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    Clinical Trial Results:
    Efficacy, Safety and Tolerability of 3 doses of Sulthiame in Patients with Obstructive Sleep Apnea. A Randomized, Double-Blind, Placebo Controlled, Dose-Ranging Study

    Summary
    EudraCT number
    		 2021-002926-26
    Trial protocol
    		 BE   ES   CZ   FR   DE  
    Global end of trial date
    08 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Sep 2024
    First version publication date
    21 Sep 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    STM-042/K
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05236842
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Desitin Arzneimittel GmbH
    Sponsor organisation address
    Weg beim Jäger 214, Hamburg, Germany, 22335
    Public contact
    Dr. Corinna Hansen, Desitin Arzneimittel GmbH, +49 4059101-234, hansen@desitin.de
    Scientific contact
    Dr. Corinna Hansen, Desitin Arzneimittel GmbH, +49 4059101-234, hansen@desitin.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Aug 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of three different doses of Sulthiame (STM) compared to placebo on sleep apnea activity in adult subjects with moderate to severe OSA after at least 12 weeks of treatment at target dose.
    Protection of trial subjects
    This study was conducted in accordance with the accepted version of the Declaration of Helsinki and/or all relevant federal regulations, in compliance with ICH GCP guidelines, and according to the appropriate regulatory requirements in the countries where the study was conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Dec 2021
    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
    Spain: 65
    Country: Number of subjects enrolled
    Belgium: 64
    Country: Number of subjects enrolled
    Czechia: 2
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 155
    Worldwide total number of subjects
    298
    EEA total number of subjects
    298
    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)
    224
    From 65 to 84 years
    74
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This study was conducted at 28 sites in Belgium, Czech Republic, France, Germany, and Spain.

    Pre-assignment
    Screening details
    		 A total of 535 subjects were enrolled, of which 237 subjects were screening failures, and 298 subjects were randomized and treated with study drug.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received STM matched placebo, tablets, orally, once daily within 1 hour prior to bedtime for 15 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered orally as tablets once daily within 1 hour prior to bedtime until Week 15.

    Arm title
    		 STM 100 mg
    Arm description
    		 Subjects received STM 50 milligrams (mg) (as initial dose level), tablets, orally, once daily within 1 hour prior to bedtime in Week 1 then up-titrated to 100 mg in Weeks 2 and 3 and continued taking 100 mg as a target dose until Week 15.
    Arm type
    		 Experimental

    Investigational medicinal product name
    STM
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    STM was administered orally as tablets once daily within 1 hour prior to bedtime until Week 15.

    Arm title
    		 STM 200 mg
    Arm description
    		 Subjects received STM 50 mg (as initial dose level), tablets, orally, once daily within 1 hour prior to bedtime in Week 1 then up-titrated to 100 mg in Week 2, 200 mg in Week 3 and continued taking 200 mg as a target dose until Week 15.
    Arm type
    		 Experimental

    Investigational medicinal product name
    STM
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    STM was administered orally as tablets once daily within 1 hour prior to bedtime until Week 15.

    Arm title
    		 STM 300 mg
    Arm description
    		 Subjects received STM 50 mg (as initial dose level), tablets, orally, once daily within 1 hour prior to bedtime in Week 1 then up-titrated to 100 mg in Week 2, 200 mg in Week 3 and continued taking STM 300 mg as a target dose until Week 15.
    Arm type
    		 Experimental

    Investigational medicinal product name
    STM
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    STM was administered orally as tablets once daily within 1 hour prior to bedtime until Week 15.

    Number of subjects in period 1
    		Placebo STM 100 mg STM 200 mg STM 300 mg
    Started
    75
    74
    74
    75
    Completed
    71
    70
    64
    67
    Not completed
    4
    4
    10
    8
         Consent withdrawn by subject
    3
    2
    1
    2
         Adverse event, non-fatal
    -
    1
    6
    4
         Other
    1
    1
    2
    1
         Lost to follow-up
    -
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received STM matched placebo, tablets, orally, once daily within 1 hour prior to bedtime for 15 weeks.

    Reporting group title
    STM 100 mg
    Reporting group description
    		 Subjects received STM 50 milligrams (mg) (as initial dose level), tablets, orally, once daily within 1 hour prior to bedtime in Week 1 then up-titrated to 100 mg in Weeks 2 and 3 and continued taking 100 mg as a target dose until Week 15.

    Reporting group title
    STM 200 mg
    Reporting group description
    		 Subjects received STM 50 mg (as initial dose level), tablets, orally, once daily within 1 hour prior to bedtime in Week 1 then up-titrated to 100 mg in Week 2, 200 mg in Week 3 and continued taking 200 mg as a target dose until Week 15.

    Reporting group title
    STM 300 mg
    Reporting group description
    		 Subjects received STM 50 mg (as initial dose level), tablets, orally, once daily within 1 hour prior to bedtime in Week 1 then up-titrated to 100 mg in Week 2, 200 mg in Week 3 and continued taking STM 300 mg as a target dose until Week 15.

    Reporting group values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg Total
    Number of subjects
    		 75 74 74 75 298
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 63 53 56 52 224
        From 65-84 years
    		 12 21 18 23 74
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.0 ( 8.8 ) 56.9 ( 11.3 ) 54.8 ( 11.6 ) 56.5 ( 10.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 23 18 19 18 78
        Male
    		 52 56 55 57 220
    Race
    Units: Subjects
        White
    		 14 15 20 16 65
        Missing
    		 60 59 53 59 231
        Other
    		 1 0 1 0 2
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 71 67 61 72 271
        Hispanic or Latino
    		 2 3 7 3 15
        Missing
    		 2 4 6 0 12

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received STM matched placebo, tablets, orally, once daily within 1 hour prior to bedtime for 15 weeks.

    Reporting group title
    STM 100 mg
    Reporting group description
    		 Subjects received STM 50 milligrams (mg) (as initial dose level), tablets, orally, once daily within 1 hour prior to bedtime in Week 1 then up-titrated to 100 mg in Weeks 2 and 3 and continued taking 100 mg as a target dose until Week 15.

    Reporting group title
    STM 200 mg
    Reporting group description
    		 Subjects received STM 50 mg (as initial dose level), tablets, orally, once daily within 1 hour prior to bedtime in Week 1 then up-titrated to 100 mg in Week 2, 200 mg in Week 3 and continued taking 200 mg as a target dose until Week 15.

    Reporting group title
    STM 300 mg
    Reporting group description
    		 Subjects received STM 50 mg (as initial dose level), tablets, orally, once daily within 1 hour prior to bedtime in Week 1 then up-titrated to 100 mg in Week 2, 200 mg in Week 3 and continued taking STM 300 mg as a target dose until Week 15.

