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

Summary
EudraCT number	2012-002271-34
Trial protocol	PT DE ES IT
Global end of trial date	30 Mar 2015

Results information
Results version number	v1(current)
This version publication date	09 Apr 2016
First version publication date	09 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

1275.10

ISRCTN number

US NCT number

NCT01778049

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

173 Binger Strasse, Ingelheim am Rhein, Germany, 55216

Public contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com

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

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

30 Apr 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

06 Mar 2015

Global end of trial reached?

Yes

Global end of trial date

30 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 linagliptin 5 mg (lina 5) compared with placebo, each administered as add-on therapy to empagliflozin (25 mg [empa 25] or 10 mg [empa 10]) and metformin, over 24 weeks in patients with type 2 diabetes (T2DM), who had met the HbA1c inclusion criterion (HbA1c ≥7% and ≤10.5%) after 16 weeks of open-label (OL) treatment with empa 25 OL or empa 10 OL and metformin background treatment.

Protection of trial subjects

Only subjects that met all the study inclusion and none of the exclusion criteria were to be 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.

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Feb 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 27

Country: Number of subjects enrolled

Germany: 111

Country: Number of subjects enrolled

Italy: 138

Country: Number of subjects enrolled

Portugal: 22

Country: Number of subjects enrolled

Russian Federation: 62

Country: Number of subjects enrolled

Spain: 131

Country: Number of subjects enrolled

Ukraine: 131

Country: Number of subjects enrolled

Argentina: 343

Country: Number of subjects enrolled

Canada: 148

Country: Number of subjects enrolled

United States: 211

Worldwide total number of subjects

1324

EEA total number of subjects

402

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)

1023

From 65 to 84 years

298

85 years and over

Subject disposition

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Recruitment details

Subjects randomised to 16 week(wk) open-label (OL) treatment with either empagliflozin (empa) 25 or empa 10 treatment, thereafter subjects entered to 1 wk open label placebo (Plc) add-on period in order to complete further eligibility evaluations before being randomised into one of the 24 wk double-blind treatment groups.

Screening details

This was a randomised, double-blind, multi-national, parallel group trial. In this trial the treatment effects of linagliptin (lina) 5 compared with Plc were analysed as add-on to either empa 25 or empa 10. All trial treatments were administered in addition to metformin background treatment.

Period 1 title

Open label treatment period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Trial medications during the initial 16 week treatment period and the placebo add-on period were open-label.

Are arms mutually exclusive

Yes

Empa 10 mg OL

Arm description

Subjects were orally administered once daily empa 10 mg film-coated (1 tablet) for 16 wk during OL treatment period, thereafter patients received once daily fixed dose combination (FDC) placebo (1 tablet) matching to FDC empa 10 mg/lina 5 mg in addition to empa 10 mg for one week during open label placebo add-on treatment period.

Arm type

Experimental

Investigational medicinal product name

empagliflozin

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 (empa) 10 mg film-coated tablet for 16 weeks during open-label treatment period.

Investigational medicinal product name

Placebo to linagliptin

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 placebo tablet matching to lina 5 mg (in combination with placebo to empa 10 mg, 1 FDC tablet) in addition to empa 10 mg for 1 week.

Investigational medicinal product name

Placebo to empagliflozin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

After 16 week open label treatment, subjects were orally administered once daily placebo tablet matching to empa 10 mg ( in combination with placebo to linagliptin (lina) 5 mg, 1 FDC tablet) in addition to empa 10 mg for 1 week.

Empa 25 mg OL

Arm description

Subjects were orally administered once daily empa 25 mg film-coated (1 tablet) for 16 week during OL treatment period, thereafter patients received once daily FDC placebo (1 tablet) matching to FDC empa 25 mg/lina 5 mg in addition to empa 25 mg for one week during open label placebo add-on treatment period.

Arm type

Experimental

Investigational medicinal product name

empagliflozin

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 (empa) 25 mg film-coated tablet for 16 weeks during open-label (OL) treatment period.

