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    Clinical Trial Results:
    A Phase III, randomised, double blind, placebo-controlled, parallel group, efficacy, safety and tolerability trial of once daily, oral doses of Empagliflozin as Adjunctive to inSulin thErapy over 52 weeks in patients with Type 1 Diabetes Mellitus (EASE-2)

    Summary
    EudraCT number
    		 2014-001922-14
    Trial protocol
    		 GB   BE   ES   SE   FI   DK   DE   NL   CZ   AT   PL  
    Global end of trial date
    23 Oct 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Nov 2018
    First version publication date
    07 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1245.69
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02414958
    WHO universal trial number (UTN)
    		 -
    Sponsors
    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
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study was to assess the efficacy, safety, tolerability and pharmacokinetics (PK) of once daily oral doses of Empagliflozin 10 milligram (mg) and 25 mg compared with placebo in patients with type 1 diabetes mellitus (T1DM) as adjunctive to optimised insulin therapy.
    Protection of trial subjects
    Only patients that met all the study inclusion and none of the exclusion criteria were to be randomised in the study. All patients were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all patients was adhered to throughout the trial conduct.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 22
    Country: Number of subjects enrolled
    Australia: 51
    Country: Number of subjects enrolled
    Belgium: 104
    Country: Number of subjects enrolled
    Canada: 147
    Country: Number of subjects enrolled
    Czech Republic: 36
    Country: Number of subjects enrolled
    Denmark: 52
    Country: Number of subjects enrolled
    Finland: 19
    Country: Number of subjects enrolled
    France: 49
    Country: Number of subjects enrolled
    Germany: 78
    Country: Number of subjects enrolled
    Netherlands: 41
    Country: Number of subjects enrolled
    Norway: 28
    Country: Number of subjects enrolled
    Poland: 62
    Country: Number of subjects enrolled
    Spain: 120
    Country: Number of subjects enrolled
    Sweden: 19
    Country: Number of subjects enrolled
    United Kingdom: 84
    Country: Number of subjects enrolled
    United States: 402
    Country: Number of subjects enrolled
    Taiwan: 24
    Worldwide total number of subjects
    1338
    EEA total number of subjects
    714
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    1228
    From 65 to 84 years
    110
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Randomised, double-blind, placebo-controlled, parallel group, 52-week trial comparing 2 oral once daily doses (10 mg and 25 mg) of empagliflozin with placebo in patients with type 1 diabetes mellitus (T1DM), each as adjunctive to optimised insulin therapy. A total of 1338 screened, 730 randomised/ treated.

    Pre-assignment
    Screening details
    		 6-week T1DM therapy (insulin) optimisation period followed by a 2-week placebo run-in period before randomisation. Patients who successfully completed both of the periods were randomised into the 52-week double-blind treatment period. All treatments were administered in addition to optimised insulin therapy.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    This is randomised and controlled trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo matching Empagliflozin
    Arm description
    		 Patients administered placebo matching empagliflozin film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo matching Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    matching Empagliflozin dosage once daily

    Arm title
    		 Empagliflozin 10 mg
    Arm description
    		 Patients administered empagliflozin 10 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.
    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
    10 mg once daily

    Arm title
    		 Empagliflozin 25 mg
    Arm description
    		 Patients administered empagliflozin 25 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.
    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
    25 mg once daily

    Number of subjects in period 1 [1]
    		Placebo matching Empagliflozin Empagliflozin 10 mg Empagliflozin 25 mg
    Started
    243
    243
    244
    Completed
    211
    223
    230
    Not completed
    32
    20
    14
         Consent withdrawn by subject
    5
    3
    5
         Adverse event, non-fatal
    6
    6
    3
         Other than specified
    4
    4
    5
         Lost to follow-up
    7
    4
    -
         Protocol deviation
    10
    3
    1
    Notes
    [1] - 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 randomised after successfully completing the screening period. .

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo matching Empagliflozin
    Reporting group description
    		 Patients administered placebo matching empagliflozin film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks

    Reporting group title
    Empagliflozin 10 mg
    Reporting group description
    		 Patients administered empagliflozin 10 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.

    Reporting group title
    Empagliflozin 25 mg
    Reporting group description
    		 Patients administered empagliflozin 25 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.

