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Clinical Trial Results:
A phase III, randomised, double-blind, parallel group, 24 week study to evaluate efficacy and safety of once daily empagliflozin 10 mg and 25 mg compared to placebo, all administered as oral fixed dose combinations with linagliptin 5 mg, in patients with type 2 diabetes mellitus and insufficient glycaemic control after 16 weeks treatment with linagliptin 5 mg once daily on metformin background therapy.

Summary
EudraCT number	2012-002270-31
Trial protocol	ES NO IT BG
Global end of trial date	23 Mar 2015

Results information
Results version number	v1(current)
This version publication date	08 Apr 2016
First version publication date	08 Apr 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

1275.9

ISRCTN number

US NCT number

NCT01734785

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, Ingelheim am Rhein, Germany, 55216

Public contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001184-PIP01-11

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

16 Apr 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

23 Mar 2015

Global end of trial reached?

Yes

Global end of trial date

23 Mar 2015

Was the trial ended prematurely?

Main objective of the trial

The objective of this trial was to investigate the efficacy, safety, and tolerability of empagliflozin 25 mg (empa 25) and empagliflozin 10 mg (empa 10) versus placebo, each administered on a background of linagliptin 5 mg (lina 5) and metformin, over 24 weeks in patients with type 2 diabetes (T2DM), who had not achieved glycaemic control after 16 weeks of treatment with lina 5 on a background of metformin.

Protection of trial subjects

Only subjects that met all the study inclusion and none of the exclusion criteria were entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.

Background therapy

Metformin was administered as background treatment to all the patients.

Evidence for comparator

Actual start date of recruitment

01 Mar 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

New Zealand: 78

Country: Number of subjects enrolled

Norway: 43

Country: Number of subjects enrolled

Spain: 176

Country: Number of subjects enrolled

Taiwan: 60

Country: Number of subjects enrolled

United States: 442

Country: Number of subjects enrolled

Australia: 19

Country: Number of subjects enrolled

Brazil: 152

Country: Number of subjects enrolled

Canada: 28

Country: Number of subjects enrolled

France: 14

Country: Number of subjects enrolled

Korea, Republic of: 122

Worldwide total number of subjects

1134

EEA total number of subjects

233

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

910

From 65 to 84 years

219

85 years and over

Subject disposition

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Recruitment details

Screening details

16-week open-label (OL) lina 5 period followed by a 1-week OL period with additional placebo administration preceded randomisation to double-blind treatment. Patients were randomised to double blind treatment only when they had not met glycaemic control criteria after the 16-week OL period. All treatments were administered in addition to metformin.

Period 1 title

Open−Label Period

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

The open label treatment period was non randomised and not controlled. Trial medications during the first 16 week treatment period and the placebo add-on period were open-label.

Linagliptin 5 mg

Arm description

Patients received 5mg dose of Linagliptin (lina 5), administered orally, once daily for 16 weeks during the OL treatment period, thereafter patients received 1 matching placebo tablet to Fixed dose combination (FDC) empa 25/lina 5, and 1 matching placebo tablet to FDC empa 10/lina 5 per day in addition to lina 5 OL, for 1 week during the open-label placebo add-on treatment period.

Arm type

Other

Investigational medicinal product name

Linagliptin 5 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 5mg dose of Linagliptin (lina 5), administered orally, once daily for 16 weeks during the OL treatment period and for 1 week during the placebo add-on treatment period.

Investigational medicinal product name

Placebo to Empagliflozin 25 mg / Linagliptin 5mg_FDC

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

After 16 weeks of open label treatment period, subjects were orally administered once daily one placebo tablet matching to empa 25 mg in combination with lina 5 mg_FDC tablet for 1 week in addition to lina 5 mg.

Investigational medicinal product name

Placebo to Empagliflozin 10 mg / Linagliptin 5mg_FDC

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

After 16 weeks of open label treatment period, subjects were orally administered once daily one placebo tablet matching to empa 10 mg in combination with lina 5 mg_FDC tablet for 1 week in addition to lina 5 mg.

Number of subjects in period 1	Linagliptin 5 mg
Started	606
Completed	333
Not completed	273
Consent withdrawn by subject	12
Adverse event, non-fatal	9
Other Reasons	224
Lost to follow-up	14
Lack of efficacy	1
Protocol deviation	13

Period 2 title

Double−Blind Period

Is this the baseline period?

Yes ^[1]

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

Medications during the 24 week treatment period were administered double-blinded.