Investigational medicinal product name

Placebo to empagliflozin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

After 16 week open label treatment period, subjects were orally administered once daily placebo tablet matching to empa 25 mg ( in combination with placebo to linagliptin (lina) 5 mg, 1 FDC tablet) in addition to empa 25 mg for 1 week.

Investigational medicinal product name

Placebo to linagliptin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

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

Number of subjects in period 1	Empa 10 mg OL	Empa 25 mg OL
Started	352	354
Completed	256	226
Not completed	96	128
Other reason not defined above	77	94
Adverse event, serious fatal	-	1
Consent withdrawn by subject	4	10
Adverse event, non-fatal	5	14
Lost to follow-up	4	3
Lack of efficacy	1	1
Protocol deviation	5	5

Period 2 title

Double blind treatment period

Is this the baseline period?

Yes ^[1]

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst

Blinding implementation details

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

Are arms mutually exclusive

Yes

Lina5 (E10)

Arm description

Subjects were orally administered FDC empa 10 mg/lina 5 mg (1 tablet) and placebo matching to empa 10 mg (1 tablet) for 24 weeks during the double-blind treatment period.

Arm type

Experimental

Investigational medicinal product name

empagliflozin

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 empa 10 mg tablet ( in combination with lina 5 mg, 1 FDC tablet) in addition to empa 10 mg for 24 weeks during the double-blind treatment period.

Investigational medicinal product name

linagliptin

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 lina 5 mg tablet ( in combination with empa 10 mg, 1 FDC tablet) for 24 weeks during the double-blind treatment period.

Investigational medicinal product name

Placebo to empagliflozin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were orally administered placebo matching to empa 10 mg for 24 weeks during the double-blind treatment period.

Plc (E10)

Arm description

Subjects were orally administered empa 10 mg (1 tablet) and matching placebo to FDC empa 10 mg/lina 5 mg (1 tablet) for 24 weeks during the double-blind treatment period. Two subjects randomised to Plc (E10) were not treated. Although actual number of subjects started is 130, 128 were reported to ensure consistent reporting with baseline characteristics that includes only treated subjects.

Arm type

Active comparator

Investigational medicinal product name

empagliflozin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were orally administered empa 10 mg for 24 weeks during the double-blind treatment period.

Investigational medicinal product name

Placebo to linagliptin

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 placebo tablet matching to lina 5 mg ( in combination with placebo to empa 10 mg, 1 FDC tablet) for 24 weeks during the double-blind treatment period.

Investigational medicinal product name

Placebo to empagliflozin

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 placebo tablet matching to empa 10 mg ( in combination with placebo to lina 5 mg, 1 FDC tablet) for 24 weeks during the double-blind treatment period.

Lina5 (E25)

Arm description

Subjects were orally administered FDC empa 25 mg/lina 5 mg (1 tablet) and placebo matching to empa 25 mg (1 tablet) for 24 weeks during the double-blind treatment period. Two subjects randomised to Lina5 (E25) were not treated. Although actual number of subjects started is 114, 112 were reported to ensure consistent reporting with baseline characteristics that includes only treated subjects.

Arm type

Experimental

Investigational medicinal product name

empagliflozin

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 empa 25 mg tablet ( in combination with lina 5 mg, 1 FDC tablet) in addition to empa 25 mg for 24 weeks during the double-blind treatment period.

Investigational medicinal product name

Placebo to empagliflozin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were orally administered placebo matching to empa 25 mg for 24 weeks during the double-blind treatment period.

Investigational medicinal product name

linagliptin

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 lina 5 mg tablet ( in combination with empa 25 mg, 1 FDC tablet) for 24 weeks during the double-blind treatment period.

Plc (E25)

Arm description

Subjects were orally administered empa 25 mg (1 tablet) and matching placebo to FDC empa 25 mg/lina 5 mg (1 tablet) for 24 weeks during the double-blind treatment period.

Arm type

Active comparator

Investigational medicinal product name

empagliflozin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were orally administered empa 25 mg for 24 weeks during the double-blind treatment period.

Investigational medicinal product name

Placebo to linagliptin

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 placebo tablet matching to lina 5 mg ( in combination with placebo to empa 25 mg, 1 FDC tablet) for 24 weeks during the double-blind treatment period.

