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    Clinical Trial Results:
    Randomized, multi-center, double-blind, placebo-controlled, group-comparison study to investigate safety, tolerability and pharmacodynamics of BAY2253651 after administration of a single nasal dose in 60 subjects with obstructive sleep apnea and open exploratory evaluation of safety and local tolerability of repeated doses in patients

    Summary
    EudraCT number
    		 2017-001851-29
    Trial protocol
    		 GB  
    Global end of trial date
    23 May 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jun 2020
    First version publication date
    04 Jun 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY2253651/19038
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03603678
    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-trialscontact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trialscontact@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
    23 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To investigate changes of apnoea-hypopnoea-index (AHI) within 4 hours after a single dose administration of BAY2253651.
    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. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could 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
    		 Placebo
    Actual start date of recruitment
    13 Aug 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Switzerland: 30
    Country: Number of subjects enrolled
    United Kingdom: 4
    Worldwide total number of subjects
    34
    EEA total number of subjects
    4
    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)
    17
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at two study centers in Switzerland and United Kingdom, between 13-Aug-2018 2018 (first subject first visit) and 23-May-2019 (study termination).

    Pre-assignment
    Screening details
    		 Overall, 168 subjects were screened at the two study centers in Switzerland and United Kingdom. 134 subjects failed screening. 34 subjects were randomized with recurring OSA of moderate to severe degree.

    Period 1
    Period 1 title
    Study Part A
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part A single dose BAY2253651
    Arm description
    		 Subjects received single dose 100 µg (500 µg/ml * 200 µl) BAY2253651 intranasally
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAY2253651
    Investigational medicinal product code
    BAY2253651
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Nasal use
    Dosage and administration details
    Subjects received single dose 100 µg (500 µg/ml * 200 µl) BAY2253651 intranasally

    Arm title
    		 Part A single dose Placebo
    Arm description
    		 Subjects received single dose matching Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Nasal use
    Dosage and administration details
    Subjects received single dose matching Placebo

    Number of subjects in period 1
    		Part A single dose BAY2253651 Part A single dose Placebo
    Started
    17
    17
    Completed
    16
    15
    Not completed
    1
    2
         Criteria for analysis set not fulfilled
    1
    2
    Period 2
    Period 2 title
    Study Part B
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Single arm, open label

    Arms
    Arm title
    		 Part B multiple dose BAY2253651
    Arm description
    		 5 days with repetitive once daily doses of 100µg intra-nasally before bed rest
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAY2253651
    Investigational medicinal product code
    BAY2253651
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Nasal use
    Dosage and administration details
    Subjects received multiple dose 100 μg (500 μg/ml * 200 μl) BAY2253651 intranasally once daily on 5 consecutive nights

    Number of subjects in period 2 [1]
    		Part B multiple dose BAY2253651
    Started
    10
    Completed
    6
    Not completed
    4
         Criteria for analysis set not fulfilled
    4
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Per Protocol Set - Part B included subjects of the Per Protocol Set Part A who additionally had dosed him/herself on at least 4 of the 5 consecutive nights with 100μg BAY 2253651 intranasally only

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A single dose BAY2253651
    Reporting group description
    		 Subjects received single dose 100 µg (500 µg/ml * 200 µl) BAY2253651 intranasally

    Reporting group title
    Part A single dose Placebo
    Reporting group description
    		 Subjects received single dose matching Placebo

    Reporting group values
    		 Part A single dose BAY2253651 Part A single dose Placebo Total
    Number of subjects
    		 17 17 34
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 5 12 17
        From 65-84 years
    		 12 5 17
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        median (full range (min-max))
    		 59.0 (46.0 to 70.0) 70.0 (57.0 to 75.0) -
    Gender Categorical
    Units: Subjects
        Female
    		 3 9 12
        Male
    		 14 8 22
    Subject analysis sets

    Subject analysis set title
    Study part A: Per Protocol Set (PPS) - BAY2253651
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PPS included all subjects: • received at least one dose of study drug • had a valid AHI by PSG in a sleep laboratory on the third and fourth night of CPAP withdrawal and • did not have an important deviation from the protocol or validity finding having an impact on the primary PD variable.