    Reporting group values
    		 Placebo matching Empagliflozin Empagliflozin 10 mg Empagliflozin 25 mg Total
    Number of subjects
    		 243 243 244 730
    Age categorical
    Randomised set (RS): All patients from the screened set (SCR) who were randomised to trial medication regardless of whether any trial medication was taken
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age Continuous
    RS
    Units: years
        arithmetic mean (standard deviation)
    		 44.2 ± 13.6 45.7 ± 12.5 45.3 ± 14.0 -
    Sex: Female, Male
    RS
    Units: Subjects
        Female
    		 133 125 131 389
        Male
    		 110 118 113 341
    Race (NIH/OMB)
    RS
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 7 6 10 23
        Native Hawaiian or Other Pacific Islander
    		 0 1 0 1
        Black or African American
    		 7 6 4 17
        White
    		 227 230 230 687
        More than one race
    		 2 0 0 2
        Unknown or Not Reported
    		 0 0 0 0
    Ethnicity (NIH/OMB)
    RS
    Units: Subjects
        Hispanic or Latino
    		 7 4 6 17
        Not Hispanic or Latino
    		 236 239 238 713
        Unknown or Not Reported
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo matching Empagliflozin
    Reporting group description
    		 Patients administered placebo matching empagliflozin film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks

    Reporting group title
    Empagliflozin 10 mg
    Reporting group description
    		 Patients administered empagliflozin 10 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.

    Reporting group title
    Empagliflozin 25 mg
    Reporting group description
    		 Patients administered empagliflozin 25 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks.

    Primary: Change from baseline in glycated haemoglobin (HbA1c) at Week 26

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    End point title
    		 Change from baseline in glycated haemoglobin (HbA1c) at Week 26
    End point description
    Change from baseline in glycated haemoglobin (HbA1c) for full analysis set (FAS) (observed cases [OC]) is presented. With regards to efficacy and safety endpoints, the term ‘baseline’ referred to the last observed measurement prior to administration of any randomised trial medication. Least squares mean is adjusted mean change from baseline. Restricted maximum likelihood estimation based on mixed-effect model for repeated measures (MMRM) analysis was used to obtain adjusted means for the treatment effects. Full analysis set (FAS) (observed cases [OC]): Patients in the Treated Set (TS) who had a baseline and at least 1 on-treatment HbA1c measurement; the FAS was the basis for the primary efficacy analysis
    End point type
    Primary
    End point timeframe
    Baseline to week 26
    End point values
    		 Placebo matching Empagliflozin Empagliflozin 10 mg Empagliflozin 25 mg
    Number of subjects analysed
    239 [1]
    243 [2]
    241 [3]
    Units: Percentage (%)
        least squares mean (standard error)
    0.09 ± 0.04
    -0.44 ± 0.04
    -0.44 ± 0.04
    Notes
    [1] - Full analysis set (FAS) (observed cases [OC])
    [2] - Full analysis set (FAS) (observed cases [OC])
    [3] - Full analysis set (FAS) (observed cases [OC])
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Model Mixed effect Model Repeated Measures (MMRM) included the fixed categorical effects of treatment, pre-existing insulin therapy, visit , and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline HbA1c, baseline estimated glomerular filtration rate (eGFR), and baseline HbA1c-by- visit interaction. Patient was included as random effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Empagliflozin 10 mg v Placebo matching Empagliflozin
    Number of subjects included in analysis
    482
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.0001
    Method
    		 Mixed effect Model Repeated Measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.54
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -0.66
         upper limit
    		 -0.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [4] - Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Model MMRM included the fixed categorical effects of treatment, pre-existing insulin therapy, visit, and treatment-by- visit interaction, as well as the continuous, fixed covariates of baseline HbA1c, baseline eGFR, and baseline HbA1c-by- visit interaction. Patient was included as random effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 25 mg
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.53
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -0.66
         upper limit
    		 -0.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [5] - Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean

    Primary: Change from baseline in glycated haemoglobin (HbA1c) at Week 26 for modified intention-to-treat population set (mITT) (observed case (OC) – all data (AD) (OC-AD) )