Investigational medicinal product name

Placebo to empagliflozin

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 placebo tablet matching to empa 25 mg ( in combination with placebo to lina 5 mg, 1 FDC tablet) 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: In this study, Period 1 evaluates open label treatment period which referred to as pre-treatment analysis , thus period 2 double blind treatment period was selected as a baseline period to define the baseline characteristics of this trial.

Number of subjects in period 2 ^[2] ^[3]	Lina5 (E10)	Plc (E10)	Lina5 (E25)	Plc (E25)
Started	126	128	112	112
Completed	111	118	102	105
Not completed	15	10	10	7
Other reason not defined above	4	2	2	1
Consent withdrawn by subject	1	2	-	1
Adverse event, non-fatal	4	5	3	2
Lost to follow-up	4	1	5	2
Protocol deviation	2	-	-	-
Lack of efficacy	-	-	-	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 last measurement prior to the administration of any double-blind randomised study medication. In this study the term “baseline” was not used to refer to measurements prior to the administration of open-label medication. Such measurements were referred to as “pre-treatment".
[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: This study was conducted in two phases, open label (OL) and double blind (DB) phase. Subjects received OL treatment for 16 weeks and thereafter patients entered a 1 week open-label placebo add-on period in order to complete further eligibility evaluations before being randomised into one of the 24 week DB treatment groups. The patients who were eligible were only randomised to DB treatemet period, thus the inconsistency within the number of subjects completed the preceding period is observed.

Baseline characteristics

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Reporting group title

Lina5 (E10)

Reporting group description

Subjects were orally administered FDC empa 10 mg/lina 5 mg (1 tablet) and placebo matching to empa 10 mg (1 tablet) for 24 weeks during the double-blind treatment period.

Reporting group title

Plc (E10)

Reporting group description

Reporting group title

Lina5 (E25)

Reporting group description

Reporting group title

Plc (E25)

Reporting group description

Subjects were orally administered empa 25 mg (1 tablet) and matching placebo to FDC empa 25 mg/lina 5 mg (1 tablet) for 24 weeks during the double-blind treatment period.

Reporting group values	Lina5 (E10)	Plc (E10)	Lina5 (E25)	Plc (E25)	Total
Number of subjects	126	128	112	112	478
Age categorical
Units: Subjects
Age Continuous \|
The Treated set (TS) was used for the double-blind treatment period. The treated set (TS) consisted of all patients who were randomised and treated with at least one dose of study drug during the double-blind part of the trial. The TS was the basis of the safety analyses for the double-blind period.
Units: years
arithmetic mean (standard deviation)	56.6 ( 9.5 )	56.6 ( 9.5 )	56.4 ( 9.9 )	56.2 ( 10.7 )	-
Gender, Male/Female
Units: participants
Female	55	56	58	47	216
Male	71	72	54	65	262

End points

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Reporting group title

Empa 10 mg OL

Reporting group description

Reporting group title

Empa 25 mg OL

Reporting group description

Reporting group title

Lina5 (E10)

Reporting group description

Subjects were orally administered FDC empa 10 mg/lina 5 mg (1 tablet) and placebo matching to empa 10 mg (1 tablet) for 24 weeks during the double-blind treatment period.

Reporting group title

Plc (E10)

Reporting group description

Reporting group title

Lina5 (E25)

Reporting group description

Reporting group title

Plc (E25)

Reporting group description

Subjects were orally administered empa 25 mg (1 tablet) and matching placebo to FDC empa 25 mg/lina 5 mg (1 tablet) for 24 weeks during the double-blind treatment period.

Primary: Change from baseline of HbA1c after 24 weeks of treatment

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End point title

Change from baseline of HbA1c after 24 weeks of treatment

End point description

Change from baseline in Glycated haemoglobin (HbA1c) [%] after 24 wk of treatment with double-blind trial medication, i.e. HbA1c change from baseline at week 24. The term "baseline" refers to the last measurement prior to the administration of any double-blind randomised study medication. It was not used to refer to measurements prior to the administration of open-label medication. Such measurements will be referred to as “pre-treatment". Observed Case (OC): This method analyse only available data that were observed while patients were on treatment, i.e., excluding the missing data. All values measured after rescue medication taken were set to missing. Full Analysis Set (FAS): Includes all patients in the Treated set who had a baseline HbA1c assessment and at least one on-treatment HbA1c assessment during the double-blind part of the trial.

