SD) exposure to double-blind treatment was comparable acrosstreatment groups: 166.3 (22.1) days in empa 25 group, 163.1 (30.3) days in empa 10 group, and 165.9 (22.8) days in placebo group. The overall treatment compliance was high in all treatment groups, with >93% of the patients in the full-analysis-set (FAS) in the 80 to 120% compliance range.

Efficacy Results: Open-label treatment period

The mean (SD) pre-treatment HbA1c was 8.95 (0.81)% for the open-label FAS (OLFAS); the mean (SD) change in HbA1c from pre-treatment to Week 16 of treatment with lina 5 OL was -1.16 (1.10)%. A total of 20.7% of the patients in the OLFAS achieved the glycaemic goal of HbA1c <7% during 16 weeks of lina 5 OL treatment. The mean (SD) pre-treatment FPG was10.72 (2.52) mmol/L; the mean (SD) change in FPG from pre-treatment toWeek 16 of treatment with lina 5 OL was -1.62 (2.62) mmol/L. The pre-treatment body weight was 85.27 (20.46) kg; the mean (SD) change in body weight from pre-treatment to Week 16 of treatment with lina 5 OL was -0.78(5.89) kg.



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1275.9 c02820144-01Synopsis

Name of company:


Synopsis



2012-002270-31



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Report Date:

03 Sep 2015


1275.9

c02820144-01

Dates of Trial:

01 Mar 2013 -23 Mar 2015

Date of Revision:

Not applicable



Double-blind treatment period

All steps in the hierarchical testing procedures were successful. Statistically significant reductions were seen in the MMRM FAS (OC) analysis of the primary endpoint as well as for both key secondary endpoints for empa 25 and empa 10, each compared with placebo as add-on therapy to lina 5 (Table 1).

Table 1 Change in HbA1c, FPG, and body weight from baseline to Week 24 − MMRM FAS (OC)

Metformin+lina 5 Empa 25 N = 110

Empa 10N = 109

PlaceboN = 108

HbA1c ([%]; primary endpoint):Mean baseline value (SE) 7.97 (0.08) 7.97 (0.08) 7.96 (0.08)Adjusted1 mean change from baseline (SE) -0.56 (0.08) -0.65 (0.08) 0.14 (0.09)

Adjusted1 mean difference empagliflozin vs. placebo (SE)

-0.70 (0.12) -0.79 (0.12)

95% confidence interval (-0.93,-0.46) (-1.02,-0.55)p-value <0.0001 <0.0001

FPG ([mmol/L]; key secondary endpoint):Mean baseline value (SE) 9.44 (0.23) 9.32 (0.21) 9.04 (0.17)Adjusted2 mean change from baseline (SE) -1.75 (0.18) -1.46 (0.18) 0.34 (0.19)


-2.09 (0.26) -1.80 (0.26)


Body weight ([kg]; key secondary endpoint):Mean baseline value (SE) 84.38 (1.83) 88.41 (1.99) 82.26 (1.94)Adjusted2 mean change from baseline (SE) -2.52 (0.25) -3.06 (0.25) -0.30 (0.26)


-2.22 (0.36) -2.77 (0.36)


CI=confidence interval, FAS (OC)=full analysis set using observed cases, FPG =fasting plasma glucose, HbA1c=glycated haemoglobin, MMRM=mixed model repeated measures, N=number of patients in analysis set, SE=standard error, 1 MMRM model included baseline HbA1c as linear covariate and baseline eGFR, geographical

region, treatment, visit, visit by treatment interaction as fixed effect(s). The covariance used to fit the model was unstructured.

2 For the MMRM analysis of FPG and body weight, baseline FPG and baseline weight were used as additional linear covariates in the corresponding models.



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Name of company:


Synopsis



2012-002270-31



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Report Date:

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1275.9

c02820144-01

Dates of Trial:

01 Mar 2013 -23 Mar 2015

Date of Revision:

Not applicable



Among patients with baseline HbA1c of ≥7.0%, 32.7% of the patients in the empa 25 group and 37.0% of the patients in the empa 10 group achievedHbA1c values <7.0% after 24 weeks of treatment, compared with 17.0% of patients in the placebo group. The corresponding odds ratios (empagliflozincompared with placebo) were 2.866 (95% confidence interval [CI]: 1.350, 6.088) for empa 25 and 4.016 (95% CI: 1.863, 8.659) for empa 10.

