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    Clinical Trial Results:
    Doubleblind, randomised, placebo-controlled clinical trial to evaluate the safety and efficacy of Gerolsteiner Heilwasser in NERD patients with heartburn

    Summary
    EudraCT number
    		 2016-000994-19
    Trial protocol
    		 DE  
    Global end of trial date
    07 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jun 2021
    First version publication date
    25 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GER/026115
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gerolsteiner Brunnen GmbH & Co. KG
    Sponsor organisation address
    Vulkanring, Gerolstein, Germany, 54567
    Public contact
    Dr. Thomas Hens, Gerolsteiner Brunnen GmbH & Co. KG, +49 659114423, drthomas.hens@gerolsteiner.com
    Scientific contact
    Dr. Thomas Hens, Gerolsteiner Brunnen GmbH & Co. KG, +49 659114423, drthomas.hens@gerolsteiner.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 Jul 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Investigation of the efficacy and tolerability of Gerolsteiner Heilwasser in NERD-patients with heartburn. Efficacy parameters: -Changes for dimension 'heartburn', 'GERD', 'regurgitation' and 'dyspepsia' of questionnaire RDQ -Changes in number of days with heartburn-episodes per week according to patient diary -Changes in HSI -Intake of rescue medication during treatment -Changes in QOLRAD scores -Changes in GLQI scores -Changes in subjective perception of well-being (SF-12 questionnaire) -"Overall Treatment Evaluation" (OTE) by patient and investigator Tolerability parameters: -Adverse events -Difference in blood pressure / pulse -Differences in safety laboratory parameters -Global assessment of tolerability by patient and investigator
    Protection of trial subjects
    The investigators ensured that the subjects were given full and adequate oral and written information (subject information) about the nature, purpose, consequences and possible risk of the clinical study. The subjects were given the opportunity to ask questions and were allowed sufficient time to consider the information provided. Subjects provided informed consent before the conduct of any study specific procedure. The collected data were made available to the CRO and the study’s sponsor only in pseudonymous form to minimize the chances of matching the data to an individual person. Rescue medication was provided to subjects with instructions in case they experience intolerable NERD discomfort.
    Background therapy
    		 Rescue medication in case of intolerable NERD discomfort: Maaloxan (Magnesium hydroxide and Aluminium hydroxide) 25 mVal; at heartburn with intensity "moderate to strong" (in patient diary); max. 2 times per day, max. 7 times per week; to be documented for efficacy analysis
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Sep 2016
    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: 80
    Worldwide total number of subjects
    80
    EEA total number of subjects
    80
    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)
    73
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment details: Recruitment period: September 2016 - September 2018 Subjects were recruited at four sites in Berlin, Germany.

    Pre-assignment
    Screening details
    		 88 patients were screened; 2 patients didn't meet in-/exclusion criteria; 3 patients withdrew their consent; 2 patients didn't meet randomisation criteria; 1 patient required enhanced medical treatment for heartburn

    Period 1
    Period 1 title
    Intervention (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject
    Blinding implementation details
    The randomisation list was prepared by an independent statistician using a random number generator. Numbers were allocated 1:1 to both treatment groups (placebo/verum). The list was available to the person responsible for labelling and packaging as well as to sponsor's representative who wasn't part of the study team. The CRO was provided with the list only after database closure.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Verum
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gerolsteiner Heilwasser
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    1,5 l of Gerolsteiner Heilwasser (at room temperature) per day: 3 times a day 300 ml before or with a meal; the remaining volume should be consumed over the day.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo water
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    1,5 l of Placebo water (at room temperature) per day: 3 times a day 300 ml before or with a meal; the remaining volume should be consumed over the day.