Are arms mutually exclusive

Yes

Empagliflozin 25 mg

Arm description

Patients received 1 fixed dose combination (FDC) Empagliflozin (empa) 25/lina 5 mg tablet and two placebo tablets (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period. One subject randomised to Empagliflozin 25 mg was not treated. Although 111 patients were randomised to this treatment arm, 110 patients were therefore treated and included in summaries of baseline characteristics on the treated set.

Arm type

Experimental

Investigational medicinal product name

Empagliflozin 25mg / Linagliptin 5mg_FDC

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were orally administered once daily Empagliflozin 25 mg in combination with lina 5 mg, 1 FDC tablet for 24 weeks during the double-blind treatment period.

Investigational medicinal product name

Placebo matching FDC Empagliflozin 10mg/ Linagliptin 5mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were orally administered once daily one placebo tablet matching to Empagliflozin 10 mg in combination with Lina 5 mg_FDC tablet for 24 weeks during the double blind treatment period.

Investigational medicinal product name

Placebo matching Linagliptin 5 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were orally administered once daily one placebo tablet matching to Linagliptin 5 mg for 24 weeks during the double blind treatment period.

Empagliflozin 10 mg

Arm description

Patients received 1 FDC empa 10/lina 5 mg tablet and two placebo tablets (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 25/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.

Arm type

Experimental

Investigational medicinal product name

Empagliflozin 10mg / Linagliptin 5mg_FDC

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were orally administered once daily Empagliflozin 10 mg in combination with lina 5 mg, 1 FDC tablet for 24 weeks during the double-blind treatment period.

Investigational medicinal product name

Placebo matching FDC Empagliflozin 25mg/ Linagliptin 5mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were orally administered once daily one placebo tablet matching to Empagliflozin 25 mg in combination with Lina 5 mg_FDC tablet for 24 weeks during the double blind treatment period.

Investigational medicinal product name

Placebo matching Linagliptin 5 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were orally administered once daily one placebo tablet matching to Linagliptin 5 mg for 24 weeks during the double blind treatment period.

Placebo

Arm description

Patients received 1 lina 5 mg tablet and two placebo tablets (1 matching placebo tablet to FDC empa 25/lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.

Arm type

Comparator

Investigational medicinal product name

Placebo matching FDC Empagliflozin 10mg/ Linagliptin 5mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were orally administered once daily one placebo tablet matching to Empagliflozin 10 mg in combination with Lina 5 mg_FDC tablet for 24 weeks during the double blind treatment period.

Investigational medicinal product name

Placebo matching FDC Empagliflozin 25mg/ Linagliptin 5mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were orally administered once daily one placebo tablet matching to Empagliflozin 25 mg in combination with Lina 5 mg_FDC tablet for 24 weeks during the double blind treatment period.

Investigational medicinal product name

Linagliptin 5 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were orally administered once daily 5mg dose of Linagliptin (lina 5) for 24 weeks during the double blind treatment period.

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: Period 2 is used to report the baseline values due to study design.

Number of subjects in period 2 ^[2] ^[3]	Empagliflozin 25 mg	Empagliflozin 10 mg	Placebo
Started	110	112	110
Completed	106	103	105
Not completed	4	9	5
Consent withdrawn by subject	2	-	-
Adverse event, non-fatal	-	3	2
Lost to follow-up	2	4	2
Lack of efficacy	-	1	-
Protocol deviation	-	1	1

Notes
[2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Baseline characteristics are based on the patients who were randomized after successfully completing the period 1 and received at least one dose of the period 2 trial medication.
[3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: 333 patients completed preceding OL treatment (Period 1). 333 patients were randomised to DB treatment (Period 2). 332 patients received DB treatment (Period 2). One patient (Empa 25mg) was randomised and did not receive treatment.

Baseline characteristics

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Reporting group title

Empagliflozin 25 mg

Reporting group description

Reporting group title

Empagliflozin 10 mg

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group values	Empagliflozin 25 mg	Empagliflozin 10 mg	Placebo	Total
Number of subjects	110	112	110	332
Age categorical
Units: Subjects
Age Continuous
The treated set (TS) consisted of all patients who were randomised and treated with at least 1 dose of study drug during the double-blind part of the trial.
Units: Years
arithmetic mean (standard deviation)	55.4 ± 9.9	54.3 ± 9.5	55.9 ± 9.6	-
Gender, Male/Female
Units: Participants
Female	39	46	49	134
Male	71	66	61	198

End points

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Reporting group title

Linagliptin 5 mg

Reporting group description

Reporting group title

Empagliflozin 25 mg

Reporting group description

Reporting group title

Empagliflozin 10 mg

Reporting group description

Reporting group title

Placebo

Reporting group description

Primary: HbA1c change from baseline after 24 weeks double-blind randomised treatment

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End point title

HbA1c change from baseline after 24 weeks double-blind randomised treatment

End point description

Change from baseline in Glycated haemoglobin (HbA1c) [%] after 24 weeks of treatment with double-blind trial medication. Baseline was defined as the last observation before the first intake of any double-blind randomised trial medication. The term ‘baseline’ was not used to refer to measurements before the administration of open-label medication. The full analysis set (FAS) consisted of all patients in the TS who had a baseline HbA1c assessment and at least 1 on-treatment HbA1c assessment during the double-blind part of the trial. Observed Case (OC): In the OC analysis, values after the use of rescue medication were set to missing.