    Primary: Relative Change From Baseline in Percentage of Score of Apnea-Hypopnea Index (AHI) at Week 15 as Measured by Polysomnography (PSG)

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    End point title
    		 Relative Change From Baseline in Percentage of Score of Apnea-Hypopnea Index (AHI) at Week 15 as Measured by Polysomnography (PSG)
    End point description
    AHI was the number of apneas or hypopneas per hour of sleep. AHI severity was classified as follows: none/minimal: less than (<) 5.0, mild: 5.0 to <15.0, moderate: 15.0 to <31.0, severe: greater than or equal to (>=) 31.0. AHI scores are events (apneas or hypopneas) per hour. PSG is a assessment of sleep. The PSG measures the physiological process of sleep by monitoring body functions including brain waves, eye movements, muscle activity or skeletal muscle activation, heart rhythm, blood oxygen saturation, and breathing functions. Scoring of the AHI was conducted in accordance with the American Academy of Sleep Medicine (AASM) version 2.6 with a definition of AHI of 3% including arousals. Relative change was calculated as 100*absolute change/baseline value. The FAS consisted of all randomized subjects.
    End point type
    Primary
    End point timeframe
    Baseline and at Week 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: percentage of score
    least squares mean (standard error)
        Primary estimand
    3.1 ( 5.3 )
    -13.2 ( 5.5 )
    -27.1 ( 5.9 )
    -31.4 ( 5.4 )
        Secondary estimand
    5.0 ( 6.0 )
    -12.8 ( 5.7 )
    -29.8 ( 6.0 )
    -34.9 ( 5.8 )
    Statistical analysis title
    		 Primary estimand: STM 100 mg versus Placebo
    Statistical analysis description
    Least square means (LSM) differences, standard error (SE), and 95% confidence intervals (CIs) as well as the p-values were obtained from an analysis of covariance (ANCOVA) with relative change from baseline in AHI as dependent variable, randomized treatment group (STM group versus placebo, reference placebo) as independent variable, and the baseline AHI score as covariate, where baseline AHI was defined as the mean of the 2 baseline PSG assessments.
    Comparison groups
    Placebo v STM 100 mg
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.0319
    Method
    		 ANCOVA
    Parameter type
    		 LSM difference
    Point estimate
    -16.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.3
         upper limit
    		 -1.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.6
    Notes
    [1] - Primary estimand followed a treatment policy approach for intercurrent events (ICEs) related to the discontinuation of study drug (where prohibited medication was not received), treatment non-compliance, emergency unblinding, and a hypothetical strategy for death and ICEs related to the receipt of prohibited medication. For primary estimand, any monotone missing data or data considered missing due to hypothetical handling of an ICE were imputed based on the set of all subjects in placebo arm.
    Statistical analysis title
    		 Primary estimand: STM 200 mg versus Placebo
    Statistical analysis description
    LSM differences, SE, and 95% CIs as well as the p-values were obtained from an ANCOVA with relative change from baseline in AHI as dependent variable, randomized treatment group (STM group versus placebo, reference placebo) as independent variable, and the baseline AHI score as covariate, where baseline AHI was defined as the mean of the 2 baseline PSG assessments.
    Comparison groups
    STM 200 mg v Placebo
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LSM difference
    Point estimate
    -30.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -45.4
         upper limit
    		 -15.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.7
    Notes
    [2] - Primary estimand followed a treatment policy approach for intercurrent events (ICEs) related to the discontinuation of study drug (where prohibited medication was not received), treatment non-compliance, emergency unblinding, and a hypothetical strategy for death and ICEs related to the receipt of prohibited medication. For primary estimand, any monotone missing data or data considered missing due to hypothetical handling of an ICE were imputed based on the set of all subjects in placebo arm.
    Statistical analysis title
    		 Primary estimand: STM 300 mg versus Placebo
    Statistical analysis description
    LSM differences, SE, and 95% CIs as well as the p-values were obtained from an ANCOVA with relative change from baseline in AHI as dependent variable, randomized treatment group (STM group versus placebo, reference placebo) as independent variable, and the baseline AHI score as covariate, where baseline AHI was defined as the mean of the 2 baseline PSG assessments.
    Comparison groups
    Placebo v STM 300 mg
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LSM difference
    Point estimate
    -34.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -49.1
         upper limit
    		 -20
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.4
    Notes
    [3] - Primary estimand followed a treatment policy approach for intercurrent events (ICEs) related to the discontinuation of study drug (where prohibited medication was not received), treatment non-compliance, emergency unblinding, and a hypothetical strategy for death and ICEs related to the receipt of prohibited medication. For primary estimand, any monotone missing data or data considered missing due to hypothetical handling of an ICE were imputed based on the set of all subjects in placebo arm.
    Statistical analysis title
    		 Secondary estimand: STM 100 mg versus Placebo
    Statistical analysis description
    Least square means (LSM) differences, standard error (SE), and 95% confidence intervals (CIs) as well as the p-values were obtained from an analysis of covariance (ANCOVA) with relative change from baseline in AHI as dependent variable, randomized treatment group (STM group versus placebo, reference placebo) as independent variable, and the baseline AHI score as covariate, where baseline AHI was defined as the mean of the 2 baseline PSG assessments.
    Comparison groups
    Placebo v STM 100 mg
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.0317
    Method
    		 ANCOVA
    Parameter type
    		 LSM difference
    Point estimate
    -17.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.1
         upper limit
    		 -1.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.3
    Notes
    [4] - The secondary estimand applied a hypothetical strategy approach for all ICEs. Missing data were multiple imputed. For the secondary estimand, any monotone missing data or data considered missing due to an ICE were imputed based on the set of all subjects data from the randomized treatment group.
    Statistical analysis title
    		 Secondary estimand: STM 200 mg versus Placebo
    Statistical analysis description
    LSM differences, SE, and 95% CIs as well as the p-values were obtained from an ANCOVA with relative change from baseline in AHI as dependent variable, randomized treatment group (STM group versus placebo, reference placebo) as independent variable, and the baseline AHI score as covariate, where baseline AHI was defined as the mean of the 2 baseline PSG assessments.
    Comparison groups
    STM 200 mg v Placebo
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LSM difference
    Point estimate
    -34.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51.8
         upper limit
    		 -17.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.7
    Notes
    [5] - The secondary estimand applied a hypothetical strategy approach for all ICEs. Missing data were multiple imputed. For the secondary estimand, any monotone missing data or data considered missing due to an ICE were imputed based on the set of all subjects data from the randomized treatment group.
    Statistical analysis title
    		 Secondary estimand: STM 300 mg versus Placebo
    Statistical analysis description
    LSM differences, SE, and 95% CIs as well as the p-values were obtained from an ANCOVA with relative change from baseline in AHI as dependent variable, randomized treatment group (STM group versus placebo, reference placebo) as independent variable, and the baseline AHI score as covariate, where baseline AHI was defined as the mean of the 2 baseline PSG assessments.
    Comparison groups
    Placebo v STM 300 mg
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LSM difference
    Point estimate
    -39.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -56
         upper limit
    		 -23.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.2
    Notes
    [6] - The secondary estimand applied a hypothetical strategy approach for all ICEs. Missing data were multiple imputed. For the secondary estimand, any monotone missing data or data considered missing due to an ICE were imputed based on the set of all subjects data from the randomized treatment group.