For SBP, the adjusted mean differences of empa 25 and empa 10 compared with placebo for the mean change from baseline to Week 24 were -2.6 mmHg (95% CI: -5.5, 0.4) and -1.3 mmHg (95% CI: -4.2, 1.7), respectively. For DBP, the adjusted mean differences of empa 25 and empa 10 compared with placebo from baseline to Week 24 were -1.1 mmHg (95% CI: -3.2, 1.0) and -0.1 mmHg (95% CI: -2.2, 2.0), respectively.

Safety Results: The focus of the following summary is on AEs assigned to the on-treatment periods, with an emphasis on double-blind treatment.

Open-label treatment period

During open-label treatment with lina 5 on a metformin background, 48.8% of patients in the open-label treated set (OLTS) were reported with at least 1 AE. Patients were most frequently reported with AEs in the system organ class (SOC) ‘infections and infestations’ (20.0%). Premature discontinuation of open-label trial medication due to AEs was rare (1.7%). The majority of patients were reported with AEs of mild or moderate intensity; severe AEs were reported for 2.1% of patients. Adverse events were assessed as drug-related by the investigator for 5.1% of patients. Eighteen patients (3.0%) hadserious adverse events (SAEs). No patient died during the open-label treatment period. Adverse events of specific interest were rare. One patient was reported with volume depletion (SAE: dehydration), 3 patients had alanine transaminase or aspartate transaminase (ALT/AST) increases ≥5x upper limit of normal (ULN). No patient was reported with a laboratory constellation potentially consistent with a Hy’s law case, or ALT/AST increases ≥10x ULN, or any other laboratory findings indicative of hepatic injury. There were no pancreatitis cases. Overall, mean changes in haematology parameters, differentials (automatic and absolute), electrolytes, enzymes, substrates, urinalysis, and plasma proteins were small and not clinically relevant.



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Synopsis



2012-002270-31



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c02820144-01

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01 Mar 2013 -23 Mar 2015

Date of Revision:

Not applicable



Double-blind treatment period

The most relevant safety information for the double-blind treatment period is summarised in Table 2.

Adverse events were reported for 52 to 68% of patients per group during double-blind treatment (add-on treatment to lina 5 and metformin). In each treatment group, patients were most frequently reported with AEs in the SOC ‘infections and infestations’. Premature discontinuations from double-blind treatment due to AEs and the occurrence of severe AEs were reported at low frequencies (<4% of patients per group). Adverse events were assessed as drug-related by the investigator for 5.5 to 10.9% of patients per group. Serious AEs were reported for 3.6 to 9.1% of patients per group. No patient died during the double-blind treatment period, post-treatment or post-study.

Two AEs in 2 patients in the placebo group were recorded as protocol-specified AESIs (to be reported in an expedited manner, similar to SAEs): hypertransaminasaemia, classified as SAE and assessed as related to trial medication by the investigator, and non-serious hepatitis E. Both patients had ALT/AST increases ≥20x ULN. They were discontinued and recovered from the AEs. None of the patients in the empa 25 or empa 10 groups had investigator reported protocol-specified AESIs. No patient was reported with a laboratory constellation potentially consistent with a Hy’s law case.

Investigator-defined confirmed hypoglycaemic AEs (i.e. hypoglycaemic events that had a glucose value ≤3.9 mmol/L or where assistance of another person was required) were reported for 4 patients (3 patients in the empa 25 group and 1 patient in the placebo group). No patient had more than 2 episodes and none of these led to hospitalisation. One confirmed hypoglycaemic AE in the empa 25 group required assistance.

Investigator-defined urinary tract infections were reported for 3.6 to 7.3% of patients across groups. Female patients were more frequently reported with urinary tract infections than male patients. Investigator-defined genital infections were reported for 1.8 to 4.5% of patients across groups. None of the reported infections were severe; none required hospitalisation or discontinuation of treatment.

Adverse events related to volume depletion were reported for 1 patient in the empa 25 group. This patient experienced an SAE of hypotension, assessed as related to trial medication by the investigator.There were no cases of pancreatitis.