    Subject analysis set title
    Study part A: Per Protocol Set (PPS) - Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PPS included all subjects: • received at least one dose of study drug • had a valid AHI by PSG in a sleep laboratory on the third and fourth night of CPAP withdrawal and • did not have an important deviation from the protocol or validity finding having an impact on the primary PD variable.

    Subject analysis set title
    Study part B: Per Protocol Set (PPS) - BAY2253651
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per Protocol Set - Part B included all subjects of the Per Protocol Set who additionally: - participated in part B and - had dosed him/herself on at least 4 of the 5 consecutive nights with 100µg BAY 2253651 intranasally

    Subject analysis sets values
    		 Study part A: Per Protocol Set (PPS) - BAY2253651 Study part A: Per Protocol Set (PPS) - Placebo Study part B: Per Protocol Set (PPS) - BAY2253651
    Number of subjects
    16
    15
    6
    Age Categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    11
    4
    4
        From 65-84 years
    5
    11
    2
        85 years and over
    0
    0
    0
    Age Continuous
    Units: years
        median (full range (min-max))
    58.6 (46.0 to 70.0)
    68.2 (57.0 to 75.0)
    63.0 (54 to 75)
    Gender Categorical
    Units: Subjects
        Female
    3
    7
    2
        Male
    13
    8
    4

    End points

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    End points reporting groups
    Reporting group title
    Part A single dose BAY2253651
    Reporting group description
    		 Subjects received single dose 100 µg (500 µg/ml * 200 µl) BAY2253651 intranasally

    Reporting group title
    Part A single dose Placebo
    Reporting group description
    		 Subjects received single dose matching Placebo
    Reporting group title
    Part B multiple dose BAY2253651
    Reporting group description
    		 5 days with repetitive once daily doses of 100µg intra-nasally before bed rest

    Subject analysis set title
    Study part A: Per Protocol Set (PPS) - BAY2253651
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PPS included all subjects: • received at least one dose of study drug • had a valid AHI by PSG in a sleep laboratory on the third and fourth night of CPAP withdrawal and • did not have an important deviation from the protocol or validity finding having an impact on the primary PD variable.

    Subject analysis set title
    Study part A: Per Protocol Set (PPS) - Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PPS included all subjects: • received at least one dose of study drug • had a valid AHI by PSG in a sleep laboratory on the third and fourth night of CPAP withdrawal and • did not have an important deviation from the protocol or validity finding having an impact on the primary PD variable.

    Subject analysis set title
    Study part B: Per Protocol Set (PPS) - BAY2253651
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per Protocol Set - Part B included all subjects of the Per Protocol Set who additionally: - participated in part B and - had dosed him/herself on at least 4 of the 5 consecutive nights with 100µg BAY 2253651 intranasally

    Primary: The rate of the responders: changes of apnoea-hypopnoea-index (AHI)

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    End point title
    		 The rate of the responders: changes of apnoea-hypopnoea-index (AHI) [1]
    End point description
    A responder is defined by the reduction of the AHI (over 0-4h) from baseline by ≥ 50% after a single dose administration of BAY2253651
    End point type
    Primary
    End point timeframe
    Apnoea-hypopnoe-index (AHI) (over 0-4h) obtained by polysomnography (PSG) at Visits 1 and 2
    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: Descriptive statistics were done, no inferential statistical analyses were planned for this endpoint.
    End point values
    		 Study part A: Per Protocol Set (PPS) - BAY2253651 Study part A: Per Protocol Set (PPS) - Placebo
    Number of subjects analysed
    16
    15
    Units: Percentage
    number (not applicable)
        Reduction of AHI (0-4h) from baseline by >=50%
    6.3
    6.7
    No statistical analyses for this end point

    Secondary: Number and severity of treatment emergent adverse events (TEAEs) - Part A

