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    Clinical Trial Results:
    A randomized, single-blind, threefold crossover, single-center study to assess the safety and the effects of 1 mg and 5 mg BAY 1193397 in comparison to placebo on skin capillary blood flow and transcutaneous oxygen pressure after single dose in type II diabetic patients

    Summary
    EudraCT number
    2015-003799-63
    Trial protocol
    GB  
    Global end of trial date
    28 Oct 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Aug 2020
    First version publication date
    27 Aug 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY1193397/17500
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03128320
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    28 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives were to: 1) Investigate the change in resting capillary blood flow velocity (CBV) before and after study drug administration; 2) Investigate the change in peak CBV during reactive hyperemia before and after study drug administration; 3) Investigate the change in time to peak CBV during reactive hyperemia before and after study drug administration; 4) Investigate the change in transcutaneous oxygen pressure (TcPO2) before and after study drug administration. The secondary objective was to analyze safety and tolerability of BAY1193397 after a single dose administration as evidenced by the incidence and severity of adverse events (AEs).
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Only after the subject voluntarily signed the informed consent form was he/she able to enter the study. If the subject was not capable of providing a signature, an oral statement of consent could have been given in the presence of a witness. Each subject was assured of the right to withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    25 May 2017
    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
    United Kingdom: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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)
    4
    From 65 to 84 years
    19
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study was conducted at one center in UK, between 25 May 2017 (first subject first visit) and 06 Sep 2019 (last subject last visit).

    Pre-assignment
    Screening details
    A total of 58 subjects were screened, of whom 23 subjects were randomized.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind [1]
    Roles blinded
    Investigator, Carer, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment sequence A-B-C
    Arm description
    Subjects received a single oral dose of matching placebo (5*1 mg placebo IR tablet) in the first intervention period (Treatment A); followed by a single oral dose of 1 mg BAY1193397 (1*1 mg IR tablet + 4*1 mg placebo IR tablet) (Treatment B); then a single oral dose of 5 mg BAY1193397 (5*1 mg IR tablet) under fasted state in the third intervention period (Treatment C). A wash-out phase of approximately 5 to 15 days was maintained between each treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Treatment A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of matching placebo to BAY1193397 given in the fasted state.

    Investigational medicinal product name
    BAY1193397 (1 mg)
    Investigational medicinal product code
    BAY1193397
    Other name
    Treatment B
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of 1 mg BAY1193397 immediate release (IR) tablet given in the fasted state.

    Investigational medicinal product name
    BAY1193397 (5 mg)
    Investigational medicinal product code
    BAY1193397
    Other name
    Treatment C
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of 5 mg BAY1193397 (5*1 mg IR tablet) given in the fasted state.

    Arm title
    Treatment sequence B-A-C
    Arm description
    Subjects received a single oral dose of 1 mg BAY1193397 (1*1 mg IR tablet + 4*1 mg placebo IR tablet) (Treatment B) in the first intervention period; followed by a single oral dose of matching placebo (5*1 mg placebo IR tablet) (Treatment A) in the second intervention period; then a single oral dose of 5 mg BAY1193397 (5*1 mg IR tablet) (Treatment C) under fasted conditions in the third intervention period. A wash-out phase of approximately 5 to 15 days was maintained between each treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    BAY1193397 (1 mg)
    Investigational medicinal product code
    BAY1193397
    Other name
    Treatment B
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of 1 mg BAY1193397 immediate release (IR) tablet given in the fasted state.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Treatment A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of matching placebo to BAY1193397 given in the fasted state.

    Investigational medicinal product name
    BAY1193397 (5 mg)
    Investigational medicinal product code
    BAY1193397
    Other name
    Treatment C
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of 5 mg BAY1193397 (5*1 mg IR tablet) given in the fasted state.

    Arm title
    Treatment sequence B-C-A
    Arm description
    Subjects received a single oral dose of 1 mg BAY1193397 (1*1 mg IR tablet + 4*1 mg placebo IR tablet) (Treatment B) in the first intervention period; followed by a single oral dose of 5 mg BAY1193397 (5*1 mg IR tablet) (Treatment C) in the second intervention period; then a single oral dose of matching placebo (5*1 mg placebo IR tablet) (Treatment A) under fasted conditions in the third intervention period. A wash-out phase of approximately 5 to 15 days was maintained between each treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    BAY1193397 (1 mg)
    Investigational medicinal product code
    BAY1193397
    Other name
    Treatment B
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of 1 mg BAY1193397 immediate release (IR) tablet given in the fasted state.