    Number of subjects in period 1
    		Verum Placebo
    Started
    40
    40
    Completed
    38
    38
    Not completed
    2
    2
         Consent withdrawn by subject
    -
    1
         no delivery of IMP to patient
    1
    -
         Adverse event, non-fatal
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Verum
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Verum Placebo Total
    Number of subjects
    		 40 40 80
    Age categorical
    Inclusion criteria (Protocol version 1.1, 27 June 2016): age 18-64 Inclusion criteria (Protocol version 2.0, 29 September 2017): age 18-85; changed due to recruitment difficulties
    Units: Subjects
        <30 years
    		 2 5 7
        30 - <40 years
    		 8 4 12
        40 - <50 years
    		 12 9 21
        50 - <60 years
    		 11 15 26
        60 - <70 years
    		 6 6 12
        70 - <80 years
    		 0 1 1
        Not recorded
    		 1 0 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.3 ( 12.3 ) 48.5 ( 13.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 25 30 55
        Male
    		 14 10 24
        Not recorded
    		 1 0 1
    Race
    Units: Subjects
        Caucasian
    		 37 39 76
        Asian
    		 1 1 2
        Other
    		 1 0 1
        Not recorded
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Verum
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: RDQ heartburn

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    End point title
    		 RDQ heartburn
    End point description
    End point type
    Primary
    End point timeframe
    V2 v. V4
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    39
    Units: Score
    arithmetic mean (standard deviation)
        V2
    2.1 ( 1.44 )
    1.71 ( 1.14 )
        V4
    1.13 ( 1.4 )
    0.69 ( 0.84 )
    Statistical analysis title
    		 Pre/post changes
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.8338
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - Explorative

    Primary: RDQ GERD

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    End point title
    		 RDQ GERD
    End point description
    End point type
    Primary
    End point timeframe
    V2 v. V4
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    39
    Units: Score
    arithmetic mean (standard deviation)
        V2
    2.38 ( 1.14 )
    2.03 ( 0.9 )
        V4
    1.09 ( 1.09 )
    0.85 ( 0.8 )
    Statistical analysis title
    		 Pre/post changes
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.6829
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [2] - Explorative

    Primary: RDQ regurgitation

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    End point title
    		 RDQ regurgitation
    End point description
    End point type
    Primary
    End point timeframe
    V2 v. V4
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    39
    Units: Score
    arithmetic mean (standard deviation)
        V2
    2.67 ( 1.29 )
    2.35 ( 1.01 )
        V4
    1.04 ( 1.10 )
    0.93 ( 0.98 )
    Statistical analysis title
    		 Pre/post changes
    Comparison groups
    Placebo v Verum
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.6357
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [3] - Explorative

    Primary: RDQ dyspepsia

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    End point title
    		 RDQ dyspepsia
    End point description
    End point type
    Primary
    End point timeframe
    V2 v. V4
    End point values
    		 Verum Placebo
    Number of subjects analysed
    37
    39
    Units: Score
    arithmetic mean (standard deviation)
        V2
    2.14 ( 1.39 )
    1.86 ( 1.23 )
        V4
    1.01 ( 1.28 )
    0.85 ( 0.93 )
    Statistical analysis title
    		 Pre/post changes
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.6703
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - Explorative

    Primary: Number of days with heartburn

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    End point title
    		 Number of days with heartburn
    End point description
    Last 7 days before visit date
    End point type
    Primary
    End point timeframe
    V2 v. V4
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    39
    Units: Days
    arithmetic mean (standard deviation)
        V2
    5.7 ( 1.4 )
    5.3 ( 1.4 )
        V4
    3.3 ( 2.5 )
    2.7 ( 2.2 )
    Statistical analysis title
    		 Pre/post changes
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.5138
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [5] - Explorative

    Primary: Heartburn Severity Index

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    End point title
    		 Heartburn Severity Index
    End point description
    End point type
    Primary
    End point timeframe
    V2 v. V4
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    39
    Units: Score
    arithmetic mean (standard deviation)
        V2
    47.3 ( 51.4 )
    25.3 ( 20.3 )
        V4
    13.9 ( 17.6 )
    9.6 ( 11.6 )
    Statistical analysis title
    		 Pre/post changes
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.0184
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [6] - Explorative

    Primary: Rescue medication days per week

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    End point title
    		 Rescue medication days per week
    End point description
    End point type
    Primary
    End point timeframe
    V2 v. V4
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    39
    Units: Days
    arithmetic mean (standard deviation)
        V2
    1.6 ( 1.7 )
    1.7 ( 2.0 )
        V4
    0.5 ( 1.0 )
    0.5 ( 1.1 )
    Statistical analysis title
    		 Pre/post changes
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.9493
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [7] - Explorative

