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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, parallel groups study to investigate the safety and tolerability, efficacy, pharmacokinetics and pharmacodynamics of three BI 187004 doses given once daily as mono-therapy and of the highest BI 187004 dose given once daily as add on treatment to metformin over 28 days in patients with type 2 diabetes mellitus

    Summary
    EudraCT number
    		 2013-003646-16
    Trial protocol
    		 DE  
    Global end of trial date
    02 Aug 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Aug 2016
    First version publication date
    13 Aug 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1307.4
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02150824
    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 , +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
    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
    10 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jul 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the current study is to investigate the safety and tolerability of a once daily oral dose of 20 mg, 80 mg or 240 mg BI 187004 as mono-therapy and 240 mg BI 187004 on a stable metformin background over 28 days in patients with type 2 diabetes mellitus.
    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. Rescue medication was allowed for all patients as required.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Jul 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 103
    Worldwide total number of subjects
    103
    EEA total number of subjects
    103
    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)
    72
    From 65 to 84 years
    31
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This was a randomised,double-blind,placebo-controlled study with parallel groups to investigate the safety, tolerability, efficacy, pharmacokinetics&pharmacodynamics of BI 187004 administered as once daily oral dose of 20mg,80mg or 240mg monotherapy,or as 240mg add-on to a metformin background,over 28 days in patients with type 2 diabetes mellitus.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility to participate in trial. Subjects attended specialist sites to ensure that they (the subjects) met all implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial drug if any of the specific entry criteria was violated. In this study,216 enrolled &103 entered & treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 The patients untreated (therapy-naïve patients or patients with no antidiabetic treatment within 4 weeks prior to giving informed consent) or previously treated with 1 oral antidiabetic drug (OAD) (underwent a 28-day wash-out period) and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered placebo tablet(s) once daily over 28 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subject were orally administered placebo tablet(s) once daily over 28 days.

    Arm title
    		 20 mg BI 187004
    Arm description
    		 The patients untreated (therapy-naïve patients or patients with no antidiabetic treatment within 4 weeks prior to giving informed consent) or previously treated with 1 OAD (underwent a 28-day wash-out period) and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered 20 mg BI 187004 tablet once daily over 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 187004 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered 20 mg BI 187004 tablet once daily over 28 days.

    Arm title
    		 80 mg BI 187004
    Arm description
    		 The patients untreated (therapy-naïve patients or patients with no antidiabetic treatment within 4 weeks prior to giving informed consent) or previously treated with 1 OAD (underwent a 28-day wash-out period) and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered 80 mg BI 187004 tablet once daily over 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 187004 80mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered 80 mg BI 187004 tablet once daily over 28 days.

    Arm title
    		 240 mg BI 187004
    Arm description
    		 The patients untreated (therapy-naïve patients or patients with no antidiabetic treatment within 4 weeks prior to giving informed consent) or previously treated with 1 OAD (underwent a 28-day wash-out period) and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered 240 mg BI 187004 once daily over 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 187004 240mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered 240 mg BI 187004 once daily over 28 days.

    Arm title
    		 Placebo + met
    Arm description
    		 The patients on a stable background monotherapy treatment with metformin for at least 12 weeks prior to the study and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered placebo tablets once daily over 28 days with metformin as background therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The patients were orally administered placebo tablets once daily over 28 days.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The patients were orally administered Metformin as a background therapy once daily over 28 days.

    Arm title
    		 240 mg BI 187004 + met
    Arm description
    		 The patients on a stable background monotherapy treatment with metformin for at least 12 weeks prior to the study and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered 240 mg BI 187004 once daily over 28 days with metformin as background therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    240 mg BI 187004
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The patients on a stable background monotherapy treatment with metformin and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered 240 mg BI 187004 once daily over 28 days.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The patients were orally administered Metformin as a background therapy once daily over 28 days.

    Number of subjects in period 1
    		Placebo 20 mg BI 187004 80 mg BI 187004 240 mg BI 187004 Placebo + met 240 mg BI 187004 + met
    Started
    15
    16
    16
    15
    21
    20
    Completed
    15
    16
    16
    15
    21
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 The patients untreated (therapy-naïve patients or patients with no antidiabetic treatment within 4 weeks prior to giving informed consent) or previously treated with 1 oral antidiabetic drug (OAD) (underwent a 28-day wash-out period) and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered placebo tablet(s) once daily over 28 days.