End point type

Primary

End point timeframe

Baseline and 24 weeks

End point values	Empagliflozin 25 mg	Empagliflozin 10 mg	Placebo
Number of subjects analysed	110 ^[1]	109 ^[2]	106 ^[3]
Units: Percentage of HbA1c
least squares mean (standard error)	-0.56 ± 0.08	-0.65 ± 0.08	0.14 ± 0.09

Notes
[1] - Patients in the FAS (OC) who were analysed in the MMRM.
[2] - Patients in the FAS (OC) who were analysed in the MMRM.
[3] - Patients in the FAS (OC) who were analysed in the MMRM.

Statistical Analysis 1

Statistical analysis description

Superiority of Empagliflozin 25 mg vs. placebo: change in HbA1c using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. Model includes baseline HbA1c as linear covariate(s) & baseline Estimated glomerula filtration rate (eGFR), geographical region, treatment, visit, visit by treatment interaction as fixed effect(s).

Comparison groups

Empagliflozin 25 mg v Placebo

Number of subjects included in analysis

216

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-0.93

upper limit

-0.46

Variability estimate

Standard error of the mean

Dispersion value

0.12

Notes
[4] - The unstructured co-variance structure has been used to fit the mixed model. Mean Difference (Final Values) is actually the Adjusted mean difference calculated as Empagliflozin 25 mg minus Placebo at week 24.

Statistical Analysis 2

Statistical analysis description

Superiority of Empagliflozin 10 mg vs. placebo: change in HbA1c using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. Model includes baseline HbA1c as linear covariate(s) & baseline Estimated glomerula filtration rate (eGFR), geographical region, treatment, visit, visit by treatment interaction as fixed effect(s).

Comparison groups

Empagliflozin 10 mg v Placebo

Number of subjects included in analysis

215

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.79

Confidence interval

level

95%

sides

2-sided

lower limit

-1.02

upper limit

-0.55

Variability estimate

Standard error of the mean

Dispersion value

0.12

Notes
[5] - The unstructured co-variance structure has been used to fit the mixed model. Mean Difference (Final Values) is actually the Adjusted mean difference calculated as Empagliflozin 10 mg minus Placebo at week 24.

Secondary: Fasting plasma glucose (FPG) change from baseline after 24 weeks of double-blind treatment.

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End point title

Fasting plasma glucose (FPG) change from baseline after 24 weeks of double-blind treatment.

End point description

Change from baseline FPG (mmol/L) after 24 weeks of treatment with double-blind trial medication.

End point type

Secondary

End point timeframe

Baseline and 24 weeks

End point values	Empagliflozin 25 mg	Empagliflozin 10 mg	Placebo
Number of subjects analysed	109 ^[6]	109 ^[7]	106 ^[8]
Units: mmol/L
least squares mean (standard error)	-1.75 ± 0.18	-1.46 ± 0.18	0.34 ± 0.19

Notes
[6] - Patients in the FAS (OC) who were analysed in the MMRM.
[7] - Patients in the FAS (OC) who were analysed in the MMRM.
[8] - Patients in the FAS (OC) who were analysed in the MMRM.

Statistical Analysis 1

Statistical analysis description

Superiority of Empagliflozin 25 mg vs. placebo: change in FPG using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. Model includes baseline FPG, baseline HbA1c as linear covariate(s) & baseline eGFR, geographical region, treatment, visit, visit by treatment interaction as fixed effect(s).

Comparison groups

Empagliflozin 25 mg v Placebo

Number of subjects included in analysis

215

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-2.09

Confidence interval

level

95%

sides

2-sided

lower limit

-2.61

upper limit

-1.57

Variability estimate

Standard error of the mean

Dispersion value

0.26

Notes
[9] - The unstructured co-variance structure has been used to fit the mixed model. Mean Difference (Final Values) is actually the Adjusted mean difference calculated as Empagliflozin 25 mg minus Placebo at week 24.