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    End point title
    		 Change from baseline in glycated haemoglobin (HbA1c) at Week 26 for modified intention-to-treat population set (mITT) (observed case (OC) – all data (AD) (OC-AD) )
    End point description
    Change from baseline in glycated haemoglobin (HbA1c) for modified intention-to-treat population set (mITT) (observed case – all data [OC-AD]) is presented. With regards to efficacy and safety endpoints, the term ‘baseline’ referred to the last observed measurement prior to administration of any randomised trial medication. Least squares mean is adjusted mean change from baseline. Restricted maximum likelihood estimation based on mixed-effect model for repeated measures (MMRM) analysis was used to obtain adjusted means for the treatment effects. Modified intention-to-treat set (mITT) (observed case – all data [OC-AD]): Patients in the TS who had a baseline and at least 1 post-baseline HbA1c measurement.
    End point type
    Primary
    End point timeframe
    Baseline to week 26
    End point values
    		 Placebo matching Empagliflozin Empagliflozin 10 mg Empagliflozin 25 mg
    Number of subjects analysed
    241 [6]
    243 [7]
    243 [8]
    Units: Percentage (%)
        least squares mean (standard error)
    0.09 ± 0.04
    -0.43 ± 0.04
    -0.42 ± 0.04
    Notes
    [6] - mITT(OC-AD)
    [7] - mITT(OC-AD)
    [8] - mITT(OC-AD)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Model MMRM includes baseline HbA1c, baseline eGFR as linear covariates and baseline pre−existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 10 mg
    Number of subjects included in analysis
    484
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.53
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -0.65
         upper limit
    		 -0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [9] - Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Model MMRM includes baseline HbA1c, baseline eGFR as linear covariates and baseline pre−existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 25 mg
    Number of subjects included in analysis
    484
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.51
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -0.64
         upper limit
    		 -0.39
    Notes
    [10] - Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

    Secondary: Rate per patient-year of investigator-reported symptomatic hypoglycaemia adverse events (AEs) with confirmed plasma glucose (PG)

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    End point title
    		 Rate per patient-year of investigator-reported symptomatic hypoglycaemia adverse events (AEs) with confirmed plasma glucose (PG)
    End point description
    This is a key secondary endpoint. Rate per patient-year of investigator-reported symptomatic hypoglycaemia adverse events (AEs) with confirmed plasma glucose (PG) <54 milligram per deciliter (mg/dL) (<3.0 millimoles per litre (mmol/L)) and/or severe hypoglycaemia AEs (i.e. all investigator-reported AEs that had confirmed PG <54 mg/dL [<3.0 mmol/L] with symptoms reported and all severe hypoglycaemia events that were confirmed by adjudication) is presented for (i) From week 5 to 26 and (ii) From week 1 to 26. Least squares mean is actually an adjusted event rate.
    End point type
    Secondary
    End point timeframe
    Week 5 to Week 26, Week 1 to Week 26
    End point values
    		 Placebo matching Empagliflozin Empagliflozin 10 mg Empagliflozin 25 mg
    Number of subjects analysed
    243 [11]
    243 [12]
    244 [13]
    Units: Event Rate per patient year
    least squares mean (confidence interval 95%)
        Week 5 to 26| (N= 238; 243; 239)
    8.92 (7.15 to 11.14)
    6.64 (5.32 to 8.28)
    6.48 (5.18 to 8.12)
        Week 1 to 26| (N= 239; 243; 241)
    9.13 (7.36 to 11.34)
    7.07 (5.70 to 8.76)
    7.15 (5.75 to 8.88)
    Notes
    [11] - FAS (OC)
    [12] - FAS (OC)
    [13] - FAS (OC)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    For week 5 to 26, negative binomial model includes baseline rate of hypoglycaemia, baseline HbA1c, and baseline eGFR as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk [days]) was used as offset.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 10 mg
    Number of subjects included in analysis
    486
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.0623
    Method
    		 Negative binomial model
    Parameter type
    		 Adjusted Rate Ratio (%)
    Point estimate
    0.744
    Confidence interval
         level
    		 97.75%
         sides
    2-sided
         lower limit
    		 0.518
         upper limit
    		 1.069
    Notes
    [14] - Empagliflozin 10 milligram (mg) adjusted rate/Placebo matching Empagliflozin adjusted rate. The automatically calculated number of subjects included in analysis (486) does not reflect the actual number of subjects analyzed for week 5 to 26 that was used for this statistical analysis. The actual number of subjects analyzed is 481.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    For week 5 to 26, negative binomial model includes baseline rate of hypoglycaemia, baseline HbA1c, and baseline eGFR as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk [days]) was used as offset
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 25 mg
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.048
    Method
    		 Negative binomial model
    Parameter type
    		 Adjusted Rate Ratio (%)
    Point estimate
    0.726
    Confidence interval
         level
    		 97.75%
         sides
    2-sided
         lower limit
    		 0.502
         upper limit
    		 1.501
    Notes
    [15] - Empagliflozin 25 milligram (mg) adjusted rate/Placebo matching Empagliflozin adjusted rate. The automatically calculated number of subjects included in analysis (487) does not reflect the actual number of subjects analyzed for week 5 to 26 that was used for this statistical analysis. The actual number of subjects analyzed is 477.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    For week 1 to 26, negative binomial model includes baseline rate of hypoglycaemia, baseline HbA1c, and baseline eGFR as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk [days]) was used as offset.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 10 mg
    Number of subjects included in analysis
    486
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.0972 [17]
    Method
    		 Negative binomial model
    Parameter type
    		 Adjusted Rate Ratio (%)
    Point estimate
    0.774
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.572
         upper limit
    		 1.048
    Notes
    [16] - Empagliflozin 10 milligram (mg) adjusted rate/Placebo matching Empagliflozin adjusted rate. The automatically calculated number of subjects included in analysis (486) does not reflect the actual number of subjects analyzed for week 1 to 26 that was used for this statistical analysis. The actual number of subjects analyzed is 482.
    [17] - This is a nominal p-value.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    For week 1 to 26, negative binomial model includes baseline rate of hypoglycaemia, baseline HbA1c, and baseline eGFR as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk [days]) was used as offset.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 25 mg
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.118 [19]
    Method
    		 MMRM
    Parameter type
    		 Adjusted Rate Ratio (%)
    Point estimate
    0.782
    Confidence interval
         level
    		 97.75%
         sides
    2-sided
         lower limit
    		 0.575
         upper limit
    		 1.064
    Notes
    [18] - Empagliflozin 25 milligram (mg) adjusted rate/Placebo matching Empagliflozin adjusted rate. The automatically calculated number of subjects included in analysis (487) does not reflect the actual number of subjects analyzed for week 1 to 26 that was used for this statistical analysis. The actual number of subjects analyzed is 480.
    [19] - Negative binomial model

