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    Clinical Trial Results:
    A 24-week phase 2, double-blind, randomized, placebo-controlled, single-centre safety and efficacy study to evaluate overall safety and tolerability of co-administration of tesofensine and metoprolol in subjects with hypothalamic injury-induced obesity (HIO), and with a 24-week open-label extension, in total 48 weeks

    Summary
    EudraCT number
    		 2018-003672-12
    Trial protocol
    		 DK  
    Global end of trial date
    16 Oct 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jun 2022
    First version publication date
    25 Jun 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TM005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03845075
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Saniona
    Sponsor organisation address
    Smedeland 26B, Glostrup, Denmark, 2600
    Public contact
    Janus Schreiber Larsen Chief Development Office, Saniona A/S, +45 70 70 52 25, janus.larsen@saniona.com
    Scientific contact
    Janus Schreiber Larsen Chief Development Office, Saniona A/S, +45 70 70 52 25, janus.larsen@saniona.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
    16 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Oct 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To examine overall safety and tolerability of co-administration of 0.5 mg tesofensine/50 mg metoprolol treatment over 24 weeks in subjects with HIO
    Protection of trial subjects
    None
    Background therapy
    		 HIO develops in approx 50% of patients undergoing surgery for suprasellar tumors including craniopharyngeomas. There is no approved therapy for HIO and conventional overweight treatment inclding food restriction has no or limited effect.
    Evidence for comparator
    		 As there is no approved therapy for HIO, placebo is the choice for comparator. All subjects were offered dietetic councelling.
    Actual start date of recruitment
    25 Feb 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 22
    Worldwide total number of subjects
    22
    EEA total number of subjects
    22
    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)
    19
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 21 subjects were recruited within the period of 28Feb2019 to 01Oct2019. Subjects recruited in Denmark only.

    Pre-assignment
    Screening details
    		 35 subjects were screened; 13 subjects were screen failures. A total of 21 unique subjects were assigned 22 randomization numbers. One subject was a screen failure who was randomized in error, and withdrawn after receiving 1 dose of Tesofensine/metoprolol; this subject was later rescreened and rerandomized to placebo.

    Period 1
    Period 1 title
    Part 1 - DB
    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
    		 Tesofensine/Metoprolol
    Arm description
    		 Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tesofensine/Metoprolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet, Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg tesofensine and 50 mg metoprolol - once daily for 24 weeks during Part 1.

    Arm title
    		 Placebo
    Arm description
    		 Subjects were randomized to receive matching placebo tesofensine and placebo metoprolol tablets once daily for 24 weeks during Part 1.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo/Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tesofensine and placebo metoprolol tablets once daily for 24 weeks during Part 1.

    Number of subjects in period 1
    		Tesofensine/Metoprolol Placebo
    Started
    14
    8
    Completed
    12
    6
    Not completed
    2
    2
         Consent withdrawn by subject
    1
    1
         screen failure, but got 1 dose of drug in error
    1
    -
         Adverse event, non-fatal
    -
    1
    Period 2
    Period 2 title
    Part 2 - OLE
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tesofensine/Metoprolol -> Tesofensine/Metoprolol
    Arm description
    		 Subjects who received co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1 and continued to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol once daily for an additional 24 weeks in Part 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tesofensine/Metoprolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet, Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg tesofensine and 50 mg metoprolol - once daily for 24 weeks during Part 2.

    Arm title
    		 Placebo -> Tesofensine/Metoprolol
    Arm description
    		 Subjects who received matching placebo tesofensine and placebo metoprolol tablets once daily for 24 weeks during Part 1 were switched to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol once daily for an additional 24 weeks in Part 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tesofensine/Metoprolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet, Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg tesofensine and 50 mg metoprolol - once daily for 24 weeks during Part 2.

    Number of subjects in period 2
    		Tesofensine/Metoprolol -> Tesofensine/Metoprolol Placebo -> Tesofensine/Metoprolol
    Started
    12
    6
    Completed
    12
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tesofensine/Metoprolol
    Reporting group description
    		 Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were randomized to receive matching placebo tesofensine and placebo metoprolol tablets once daily for 24 weeks during Part 1.