    Primary: QOLRAD emotional stress

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    End point title
    		 QOLRAD emotional stress
    End point description
    End point type
    Primary
    End point timeframe
    V2 v. V4
    End point values
    		 Verum Placebo
    Number of subjects analysed
    38
    39
    Units: Score
    arithmetic mean (standard deviation)
        V2
    28.58 ( 9.96 )
    30.95 ( 8.77 )
        V4
    36.76 ( 7.73 )
    37.03 ( 7.10 )
    Statistical analysis title
    		 Pre/post changes
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.2006
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [8] - Explorative

    Primary: QOLRAD sleep disturbance

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    End point title
    		 QOLRAD sleep disturbance
    End point description
    End point type
    Primary
    End point timeframe
    V2 v. V4
    End point values
    		 Verum Placebo
    Number of subjects analysed
    38
    39
    Units: Score
    arithmetic mean (standard deviation)
        V2
    24.18 ( 7.81 )
    26.46 ( 6.74 )
        V4
    31.11 ( 5.76 )
    31.85 ( 4.37 )
    Statistical analysis title
    		 Pre/post changes
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.4831
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [9] - Explorative

    Primary: QOLRAD food and drink

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    End point title
    		 QOLRAD food and drink
    End point description
    End point type
    Primary
    End point timeframe
    V2 v. V4
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    39
    Units: Score
    arithmetic mean (standard deviation)
        V2
    26.22 ( 9.21 )
    28.46 ( 8.67 )
        V4
    36.31 ( 7.33 )
    36.12 ( 6.45 )
    Statistical analysis title
    		 Pre/post changes
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.2024
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [10] - Explorative

    Primary: QOLRAD physical/social functioning

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    End point title
    		 QOLRAD physical/social functioning
    End point description
    End point type
    Primary
    End point timeframe
    V2 v. V4
    End point values
    		 Verum Placebo
    Number of subjects analysed
    38
    39
    Units: Score
    arithmetic mean (standard deviation)
        V2
    27.26 ( 6.86 )
    28.92 ( 5.4 )
        V4
    32.37 ( 4.78 )
    32.46 ( 3.32 )
    Statistical analysis title
    		 Pre/post changes
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.1619
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [11] - Explorative

    Primary: QOLRAD vitality

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    End point title
    		 QOLRAD vitality
    End point description
    End point type
    Primary
    End point timeframe
    V2 v. V4
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    39
    Units: Score
    arithmetic mean (standard deviation)
        V2
    13.26 ( 4.47 )
    13.54 ( 4.64 )
        V4
    17.64 ( 3.94 )
    17.92 ( 3.34 )
    Statistical analysis title
    		 Pre/post changes
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.8338
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [12] - Explorative

    Primary: GLQI

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    End point title
    		 GLQI
    End point description
    End point type
    Primary
    End point timeframe
    V2 v. V4
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    39
    Units: Score
    arithmetic mean (standard deviation)
        V2
    95.8 ( 22.3 )
    96.6 ( 17.9 )
        V4
    110.4 ( 22.7 )
    110.8 ( 18.5 )
    Statistical analysis title
    		 Pre/post changes
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.9276
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [13] - Explorative

    Primary: SF-12 Physical Composite Scale

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    End point title
    		 SF-12 Physical Composite Scale
    End point description
    End point type
    Primary
    End point timeframe
    V2 v. V4
    End point values
    		 Verum Placebo
    Number of subjects analysed
    36
    37
    Units: Score
    arithmetic mean (standard deviation)
        V2
    46 ( 9.2 )
    46.5 ( 8.1 )
        V4
    49 ( 7.3 )
    48.6 ( 8.7 )
    Statistical analysis title
    		 Pre/post changes
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.9605
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [14] - Explorative

    Primary: SF-12 Mental Composite Scale

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    End point title
    		 SF-12 Mental Composite Scale
    End point description
    End point type
    Primary
    End point timeframe
    V2 v. V4
    End point values
    		 Verum Placebo
    Number of subjects analysed
    36
    37
    Units: Score
    arithmetic mean (standard deviation)
        V2
    46.2 ( 10.8 )
    47 ( 10.8 )
        V4
    51 ( 9.8 )
    50 ( 10.4 )
    Statistical analysis title
    		 Pre/post changes
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.6478
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [15] - Explorative

    Primary: Overall Treatment Evaluation (Investigator)