    Reporting group title
    20 mg BI 187004
    Reporting group description
    		 The patients untreated (therapy-naïve patients or patients with no antidiabetic treatment within 4 weeks prior to giving informed consent) or previously treated with 1 OAD (underwent a 28-day wash-out period) and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered 20 mg BI 187004 tablet once daily over 28 days.

    Reporting group title
    80 mg BI 187004
    Reporting group description
    		 The patients untreated (therapy-naïve patients or patients with no antidiabetic treatment within 4 weeks prior to giving informed consent) or previously treated with 1 OAD (underwent a 28-day wash-out period) and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered 80 mg BI 187004 tablet once daily over 28 days.

    Reporting group title
    240 mg BI 187004
    Reporting group description
    		 The patients untreated (therapy-naïve patients or patients with no antidiabetic treatment within 4 weeks prior to giving informed consent) or previously treated with 1 OAD (underwent a 28-day wash-out period) and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered 240 mg BI 187004 once daily over 28 days.

    Reporting group title
    Placebo + met
    Reporting group description
    		 The patients on a stable background monotherapy treatment with metformin for at least 12 weeks prior to the study and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered placebo tablets once daily over 28 days with metformin as background therapy.

    Reporting group title
    240 mg BI 187004 + met
    Reporting group description
    		 The patients on a stable background monotherapy treatment with metformin for at least 12 weeks prior to the study and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered 240 mg BI 187004 once daily over 28 days with metformin as background therapy.

    Reporting group values
    		 Placebo 20 mg BI 187004 80 mg BI 187004 240 mg BI 187004 Placebo + met 240 mg BI 187004 + met Total
    Number of subjects
    		 15 16 16 15 21 20 103
    Age categorical
    Units: Subjects
    Age continuous
    Treated Set(TS): The patients who were treated with ≥1 dose of study medication were all included in the Treated Set.
    Units: years
        arithmetic mean (standard deviation)
    		 57.6 ( 7.3 ) 58.6 ( 11.6 ) 59.4 ( 8.6 ) 55.7 ( 7.8 ) 57.2 ( 9.8 ) 62.1 ( 7.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 3 5 3 5 2 22
        Male
    		 11 13 11 12 16 18 81

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 The patients untreated (therapy-naïve patients or patients with no antidiabetic treatment within 4 weeks prior to giving informed consent) or previously treated with 1 oral antidiabetic drug (OAD) (underwent a 28-day wash-out period) and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered placebo tablet(s) once daily over 28 days.

    Reporting group title
    20 mg BI 187004
    Reporting group description
    		 The patients untreated (therapy-naïve patients or patients with no antidiabetic treatment within 4 weeks prior to giving informed consent) or previously treated with 1 OAD (underwent a 28-day wash-out period) and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered 20 mg BI 187004 tablet once daily over 28 days.

    Reporting group title
    80 mg BI 187004
    Reporting group description
    		 The patients untreated (therapy-naïve patients or patients with no antidiabetic treatment within 4 weeks prior to giving informed consent) or previously treated with 1 OAD (underwent a 28-day wash-out period) and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered 80 mg BI 187004 tablet once daily over 28 days.

    Reporting group title
    240 mg BI 187004
    Reporting group description
    		 The patients untreated (therapy-naïve patients or patients with no antidiabetic treatment within 4 weeks prior to giving informed consent) or previously treated with 1 OAD (underwent a 28-day wash-out period) and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered 240 mg BI 187004 once daily over 28 days.

    Reporting group title
    Placebo + met
    Reporting group description
    		 The patients on a stable background monotherapy treatment with metformin for at least 12 weeks prior to the study and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered placebo tablets once daily over 28 days with metformin as background therapy.

    Reporting group title
    240 mg BI 187004 + met
    Reporting group description
    		 The patients on a stable background monotherapy treatment with metformin for at least 12 weeks prior to the study and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered 240 mg BI 187004 once daily over 28 days with metformin as background therapy.