    Investigational medicinal product name
    BAY1193397 (5 mg)
    Investigational medicinal product code
    BAY1193397
    Other name
    Treatment C
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of 5 mg BAY1193397 (5*1 mg IR tablet) given in the fasted state.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Treatment A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single dose of matching placebo to BAY1193397 given in the fasted state.

    Notes
    [1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
    Justification: The sponsor’s early clinical leader and clinical pharmacology lead were unblinded to allow for additional safety monitoring.
    Number of subjects in period 1
    Treatment sequence A-B-C Treatment sequence B-A-C Treatment sequence B-C-A
    Started
    7
    6
    10
    Treated
    6
    5
    8
    Completed
    5
    3
    8
    Not completed
    2
    3
    2
         Not treated, unable to find capillaries
    1
    1
    2
         drop out after treatment 1
    -
    1
    -
         miss schedule visits
    1
    -
    -
         withdrawn by sponsor
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment sequence A-B-C
    Reporting group description
    Subjects received a single oral dose of matching placebo (5*1 mg placebo IR tablet) in the first intervention period (Treatment A); followed by a single oral dose of 1 mg BAY1193397 (1*1 mg IR tablet + 4*1 mg placebo IR tablet) (Treatment B); then a single oral dose of 5 mg BAY1193397 (5*1 mg IR tablet) under fasted state in the third intervention period (Treatment C). A wash-out phase of approximately 5 to 15 days was maintained between each treatment.

    Reporting group title
    Treatment sequence B-A-C
    Reporting group description
    Subjects received a single oral dose of 1 mg BAY1193397 (1*1 mg IR tablet + 4*1 mg placebo IR tablet) (Treatment B) in the first intervention period; followed by a single oral dose of matching placebo (5*1 mg placebo IR tablet) (Treatment A) in the second intervention period; then a single oral dose of 5 mg BAY1193397 (5*1 mg IR tablet) (Treatment C) under fasted conditions in the third intervention period. A wash-out phase of approximately 5 to 15 days was maintained between each treatment.

    Reporting group title
    Treatment sequence B-C-A
    Reporting group description
    Subjects received a single oral dose of 1 mg BAY1193397 (1*1 mg IR tablet + 4*1 mg placebo IR tablet) (Treatment B) in the first intervention period; followed by a single oral dose of 5 mg BAY1193397 (5*1 mg IR tablet) (Treatment C) in the second intervention period; then a single oral dose of matching placebo (5*1 mg placebo IR tablet) (Treatment A) under fasted conditions in the third intervention period. A wash-out phase of approximately 5 to 15 days was maintained between each treatment.

    Reporting group values
    Treatment sequence A-B-C Treatment sequence B-A-C Treatment sequence B-C-A Total
    Number of subjects
    7 6 10 23
    Age Categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    70.6 ± 3.6 67.0 ± 6.1 68.9 ± 7.4 -
    Gender Categorical
    Units: Subjects
        Female
    2 2 3 7
        Male
    5 4 7 16
    Presence of Peripheral Neuropathy
    Units: Subjects
        No
    3 3 6 12
        Yes
    4 3 4 11

    End points

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    End points reporting groups
    Reporting group title
    Treatment sequence A-B-C
    Reporting group description
    Subjects received a single oral dose of matching placebo (5*1 mg placebo IR tablet) in the first intervention period (Treatment A); followed by a single oral dose of 1 mg BAY1193397 (1*1 mg IR tablet + 4*1 mg placebo IR tablet) (Treatment B); then a single oral dose of 5 mg BAY1193397 (5*1 mg IR tablet) under fasted state in the third intervention period (Treatment C). A wash-out phase of approximately 5 to 15 days was maintained between each treatment.

    Reporting group title
    Treatment sequence B-A-C
    Reporting group description
    Subjects received a single oral dose of 1 mg BAY1193397 (1*1 mg IR tablet + 4*1 mg placebo IR tablet) (Treatment B) in the first intervention period; followed by a single oral dose of matching placebo (5*1 mg placebo IR tablet) (Treatment A) in the second intervention period; then a single oral dose of 5 mg BAY1193397 (5*1 mg IR tablet) (Treatment C) under fasted conditions in the third intervention period. A wash-out phase of approximately 5 to 15 days was maintained between each treatment.