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    End point title
    		 Overall Treatment Evaluation (Investigator)
    End point description
    0 = no change, +1 = marginally better, +2 = a little better, +3 = somewhat better, +4 = moderately better, +5 = clearly better, +6 = much better, +7 = very much better Reporting group 1 (Verum; n=38): 4.0±1.9 (arithmetic mean; standard deviation) Reporting group 2 (Placebo; n=38): 3.5±2.5 (arithmetic mean; standard deviation)
    End point type
    Primary
    End point timeframe
    V4
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    39
    Units: Patients
        no change
    3
    6
        marginally better
    2
    4
        a little better
    3
    6
        somewhat better
    3
    4
        moderately better
    8
    1
        clearly better
    12
    7
        much better
    5
    3
        very much better
    2
    7
        no data
    1
    1
    Statistical analysis title
    		 Group comparison
    Statistical analysis description
    0 = no change, +1 = marginally better, +2 = a little better, +3 = somewhat better, +4 = moderately better, +5 = clearly better, +6 = much better, +7 = very much better
    Comparison groups
    Placebo v Verum
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.4638
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [16] - Explorative

    Primary: Overall Treatment Evaluation (Patient)

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    End point title
    		 Overall Treatment Evaluation (Patient)
    End point description
    0 = no change, +1 = marginally better, +2 = a little better, +3 = somewhat better, +4 = moderately better, +5 = clearly better, +6 = much better, +7 = very much better Reporting group 1 (Verum; n=38): 4.0±2.0 (arithmetic mean; standard deviation) Reporting group 2 (Placebo; n=38): 3.5±2.5 (arithmetic mean; standard deviation)
    End point type
    Primary
    End point timeframe
    V4
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    39
    Units: Patients
        no change
    4
    7
        marginally better
    2
    3
        a little better
    3
    5
        somewhat better
    3
    5
        moderately better
    7
    1
        clearly better
    10
    8
        much better
    7
    1
        very much better
    2
    8
        no data
    1
    1
    Statistical analysis title
    		 Group comparison
    Statistical analysis description
    0 = no change, +1 = marginally better, +2 = a little better, +3 = somewhat better, +4 = moderately better, +5 = clearly better, +6 = much better, +7 = very much better
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.4867
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [17] - Explorative

    Primary: AE/ADR (Patients)

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    End point title
    		 AE/ADR (Patients) [18]
    End point description
    End point type
    Primary
    End point timeframe
    V1-V4
    Notes
    [18] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    40
    Units: Patients
        AE
    6
    14
        ADR
    0
    1
    No statistical analyses for this end point

    Primary: AE/ADR (Occurrences)

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    End point title
    		 AE/ADR (Occurrences) [19]
    End point description
    End point type
    Primary
    End point timeframe
    V1-V4
    Notes
    [19] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    40
    Units: Occurrence AE/ADR
        AE
    12
    22
        ADR
    0
    1
    No statistical analyses for this end point

    Primary: AE Causality

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    End point title
    		 AE Causality [20]
    End point description
    End point type
    Primary
    End point timeframe
    V1-V4
    Notes
    [20] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    40
    Units: Patients
        Causality likely
    0
    1
        Causality unlikely
    6
    13
    No statistical analyses for this end point

    Primary: AE Intensity

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    End point title
    		 AE Intensity [21]
    End point description
    End point type
    Primary
    End point timeframe
    V1-V4
    Notes
    [21] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    40
    Units: Patients
        Light
    3
    4
        Moderate
    3
    9
        Severe
    0
    1
    No statistical analyses for this end point

    Primary: Blood pressure (systolic)

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    End point title
    		 Blood pressure (systolic) [22]
    End point description
    End point type
    Primary
    End point timeframe
    V2 v. V4
    Notes
    [22] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    37
    38
    Units: mmHg
    arithmetic mean (standard deviation)
        V2
    123.3 ( 11.0 )
    125.7 ( 13.2 )
        V4
    121.5 ( 10.9 )
    120.6 ( 10.8 )
    No statistical analyses for this end point

    Primary: Blood pressure (diastolic)