    Secondary: Change from baseline in body weight at Week 26

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    End point title
    		 Change from baseline in body weight at Week 26
    End point description
    Change from baseline in body weight is presented. With regards to efficacy and safety endpoints, the term ‘baseline’ referred to the last observed measurement prior to administration of any randomised trial medication. Least squares mean is adjusted mean change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to week 26
    End point values
    		 Placebo matching Empagliflozin Empagliflozin 10 mg Empagliflozin 25 mg
    Number of subjects analysed
    238 [20]
    243 [21]
    240 [22]
    Units: Kilogram (kg)
        least squares mean (standard error)
    -0.10 ± 0.21
    -2.79 ± 0.20
    -3.37 ± 0.20
    Notes
    [20] - FAS (OC)
    [21] - FAS (OC)
    [22] - FAS (OC)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Model MMRM includes baseline weight, baseline eGFR, baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, visit by treatment interaction, baseline weight by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 10 mg
    Number of subjects included in analysis
    481
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.69
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 -3.57
         upper limit
    		 -1.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.29
    Notes
    [23] - Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Model MMRM includes baseline weight, baseline eGFR, baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, visit by treatment interaction, baseline weight by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 25 mg
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.27
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 -4.15
         upper limit
    		 -2.39
    Notes
    [24] - Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

    Secondary: Change from baseline in percentage of time spent in target glucose range from Weeks 23 to 26