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1275.9 c02820144-01Synopsis

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Synopsis



2012-002270-31



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1275.9

c02820144-01

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01 Mar 2013 -23 Mar 2015

Date of Revision:

Not applicable



Table 2 Overall summary of patients with AEs occurring during double-blind treatment – TS

Metformin+lina 5Empa 25

N (%)Empa 10

N (%)PlaceboN (%)

Patients 110 (100) 112 (100) 110 (100)

Patients with any AE 57 (51.8) 62 (55.4) 75 (68.2)

Severe1 1 (0.9) 4 (3.6) 3 (2.7)

Drug-related2 12 (10.9) 8 (7.1) 6 (5.5)

Other significant3 0 2 (1.8) 1 (0.9)

Discontinuation4 0 2 (1.8) 2 (1.8)

Serious (SAE) 4 (3.6) 5 (4.5) 10 (9.1)

Fatal 0 0 0

Protocol-specified AEs5 0 0 2 (1.8)Infections and infestations6 28 (25.5) 27 (24.1) 33 (3.0)

Confirmed hypoglycaemic AEs7 3 (2.7) 0 1 (0.9)

Urinary tract infection7 4 (3.6) 7 (6.3) 8 (7.3)

Genital infection7 5 (4.5) 3 (2.7) 2 (1.8)

Volume depletion8 1 (0.9) 0 0

Pancreatitis9 0 0 0

AE=adverse event, ALT=alanine transaminase, AST=aspartate transaminase, MedDRA=Medical Dictionary for Drug Regulatory Activities, SAE=serious adverse event, TS=treated set, ULN=upper limit of normal1 Worst intensity recorded.2 In the opinion of the investigator.3 Other significant (ICH-E3), defined as non-SAEs that led to premature discontinuation of trial

medication, or to dose reduction of trial medication, or were deemed otherwise significant by the sponsor or the investigator.

4 Leading to premature discontinuation of trial medication, including both SAEs and non-SAEs.5 Protocol-specified AESIs required expedited reporting to the sponsor by the investigator, i.e.

decreased renal function (creatinine ≥2x pre-treatment and >ULN) or hepatic injury (AST/ALT ≥3xULN combined with total bilirubin ≥2xULN measured in the same blood sample; or an isolated elevation of AST and /or ALT ≥5x ULN [without an elevation of bilirubin ≥2x ULN]), skin reactions, pancreatitis, and hypersensitivity, as reported by the investigator.

6 Most common system organ class (SOC).7 Investigator-defined. 8 Boehringer Ingelheim-customised MedDRA query (BIcMQ) search.9 Standardised MedDRA query (narrow SMQ).



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Name of company:


Synopsis



2012-002270-31



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Report Date:

03 Sep 2015


1275.9

c02820144-01

Dates of Trial:

01 Mar 2013 -23 Mar 2015

Date of Revision:

Not applicable



Overall, mean changes in haematology parameters, differentials (automatic and absolute), electrolytes, enzymes, substrates, urinalysis, and plasma proteins were small after 24 weeks of double-blind treatment. Mean haematocrit values increased from baseline to Week 24 with both empagliflozin doses (empa 25: 4.2%; empa 10: 3.3%). No notable change was seen in the placebo group (0.2%).

Small numerical increases in mean absolute change from baseline to Week 24 were seen for HDL cholesterol in both empagliflozin groups. There were no relevant differences to placebo in total cholesterol, LDL cholesterol, LDL/HDL cholesterol ratio, non-HDL cholesterol, or triglycerides for either of the empagliflozin groups. Changes in mean pulse rate over time were small and comparable across groups.

Conclusions: Treatment with empagliflozin 25 mg or empagliflozin 10 mg resulted in statistically significant and clinically meaningful improvements in HbA1c,FPG and body weight compared with placebo as add-on treatment to linagliptin 5 mg and metformin after 24 weeks of treatment in patients with T2DM having met the HbA1c criterion (HbA1c ≥7.0% and ≤10.5%) after 16 weeks of treatment with linagliptin 5 mg and metformin. The proportion of patients reaching target levels of HbA1c<7% after 24 weeks of treatment was higher after empagliflozin (25 mg and 10 mg) treatment than afterplacebo treatment. The treatment over 24 weeks with empagliflozin (25 mg or 10 mg) as add-on therapy to linagliptin 5 mg and metformin was safe and well tolerated.



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1275.9 c02820144-01Synopsis

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