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    End point title
    		 Blood pressure (diastolic) [23]
    End point description
    End point type
    Primary
    End point timeframe
    V2 v. V4
    Notes
    [23] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    37
    38
    Units: mmHg
    arithmetic mean (standard deviation)
        V2
    76.0 ( 5.7 )
    77.1 ( 9.4 )
        V4
    78.3 ( 6.0 )
    78.0 ( 7.6 )
    No statistical analyses for this end point

    Primary: Pulse

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    End point title
    		 Pulse [24]
    End point description
    End point type
    Primary
    End point timeframe
    V2 v. V4
    Notes
    [24] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    37
    38
    Units: Beats per minute
    arithmetic mean (standard deviation)
        V2
    70.2 ( 6.7 )
    68.0 ( 5.2 )
        V4
    68.4 ( 5.4 )
    69.7 ( 6.7 )
    No statistical analyses for this end point

    Primary: ALT, 37°C

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    End point title
    		 ALT, 37°C [25]
    End point description
    End point type
    Primary
    End point timeframe
    V1 v. V4
    Notes
    [25] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    37
    Units: U/L
    arithmetic mean (standard deviation)
        V1
    28.43 ( 17.62 )
    33.00 ( 26.65 )
        V4
    27.29 ( 18.38 )
    32.85 ( 23.85 )
    No statistical analyses for this end point

    Primary: Alkaline phosphatase, 37°C

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    End point title
    		 Alkaline phosphatase, 37°C [26]
    End point description
    End point type
    Primary
    End point timeframe
    V1 v. V4
    Notes
    [26] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    37
    Units: U/L
    arithmetic mean (standard deviation)
        V1
    72.02 ( 19.2 )
    83.56 ( 31.79 )
        V4
    71.22 ( 19.07 )
    84.05 ( 31.68 )
    No statistical analyses for this end point

    Primary: AST, 37°C

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    End point title
    		 AST, 37°C [27]
    End point description
    End point type
    Primary
    End point timeframe
    V1 v. V4
    Notes
    [27] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    37
    Units: U/L
    arithmetic mean (standard deviation)
        V1
    26.00 ( 11.64 )
    28.84 ( 22.74 )
        V4
    25.73 ( 8.75 )
    25.86 ( 10.49 )
    No statistical analyses for this end point

    Primary: Bilirubin, total

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    End point title
    		 Bilirubin, total [28]
    End point description
    End point type
    Primary
    End point timeframe
    V1 v. V4
    Notes
    [28] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    37
    Units: μmol/L
    arithmetic mean (standard deviation)
        V1
    11.09 ( 4.74 )
    10.54 ( 5.77 )
        V4
    11.37 ( 6.91 )
    10.41 ( 5.19 )
    No statistical analyses for this end point

    Primary: Blood urea nitrogen

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    End point title
    		 Blood urea nitrogen [29]
    End point description
    End point type
    Primary
    End point timeframe
    V1 v. V4
    Notes
    [29] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    37
    Units: mmol/L
    arithmetic mean (standard deviation)
        V1
    4.56 ( 1.37 )
    4.81 ( 1.24 )
        V4
    4.99 ( 1.29 )
    5.12 ( 1.66 )
    No statistical analyses for this end point

    Primary: Creatinine

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    End point title
    		 Creatinine [30]
    End point description
    End point type
    Primary
    End point timeframe
    V1 v. V4
    Notes
    [30] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    37
    Units: μmol/L
    arithmetic mean (standard deviation)
        V1
    71.96 ( 13.26 )
    67.19 ( 11.79 )
        V4
    72.18 ( 15.63 )
    66.09 ( 12.74 )
    No statistical analyses for this end point

    Primary: Gamma-GT, 37°C

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    End point title
    		 Gamma-GT, 37°C [31]
    End point description
    End point type
    Primary
    End point timeframe
    V1 v. V4
    Notes
    [31] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    37
    Units: U/L
    arithmetic mean (standard deviation)
        V1
    35.07 ( 30.53 )
    41.17 ( 68.46 )
        V4
    31.58 ( 24.34 )
    40.54 ( 74.51 )
    No statistical analyses for this end point

    Primary: Uric acid

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    End point title
    		 Uric acid [32]
    End point description
    End point type
    Primary
    End point timeframe
    V1 v. V4
    Notes
    [32] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    37
    Units: μmol/L
    arithmetic mean (standard deviation)
        V1
    324.57 ( 85.1 )
    295.55 ( 79.29 )
        V4
    323.61 ( 89 )
    293.87 ( 76.02 )
    No statistical analyses for this end point