    Secondary: Relative Change From Baseline in Percentage of Score of AHI at Week 4 as Measured by PSG

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    End point title
    		 Relative Change From Baseline in Percentage of Score of AHI at Week 4 as Measured by PSG
    End point description
    AHI was the number of apneas or hypopneas per hour of sleep. AHI severity was classified as follows: none/minimal: <5.0, mild: 5.0 to <15.0, moderate: 15.0 to <31.0, severe: >=31.0. AHI scores are events (apneas or hypopneas) per hour. PSG is a assessment of sleep. The PSG measures the physiological process of sleep by monitoring body functions including brain waves, eye movements, muscle activity or skeletal muscle activation, heart rhythm, blood oxygen saturation, and breathing functions. Scoring of the AHI was conducted in accordance with the American Academy of Sleep Medicine (AASM) version 2.6 with a definition of AHI of 3% including arousals. Relative change was calculated as 100*absolute change/baseline value. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and at Week 4
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: percentage of score
        least squares mean (standard error)
    4.1 ( 5.0 )
    -9.0 ( 5.3 )
    -36.1 ( 5.3 )
    -43.3 ( 4.9 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in AHI at Weeks 4 and 15 as Measured by PSG

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    End point title
    		 Absolute Change From Baseline in AHI at Weeks 4 and 15 as Measured by PSG
    End point description
    AHI was the number of apneas or hypopneas per hour of sleep. AHI severity was classified as follows: none/minimal: <5.0, mild: 5.0 to <15.0, moderate: 15.0 to <31.0, severe: >=31.0. PSG is a assessment of sleep. The PSG measures the physiological process of sleep by monitoring body functions including brain waves, eye movements, muscle activity or skeletal muscle activation, heart rhythm, blood oxygen saturation, and breathing functions. Scoring of the AHI was conducted in accordance with the American Academy of Sleep Medicine (AASM) version 2.6 with a definition of AHI of 3% including arousals. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 4 and 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: event/hour
    least squares mean (standard error)
        Change at Week 4
    1.3549 ( 1.3599 )
    -2.9822 ( 1.4159 )
    -10.5746 ( 1.3932 )
    -12.5846 ( 1.3334 )
        Change at Week 15
    1.0526 ( 1.5157 )
    -3.7406 ( 1.5607 )
    -8.1983 ( 1.6038 )
    -9.3395 ( 1.5491 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving >= 50% Reduction From Baseline in AHI and Achieving AHI < 15 at Weeks 4 and 15

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    End point title
    		 Percentage of Subjects Achieving >= 50% Reduction From Baseline in AHI and Achieving AHI < 15 at Weeks 4 and 15
    End point description
    AHI was the number of apneas or hypopneas per hour of sleep. AHI severity was classified as follows: none/minimal: <5.0, mild: 5.0 to <15.0, moderate: 15.0 to <31.0, severe: >=31.0. Scoring of the AHI was conducted in accordance with the American Academy of Sleep Medicine (AASM) version 2.6 with a definition of AHI of 3% including arousals. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 4 and 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: percentage of subjects
    number (not applicable)
        >= 50% reduction from Baseline in AHI at Week 4
    12.0
    16.2
    36.5
    50.7
        >= 50% reduction from Baseline in AHI at Week 15
    9.3
    23.0
    32.4
    33.3
        AHI <15 at Week 4
    17.3
    23.0
    47.3
    54.7
        AHI <15 at Week 15
    18.7
    29.7
    39.2
    46.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who Transitioned to a Lower AHI Severity Class From Baseline at Week 4 and 15

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    End point title
    		 Percentage of Subjects who Transitioned to a Lower AHI Severity Class From Baseline at Week 4 and 15
    End point description
    AHI was the number of apneas or hypopneas per hour of sleep. AHI severity was classified as follows: none/minimal: <5.0, mild: 5.0 to <15.0, moderate: 15.0 to <31.0, severe: >=31.0. A transition in a lower AHI severity class was defined as None/Minimal (AHI <5.0), Mild (AHI 5.0 to <15.0) or Moderate (AHI 15.0 to <31.0) (for Severe AHI at Baseline) at Weeks 4 or 15, respectively. Scoring of the AHI was conducted in accordance with the American Academy of Sleep Medicine (AASM) version 2.6 with a definition of AHI of 3% including arousals. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4 and 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: percentage of subjects
    number (not applicable)
        Week 4
    26.7
    37.8
    67.6
    76.0
        Week 15
    34.7
    36.5
    56.8
    61.3
    No statistical analyses for this end point

    Secondary: Change From Baseline in Oxygen Desaturation Index (ODI) 3 Percentage (%) and 4% at Weeks 4 and 15

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    End point title
    		 Change From Baseline in Oxygen Desaturation Index (ODI) 3 Percentage (%) and 4% at Weeks 4 and 15
    End point description
    ODI 3% was the number of times per hour where the oxygen saturation falls by at least 3% from baseline and ODI 4% was the number of times per hour during time in bed where the oxygen saturation falls by at least 4% from baseline. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 4 and 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: events per hour
    least squares mean (standard error)
        Change in ODI 3% at Week 4
    1.2446 ( 1.0278 )
    -1.6424 ( 1.0487 )
    -7.9822 ( 1.0507 )
    -8.7869 ( 1.0009 )
        Change in ODI 3% at Week 15
    0.2052 ( 1.1232 )
    -1.9362 ( 1.1405 )
    -5.3416 ( 1.1951 )
    -6.2627 ( 1.1372 )
        Change in ODI 4% at Week 4
    1.3730 ( 0.8322 )
    -0.7597 ( 0.8486 )
    -5.3371 ( 0.8505 )
    -5.5038 ( 0.8103 )
        Change in ODI 4% at Week 15
    0.5858 ( 0.9316 )
    -0.7579 ( 0.9458 )
    -2.9943 ( 0.9906 )
    -3.5966 ( 0.9427 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Overnight Oxygen Saturation (SaO2) at Weeks 4 and 15

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    End point title
    		 Change From Baseline in Mean Overnight Oxygen Saturation (SaO2) at Weeks 4 and 15
    End point description
    Change from baseline mean SaO2 during time in bed was reported. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 4 and 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: percentage of oxygen saturation
    least squares mean (standard error)
        Change in Mean Overnight SaO2 at Week 4
    0.0967 ( 0.2040 )
    0.5069 ( 0.2086 )
    1.1477 ( 0.2087 )
    1.1106 ( 0.1983 )
        Change in Mean Overnight SaO2 at Week 15
    0.0737 ( 0.1282 )
    0.3520 ( 0.1303 )
    1.0190 ( 0.1382 )
    0.9467 ( 0.1312 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Minimum Overnight SaO2 at Week 4 and 15

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    End point title
    		 Change From Baseline in Minimum Overnight SaO2 at Week 4 and 15
    End point description
    Change from baseline minimum SaO2 during time in bed was reported. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 4 and 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: percentage of oxygen saturation
    least squares mean (standard error)
        Change in Minimum Overnight SaO2 at Week 4
    0.7067 ( 0.5759 )
    -0.6282 ( 0.5877 )
    0.2362 ( 0.5886 )
    0.2613 ( 0.5595 )
        Change in Minimum Overnight SaO2 at Week 15
    1.5396 ( 0.5569 )
    -0.3602 ( 0.5650 )
    0.3908 ( 0.5972 )
    -0.1846 ( 0.5671 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Percentage of Total Sleep Time (TST) With SaO2 <90% on PSG Night at Week 4 and 15