    Primary: The percentage of patients with drug-related AEs

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    End point title
    		 The percentage of patients with drug-related AEs [1]
    End point description
    The percentage of patients with drug-related AEs.
    End point type
    Primary
    End point timeframe
    from first drug administration until 14 days after the last drug administration, up to 42 days.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis test were tested.
    End point values
    		 Placebo 20 mg BI 187004 80 mg BI 187004 240 mg BI 187004 Placebo + met 240 mg BI 187004 + met
    Number of subjects analysed
    15 [2]
    16 [3]
    16 [4]
    15 [5]
    21 [6]
    20 [7]
    Units: Percentage of participants
        number (not applicable)
    33.3
    0
    31.3
    26.7
    19
    30
    Notes
    [2] - Treated Set
    [3] - Treated Set
    [4] - Treated Set
    [5] - Treated Set
    [6] - Treated Set
    [7] - Treated Set
    No statistical analyses for this end point

    Secondary: Change from baseline in FPG after 28 days of treatment

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    End point title
    		 Change from baseline in FPG after 28 days of treatment
    End point description
    Change from baseline in fasting plasma glucose (FPG) after 28 days of treatment.The ANCOVA model was used to calculate the least squares mean and standard error. Observed case analysis for FPG (OC-G): This method was used to impute the missing values. The number of participants analysed displays the number of participants with available data at the timepoint of interest.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 29
    End point values
    		 Placebo 20 mg BI 187004 80 mg BI 187004 240 mg BI 187004 Placebo + met 240 mg BI 187004 + met
    Number of subjects analysed
    15 [8]
    16 [9]
    16 [10]
    14 [11]
    21 [12]
    20 [13]
    Units: mg/dL
        least squares mean (standard error)
    0.9 ( 5.2 )
    6.6 ( 5 )
    8 ( 5 )
    6.8 ( 5.4 )
    4.5 ( 4.4 )
    6.1 ( 4.5 )
    Notes
    [8] - TS (OC-G)
    [9] - TS (OC-G)
    [10] - TS (OC-G)
    [11] - TS (OC-G)
    [12] - TS (OC-G)
    [13] - TS (OC-G)
    Statistical analysis title
    		 All groups
    Statistical analysis description
    The statistical model used for the analysis of change from baseline (Day 1 of Visit 3) in FPG after 28 days of treatment was an Analysis of Covariance (ANCOVA) model. In model, the treatment was considered as a categorical effect, baseline FPG was included as a continuous covariate. Missing FPG values after 28 days of treatment were not replaced, whereas values after the potential introduction of another antidiabetic drug were not included in the primary analysis.
    Comparison groups
    Placebo v 20 mg BI 187004 v 80 mg BI 187004 v 240 mg BI 187004 v Placebo + met v 240 mg BI 187004 + met
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9414
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from first drug administration until 14 days after the last drug administration, upto 42 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 The patients untreated (therapy-naïve patients or patients with no antidiabetic treatment within 4 weeks prior to giving informed consent) or previously treated with 1 OAD (underwent a 28-day wash-out period) and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered placebo tablet(s) once daily over 28 days.

    Reporting group title
    20 mg BI 187004
    Reporting group description
    		 The patients untreated (therapy-naïve patients or patients with no antidiabetic treatment within 4 weeks prior to giving informed consent) or previously treated with 1 OAD (underwent a 28-day wash-out period) and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered 20 mg BI 187004 tablet once daily over 28 days.

    Reporting group title
    80 mg BI 187004
    Reporting group description
    		 The patients untreated (therapy-naïve patients or patients with no antidiabetic treatment within 4 weeks prior to giving informed consent) or previously treated with 1 OAD (underwent a 28-day wash-out period) and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered 80 mg BI 187004 tablet once daily over 28 days.

    Reporting group title
    240 mg BI 187004
    Reporting group description
    		 The patients untreated (therapy-naïve patients or patients with no antidiabetic treatment within 4 weeks prior to giving informed consent) or previously treated with 1 OAD (underwent a 28-day wash-out period) and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered 240 mg BI 187004 once daily over 28 days.

    Reporting group title
    Placebo + met
    Reporting group description
    		 The patients on a stable background monotherapy treatment with metformin for at least 12 weeks prior to the study and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered placebo tablets once daily over 28 days with metformin as background therapy.