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    End point title
    		 Change from baseline in percentage of time spent in target glucose range from Weeks 23 to 26
    End point description
    Change from baseline in the percentage of time spent in target glucose range of >70 to ≤180 mg/dL (>3.9 to ≤10.0 mmol/L) as determined by continuous glucose monitoring (CGM) is presented in week 23 to 26. Least squares mean is actually an adjusted event rate. FAS observed cases excluding data after use of paracetamol (OC-P)
    End point type
    Secondary
    End point timeframe
    Week 23 to 26
    End point values
    		 Placebo matching Empagliflozin Empagliflozin 10 mg Empagliflozin 25 mg
    Number of subjects analysed
    179 [25]
    188 [26]
    192 [27]
    Units: Percentage
        least squares mean (standard error)
    -1.13 ± 0.72
    10.73 ± 0.71
    11.74 ± 0.70
    Notes
    [25] - FAS (OC-P)
    [26] - FAS (OC-P)
    [27] - FAS (OC-P)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The analysis of covariance (ANCOVA) model includes baseline time in the target range, baseline HbA1c, and baseline eGFR as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 10 mg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    11.86
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 8.78
         upper limit
    		 14.93
    Notes
    [28] - Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The analysis of covariance (ANCOVA) model includes baseline time in the target range, baseline HbA1c, and baseline eGFR as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 25 mg
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    12.87
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 9.81
         upper limit
    		 15.93
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.01
    Notes
    [29] - Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

    Secondary: Change from baseline in interstitial glucose variability based on the interquartile range (IQR) as determined by CGM in Weeks 23 to 26

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    End point title
    		 Change from baseline in interstitial glucose variability based on the interquartile range (IQR) as determined by CGM in Weeks 23 to 26
    End point description
    Change from baseline in interstitial glucose variability based on the IQR as determined by CGM is presented for week 23 to 26. Least squares mean is actually an adjusted event rate.
    End point type
    Secondary
    End point timeframe
    Week 23 to 26
    End point values
    		 Placebo matching Empagliflozin Empagliflozin 10 mg Empagliflozin 25 mg
    Number of subjects analysed
    179 [30]
    188 [31]
    192 [32]
    Units: milligrams (mg)/ deciliter (dL)
        least squares mean (standard error)
    1.62 ± 1.21
    -15.30 ± 1.18
    -17.41 ± 1.16
    Notes
    [30] - FAS (OC-P)
    [31] - FAS (OC-P)
    [32] - FAS (OC-P)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The analysis of covariance (ANCOVA) model includes model includes baseline IQR of glucose, baseline HbA1c, and baseline eGFR as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 10 mg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -16.92
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 -22.04
         upper limit
    		 -11.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.68
    Notes
    [33] - Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The analysis of covariance (ANCOVA) model includes model includes baseline IQR of glucose, baseline HbA1c, and baseline eGFR as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 25 mg
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [34]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -19.04
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 -24.13
         upper limit
    		 -13.95
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.68
    Notes
    [34] - Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

    Secondary: Change from baseline in total daily insulin dose (TDID) at Week 26

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    End point title
    		 Change from baseline in total daily insulin dose (TDID) at Week 26
    End point description
    Change from baseline in TDID is presented. With regards to efficacy and safety endpoints, the term ‘baseline’ referred to the last observed measurement prior to administration of any randomised trial medication. Least squares mean is adjusted mean change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to week 26
    End point values
    		 Placebo matching Empagliflozin Empagliflozin 10 mg Empagliflozin 25 mg
    Number of subjects analysed
    223 [35]
    227 [36]
    226 [37]
    Units: Unit/kilogram (U/kg)
        least squares mean (standard error)
    -0.010 ± 0.007
    -0.102 ± 0.007
    -0.100 ± 0.007
    Notes
    [35] - FAS (OC)
    [36] - FAS (OC)
    [37] - FAS (OC)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Model MMRM includes baseline total daily insulin dose, baseline estimated eGFR, baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, visit by treatment interaction, baseline total daily insulin dose by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 10 mg
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [38]
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.092
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 -0.121
         upper limit
    		 -0.063
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.009
    Notes
    [38] - Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Model MMRM includes baseline total daily insulin dose, baseline estimated eGFR, baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, visit by treatment interaction, baseline total daily insulin dose by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 25 mg
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.09
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 -0.119
         upper limit
    		 -0.062
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.009
    Notes
    [39] - Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean.