    Primary: Hemoglobin

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    End point title
    		 Hemoglobin [33]
    End point description
    End point type
    Primary
    End point timeframe
    V1 v. V4
    Notes
    [33] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    37
    Units: g/L
    arithmetic mean (standard deviation)
        V1
    142.51 ( 9.86 )
    140.22 ( 14.59 )
        V4
    141.38 ( 10.37 )
    138.95 ( 14.09 )
    No statistical analyses for this end point

    Primary: Hematocrit

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    End point title
    		 Hematocrit [34]
    End point description
    End point type
    Primary
    End point timeframe
    V1 v. V4
    Notes
    [34] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    37
    Units: L/L
    arithmetic mean (standard deviation)
        V1
    0.42 ( 0.03 )
    0.42 ( 0.04 )
        V4
    0.42 ( 0.03 )
    0.42 ( 0.04 )
    No statistical analyses for this end point

    Primary: Platelets

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    End point title
    		 Platelets [35]
    End point description
    End point type
    Primary
    End point timeframe
    V1 v. V4
    Notes
    [35] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    37
    Units: 10^9/L
    arithmetic mean (standard deviation)
        V1
    270.79 ( 62.01 )
    259.86 ( 58.86 )
        V4
    273.56 ( 61.09 )
    261.32 ( 57.88 )
    No statistical analyses for this end point

    Primary: Red blood cells

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    End point title
    		 Red blood cells [36]
    End point description
    End point type
    Primary
    End point timeframe
    V1 v. V4
    Notes
    [36] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    37
    Units: 10^12/L
    arithmetic mean (standard deviation)
        V1
    4.64 ( 0.33 )
    4.58 ( 0.46 )
        V4
    4.64 ( 0.37 )
    4.57 ( 0.46 )
    No statistical analyses for this end point

    Primary: White blood cells

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    End point title
    		 White blood cells [37]
    End point description
    End point type
    Primary
    End point timeframe
    V1 V. V4
    Notes
    [37] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    37
    Units: 10^9/L
    arithmetic mean (standard deviation)
        V1
    7.47 ( 2.26 )
    6.92 ( 1.88 )
        V4
    7.62 ( 2.3 )
    6.78 ( 2.03 )
    No statistical analyses for this end point

    Primary: Overall tolerability evaluation (Investigator)

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    End point title
    		 Overall tolerability evaluation (Investigator) [38]
    End point description
    End point type
    Primary
    End point timeframe
    V4
    Notes
    [38] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    40
    Units: Patients
        very good
    28
    30
        good
    9
    8
        moderate
    1
    0
        poor
    0
    0
        no data
    1
    2
    No statistical analyses for this end point

    Primary: Overall tolerability evaluation (Patient)

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    End point title
    		 Overall tolerability evaluation (Patient) [39]
    End point description
    End point type
    Primary
    End point timeframe
    V4
    Notes
    [39] - 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: Based on the statistical analysis plan, no detailed statistical analysis (except from display of frequency tables) for this endpoint was foreseen and can therefore not be provided here.
    End point values
    		 Verum Placebo
    Number of subjects analysed
    39
    40
    Units: Patients
        very good
    27
    28
        good
    10
    8
        moderate
    1
    2
        poor
    0
    0
        no data
    1
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    V1-V4
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Verum
    Reporting group description
    		 40 patients were enrolled, 39 patients received IMP

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Verum Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 40 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Verum Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 39 (15.38%)
    14 / 40 (35.00%)
    Vascular disorders
    Blood pressure fluctuation
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Nervous system disorders
    Migraine
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Headache
         subjects affected / exposed
    0 / 39 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal tenderness
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Aphthous ulcer
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Eructation
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Menstrual discomfort
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Photosensitivity reaction
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Fibromyalgia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 40 (5.00%)
         occurrences all number
    2
    2
    Gastroenteritis
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Sinusitis
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Bronchitis
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 39 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Acute sinusitis
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Sep 2017
    1) Increase of maximum age for study participation from 64 years to 85 years. 2) Striking of one manager from project management list.

    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
    For support, Contact us.
    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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