    Reporting group title
    240 mg BI 187004 + met
    Reporting group description
    		 The patients on a stable background monotherapy treatment with metformin for at least 12 weeks prior to the study and who successfully completed the placebo run-in period of 2 weeks were randomised and orally administered 240 mg BI 187004 once daily over 28 days with metformin as background therapy.

    Serious adverse events
    		 Placebo 20 mg BI 187004 80 mg BI 187004 240 mg BI 187004 Placebo + met 240 mg BI 187004 + met
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo 20 mg BI 187004 80 mg BI 187004 240 mg BI 187004 Placebo + met 240 mg BI 187004 + met
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 15 (86.67%)
    14 / 16 (87.50%)
    15 / 16 (93.75%)
    15 / 15 (100.00%)
    18 / 21 (85.71%)
    18 / 20 (90.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    10 / 15 (66.67%)
    14 / 16 (87.50%)
    12 / 16 (75.00%)
    14 / 15 (93.33%)
    17 / 21 (80.95%)
    14 / 20 (70.00%)
         occurrences all number
    10
    14
    12
    14
    17
    14
    Orthostatic hypotension
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    2 / 21 (9.52%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    2
    0
    3
    3
    Peripheral coldness
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Chills
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Feeling abnormal
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Psychiatric disorders
    Listless
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Mood swings
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Dysgeusia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    6 / 16 (37.50%)
    2 / 15 (13.33%)
    0 / 21 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    1
    0
    8
    2
    0
    3
    Hypogeusia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    Epigastric discomfort
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Toothache
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Eczema
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Rash generalised
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Nocturia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Back pain
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 16 (0.00%)
    2 / 16 (12.50%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Infections and infestations
    Adenoviral conjunctivitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    3 / 21 (14.29%)
    3 / 20 (15.00%)
         occurrences all number
    1
    1
    0
    1
    3
    3
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Polydipsia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jun 2014
    A new statement has been added to clarify on the meaning of the original sentence and make sure it is clear that all statins are allowed as co-medications regardless of their inhibition on the CYP3A4. As proposed and agreed with regulatory bodies, the blood glucose threshold for the initiation of rescue therapy has been lowered. Thus all instances of 270 mg/dL were replaced with 240 mg/dl. The text “(with the exception of GLP-1 receptor agonist)” was added to clarify GLP-1 analogues, though injectable antidiabetics, are allowed rescue medications. As proposed and agreed with Central EC , a process has been added to verify if it is medically acceptable for a patient to continue its participation when more repeated values greater than 140 mg/dL are detected. The clear guidance on where to find detailed instructions on how to handle the urine samples for pharmacodynamic assessments and on how to collect the weight of the containers was added.
    05 Sep 2014
    Flow chart &all other relevant sections of protocol were updated,In order to provide reliable results, prior to testing cortisol,ACTH &other pituitary axis hormones,resting time of approximately 30 minutes (min) was implemented &In order to accommodate the resting time,60 min window has been introduced & also time interval for the test was increase. An exclusion criterion has been updated based on a publication referenced in protocol.The conversion from mg/dl to mmol/L for blood glucose levels has been changed from 15.0 to 13,3. The μg/l values for cortisol & pg/ml values for Adrenocorticotrophin hormone(ACTH) were removed.The plasma cortisol cut-off point has been updated from 595 nmol/L to 377 nmol/L. A clarification on how to handle the 3 supine measurements &how to perform the comparison to individual standing measurements was updated.
    01 Apr 2015
    Change in sample size was updated. In Sampling flow chart the typographical error was corrected and updated that the Day 28 3:00 am sample for WMG is meant to be at a specific point in time and not relative to the study drug intake. In order to minimized or prevented any bias during the interim analysis as certain functions within Boehringer Ingelheim will be required to be unblinded. It was updated that though certain patient will be unblinded, the unblinded information will not be shared or disclosed with team members that have a significant influence in the conduct of the study. Therefore, any bias will be minimized or prevented. The scope and purpose of the interim analysis was updated. The clarification was provided to emphasize that symptom compatible with low blood pressure or sudden changes in blood pressure are enough to declare the orthostatic test as abnormal. The definition of Postural Orthostatic Tachycardia Syndrome was updated.

    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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