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    End point title
    		 Change From Baseline in Percentage of Total Sleep Time (TST) With SaO2 <90% on PSG Night at Week 4 and 15
    End point description
    TST was defined as the total time asleep using PSG. PSG is a assessment of sleep. The PSG measures the physiological process of sleep by monitoring body functions including brain waves, eye movements, muscle activity or skeletal muscle activation, heart rhythm, blood oxygen saturation, and breathing functions. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 4 and 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: percentage of TST
    median (inter-quartile range (Q1-Q3))
        Change in SaO2<90% at Week 4 (n=72,69,68,72)
    -0.200 (-2.310 to 1.440)
    -0.260 (-2.620 to 0.640)
    -0.970 (-2.535 to -0.065)
    -0.510 (-3.845 to 0.000)
        Change in SaO2<90% at Week 15 (n=68,67,59,61)
    -0.295 (-2.580 to 1.110)
    -0.420 (-3.100 to 0.280)
    -0.480 (-3.090 to 0.040)
    -0.300 (-3.130 to 0.470)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Percentage of Stage Non-rapid Eye Movement (NREM) 1 (N1), NREM Stage 2 (N2), and NREM Stage 3 (N3) Sleeps, Rapid Eye Movement (REM) Sleep Time at Week 4 and 15

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    End point title
    		 Change From Baseline in Percentage of Stage Non-rapid Eye Movement (NREM) 1 (N1), NREM Stage 2 (N2), and NREM Stage 3 (N3) Sleeps, Rapid Eye Movement (REM) Sleep Time at Week 4 and 15
    End point description
    The change from baseline in percentage of sleep time of NREM sleep stages N1 (light sleep), N2 (also fairly light, with sudden increases in brain wave frequency known as sleep spindles), N3 (slow wave or deep sleep) and REM sleep was reported. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 4 and 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: percentage of sleep time
    least squares mean (standard error)
        Change in Percentage of N1 Sleep at Week 4
    0.2126 ( 0.6174 )
    -0.1827 ( 0.6337 )
    -0.1886 ( 0.6333 )
    -2.0885 ( 0.6014 )
        Change in Percentage of N1 Sleep at Week 15
    0.4373 ( 0.6748 )
    0.3042 ( 0.6878 )
    -0.5791 ( 0.7231 )
    -1.2720 ( 0.6864 )
        Change in Percentage of N2 Sleep at Week 4
    2.4328 ( 0.8665 )
    4.3508 ( 0.8885 )
    5.1058 ( 0.8860 )
    6.7771 ( 0.8430 )
        Change in Percentage of N2 Sleep at Week 15
    3.0319 ( 0.9403 )
    1.0809 ( 0.9577 )
    5.8111 ( 1.0067 )
    5.3470 ( 0.9572 )
        Change in Percentage of N3 Sleep at Week 4
    -1.2726 ( 0.7378 )
    -2.2645 ( 0.7564 )
    -1.1551 ( 0.7550 )
    -0.5577 ( 0.7195 )
        Change in Percentage of N3 Sleep at Week 15
    -2.2449 ( 0.7980 )
    -0.5508 ( 0.8134 )
    -2.5343 ( 0.8522 )
    -0.3423 ( 0.8118 )
        Change in Percentage of REM Sleep at Week 4
    -1.2591 ( 0.6097 )
    -1.9773 ( 0.6271 )
    -3.6887 ( 0.6232 )
    -4.1920 ( 0.5912 )
        Change in Percentage of REM Sleep at Week 15
    -1.0971 ( 0.6424 )
    -0.9321 ( 0.6556 )
    -2.6377 ( 0.6898 )
    -3.7777 ( 0.6544 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Other Sleep Quality Parameter: Total Arousal Index During TST Based on PSG at Weeks 4 and 15

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    End point title
    		 Change From Baseline in Other Sleep Quality Parameter: Total Arousal Index During TST Based on PSG at Weeks 4 and 15
    End point description
    The arousal index indicates the number of arousals from sleep per hour which last at least 3 seconds. TST was defined as the total time asleep using PSG. PSG is a assessment of sleep. The PSG measures the physiological process of sleep by monitoring body functions including brain waves, eye movements, muscle activity or skeletal muscle activation, heart rhythm, blood oxygen saturation, and breathing functions. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 4 and 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: events per hour
    least squares mean (standard error)
        Change at Week 4
    1.1559 ( 0.9549 )
    -1.2494 ( 0.9773 )
    -4.5463 ( 0.9769 )
    -5.9754 ( 0.9288 )
        Change at Week 15
    0.8981 ( 1.0447 )
    -2.2124 ( 1.0626 )
    -4.8210 ( 1.1191 )
    -5.8134 ( 1.0629 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Other Sleep Quality Parameter: Sleep efficiency Based on PSG at Weeks 4 and 15

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    End point title
    		 Change From Baseline in Other Sleep Quality Parameter: Sleep efficiency Based on PSG at Weeks 4 and 15
    End point description
    Sleep efficiency refers to the percentage of time a subject sleeps, in relation to the amount of time the subject spends in bed. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 4 and 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: percentage of time in bed sleeping
    least squares mean (standard error)
        Change at Week 4
    -1.6357 ( 1.1796 )
    0.3630 ( 1.2034 )
    -0.0241 ( 1.2046 )
    -1.1997 ( 1.1457 )
        Change at Week 15
    -2.0994 ( 1.1010 )
    0.6276 ( 1.1177 )
    2.3200 ( 1.1750 )
    -0.0647 ( 1.1169 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Other Sleep Quality Parameter: Total Sleep Time (TST) Based on PSG at Weeks 4 and 15

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    End point title
    		 Change From Baseline in Other Sleep Quality Parameter: Total Sleep Time (TST) Based on PSG at Weeks 4 and 15
    End point description
    TST was defined as the total time asleep (in minutes) using PSG. PSG is a assessment of sleep. The PSG measures the physiological process of sleep by monitoring body functions including brain waves, eye movements, muscle activity or skeletal muscle activation, heart rhythm, blood oxygen saturation, and breathing functions. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 4 and 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: minutes
    least squares mean (standard error)
        Change at Week 4
    -6.8285 ( 5.6058 )
    2.5871 ( 5.7197 )
    -3.0824 ( 5.7250 )
    -6.0265 ( 5.4433 )
        Change at Week 15
    -9.4841 ( 5.3791 )
    2.8998 ( 5.4617 )
    12.4267 ( 5.7446 )
    -0.6546 ( 5.4597 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Score of Patient Global Impression Scale Rating Severity (PGI-S) Score at Weeks 4, 8 and 15