    Reporting group values
    		 Tesofensine/Metoprolol Placebo Total
    Number of subjects
    		 14 8 22
    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)
    		 12 6 18
        From 65-84 years
    		 2 2 4
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 51 (26 to 70) 43 (25 to 67) -
    Gender categorical
    Units: Subjects
        Female
    		 11 6 17
        Male
    		 3 2 5
    Weight
    Units: kg
        median (full range (min-max))
    		 120.3 (86.1 to 144.4) 111.5 (80.4 to 163.1) -

    End points

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    End points reporting groups
    Reporting group title
    Tesofensine/Metoprolol
    Reporting group description
    		 Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were randomized to receive matching placebo tesofensine and placebo metoprolol tablets once daily for 24 weeks during Part 1.
    Reporting group title
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol
    Reporting group description
    		 Subjects who received co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1 and continued to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol once daily for an additional 24 weeks in Part 2.

    Reporting group title
    Placebo -> Tesofensine/Metoprolol
    Reporting group description
    		 Subjects who received matching placebo tesofensine and placebo metoprolol tablets once daily for 24 weeks during Part 1 were switched to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol once daily for an additional 24 weeks in Part 2.

    Primary: Frequency of Treatment Emergent Adverse Events

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    End point title
    		 Frequency of Treatment Emergent Adverse Events [1]
    End point description
    Number and percentage of adverse events in each of the two treatment arms
    End point type
    Primary
    End point timeframe
    from Baseline to week 24
    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: No statistical analyses have been specified for this primary end point. Only descriptive analyses were planned for
    End point values
    		 Tesofensine/Metoprolol Placebo
    Number of subjects analysed
    14
    8
    Units: count of participants
        Frequency of Treatment Emergent Adverse Events
    12
    7
    No statistical analyses for this end point

    Primary: Severity of Treatment Emergent Adverse Events

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    End point title
    		 Severity of Treatment Emergent Adverse Events [2]
    End point description
    Number and percentage of mild, moderate and severe adverse events in each of the two treatment arms
    End point type
    Primary
    End point timeframe
    from Baseline to week 24
    Notes
    [2] - 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: No statistical analyses have been specified for this primary end point. Only descriptive analyses were planned for
    End point values
    		 Tesofensine/Metoprolol Placebo
    Number of subjects analysed
    14
    8
    Units: count of participants
        At least one mild AE
    11
    7
        At least one moderate AE
    10
    5
        At least one severe AE
    2
    2
    No statistical analyses for this end point

    Primary: Frequency and Type of Serious Adverse Events

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    End point title
    		 Frequency and Type of Serious Adverse Events [3]
    End point description
    Number, percentage and type of serious adverse events in each of the two treatment arms
    End point type
    Primary
    End point timeframe
    from Baseline to week 24
    Notes
    [3] - 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: No statistical analyses have been specified for this primary end point. Only descriptive analyses were planned for
    End point values
    		 Tesofensine/Metoprolol Placebo
    Number of subjects analysed
    14
    8
    Units: count of participants
        At least one SAE
    2
    1
        Preferred Term: Anxiety
    1
    0
        Preferred Term: Craniopharyngioma
    1
    0
        Preferred Term: Hyponatraemia
    0
    1
        Preferred Term: Post procedural complication
    1
    0
    No statistical analyses for this end point

    Primary: Safety as Assessed by Systolic Blood Pressure [mmHg]