Statistical Analysis 2

Statistical analysis description

Superiority of Empagliflozin 10 mg vs. placebo: change in FPG using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. Model includes baseline FPG, baseline HbA1c as linear covariate(s) & baseline eGFR, geographical region, treatment, visit, visit by treatment interaction as fixed effect(s).

Comparison groups

Empagliflozin 10 mg v Placebo

Number of subjects included in analysis

215

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-2.31

upper limit

-1.28

Variability estimate

Standard error of the mean

Dispersion value

0.26

Notes
[10] - The unstructured co-variance structure has been used to fit the mixed model. Mean Difference (Final Values) is actually the Adjusted mean difference calculated as Empagliflozin 10 mg minus Placebo at week 24.

Secondary: Body weight change from baseline after 24 weeks of double-blind treatment.

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End point title

Body weight change from baseline after 24 weeks of double-blind treatment.

End point description

Change from baseline Body weight after 24 weeks of treatment with double-blind trial medication.

End point type

Secondary

End point timeframe

Baseline and 24 weeks

End point values	Empagliflozin 25 mg	Empagliflozin 10 mg	Placebo
Number of subjects analysed	110 ^[11]	109 ^[12]	106 ^[13]
Units: kg
least squares mean (standard error)	-2.52 ± 0.25	-3.06 ± 0.25	-0.3 ± 0.26

Notes
[11] - Patients in the FAS (OC) who were analysed in the MMRM.
[12] - Patients in the FAS (OC) who were analysed in the MMRM.
[13] - Patients in the FAS (OC) who were analysed in the MMRM.

Statistical Analysis 1

Statistical analysis description

Superiority of Empagliflozin 25 mg vs. placebo: change in body weight using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. Model includes baseline weight, baseline HbA1c as linear covariate(s) & baseline eGFR, geographical region, treatment, visit, visit by treatment interaction as fixed effect(s).

Comparison groups

Empagliflozin 25 mg v Placebo

Number of subjects included in analysis

216

Analysis specification

Pre-specified

Analysis type

superiority ^[14]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-2.22

Confidence interval

level

95%

sides

2-sided

lower limit

-2.92

upper limit

-1.52

Variability estimate

Standard error of the mean

Dispersion value

0.36

Notes
[14] - The unstructured co-variance structure has been used to fit the mixed model. Mean Difference (Final Values) is actually the Adjusted mean difference calculated as Empagliflozin 25 mg minus Placebo at week 24.

Statistical Analysis 2

Statistical analysis description

Superiority of Empagliflozin 10 mg vs. placebo:change in body weight using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. Model includes baseline weight, baseline HbA1c as linear covariate(s) & baseline eGFR, geographical region, treatment, visit, visit by treatment interaction as fixed effect(s).

Comparison groups

Empagliflozin 10 mg v Placebo

Number of subjects included in analysis

215

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-2.77

Confidence interval

level

95%

sides

2-sided

lower limit

-3.47

upper limit

-2.07

Variability estimate

Standard error of the mean

Dispersion value

0.36

Notes
[15] - The unstructured co-variance structure has been used to fit the mixed model. Mean Difference (Final Values) is actually the Adjusted mean difference calculated as Empagliflozin 10 mg minus Placebo at week 24.

Adverse events

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Timeframe for reporting adverse events

From first drug administration until 7 days after the last drug administration, up to 126 days (open label treatment period) and 176 days (double blind treatment period).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

Empagliflozin 25 mg

Reporting group description

Patients received 1 FDC Empagliflozin (empa) 25/lina 5 mg tablet and two placebo tablets (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period.

Reporting group title

Empagliflozin 10 mg

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group title

Linagliptin 5 mg

Reporting group description

Patients received 5mg dose of Linagliptin (lina 5), administered orally, once daily for 16 weeks during the OL treatment period, thereafter patients received 1 matching placebo tablet to FDC empa 25/lina 5, and 1 matching placebo tablet to FDC empa 10/lina 5 per day in addition to lina 5 OL, for 1 week during the open-label placebo add-on treatment period.