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    End point title
    		 Change From Baseline in Mean Score of Patient Global Impression Scale Rating Severity (PGI-S) Score at Weeks 4, 8 and 15
    End point description
    PGI-S was self-administered questionnaire employed a 4-point scale ranging from 1 to 4, where 1=normal, 2=mild, 3=moderate, 4=severe. The higher score indicates severe outcomes. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 4, 8 and 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: score on a scale
    least squares mean (standard error)
        Change at Week 4
    -0.1941 ( 0.0861 )
    -0.1040 ( 0.0861 )
    -0.3288 ( 0.0881 )
    -0.1445 ( 0.0831 )
        Change at Week 8
    -0.3336 ( 0.0906 )
    -0.2439 ( 0.0906 )
    -0.3620 ( 0.0929 )
    -0.1991 ( 0.0885 )
        Change at Week 15
    -0.3731 ( 0.0954 )
    -0.1210 ( 0.0954 )
    -0.5385 ( 0.0997 )
    -0.1159 ( 0.0943 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Score of Clinical Global Impression Scale Rating Severity (CGI-S) Score at Weeks 4, 8 and 15

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    End point title
    		 Change From Baseline in Mean Score of Clinical Global Impression Scale Rating Severity (CGI-S) Score at Weeks 4, 8 and 15
    End point description
    CGI-S questionnaire was completed by the investigator, employed a 7-point scale to assess the severity of the subject's condition, ranging from 1 to 7, where 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill. The higher score indicates severe outcomes. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 4, 8 and 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: score on a scale
    least squares mean (standard error)
        Change at Week 4
    -0.2319 ( 0.0813 )
    -0.1376 ( 0.0819 )
    -0.3096 ( 0.0826 )
    -0.1924 ( 0.0794 )
        Change at Week 8
    -0.3838 ( 0.0969 )
    -0.2842 ( 0.0977 )
    -0.3617 ( 0.0993 )
    -0.3994 ( 0.0958 )
        Change at Week 15
    -0.4786 ( 0.1021 )
    -0.2242 ( 0.1029 )
    -0.4837 ( 0.1071 )
    -0.3427 ( 0.1019 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reported as Improved (Scores 1 to 2) on Patient Global Impression Scale Rating Improvement (PGI-I) at Weeks 4, 8 and 15

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    End point title
    		 Percentage of Subjects Reported as Improved (Scores 1 to 2) on Patient Global Impression Scale Rating Improvement (PGI-I) at Weeks 4, 8 and 15
    End point description
    The PGI-I was a self-administered questionnaire, and improvement was rated using the PGI-I. PGI-I employed a 7-point scale, where the scale ranged from 1 to 7, where 1= very much better, 2= much better, 3= a little better, 4= no change, 5= a little worse, 6= much worse, 7= very much worse. The higher score indicates severe outcomes. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    At Weeks 4, 8 and 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: percentage of subjects
    number (not applicable)
        Improved (Scores 1 or 2) at Week 4
    10.7
    9.5
    14.9
    13.3
        Improved (Scores 1 or 2) at Week 8
    12.0
    13.5
    16.2
    17.3
        Improved (Scores 1 or 2) at Week 15
    20.0
    17.6
    23.0
    18.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reported as Improved (Scores 1 to 2) on Clinical Global Impression Scale Rating Improvement (CGI-I) at Weeks 4, 8 and 15

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    End point title
    		 Percentage of Subjects Reported as Improved (Scores 1 to 2) on Clinical Global Impression Scale Rating Improvement (CGI-I) at Weeks 4, 8 and 15
    End point description
    The CGI-I was a investigator administered questionnaire, and improvement was rated using the CGI-I scale. CGI-I employed a 7-point scale, where the scale ranged from 1 to 7, where 1= very much improved, 2=much improved, 3=minimally improved, 4= no change, 5=minimally worse, 6= much worse, 7= very much worse due to treatment. The higher score indicates severe outcomes. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    At Weeks 4, 8 and 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: percentage of subjects
    number (not applicable)
        Improved (Scores 1 or 2) at Week 4
    5.3
    6.8
    9.5
    17.3
        Improved (Scores 1 or 2) at Week 8
    10.7
    10.8
    20.3
    16.0
        Improved (Scores 1 or 2) at Week 15
    17.3
    12.2
    21.6
    20.0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Total Score of Epworth Sleepiness Scale (ESS) at Weeks 4, 8 and 15

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    End point title
    		 Change From Baseline in Mean Total Score of Epworth Sleepiness Scale (ESS) at Weeks 4, 8 and 15
    End point description
    The ESS was a self-administered questionnaire that employed a total score ranging from 0 to 24, where higher score indicated severe excessive daytime sleepiness. ESS values greater than or equal to (>=) 11 indicate excessive daytime sleepiness and are considered pathological. The FAS consisted of all randomized subjects. Here, “overall number of participants analyzed” signifies participants who were evaluable for this outcome measure and “number analyzed” signifies those participants who were evaluable for the specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 4, 8 and 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: score on a scale
    least squares mean (standard error)
        ESS-Total Score, Change at Week 4 (n=75,74,74,75)
    -0.8120 ( 0.3640 )
    -1.2412 ( 0.3666 )
    -1.4683 ( 0.3693 )
    -0.6610 ( 0.3538 )
        ESS-Total Score, Change at Week 8 (n=75,74,74,75)
    -1.1895 ( 0.3706 )
    -1.4341 ( 0.3741 )
    -1.8111 ( 0.3809 )
    -1.4415 ( 0.3647 )
        ESS-Total Score, Change at Week 15 (n=75,74,74,75)
    -1.214 ( 0.3966 )
    -1.7521 ( 0.4004 )
    -1.6230 ( 0.4136 )
    -1.2856 ( 0.3939 )
        15-<31(Stratum I),Change at Week 4(n= 44,44,44,44)
    -1.1799 ( 0.4391 )
    -0.9841 ( 0.4445 )
    -2.1284 ( 0.4561 )
    -0.7926 ( 0.4287 )
        15-<31(Stratum I), Change at Week8(n=44,44,44,44)
    -1.2191 ( 0.4898 )
    -1.8400 ( 0.4927 )
    -2.2115 ( 0.5094 )
    -1.3065 ( 0.4793 )
        15-<31(Stratum I), Change at Week15(n=44,44,44,44)
    -1.5054 ( 0.5500 )
    -2.2815 ( 0.5570 )
    -1.8277 ( 0.5853 )
    -0.9905 ( 0.5495 )
        31-50(Stratum II), Change at Week4(n=31,30,30,31)
    -0.2302 ( 0.6212 )
    -1.6556 ( 0.6213 )
    -0.5701 ( 0.6098 )
    -0.4854 ( 0.5988 )
        31-50(Stratum II), Change at Week8(n=31,30,30,31)
    -1.0873 ( 0.5687 )
    -0.9112 ( 0.5777 )
    -1.2599 ( 0.5745 )
    -1.6706 ( 0.5637 )
        31-50(Stratum II), Change at Week15(n=31,30,30,31)
    -0.7247 ( 0.5538 )
    -1.0591 ( 0.5565 )
    -1.3322 ( 0.5604 )
    -1.7377 ( 0.5431 )
        ESS <= 10, Change at Week 4 (n=44,43,44,47)
    -0.6582 ( 0.4088 )
    -0.1853 ( 0.4136 )
    -0.1275 ( 0.4241 )
    -0.3671 ( 0.3908 )
        ESS <= 10, Change at Week 8 (n=44,43,44,47)
    -0.6621 ( 0.4353 )
    -0.3331 ( 0.4450 )
    -0.1869 ( 0.4568 )
    -0.3367 ( 0.4233 )
        ESS <= 10, Change at Week 15 (n=44,43,44,47)
    -1.0227 ( 0.4512 )
    -0.8469 ( 0.4580 )
    -0.1370 ( 0.4865 )
    -0.3603 ( 0.4418 )
        ESS >= 11, Change at Week 4 (n=31,31,30,28)
    -0.9511 ( 0.6599 )
    -2.9512 ( 0.6628 )
    -3.2734 ( 0.6530 )
    -1.0750 ( 0.6610 )
        ESS >= 11, Change at Week 8 (n=31,31,30,28)
    -1.9191 ( 0.6396 )
    -3.2104 ( 0.6357 )
    -4.0302 ( 0.6418 )
    -3.1928 ( 0.6433 )
        ESS >= 11, Change at Week 15 (n=31,31,30,28)
    -1.4326 ( 0.7046 )
    -3.2474 ( 0.7074 )
    -3.6138 ( 0.7071 )
    -2.7237 ( 0.7171 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Total Score of Sleep Apnea Quality of Life Index (SAQLI) at Weeks 4, 8 and 15