    Secondary: Change from baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Week 26

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    End point title
    		 Change from baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Week 26
    End point description
    Change from baseline in SBP and DBP is presented. With regards to efficacy and safety endpoints, the term ‘baseline’ referred to the last observed measurement prior to administration of any randomised trial medication. Least squares mean is adjusted mean change from baseline. FAS observed cases excluding data after change in use of anti-hypertensives (OC-H)
    End point type
    Secondary
    End point timeframe
    Baseline to week 26
    End point values
    		 Placebo matching Empagliflozin Empagliflozin 10 mg Empagliflozin 25 mg
    Number of subjects analysed
    243 [40]
    243 [41]
    244 [42]
    Units: Millimeters of mercury (mmHg)
    least squares mean (standard error)
        SBP (N= 238; 243; 238)
    -0.8 ± 0.7
    -2.9 ± 0.7
    -4.5 ± 0.7
        DBP (N= 239; 243; 241)
    -0.3 ± 0.5
    -1.6 ± 0.5
    -2.6 ± 0.5
    Notes
    [40] - FAS (OC-H)
    [41] - FAS (OC-H)
    [42] - FAS (OC-H)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    For SBP, the model MMRM includes baseline SBP seated, baseline estimated eGFR, baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, treatment by visit interaction, baseline SBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 10 mg
    Number of subjects included in analysis
    486
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [43]
    P-value
    		 = 0.0397
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.1
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 -5.2
         upper limit
    		 1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1
    Notes
    [43] - Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean. The automatically calculated number of subjects included in analysis (486) does not reflect the actual number of subjects analyzed for SBP that was used for this statistical analysis. The actual number of subjects analyzed is 481.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    For SBP, the model includes baseline SBP seated, baseline estimated eGFR, baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, treatment by visit interaction, baseline SBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 25 mg
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [44]
    P-value
    		 = 0.0003
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.7
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 -6.8
         upper limit
    		 -0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    1
    Notes
    [44] - Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean. The automatically calculated number of subjects included in analysis (487) does not reflect the actual number of subjects analyzed for SBP that was used for this statistical analysis. The actual number of subjects analyzed is 476.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    For DBP, the model MMRM includes baseline DBP seated, baseline eGFR baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, treatment by visit interaction, baseline DBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 10 mg
    Number of subjects included in analysis
    486
    Analysis specification
    Pre-specified
    Analysis type
    		 [45]
    P-value
    		 = 0.0457 [46]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.3
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.7
    Notes
    [45] - Mean Difference= Empagliflozin 10 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean. The automatically calculated number of subjects included in analysis (486) does not reflect the actual number of subjects analyzed for DBP that was used for this statistical analysis. The actual number of subjects analyzed is 482.
    [46] - Nominal p-value
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    For DBP, the model MMRM includes baseline DBP seated, baseline estimated eGFR, baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, treatment by visit interaction, baseline DBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 25 mg
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    		 [47]
    P-value
    		 = 0.0006
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.3
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 -4.3
         upper limit
    		 -0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.7
    Notes
    [47] - Mean Difference= Empagliflozin 25 milligram (mg) adjusted mean - Placebo matching Empagliflozin adjusted mean. The automatically calculated number of subjects included in analysis (487) does not reflect the actual number of subjects analyzed for DBP that was used for this statistical analysis. The actual number of subjects analyzed is 480.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of trial medication until 7 days after last in-take of trial medication, up to 422 days
    Adverse event reporting additional description
    Treated set (TS): all patients who were treated with at least one dose of randomised trial medication; the TS was the basis for safety analyses. The total number of participants at risk is based on treated set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo matching Empagliflozin
    Reporting group description
    		 Patients administered placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimised insulin therapy for 52 weeks.

    Reporting group title
    Empagliflozin 25 mg
    Reporting group description
    		 Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimised insulin therapy for 52 weeks.

    Reporting group title
    Empagliflozin 10 mg
    Reporting group description
    		 Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimised insulin therapy for 52 weeks.