Serious adverse events	Empagliflozin 25 mg	Empagliflozin 10 mg	Placebo	Linagliptin 5 mg
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 110 (3.64%)	5 / 112 (4.46%)	10 / 110 (9.09%)	18 / 606 (2.97%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder neoplasm
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	1 / 110 (0.91%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 110 (0.00%)	1 / 112 (0.89%)	0 / 110 (0.00%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Abortion induced
subjects affected / exposed	0 / 110 (0.00%)	1 / 112 (0.89%)	0 / 110 (0.00%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Oedema
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	1 / 110 (0.91%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	1 / 110 (0.91%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pneumothorax
subjects affected / exposed	0 / 110 (0.00%)	1 / 112 (0.89%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Major depression
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mania
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	1 / 110 (0.91%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	1 / 110 (0.91%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaw fracture
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 110 (0.91%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	1 / 110 (0.91%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cervical radiculopathy
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	1 / 110 (0.91%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	1 / 110 (0.91%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 110 (0.91%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 110 (0.00%)	1 / 112 (0.89%)	0 / 110 (0.00%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	1 / 110 (0.91%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatotoxicity
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertransaminasaemia
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	1 / 110 (0.91%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Calculus ureteric
subjects affected / exposed	1 / 110 (0.91%)	0 / 112 (0.00%)	1 / 110 (0.91%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	1 / 110 (0.91%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 110 (0.91%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	1 / 110 (0.91%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 110 (0.00%)	1 / 112 (0.89%)	0 / 110 (0.00%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc disorder
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	1 / 110 (0.91%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	1 / 110 (0.91%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea infectious
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	1 / 110 (0.91%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis bacterial
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	1 / 110 (0.91%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	1 / 110 (0.91%)	0 / 112 (0.00%)	0 / 110 (0.00%)	0 / 606 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	0 / 110 (0.00%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	0 / 110 (0.00%)	0 / 112 (0.00%)	1 / 110 (0.91%)	1 / 606 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Empagliflozin 25 mg	Empagliflozin 10 mg	Placebo	Linagliptin 5 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	11 / 110 (10.00%)	19 / 112 (16.96%)	34 / 110 (30.91%)	78 / 606 (12.87%)
Investigations
Lipase increased
subjects affected / exposed	3 / 110 (2.73%)	4 / 112 (3.57%)	6 / 110 (5.45%)	10 / 606 (1.65%)
occurrences all number	3	6	6	11
Nervous system disorders
Headache
subjects affected / exposed	2 / 110 (1.82%)	3 / 112 (2.68%)	8 / 110 (7.27%)	14 / 606 (2.31%)
occurrences all number	2	5	9	21
Infections and infestations
Nasopharyngitis
subjects affected / exposed	4 / 110 (3.64%)	5 / 112 (4.46%)	8 / 110 (7.27%)	25 / 606 (4.13%)
occurrences all number	6	5	11	27
Urinary tract infection
subjects affected / exposed	3 / 110 (2.73%)	8 / 112 (7.14%)	7 / 110 (6.36%)	28 / 606 (4.62%)
occurrences all number	3	8	7	28
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	1 / 110 (0.91%)	1 / 112 (0.89%)	7 / 110 (6.36%)	6 / 606 (0.99%)
occurrences all number	1	1	7	10

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Were there any global substantial amendments to the protocol? Yes

06 Jun 2013

Stopping of trial treatment in case of changes in metformin background treatment or with suspected pancreatitis (included in the linagliptin labelling) were added as discontinuation criteria. Minor corrections and clarifications for consistency within the CTP and within the development program were introduced.

17 Dec 2013

Based upon comments in an advice letter received from health authority on 24 Apr 2013 the primary analysis model was changed from ANCOVA (LOCF) to MMRM (OC). Subsequent changes to the sensitivity analyses of the primary endpoint included the analysis of the primary endpoint using an ANCOVA (LOCF) model. The analysis of key secondary endpoints and the subgroup analyses were updated accordingly. For consistency with the TSAP, the planned analyses were updated by adding definitions of the different analysis sets (SCR, OLS, and OLFAS). The description of the trial objective and the trial design was amended to clarify the use of FDCs of empagliflozin and linagliptin. External independent committees were set-up for the adjudication of safety relevant events (pancreatic events, hepatic events, cancer assessments). To match new requirement for public disclosure AEs, hypoglycaemic events, AESIs and cardiovascular events were part of the safety assessment without being classified as further endpoints. Processes for expedited AE reporting were updated and clarified. Administration of herbal/nutritional supplements/medication that interfered with the investigational products was included as a reason for patient withdrawal. Administrative changes including updates and clarifications on AE reporting requirements including the definition of the REP, minor corrections and further clarifications were introduced.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Baseline characteristics

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End points

Primary: HbA1c change from baseline after 24 weeks double-blind randomised treatment

Primary: HbA1c change from baseline after 24 weeks double-blind randomised treatment

Secondary: Fasting plasma glucose (FPG) change from baseline after 24 weeks of double-blind treatment.

Secondary: Fasting plasma glucose (FPG) change from baseline after 24 weeks of double-blind treatment.

Secondary: Body weight change from baseline after 24 weeks of double-blind treatment.

Secondary: Body weight change from baseline after 24 weeks of double-blind treatment.

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