    Reporting group title
    Treatment sequence B-C-A
    Reporting group description
    Subjects received a single oral dose of 1 mg BAY1193397 (1*1 mg IR tablet + 4*1 mg placebo IR tablet) (Treatment B) in the first intervention period; followed by a single oral dose of 5 mg BAY1193397 (5*1 mg IR tablet) (Treatment C) in the second intervention period; then a single oral dose of matching placebo (5*1 mg placebo IR tablet) (Treatment A) under fasted conditions in the third intervention period. A wash-out phase of approximately 5 to 15 days was maintained between each treatment.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomized subjects who received at least one dose of the study medication.

    Subject analysis set title
    Per-protocol analysis set (PPS)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All subjects of the SAF without validity findings who completed all three study periods with valid measurements for all four primary variables.

    Subject analysis set title
    BAY1193397 (1 mg)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received a single dose of 1 mg BAY1193397 immediate release (IR) tablet given in the fasted state.

    Subject analysis set title
    BAY1193397 (5 mg)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received a single dose of 5 mg BAY1193397 (5*1 mg IR tablet) given in the fasted state.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received a single dose of matching placebo to BAY1193397 given in the fasted state.

    Primary: Change in resting capillary blood flow velocity (CBV)

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    End point title
    Change in resting capillary blood flow velocity (CBV)
    End point description
    In each treatment period, capillaroscopy was performed twice – before and after study drug administration. Capillary images were recorded live and capillary blood flow velocity (CBV) was then analyzed offline. CBV was continuously computed during 2 min and the mean value during this period was termed resting CBV. Change in resting CBV = resting CBV after study drug administration – resting CBV before study drug administration.
    End point type
    Primary
    End point timeframe
    Before and after treatment with study drug (within 1-3 hours after treatment with study drug)
    End point values
    BAY1193397 (1 mg) BAY1193397 (5 mg) Placebo
    Number of subjects analysed
    15 [1]
    15 [2]
    15 [3]
    Units: μm/s
        arithmetic mean (standard deviation)
    -94.73 ± 278.74
    -23.64 ± 249.52
    -63.28 ± 195.10
    Notes
    [1] - PPS
    [2] - PPS
    [3] - PPS
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The Holm procedure was applied on the 4 primary variables. This is a step-down procedure that starts with the hypothesis associated with the most significant p-value of the one-sided exact Page test and rejects it if the p-value is not greater than α/4 = 0.2/4 = 0.05. The overall α-level of this procedure is 0.20. Erroneously, database auto calculates the total number of subjects for the selected arms. Number of subjects evaluated in this analysis was 15.
    Comparison groups
    BAY1193397 (1 mg) v BAY1193397 (5 mg) v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2634 [4]
    Method
    one-sided exact Page test
    Confidence interval
    Notes
    [4] - Since this primary variable had the smallest one-sided p-value of the exact Page test and the p-value was larger than 0.05, the associated null hypothesis H was not rejected. The Holm procedure was therefore stopped.

    Primary: Change in peak CBV during reactive hyperemia

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    End point title
    Change in peak CBV during reactive hyperemia [5]
    End point description
    In each treatment period, capillaroscopy was performed twice – before and after study drug administration. Peak CBV was measured following release of a 1-min arterial occlusion at the proximal phalanx of the great toe with a cuff pressure of 200 mmHg. Three 1-min arterial occlusions were performed at least 1 min apart. Results from the 3 independent measurements of peak CBV was entered in the eCRF and the mean was calculated by data management. Change in peak CBV during reactive hyperemia = peak CBV after study drug administration – peak CBV before study drug administration. During the study, the “no peak phenomenon” was observed in rare cases. The resulting missing quantitative data for peak CBV were replaced by imputed values to get semi quantitative information for the changes from baseline. In these cases, peak CBV was set to 0 which was considered as an approximation of infinity.
    End point type
    Primary
    End point timeframe
    Before and after treatment with study drug (within 1-3 hours after treatment with study drug)
    Notes
    [5] - 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: Since the p-value of the primary variable with the smallest one-sided p-value of the exact Page test was larger than 0.05, the associated null hypothesis H was not rejected. The Holm procedure was therefore stopped.
    End point values
    BAY1193397 (1 mg) BAY1193397 (5 mg) Placebo
    Number of subjects analysed
    15 [6]
    15 [7]
    15 [8]
    Units: μm/s
        median (full range (min-max))
    -27.80 (-1350.4 to 412.5)
    144.50 (-1598.3 to 1153.1)
    0.00 (-519.0 to 751.5)
    Notes
    [6] - PPS
    [7] - PPS
    [8] - PPS
    No statistical analyses for this end point