End point type

Primary

End point timeframe

Baseline and 24 weeks

End point values	Lina5 (E10)	Plc (E10)	Lina5 (E25)	Plc (E25)
Number of subjects analysed	111 ^[1]	110 ^[2]	98 ^[3]	98 ^[4]
Units: Percentage of HbA1c
least squares mean (standard error)	-0.53 ( 0.07 )	-0.21 ( 0.07 )	-0.58 ( 0.07 )	-0.1 ( 0.07 )

Notes
[1] - FAS (OC)
[2] - FAS (OC)
[3] - FAS (OC)
[4] - FAS (OC)

Statistical Analysis 1

Statistical analysis description

Superiority of lina 5 (E10) vs. Plc (E10): change in HbA1c using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. The model includes baseline HbA1c as linear covariate & baseline estimated glomerula filtration rate (eGFR), geographical region, treatment, visit, visit by treatment interaction as fixed effects.

Comparison groups

Lina5 (E10) v Plc (E10)

Number of subjects included in analysis

221

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.0013

Method

Mixed Model Repeated Measure (MMRM)

Parameter type

Mean difference (final values)

Point estimate

-0.32

Confidence interval

level

95%

sides

2-sided

lower limit

-0.52

upper limit

-0.13

Variability estimate

Standard error of the mean

Dispersion value

0.1

Notes
[5] - The unstructured covariance structure has been used to fit the mixed model. Mean Difference (Final Values) is actually the adjusted mean difference calculated as Lina 5 (E10) minus Plc (E10) value.

Statistical Analysis 2

Statistical analysis description

Superiority of lina 5 (E25) vs.Plc (E25): change in HbA1c using a restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach. The model includes baseline HbA1c as linear covariate & baseline eGFR, geographical region, treatment, visit, visit by treatment interaction as fixed effects.

Comparison groups

Lina5 (E25) v Plc (E25)

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

< 0.0001

Method

MMRM

Parameter type

Mean difference (final values)

Point estimate

-0.47

Confidence interval

level

95%

sides

2-sided

lower limit

-0.66

upper limit

-0.28

Variability estimate

Standard error of the mean

Dispersion value

0.1

Notes
[6] - The unstructured covariance structure has been used to fit the mixed model. Mean Difference (Final Values) is actually the adjusted mean difference value calculated as Lina 5 (E25) minus Plc (E25).

Secondary: Change from baseline in FPG (mmol/L) after 24 weeks

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End point title

Change from baseline in FPG (mmol/L) after 24 weeks

End point description

Change from baseline in fasting plasma glucose (FPG) (mmol/L) after 24 weeks of treatment with double-blind trial medication, i.e. FPG change from baseline at Week 24.

End point type

Secondary

End point timeframe

Baseline and 24 weeks

End point values	Lina5 (E10)	Plc (E10)	Lina5 (E25)	Plc (E25)
Number of subjects analysed	108 ^[7]	107 ^[8]	93 ^[9]	94 ^[10]
Units: mmol/L
least squares mean (standard error)	-0.44 ( 0.18 )	0.21 ( 0.18 )	-0.68 ( 0.15 )	-0.24 ( 0.15 )

Notes
[7] - FAS (OC)
[8] - FAS (OC)
[9] - FAS (OC)
[10] - FAS (OC)

Statistical Analysis 1

Statistical analysis description

Superiority of lina5 (E10) vs. Plc (E10): change in FPG using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. The model includes baseline HbA1c & baseline eGFR as linear covariates, geographical region, treatment, visit, visit by treatment interaction as fixed effects.

Comparison groups

Lina5 (E10) v Plc (E10)

Number of subjects included in analysis

215

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

= 0.0103

Method

MMRM

Parameter type

Mean difference (final values)

Point estimate

-0.65

Confidence interval

level

95%

sides

2-sided

lower limit

-1.15

upper limit

-0.16

Variability estimate

Standard error of the mean

Dispersion value

0.25

Notes
[11] - The unstructured covariance structure has been used to fit the mixed model. Mean Difference (Final Values) is actually the adjusted mean difference value calculated as Lina 5 (E10) minus Plc (E10).