    Serious adverse events
    		 Placebo matching Empagliflozin Empagliflozin 25 mg Empagliflozin 10 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 243 (11.52%)
    26 / 244 (10.66%)
    43 / 243 (17.70%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign breast neoplasm
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Acquired phimosis
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Menstrual disorder
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric decompensation
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Bacterial test positive
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood ketone body increased
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium test positive
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Carbon monoxide poisoning
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shunt malfunction
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dystonia
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic coma
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lacunar stroke
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radicular syndrome
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sensory disturbance
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 243 (0.00%)
    2 / 244 (0.82%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Macular fibrosis
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Normal tension glaucoma
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermal cyst
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 243 (0.41%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleurisy viral
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 243 (0.00%)
    2 / 244 (0.82%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tinea versicolour
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    4 / 243 (1.65%)
    8 / 244 (3.28%)
    12 / 243 (4.94%)
         occurrences causally related to treatment / all
    1 / 6
    8 / 9
    8 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 243 (0.82%)
    1 / 244 (0.41%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    6 / 243 (2.47%)
    3 / 244 (1.23%)
    9 / 243 (3.70%)
         occurrences causally related to treatment / all
    3 / 9
    1 / 3
    9 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ketoacidosis
         subjects affected / exposed
    2 / 243 (0.82%)
    2 / 244 (0.82%)
    4 / 243 (1.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ketosis
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo matching Empagliflozin Empagliflozin 25 mg Empagliflozin 10 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    197 / 243 (81.07%)
    195 / 244 (79.92%)
    197 / 243 (81.07%)
    Investigations
    Blood ketone body increased
         subjects affected / exposed
    10 / 243 (4.12%)
    20 / 244 (8.20%)
    18 / 243 (7.41%)
         occurrences all number
    17
    52
    21
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 243 (3.70%)
    8 / 244 (3.28%)
    13 / 243 (5.35%)
         occurrences all number
    9
    10
    14
    Nausea
         subjects affected / exposed
    14 / 243 (5.76%)
    14 / 244 (5.74%)
    12 / 243 (4.94%)
         occurrences all number
    15
    15
    13
    Vomiting
         subjects affected / exposed
    12 / 243 (4.94%)
    12 / 244 (4.92%)
    19 / 243 (7.82%)
         occurrences all number
    14
    13
    20
    Infections and infestations
    Influenza
         subjects affected / exposed
    11 / 243 (4.53%)
    12 / 244 (4.92%)
    20 / 243 (8.23%)
         occurrences all number
    13
    14
    22
    Nasopharyngitis
         subjects affected / exposed
    41 / 243 (16.87%)
    43 / 244 (17.62%)
    52 / 243 (21.40%)
         occurrences all number
    60
    57
    68
    Sinusitis
         subjects affected / exposed
    13 / 243 (5.35%)
    9 / 244 (3.69%)
    14 / 243 (5.76%)
         occurrences all number
    14
    10
    15
    Upper respiratory tract infection
         subjects affected / exposed
    25 / 243 (10.29%)
    27 / 244 (11.07%)
    15 / 243 (6.17%)
         occurrences all number
    32
    28
    19
    Urinary tract infection
         subjects affected / exposed
    29 / 243 (11.93%)
    20 / 244 (8.20%)
    37 / 243 (15.23%)
         occurrences all number
    49
    26
    46
    Vulvovaginal mycotic infection
         subjects affected / exposed
    2 / 243 (0.82%)
    14 / 244 (5.74%)
    9 / 243 (3.70%)
         occurrences all number
    4
    30
    11
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    152 / 243 (62.55%)
    147 / 244 (60.25%)
    154 / 243 (63.37%)
         occurrences all number
    3186
    2773
    2656

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Apr 2016
    Amendment 1 was implemented when 385 patients (about half of all randomised) had been randomised. The main effect of this amendment was to clarify the eligibility criteria, which were made consistent with the other pivotal trial 1245.72. The amendment also introduced additional blood ketone measurements for improved safety monitoring. Insulin titration was clarified and optimised: in the original clinical trial protocol (CTP) investigators were advised to reduce the total insulin dose by 10% regardless of HbA1c values. The amendment maintained this advice for patients with glycated haemoglobin (HbA1c) of 7.5 to <8%, and advised investigators to adjust the total insulin dose based on need for patients with HbA1c of ≥8%. Furthermore, the amendment introduced more details on the hierarchical testing procedure, based on regulatory feedback. The inclusion and exclusion criteria were modified for the purpose of safety, clarification, and for alignment with the trial 1245.72.
    04 Jan 2017
    Amendment 2 was implemented when all patients had been randomised. The main effect of this amendment was to introduce 2 continuous glucose monitoring (CGM)-related endpoints as key secondary endpoints, given that sodium-glucose co-transporter (SGLT-2)inhibitor treatment in T1DM may improve the burden of glycaemic variability, which remains a fundamental treatment challenge in the management of this disease. Accordingly, the hierarchical testing procedure was revised to accommodate the added confirmatory endpoints based on CGM. Events involving lower-limb amputation were added as an adverse event of special interest (AESI) to meet new regulatory requirements. The inclusion criteria were modified with regard to the definition of women of child-bearing potential. In addition, the removal of patients from the trial was modified with regard to concomitant medications.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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