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    End point title
    		 Change From Baseline in Mean Total Score of Sleep Apnea Quality of Life Index (SAQLI) at Weeks 4, 8 and 15
    End point description
    The SAQLI was a 35-item interview-administered scale that evaluated quality of life associated with sleep apnea in adults. It included four domains (A to D): daily functioning, social interactions, emotional functioning, and symptoms. Items were scored on a 7-point scale ranging from 1 to 7, where 1= all the time to 7= not at all, being the most extreme responses. Item and domain scores were averaged to yield a composite total score between 1 and 7. Higher scores represented better quality of life. For each domain (A to D), the mean score was derived. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 4, 8 and 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change at Week 4
    0.205 ( 0.7720 )
    0.233 ( 0.6169 )
    0.162 ( 0.6025 )
    0.242 ( 0.6697 )
        Change at Week 8
    0.144 ( 0.8624 )
    0.200 ( 0.6777 )
    0.162 ( 0.6639 )
    0.066 ( 0.5729 )
        Change at Week 15
    0.230 ( 0.8094 )
    0.292 ( 0.6751 )
    0.189 ( 0.7042 )
    0.177 ( 0.6394 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Global Score and Mean Domains of Pittsburgh Sleep Quality Index (PSQI) at Weeks 4, 8 and 15

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    End point title
    		 Change From Baseline in Mean Global Score and Mean Domains of Pittsburgh Sleep Quality Index (PSQI) at Weeks 4, 8 and 15
    End point description
    The PSQI was a self-administered questionnaire that assessed sleep quality. It generated seven sub scores of domains/component: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The seven component scores were derived, each scored 0 (no difficulty) to 3 (severe difficulty). The component scores were summed to produce a global score (range 0 to 21). Higher scores indicate worse sleep quality. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 4, 8 and 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: score on a scale
    least squares mean (standard error)
        Global Score at Week 4
    -1.0762 ( 0.2891 )
    -0.9754 ( 0.2916 )
    -1.2147 ( 0.2955 )
    -1.2060 ( 0.2812 )
        Global Score at Week 8
    -0.9515 ( 0.3034 )
    -1.1204 ( 0.3076 )
    -0.9417 ( 0.3122 )
    -1.5333 ( 0.2981 )
        Global Score at Week 15
    -1.3142 ( 0.3078 )
    -1.1400 ( 0.3108 )
    -1.5175 ( 0.3241 )
    -1.7706 ( 0.3060 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment Satisfaction as Assessed by End of Study Interview

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    End point title
    		 Number of Subjects With Treatment Satisfaction as Assessed by End of Study Interview
    End point description
    Subjects satisfaction with the treatment was assessed using an end of study questionnaire developed for this study. Subjects were asked for their satisfaction with treatment and how likely they would continue treatment. Answers ranged from 1 “extremely satisfied/extremely likely” to 7 “extremely dissatisfied/extremely unlikely.” Question asked were: Question 1: Overall, how satisfied or dissatisfied are you with the ability of the medication to treat your obstructive sleep apnea?; Question 2: How likely would you be to continue to take the medication?; Question 3: If you have selected one of answers 4-7 ('Not very likely' to 'Extremely unlikely'), what is the primary reason you chose that you are not very likely or unlikely to take the medication?. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    At Week 17
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: subjects
        Question 1: Extremely satisfied
    7
    4
    6
    1
        Question 1: Very satisfied
    10
    7
    10
    13
        Question 1: Satisfied
    15
    10
    18
    18
        Question 1: Ambivalent
    22
    30
    20
    23
        Question 1: Dissatisfied
    8
    7
    3
    6
        Question 1: Very dissatisfied
    2
    4
    1
    1
        Question 1: Extremely dissatisfied
    2
    3
    1
    5
        Question 2: Extremely Likely
    8
    4
    8
    5
        Question 2: Very Likely
    16
    10
    14
    13
        Question 2: Likely
    13
    17
    13
    14
        Question 2: Not very likely
    17
    17
    14
    18
        Question 2: Unlikely
    4
    4
    6
    7
        Question 2: Very unlikely
    3
    7
    1
    1
        Question 2: Extremely unlikely
    6
    6
    2
    9
        Question 3: Side Effects
    3
    10
    3
    16
        Question 3: Medication ineffective
    23
    22
    13
    16
        Question 3: More effective treatment elsewhere
    0
    1
    1
    1
        Question 3: Inconvenient
    1
    0
    2
    1
        Question 3: Other
    3
    1
    4
    2
        Question 3: Not applicable/no answer
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Systolic Blood pressure (SBP) and Diastolic Blood Pressure (DBP) at Weeks 2, 4, 8, 15 and 17

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    End point title
    		 Change From Baseline in Systolic Blood pressure (SBP) and Diastolic Blood Pressure (DBP) at Weeks 2, 4, 8, 15 and 17
    End point description
    Blood pressure was measured after the subject had been sitting in a quiet room for 5 minutes of rest. The change from baseline in blood pressure at Week 2, 4, 8, 15, and 17 was reported. The FAS consisted of all randomized subjects. Here, "n" refers to number of subjects evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 2, 4, 8, 15 and 17
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: millimetre of mercury (mmHg)
    arithmetic mean (standard deviation)
        DBP at Week 2 (n=72,70,68,73)
    -0.63 ( 8.541 )
    -2.59 ( 6.120 )
    -1.57 ( 7.527 )
    -3.55 ( 7.618 )
        DBP at Week 4 (n=69,68,67,73)
    -0.39 ( 4.935 )
    -1.27 ( 6.221 )
    -1.88 ( 6.052 )
    -1.62 ( 5.466 )
        DBP at Week 8 (n=68,66,64,69)
    -1.44 ( 8.454 )
    -0.68 ( 6.372 )
    -1.64 ( 6.836 )
    -2.36 ( 6.501 )
        DBP at Week 15 (n=66,64,58,65)
    -1.07 ( 6.215 )
    -1.12 ( 6.858 )
    -2.06 ( 5.643 )
    -2.49 ( 5.411 )
        DBP at Week 17 (n=67,60,57,61)
    -2.61 ( 9.468 )
    -2.54 ( 8.112 )
    -0.35 ( 6.541 )
    -2.26 ( 6.771 )
        SBP at Week 2 (n=72,70,68,73)
    -0.72 ( 10.721 )
    -2.57 ( 10.633 )
    -0.86 ( 8.759 )
    -4.87 ( 9.891 )
        SBP at Week 4 (n=69,68,67,73)
    -0.45 ( 7.155 )
    -3.09 ( 9.259 )
    -1.24 ( 7.881 )
    -2.57 ( 8.973 )
        SBP at Week 8 (n=68,66,64,69)
    -2.09 ( 10.528 )
    -0.95 ( 8.858 )
    -2.35 ( 10.169 )
    -4.50 ( 10.716 )
        SBP at Week 15 (n=66,64,58,65)
    -1.08 ( 7.933 )
    -0.12 ( 8.118 )
    -3.14 ( 9.039 )
    -2.62 ( 9.440 )
        SBP at Week 17 (n=67,60,57,61)
    -2.07 ( 13.816 )
    -1.92 ( 11.764 )
    0.18 ( 9.023 )
    0.01 ( 11.756 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Body Weight at Week 15