    Primary: Change in time to peak CBV during reactive hyperemia

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    End point title
    Change in time to peak CBV during reactive hyperemia [9]
    End point description
    In each treatment period, capillaroscopy was performed twice – before and after study drug administration. Time to peak CBV was measured following release of a 1-min arterial occlusion at the proximal phalanx of the great toe with a cuff pressure of 200 mmHg. Three 1-min arterial occlusions were performed at least 1 min apart. Results from the 3 independent measurements of time to peak was entered in the eCRF and the mean was calculated by data management. Change in time to peak CBV during reactive hyperemia = time to peak CBV after study drug administration – time to peak CBV before study drug administration. During the study, the “no peak phenomenon” was observed in rare cases. The resulting missing quantitative data for time to peak CBV were replaced by imputed values to get semi quantitative information for the changes from baseline. In these cases, time to peak was set to 100000 which was considered as an approximation of infinity.
    End point type
    Primary
    End point timeframe
    Before and after treatment with study drug (within 1-3 hours after treatment with study drug)
    Notes
    [9] - 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: Since the p-value of the primary variable with the smallest one-sided p-value of the exact Page test was larger than 0.05, the associated null hypothesis H was not rejected. The Holm procedure was therefore stopped.
    End point values
    BAY1193397 (1 mg) BAY1193397 (5 mg) Placebo
    Number of subjects analysed
    15 [10]
    15 [11]
    15 [12]
    Units: second
        median (full range (min-max))
    2.10 (-12.7 to 99992.4)
    1.40 (-99992.8 to 99977.5)
    0.00 (-3.9 to 4.6)
    Notes
    [10] - PPS
    [11] - PPS
    [12] - PPS
    No statistical analyses for this end point

    Primary: Change in transcutaneous oxygen pressure (TcPO2)

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    End point title
    Change in transcutaneous oxygen pressure (TcPO2) [13]
    End point description
    Local skin oxygenation was evaluated by measurement of transcutaneous oxygen pressure (TcPO2) at the dorsum of the foot in the first intermetatarsal space using the Periflux System 5000 (PF5040) and, as reference, at the left upper quadrant of the chest. TcPO2 is a non-invasive method reflecting local arterial skin blood flow and oxygenation. The same foot was used for capillaroscopy and TcPO2 measurements. For each TcPO2 determination, 3 measurements were performed at the foot and chest, 15, 17, and 19 min after heating, and documented in the eCRF. Means for foot and chest TcPO2 were calculated by data management. At least 2 out of 3 TcPO2 measurements had to be valid (as judged by skin temperature measurement) for mean calculation. Change in foot TcPO2 = TcPO2 after study drug administration – TcPO2 before study drug administration.
    End point type
    Primary
    End point timeframe
    Before and after treatment with study drug (within 1-3 hours after treatment with study drug)
    Notes
    [13] - 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: Since the p-value of the primary variable with the smallest one-sided p-value of the exact Page test was larger than 0.05, the associated null hypothesis H was not rejected. The Holm procedure was therefore stopped.
    End point values
    BAY1193397 (1 mg) BAY1193397 (5 mg) Placebo
    Number of subjects analysed
    15 [14]
    15 [15]
    15 [16]
    Units: mmHg
        arithmetic mean (standard deviation)
    -0.99 ± 11.27
    6.09 ± 21.19
    2.68 ± 10.01
    Notes
    [14] - PPS
    [15] - PPS
    [16] - PPS
    No statistical analyses for this end point

    Secondary: Number of subjects with treatment-emergent adverse events (TEAEs)

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    End point title
    Number of subjects with treatment-emergent adverse events (TEAEs)
    End point description
    An AE is any untoward medical occurrence (i.e. any unfavorable and unintended sign [including abnormal laboratory findings], symptom, or disease) in a patient or clinical investigation subject after providing written informed consent for participation in the study. An SAE was classified as any untoward medical occurrence that, at any dose, met any of the following criteria: Resulted in death; Was life-threatening; Required inpatient hospitalization or prolongation of existing hospitalization; Resulted in persistent or significant disability/incapacity; Was a congenital anomaly/birth defect; Was another serious or important medical event as judged by the investigator. AEs were considered to be treatment-emergent if they had started or worsened after first application of study medication up to 2 days after end of treatment with study medication.
    End point type
    Secondary
    End point timeframe
    From first application of study medication up to 2 days after end of treatment with study medication
    End point values
    BAY1193397 (1 mg) BAY1193397 (5 mg) Placebo
    Number of subjects analysed
    18 [17]
    16 [18]
    18 [19]
    Units: subjects
    number (not applicable)
        Any AE
    9
    6
    5
        Any SAE
    0
    0
    0
        Any study drug-related AE
    5
    6
    3
        Related to protocol required procedures
    3
    3
    1
        Leading to study drug discontinuation
    0
    0
    0
    Notes
    [17] - SAF
    [18] - SAF
    [19] - SAF
    No statistical analyses for this end point