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    End point title
    		 Safety as Assessed by Systolic Blood Pressure [mmHg]
    End point description
    Systolic blood pressure in mmHg measured at each visit in each of the two treatment arms
    End point type
    Primary
    End point timeframe
    from Baseline to week 24
    End point values
    		 Tesofensine/Metoprolol Placebo
    Number of subjects analysed
    13 [4]
    8 [5]
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline
    124.0 ( 9 )
    134.5 ( 16 )
        Week 4
    126.6 ( 12 )
    131.8 ( 17 )
        Week 8
    129.2 ( 17 )
    126.3 ( 23 )
        Week 12
    126.3 ( 13 )
    126.2 ( 14 )
        Week 16
    123.9 ( 14 )
    126.0 ( 17 )
        Week 20
    127.3 ( 12 )
    129.2 ( 18 )
        Week 24
    125.3 ( 16 )
    130.5 ( 22 )
    Notes
    [4] - number of participants at baseline/W4/W8/W12/W16/20/W24: 13/13/12/12/12/12/12
    [5] - number of participants at baseline/W4/W8/W12/W16/20/W24: 8/8/6/6/6/6/6
    Statistical analysis title
    		 1 for Safety as Assess. by Systolic blood press
    Statistical analysis description
    Week 4; Safety set LOCF
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4671 [6]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.58
         upper limit
    		 13.78
    Notes
    [6] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 2 for Safety as Assess. by Systolic blood press
    Statistical analysis description
    Week 8; Safety set, LOCF
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1808 [7]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    10.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.14
         upper limit
    		 25.36
    Notes
    [7] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 3 for Safety as Assess. by Systolic blood press
    Statistical analysis description
    Week 12; Safety set; LOCF
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4171 [8]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    4.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.08
         upper limit
    		 16.33
    Notes
    [8] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 4 for Safety as Assess. by Systolic blood press
    Statistical analysis description
    Week 16; Safety set; LOCF
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3116 [9]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    5.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.43
         upper limit
    		 16.1
    Notes
    [9] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 5 for Safety as Assess. by Systolic blood press
    Statistical analysis description
    Week 20; Safety set; LOCF
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2353 [10]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    5.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.12
         upper limit
    		 15.72
    Notes
    [10] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 6 for Safety as Assess. by Systolic blood press
    Statistical analysis description
    Week 24; Safety set; LOCF
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3037 [11]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    5.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.76
         upper limit
    		 17.48
    Notes
    [11] - P-value from an ANCOVA model with treatment as factor and baseline as covariate

    Primary: Safety as Assessed by Diastolic Blood Pressure [mmHg]

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    End point title
    		 Safety as Assessed by Diastolic Blood Pressure [mmHg]
    End point description
    Diastolic blood pressure in mmHg measured at each visit in each of the two treatment arms
    End point type
    Primary
    End point timeframe
    from Baseline to week 24
    End point values
    		 Tesofensine/Metoprolol Placebo
    Number of subjects analysed
    13 [12]
    8 [13]
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline
    83.2 ( 14 )
    85.9 ( 8 )
        Week 4
    84.2 ( 8 )
    86.8 ( 8 )
        Week 8
    84.5 ( 9 )
    86.0 ( 9 )
        Week 12
    81.5 ( 10 )
    86.5 ( 8 )
        Week 16
    81.4 ( 9 )
    80.3 ( 13 )
        Week 20
    84.3 ( 9 )
    85.7 ( 9 )
        Week 24
    83.1 ( 9 )
    84.2 ( 13 )
    Notes
    [12] - number of participants at baseline/W4/W8/W12/W16/20/W24: 13/13/12/12/12/12/12
    [13] - number of participants at baseline/W4/W8/W12/W16/20/W24: 8/8/6/6/6/6/6
    Statistical analysis title
    		 1 Safety as assessed by Diastolic Blook Pressure
    Statistical analysis description
    Week 4; Safety set LOCF
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6543 [14]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.33
         upper limit
    		 4.72
    Notes
    [14] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 2 Safety as assessed by Diastolic Blook Pressure
    Statistical analysis description
    Week 8; Safety set LOCF
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7941 [15]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.5
         upper limit
    		 8.38
    Notes
    [15] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 3 Safety as assessed by Diastolic Blook Pressure
    Statistical analysis description
    Week 12; Safety set LOCF
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5937 [16]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.72
         upper limit
    		 5.73
    Notes
    [16] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 4 Safety as assessed by Diastolic Blook Pressure
    Statistical analysis description
    Week 16; Safety set LOCF
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5423 [17]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    2.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.11
         upper limit
    		 11.23
    Notes
    [17] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 5 Safety as assessed by Diastolic Blook Pressure
    Statistical analysis description
    Week 20; Safety set LOCF
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7226 [18]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.77
         upper limit
    		 8.16
    Notes
    [18] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 6 Safety as assessed by Diastolic Blook Pressure
    Statistical analysis description
    Week 24; Safety set LOCF
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7912 [19]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.85
         upper limit
    		 10.16
    Notes
    [19] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.