Statistical Analysis 2

Statistical analysis description

Superiority of lina5 (E25) vs. Plc (E25): change in FPG using a restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach. The model includes baseline HbA1c & baseline eGFR as linear covariates, geographical region, treatment, visit, visit by treatment interaction as fixed effects.

Comparison groups

Lina5 (E25) v Plc (E25)

Number of subjects included in analysis

187

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

P-value

= 0.0452

Method

MMRM

Parameter type

Mean difference (final values)

Point estimate

-0.44

Confidence interval

level

95%

sides

2-sided

lower limit

-0.87

upper limit

-0.01

Variability estimate

Standard error of the mean

Dispersion value

0.22

Notes
[12] - The unstructured covariance structure has been used to fit the mixed model. Mean Difference (Final Values) is actually the adjusted mean difference value calculated as Lina 5 (E25) minus Plc (E25).

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 212 days (OL treatment period) and 205 days (double blind treatment period).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

empa 10 mg OL

Reporting group description

Reporting group title

empa 25 mg OL

Reporting group description

Reporting group title

Lina5 (E10)

Reporting group description

Subjects were orally administered FDC empa 10 mg/lina 5 mg (1 tablet) and placebo matching to empa 10 mg (1 tablet) for 24 weeks during the double-blind treatment period.

Reporting group title

Plc (E10)

Reporting group description

Reporting group title

Lina5 (E25)

Reporting group description

Reporting group title

Plc (E25)

Reporting group description

Subjects were orally administered empa 25 mg (1 tablet) and matching placebo to FDC empa 25 mg/lina 5 mg (1 tablet) for 24 weeks during the double-blind treatment period.