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    End point title
    		 Change From Baseline in Body Weight at Week 15
    End point description
    The change from baseline in body weight at Week 15 was reported. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and at Week 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: kilogram (kg)
        arithmetic mean (standard deviation)
    0.29 ( 2.276 )
    0.29 ( 2.367 )
    -1.12 ( 2.456 )
    -0.90 ( 2.268 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Circumference of Waist and Hip at Week 15

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    End point title
    		 Change From Baseline in Circumference of Waist and Hip at Week 15
    End point description
    The change from baseline in circumference of waist and hip at Week 15 was reported. The FAS consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and at Week 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: centimetre (cm)
    arithmetic mean (standard deviation)
        Change in Circumference of Waist at Week 15
    0.18 ( 5.074 )
    0.12 ( 5.084 )
    0.08 ( 4.272 )
    -0.78 ( 4.301 )
        Change in Circumference of Hip at Week 15
    0.37 ( 4.267 )
    -0.81 ( 4.092 )
    -1.26 ( 8.932 )
    0.16 ( 7.152 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Metabolic Parameters: Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 15

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    End point title
    		 Change From Baseline in Metabolic Parameters: Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 15
    End point description
    The change from baseline in metabolic parameters, including cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, at Week 15 was reported. The FAS consisted of all randomized subjects. Here, "n" refers to number of subjects evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and at Week 15
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: millimoles per litre (mmol/L)
    arithmetic mean (standard deviation)
        Cholesterol at Week 15 (n=75,74,74,75)
    0.06 ( 0.714 )
    -0.11 ( 0.567 )
    -0.19 ( 0.637 )
    -0.19 ( 0.686 )
        LDL Cholesterol at Week 15 (n=75,73,74,75)
    0.00 ( 0.606 )
    -0.14 ( 0.422 )
    -0.17 ( 0.501 )
    -0.15 ( 0.532 )
        HDL Cholesterol at Week 15 (n=75,74,74,75)
    0.02 ( 0.186 )
    0.02 ( 0.168 )
    0.01 ( 0.119 )
    0.00 ( 0.132 )
        Triglycerides at Week 15 (n=75,74,74,75)
    0.10 ( 0.707 )
    0.15 ( 1.051 )
    -0.07 ( 0.488 )
    -0.01 ( 0.449 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs
    End point description
    A TEAEs was defined as any event emerging or manifesting at or after the initiation of treatment with an investigational product or medicinal product or any existing event that worsened in either intensity or frequency following exposure to the investigational product or medicinal product. An SAE was any untoward medical occurrence or effect that at any dose 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 or was medically important due to other reasons than the above mentioned criteria. Safety analysis set (SAF) included all randomized subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to Week 17
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: subjects
        TEAEs
    46
    54
    62
    68
        Serious TEAEs
    2
    2
    3
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With TEAEs Regarding Clinically Significant Changes in Laboratory Parameters

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    End point title
    		 Number of Subjects With TEAEs Regarding Clinically Significant Changes in Laboratory Parameters
    End point description
    Clinical laboratory parameters included evaluations of hematology, serum chemistry, coagulation, urinalysis, glycated haemoglobin (HbA1c), blood glucose and lipid panel. Any clinically significant change in laboratory parameters was based on the investigator judgment. SAF included all randomized subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to Week 17
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: subjects
        Leukopenia
    0
    0
    0
    1
        Anaemia
    1
    1
    0
    0
        Neutropenia
    0
    1
    0
    0
        Hypothyroidism
    0
    0
    0
    1
        Gamma-glutamyltransferase increased
    0
    1
    0
    1
        Mean cell volume increased
    0
    0
    0
    1
        Activated partial thromboplastin time prolonged
    0
    2
    0
    0
        Alanine aminotransferase increased
    0
    1
    0
    0
        Aspartate aminotransferase increased
    0
    1
    0
    0
        Blood alkaline phosphatase increased
    0
    1
    0
    0
        Blood bilirubin increased
    1
    1
    1
    0
        Blood thyroid stimulating hormone increased
    0
    2
    0
    0
        Hepatic enzyme increased
    0
    1
    0
    0
        Liver function test increased
    1
    0
    0
    0
        Pancreatic enzymes increased
    1
    0
    0
    0
        Urine leukocyte esterase
    0
    0
    1
    0
        Hyperglycaemia
    0
    1
    0
    1
        Type 2 diabetes mellitus
    0
    0
    0
    1
        Hypercholesterolaemia
    0
    0
    1
    0
        Hyperlactacidaemia
    0
    0
    1
    0
        Hypertriglyceridaemia
    0
    2
    0
    0
        Iron deficiency
    0
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Significant Changes in Vital Signs

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    End point title
    		 Number of Subjects With Clinically Significant Changes in Vital Signs
    End point description
    Vital signs included evaluations of systolic and diastolic blood pressure, body temperature, respiratory rate, and pulse. Any clinically significant change in vital signs was based on the investigator judgment. SAF included all randomized subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to Week 17
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: subjects
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Significant Abnormal Body Weight and Body Mass Index (BMI)

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    End point title
    		 Number of Subjects With Clinically Significant Abnormal Body Weight and Body Mass Index (BMI)
    End point description
    Any clinically significant abnormal change in body weight and BMI was based on the investigator judgment. SAF included all randomized subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to Week 17
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: subjects
    0
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Significant Abnormal 12-lead Electrocardiogram (ECG)

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    End point title
    		 Number of Subjects With Clinically Significant Abnormal 12-lead Electrocardiogram (ECG)
    End point description
    12-lead ECG were evaluated. Any clinically significant abnormal change in 12-lead ECG was based on the investigator judgment. SAF included all randomized subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to Week 17
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: subjects
    1
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Significant Abnormal Physical Examination

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    End point title
    		 Number of Subjects With Clinically Significant Abnormal Physical Examination
    End point description
    Physical examination included assessments of the head, eyes, ears, nose and throat, cardiovascular, respiratory, abdomen, skin, cervical and axillary lymph nodes, and neurological and musculoskeletal systems. Any clinically significant abnormal change in physical examination was based on the investigator judgment. SAF included all randomized subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to Week 17
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: subjects
    2
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Any Suicidal Ideation (SI) and Suicidal Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS)