    Secondary: Number of subjects with TEAEs in different severity

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    End point title
    Number of subjects with TEAEs in different severity
    End point description
    An AE is any untoward medical occurrence (i.e. any unfavorable and unintended sign [including abnormal laboratory findings], symptom, or disease) in a patient or clinical investigation subject after providing written informed consent for participation in the study. An SAE was classified as any untoward medical occurrence that, at any dose, met any of the following criteria: Resulted in death; Was life-threatening; Required inpatient hospitalization or prolongation of existing hospitalization; Resulted in persistent or significant disability/incapacity; Was a congenital anomaly/birth defect; Was another serious or important medical event as judged by the investigator. AEs were considered to be treatment-emergent if they had started or worsened after first application of study medication up to 2 days after end of treatment with study medication.
    End point type
    Secondary
    End point timeframe
    From first application of study medication up to 2 days after end of treatment with study medication
    End point values
    BAY1193397 (1 mg) BAY1193397 (5 mg) Placebo
    Number of subjects analysed
    18 [20]
    16 [21]
    18 [22]
    Units: subjects
    number (not applicable)
        Any AE-Mild
    8
    6
    5
        Any AE-Moderate
    1
    0
    0
        Any study drug-related AE-Mild
    4
    6
    3
        Any study drug-related AE-Moderate
    1
    0
    0
    Notes
    [20] - SAF
    [21] - SAF
    [22] - SAF
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first application of study medication up to 2 days after end of treatment with study medication
    Adverse event reporting additional description
    In this cross-over study, some subjects could be experiencing the same adverse event in more than one period.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    BAY1193397 (1 mg)
    Reporting group description
    Subjects received a single dose of 1 mg BAY1193397 immediate release (IR) tablet given in the fasted state.

    Reporting group title
    BAY1193397 (5 mg)
    Reporting group description
    Subjects received a single dose of 5 mg BAY1193397 (5*1 mg IR tablet) given in the fasted state.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received a single dose of matching placebo to BAY1193397 given in the fasted state.

    Serious adverse events
    BAY1193397 (1 mg) BAY1193397 (5 mg) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    BAY1193397 (1 mg) BAY1193397 (5 mg) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 18 (50.00%)
    6 / 16 (37.50%)
    5 / 18 (27.78%)
    Investigations
    Blood pressure increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Mean cell volume decreased
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Reticulocyte count decreased
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Head discomfort
         subjects affected / exposed
    1 / 18 (5.56%)
    3 / 16 (18.75%)
    1 / 18 (5.56%)
         occurrences all number
    1
    3
    1
    Headache
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    2
    1
    0
    Tension headache
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Medical device site erythema
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Medical device site dryness
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Medical device site scab
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Ocular hyperaemia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal pain lower
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    3 / 18 (16.67%)
    0 / 16 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    3
    0
    2
    Dry mouth
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Spontaneous penile erection
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Skin discolouration
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Mar 2017
    This amendment was initiated to include restrictions for sunlight exposure of patients during study conduction.
    24 Aug 2017
    Modifications due to this amendment included the addition of inclusion criteria for diagnosis of PAD and the addition of exclusion criteria for patients with diabetes mellitus induced by immunosuppressive treatment, patients with renal replacement therapy, patients with organ transplants, and patients with a medical history of autoimmune disease.
    12 Jul 2018
    This amendment was issued to facilitate the enrollment of type II diabetes mellitus patients with impaired capillary microcirculation into the study. Modifications included the amendment of inclusion criteria to expand recruitment in type 2 diabetic patient populations also to individuals suffering from microangiopathy, the inclusion of final results from the multiple dose escalation study (EudraCT No. 2016-000038-23), and the amendment of the screening visit period from ‘‘Day -28 to Day -4’’ to “Day -28 to Day -1’’.

    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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