    Primary: Safety as Assessed by Heart Rate [Bpm]

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    End point title
    		 Safety as Assessed by Heart Rate [Bpm]
    End point description
    Heart rate measured in beats per minute (bpm) at each visit in each of the two treatment arms
    End point type
    Primary
    End point timeframe
    from Baseline to week 24
    End point values
    		 Tesofensine/Metoprolol Placebo
    Number of subjects analysed
    13 [20]
    8 [21]
    Units: bpm
    arithmetic mean (standard deviation)
        Baseline
    75.5 ( 8 )
    78.9 ( 11 )
        Week 4
    71.9 ( 9 )
    75.9 ( 12 )
        Week 8
    72.7 ( 8 )
    76.0 ( 13 )
        Week 12
    74.2 ( 10 )
    73.3 ( 8 )
        Week 16
    73.8 ( 13 )
    74.8 ( 6 )
        Week 20
    74.8 ( 11 )
    77.2 ( 13 )
        Week 24
    73.6 ( 10 )
    71.5 ( 9 )
    Notes
    [20] - number of participants at baseline/W4/W8/W12/W16/20/W24: 13/13/12/12/12/12/12
    [21] - number of participants at baseline/W4/W8/W12/W16/20/W24: 8/8/6/6/6/6/6
    Statistical analysis title
    		 1 Safety as assessed by Heart Rate
    Statistical analysis description
    Week 4; Safety set LOCF
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7023 [22]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.67
         upper limit
    		 5.97
    Notes
    [22] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 2 Safety as assessed by Heart Rate
    Statistical analysis description
    Week 8; Safety set LOCF
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9012 [23]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.58
         upper limit
    		 7.61
    Notes
    [23] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 3 Safety as assessed by Heart Rate
    Statistical analysis description
    Week 12; Safety set LOCF
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6138
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    2.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.63
         upper limit
    		 10.92
    Statistical analysis title
    		 4 Safety as assessed by Heart Rate
    Statistical analysis description
    Week 16; Safety set LOCF
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7889 [24]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.26
         upper limit
    		 10.72
    Notes
    [24] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 5 Safety as assessed by Heart Rate
    Statistical analysis description
    Week 20; Safety set LOCF
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9536 [25]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.34
         upper limit
    		 10.94
    Notes
    [25] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 6 Safety as assessed by Heart Rate
    Statistical analysis description
    Week 24; Safety set LOCF
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5551 [26]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.72
         upper limit
    		 12.12
    Notes
    [26] - P-value from an ANCOVA model with treatment as factor and baseline as covariate

    Primary: Safety as Assessed by Hematology Parameters

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    End point title
    		 Safety as Assessed by Hematology Parameters [27]
    End point description
    Number and percentage of deviations from normal range for hemoglobin, platelet counts, white cells count, differential counts at baseline, week 12 and week 24 in each of the two treatment arms
    End point type
    Primary
    End point timeframe
    from Baseline to week 24
    Notes
    [27] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been specified for this primary end point. Only descriptive analyses were planned for
    End point values
    		 Tesofensine/Metoprolol Placebo
    Number of subjects analysed
    14 [28]
    8 [29]
    Units: counts of participants
        Hemoglobin: Baseline - Low
    0
    0
        Hemoglobin: Baseline - High
    0
    1
        Hemoglobin: Week 12 - Low
    0
    0
        Hemoglobin: Week 12 - High
    0
    0
        Hemoglobin: Week 24 - Low
    1
    0
        Hemoglobin: Week 24 - High
    0
    0
        Platelets: Baseline - Low
    0
    0
        Platelets: Baseline - High
    1
    0
        Platelets: Week 12 - Low
    0
    0
        Platelets: Week 12 - High
    1
    0
        Platelets: Week 24 - Low
    0
    0
        Platelets: Week 24 - High
    1
    0
        WBC: Baseline - Low
    0
    0
        WBC: Baseline - High
    3
    2
        WBC: Week 12 - Low
    0
    0
        WBC: Week 12 - High
    5
    1
        WBC: Week 24 - Low
    0
    0
        WBC: Week 24 - High
    0
    1
        Neutrophils: Baseline - Low
    1
    0
        Neutrophils: Baseline - High
    1
    1
        Neutrophils: Week 12 - Low
    0
    0
        Neutrophils: Week 12 - High
    4
    1
        Neutrophils: Week 24 - Low
    1
    0
        Neutrophils: Week 24 - High
    1
    1
        Monocytes: Baseline - Low
    0
    0
        Monocytes: Baseline - High
    0
    0
        Monocytes: Week 12 - Low
    0
    0
        Monocytes: Week 12 - High
    1
    0
        Monocytes: Week 24 - Low
    0
    0
        Monocytes: Week 24 - High
    1
    0
        Lymphocytes: Baseline - Low
    0
    1
        Lymphocytes: Baseline - High
    1
    2
        Lymphocytes: Week 12 - Low
    0
    1
        Lymphocytes: Week 12 - High
    0
    0
        Lymphocytes: Week 24 - Low
    0
    0
        Lymphocytes: Week 24 - High
    1
    0
    Notes
    [28] - Number of participants at baseline/week 12/week 24: 14/13/12
    [29] - Number of participants at baseline/week 12/week 24: 8/8/6
    No statistical analyses for this end point