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    End point title
    		 Number of Subjects With Any Suicidal Ideation (SI) and Suicidal Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS)
    End point description
    The C-SSRS is described as a scale developed at Columbia University that has 2-6 questions each in categories of suicidal ideation (SI), Intensity of Ideation, suicidal behavior, and actual attempts. Four constructs were measured. Severity of Suicidal ideation is rated on a 5-point ordinal scale. Intensity of ideation is comprised of 5 items (frequency, duration, controllability, deterrents, and reason for ideation), each rated on a 5-point ordinal scale. Suicidal behavior is rated on a nominal scale that includes actual, aborted, and interrupted attempts; preparatory behavior; and non-suicidal self-injurious behavior. Lethality, assesses actual attempts; actual lethality is rated on a 6-point ordinal scale, and if actual lethality is 0, potential lethality of attempts is rated on a 3-point ordinal scale. The higher the C-SSRS score, the higher the suicide risk (i.e. worse outcome). SAF included all randomized subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 17
    End point values
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Number of subjects analysed
    75
    74
    74
    75
    Units: subjects
        Any SI
    0
    1
    1
    2
        Any Suicidal Behavior
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug up to Week 17
    Adverse event reporting additional description
    SAF included all randomized subjects who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received STM matched placebo, tablets, orally, once daily within 1 hour prior to bedtime for 15 weeks.

    Reporting group title
    STM 100 mg
    Reporting group description
    		 Subjects received STM 50 milligrams (mg) (as initial dose level), tablets, orally, once daily within 1 hour prior to bedtime in Week 1 then up-titrated to 100 mg in Weeks 2 and 3 and continued taking 100 mg as a target dose until Week 15.

    Reporting group title
    STM 200 mg
    Reporting group description
    		 Subjects received STM 50 mg (as initial dose level), tablets, orally, once daily within 1 hour prior to bedtime in Week 1 then up-titrated to 100 mg in Week 2, 200 mg in Week 3 and continued taking 200 mg as a target dose until Week 15.

    Reporting group title
    STM 300 mg
    Reporting group description
    		 Subjects received STM 50 mg (as initial dose level), tablets, orally, once daily within 1 hour prior to bedtime in Week 1 then up-titrated to 100 mg in Week 2, 200 mg in Week 3 and continued taking STM 300 mg as a target dose until Week 15.

    Serious adverse events
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 75 (2.67%)
    2 / 74 (2.70%)
    3 / 74 (4.05%)
    1 / 75 (1.33%)
         number of deaths (all causes)
    0
    1
    0
    0
         number of deaths resulting from adverse events
    0
    1
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Meniscus injury
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Trigeminal nerve disorder
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Somatic symptom disorder
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo STM 100 mg STM 200 mg STM 300 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 75 (44.00%)
    36 / 74 (48.65%)
    55 / 74 (74.32%)
    60 / 75 (80.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 75 (4.00%)
    6 / 74 (8.11%)
    1 / 74 (1.35%)
    3 / 75 (4.00%)
         occurrences all number
    3
    6
    1
    3
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    7 / 75 (9.33%)
    16 / 74 (21.62%)
    32 / 74 (43.24%)
    43 / 75 (57.33%)
         occurrences all number
    8
    17
    38
    53
    Headache
         subjects affected / exposed
    7 / 75 (9.33%)
    5 / 74 (6.76%)
    14 / 74 (18.92%)
    11 / 75 (14.67%)
         occurrences all number
    9
    5
    15
    13
    Dizziness
         subjects affected / exposed
    1 / 75 (1.33%)
    2 / 74 (2.70%)
    4 / 74 (5.41%)
    2 / 75 (2.67%)
         occurrences all number
    1
    3
    4
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 75 (4.00%)
    5 / 74 (6.76%)
    4 / 74 (5.41%)
    6 / 75 (8.00%)
         occurrences all number
    3
    5
    4
    6
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 75 (2.67%)
    1 / 74 (1.35%)
    4 / 74 (5.41%)
    6 / 75 (8.00%)
         occurrences all number
    2
    1
    4
    7
    Diarrhoea
         subjects affected / exposed
    3 / 75 (4.00%)
    5 / 74 (6.76%)
    5 / 74 (6.76%)
    3 / 75 (4.00%)
         occurrences all number
    3
    6
    7
    3
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    4 / 75 (5.33%)
         occurrences all number
    1
    0
    1
    4
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 74 (1.35%)
    4 / 74 (5.41%)
    3 / 75 (4.00%)
         occurrences all number
    1
    1
    4
    3
    Infections and infestations
    COVID-19
         subjects affected / exposed
    3 / 75 (4.00%)
    4 / 74 (5.41%)
    7 / 74 (9.46%)
    11 / 75 (14.67%)
         occurrences all number
    3
    5
    7
    11
    Nasopharyngitis
         subjects affected / exposed
    10 / 75 (13.33%)
    4 / 74 (5.41%)
    7 / 74 (9.46%)
    7 / 75 (9.33%)
         occurrences all number
    10
    4
    7
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 75 (0.00%)
    4 / 74 (5.41%)
    0 / 74 (0.00%)
    3 / 75 (4.00%)
         occurrences all number
    0
    5
    0
    3
    Glucose tolerance impaired
         subjects affected / exposed
    5 / 75 (6.67%)
    3 / 74 (4.05%)
    2 / 74 (2.70%)
    2 / 75 (2.67%)
         occurrences all number
    5
    3
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jan 2022
    Amendment 1 - An exclusion criterion was added to exclude subjects who are kept in an institution or who might not consent entirely voluntarily - Guidance was added about study withdrawal or continuation regarding patients with an active SARS-CoV-2 infection - SAE reporting timelines were updated according to German ordinance
    29 Mar 2022
    Amendment 2 - The “FLOW” logo and study name were added for consistency with other study-related material - Inclusion criterion #3 was updated in the synopsis to exactly match inclusion criterion #3 in Section 8.1. - Errors regarding the number of weeks of treatment and weeks on target dose related to the PSG sleep studies at Visit 5 were corrected. - Determination of PLMAI for exclusion criterion #3 was clarified. - Exclusion criterion #22 was updated to include patients with infections to be more precise; accordingly, exclusion criterion #24 was removed. - Because of the variability of the COVID-19 situation in different countries, COVID-19 testing will be done per applicable local requirements. The mandatory PCR test at screening was removed. Exclusion criterion #24 (previously #25) was updated accordingly. - To reduce patient burden, the sample frequency for specific laboratory tests was reduced. - Further clarifications were added to the schedule of assessments (Section 10.1). - It was clarified that capillary blood gas analysis will be done locally at selected sites (Section 14). - For consistency with the statistical analysis plan, it was clarified that demographic and baseline characteristics include country and not region (Section 15.4). - The record retention period was changed from 25 years to a minimum of 15 years to account for various country-specific requirements (Section 16.4).
    15 Dec 2022
    Amendment 3 The purpose of this amendment was to decrease the sample size.

    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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