Serious adverse events	empa 10 mg OL	empa 25 mg OL	Lina5 (E10)	Plc (E10)	Lina5 (E25)	Plc (E25)
Total subjects affected by serious adverse events
subjects affected / exposed	12 / 352 (3.41%)	12 / 354 (3.39%)	4 / 126 (3.17%)	5 / 128 (3.91%)	3 / 112 (2.68%)	4 / 112 (3.57%)
number of deaths (all causes)	0	1	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pancreatic carcinoma metastatic
subjects affected / exposed	0 / 352 (0.00%)	1 / 354 (0.28%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostatic adenoma
subjects affected / exposed	1 / 352 (0.28%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Extremity necrosis
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subclavian vein thrombosis
subjects affected / exposed	1 / 352 (0.28%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Calcinosis
subjects affected / exposed	0 / 352 (0.00%)	1 / 354 (0.28%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 352 (0.28%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 352 (0.00%)	1 / 354 (0.28%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	1 / 126 (0.79%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Balanoposthitis
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	0 / 126 (0.00%)	1 / 128 (0.78%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metrorrhagia
subjects affected / exposed	0 / 352 (0.00%)	1 / 354 (0.28%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 352 (0.28%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nasal septum deviation
subjects affected / exposed	0 / 352 (0.00%)	1 / 354 (0.28%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nasal turbinate hypertrophy
subjects affected / exposed	0 / 352 (0.00%)	1 / 354 (0.28%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngeal lesion
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	1 / 112 (0.89%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Amylase increased
subjects affected / exposed	1 / 352 (0.28%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 352 (0.28%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skull fractured base
subjects affected / exposed	1 / 352 (0.28%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina unstable
subjects affected / exposed	1 / 352 (0.28%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 352 (0.28%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	1 / 112 (0.89%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	0 / 126 (0.00%)	1 / 128 (0.78%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 352 (0.28%)	0 / 354 (0.00%)	0 / 126 (0.00%)	1 / 128 (0.78%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 352 (0.28%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	1 / 112 (0.89%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral haematoma
subjects affected / exposed	1 / 352 (0.28%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	1 / 352 (0.28%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	0 / 126 (0.00%)	1 / 128 (0.78%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	1 / 352 (0.28%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Pancytopenia
subjects affected / exposed	0 / 352 (0.00%)	1 / 354 (0.28%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diverticulum intestinal
subjects affected / exposed	0 / 352 (0.00%)	1 / 354 (0.28%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 352 (0.00%)	1 / 354 (0.28%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal polyp
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	2 / 352 (0.57%)	0 / 354 (0.00%)	1 / 126 (0.79%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 352 (0.00%)	1 / 354 (0.28%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	1 / 126 (0.79%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	2 / 352 (0.57%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Liver injury
subjects affected / exposed	1 / 352 (0.28%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis bullous
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	1 / 112 (0.89%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyshidrotic eczema
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	1 / 112 (0.89%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	1 / 126 (0.79%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemarthrosis
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neck pain
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	0 / 126 (0.00%)	1 / 128 (0.78%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	1 / 126 (0.79%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	0 / 126 (0.00%)	1 / 128 (0.78%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess limb
subjects affected / exposed	0 / 352 (0.00%)	1 / 354 (0.28%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 352 (0.00%)	1 / 354 (0.28%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gangrene
subjects affected / exposed	0 / 352 (0.00%)	1 / 354 (0.28%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infectious colitis
subjects affected / exposed	0 / 352 (0.00%)	1 / 354 (0.28%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	2 / 112 (1.79%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	1 / 126 (0.79%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 352 (0.28%)	0 / 354 (0.00%)	0 / 126 (0.00%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 352 (0.00%)	0 / 354 (0.00%)	1 / 126 (0.79%)	0 / 128 (0.00%)	0 / 112 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	empa 10 mg OL	empa 25 mg OL	Lina5 (E10)	Plc (E10)	Lina5 (E25)	Plc (E25)
Total subjects affected by non serious adverse events
subjects affected / exposed	47 / 352 (13.35%)	38 / 354 (10.73%)	22 / 126 (17.46%)	10 / 128 (7.81%)	18 / 112 (16.07%)	21 / 112 (18.75%)
Investigations
Lipase increased
subjects affected / exposed	15 / 352 (4.26%)	10 / 354 (2.82%)	4 / 126 (3.17%)	1 / 128 (0.78%)	7 / 112 (6.25%)	7 / 112 (6.25%)
occurrences all number	15	10	4	1	7	7
Infections and infestations
Nasopharyngitis
subjects affected / exposed	17 / 352 (4.83%)	5 / 354 (1.41%)	8 / 126 (6.35%)	3 / 128 (2.34%)	2 / 112 (1.79%)	8 / 112 (7.14%)
occurrences all number	18	5	11	3	2	8
Urinary tract infection
subjects affected / exposed	16 / 352 (4.55%)	23 / 354 (6.50%)	10 / 126 (7.94%)	6 / 128 (4.69%)	11 / 112 (9.82%)	7 / 112 (6.25%)
occurrences all number	17	26	13	9	14	8

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Were there any global substantial amendments to the protocol? Yes

05 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.

27 Nov 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). According to published literature, MMRM analysis appears to be a superior approach for controlling Type I error rates and minimizing bias as compared to single imputation approaches such as LOCF ANCOVA analysis particularly in the presence of missing completely at random or missing at random data [R10-5462]. The MMRM approach included treatment, baseline renal function, region, visit, and visit-by-treatment interaction as fixed effects, and HbA1c baseline as linear covariate. An unstructured covariance structure was used to model the within-patient errors. Subsequent changes to the sensitivity analyses of the primary endpoint included the analysis of the primary endpoint using an ANCOVA model. The analysis of the key secondary endpoint 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 [001-MCS-40-106_RD-03]. 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.

11 Jun 2014

This revision of the CTP involved only minor administrative aspects and clarifications and did not require IRB/IEC approval.

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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Primary: Change from baseline of HbA1c after 24 weeks of treatment

Primary: Change from baseline of HbA1c after 24 weeks of treatment

Secondary: Change from baseline in FPG (mmol/L) after 24 weeks

Secondary: Change from baseline in FPG (mmol/L) after 24 weeks

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