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    End point title
    		 Number and severity of treatment emergent adverse events (TEAEs) - Part A
    End point description
    SAF
    End point type
    Secondary
    End point timeframe
    From the start of study medication administration up to 2 days after the end of treatment with study medication
    End point values
    		 Part A single dose BAY2253651 Part A single dose Placebo
    Number of subjects analysed
    17
    17
    Units: Subjects
        Any AE
    12
    9
        Intensity for any AE: mild
    11
    8
        Intensity for any AE: moderate
    1
    0
        Any study drug related AE
    11
    8
        Intensity for study drug related AE: mild
    11
    7
        Intensity for study drug related AE: severe
    0
    1
        Any AE related to protocol procedures
    1
    1
        Any AE leading to discontinuation of study drug
    0
    0
        Any SAE
    0
    0
        Study drug related SAEs
    0
    0
        SAE related to protocol procedures
    0
    0
        SAE leading to discontinuation of study drug
    0
    0
        AE with the outcome death
    0
    0
    No statistical analyses for this end point

    Secondary: Number and severity of treatment emergent adverse events (TEAEs) - Part B

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    End point title
    		 Number and severity of treatment emergent adverse events (TEAEs) - Part B
    End point description
    SAF
    End point type
    Secondary
    End point timeframe
    From the start of study medication administration up to 2 days after the end of treatment with study medication
    End point values
    		 Part B multiple dose BAY2253651
    Number of subjects analysed
    6
    Units: Subjects
        Any AE
    5
        Intensity for any AE: mild
    5
        Any BAY 2253651 related AE
    5
        Intensity for BAY 2253651 related AE: mild
    5
        Any AE related to protocol procedures
    0
        Any AE leading to discontinuation of BAY 2253651
    0
        Any SAE
    0
        BAY 2253651 related SAEs
    0
        SAE related to protocol procedures
    0
        SAE leading to discontinuation of BAY 2253651
    0
        AE with the outcome death
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study treatment up to 2 days after end of treatment with study medication
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    BAY2253651 Part A
    Reporting group description
    		 -

    Reporting group title
    Placebo Part A
    Reporting group description
    		 -

    Reporting group title
    BAY2253651 Part B
    Reporting group description
    		 -

    Serious adverse events
    		 BAY2253651 Part A Placebo Part A BAY2253651 Part B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (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
    		 BAY2253651 Part A Placebo Part A BAY2253651 Part B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 17 (70.59%)
    9 / 17 (52.94%)
    5 / 10 (50.00%)
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    7 / 17 (41.18%)
    2 / 17 (11.76%)
    3 / 10 (30.00%)
         occurrences all number
    7
    2
    3
    Head discomfort
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Application site pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Thirst
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 17 (11.76%)
    2 / 10 (20.00%)
         occurrences all number
    1
    2
    2
    Glossitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Glossodynia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Toothache
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Dry throat
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Nasal congestion
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal dryness
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Throat irritation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Throat tightness
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    Intranasal paraesthesia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Laryngeal discomfort
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Pharyngeal hypoaesthesia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Pharyngeal paraesthesia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Skin discomfort
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Gouty arthritis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Aug 2018
    Amendment 1, dated 06 Aug 2018 was issued to incorporate modifications requested by the British Competent Authority (MHRA). All changes were implemented prior to study start: • Clarification of study inclusion criteria for adequate contraception • Inclusion of non-REM AHI for Polysomnography exploratory objectives and analysis • Standardization of blood pressure measurement • Updated Short Form Health Survey (SF-36, Version 2) • Removal of IxRS from drug accountability processes
    10 Dec 2018
    Amendment 2, dated 10 Dec 2018 was implemented to include the following modifications: • Combining Visit 4 (Part A) and Visit 5 (Part B) study activities • Clarification of estimated AHI count procedures • Revised ODI screening range (Part A) • Manual adjustment of screening oximetry data • Repeat of non-evaluable CPAP assessments • Extension of screening phase from 6 to 12 weeks • Revised scheduling of assessments conducted at Screening Visit 2 and Visit 2 • Addition of criteria for evaluating PSG assessment at Visit 2

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    23 May 2019
    Study termination
    -

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

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