    Primary: Safety as Assessed by Electrolytes and Creatinine

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    End point title
    		 Safety as Assessed by Electrolytes and Creatinine [30]
    End point description
    Number and percentage of deviations from normal range for sodium, potassium, creatinine at each visit in each of the two treatment arms
    End point type
    Primary
    End point timeframe
    from Baseline to week 24
    Notes
    [30] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been specified for this primary end point. Only descriptive analyses were planned for
    End point values
    		 Tesofensine/Metoprolol Placebo
    Number of subjects analysed
    14 [31]
    8 [32]
    Units: counts of participants
        Sodium: Baseline - Low
    0
    0
        Sodium: Baseline - High
    2
    2
        Sodium: Week 4 - Low
    0
    0
        Sodium: Week 4 - High
    0
    0
        Sodium: Week 8 - Low
    0
    0
        Sodium: Week 8 - High
    1
    1
        Sodium: Week 12 - Low
    0
    0
        Sodium: Week 12 - High
    1
    0
        Sodium: Week 16 - Low
    0
    0
        Sodium: Week 16 - High
    1
    0
        Sodium: Week 20 - Low
    0
    0
        Sodium: Week 20 - High
    2
    2
        Sodium: Week 24 - Low
    1
    0
        Sodium: Week 24 - High
    0
    1
        Potassium: Baseline - Low
    0
    0
        Potassium: Baseline - High
    0
    1
        Potassium: Week 4 - Low
    2
    1
        Potassium: Week 4 - High
    0
    1
        Potassium: Week 8 - Low
    2
    0
        Potassium: Week 8 - High
    0
    0
        Potassium: Week 12 - Low
    1
    0
        Potassium: Week 12 - High
    0
    0
        Potassium: Week 16 - Low
    1
    0
        Potassium: Week 16 - High
    0
    1
        Potassium: Week 20 - Low
    1
    0
        Potassium: Week 20 - High
    0
    0
        Potassium: Week 24 - Low
    0
    1
        Potassium: Week 24 - High
    0
    0
        Creatinine: Baseline - Low
    3
    2
        Creatinine: Baseline - High
    0
    0
        Creatinine: Week 4 - Low
    2
    4
        Creatinine: Week 4 - High
    0
    0
        Creatinine: Week 8 - Low
    2
    3
        Creatinine: Week 8 - High
    0
    0
        Creatinine: Week 12 - Low
    2
    2
        Creatinine: Week 12 - High
    0
    0
        Creatinine: Week 16 - Low
    3
    2
        Creatinine: Week 16 - High
    0
    0
        Creatinine: Week 20 - Low
    4
    2
        Creatinine: Week 20 - High
    0
    0
        Creatinine: Week 24 - Low
    3
    1
        Creatinine: Week 24 - High
    0
    0
    Notes
    [31] - number of participants: at baseline/W 4/W 8/W 12/W 16/W 20/W 24: 14/13/13/12/12/12/12
    [32] - number of participants: at baseline/W 4/W 8/W 12/W 16/W 20/W 24: 8/8/7/6/6/6/6
    No statistical analyses for this end point

    Primary: Safety as Assessed by Liver and Kidney Function Tests

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    End point title
    		 Safety as Assessed by Liver and Kidney Function Tests [33]
    End point description
    Number and percentage of deviations from normal range for gamma glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), glomerular filtration rate (GFR), and urea at baseline, week 12, and week 24 in each of the two treatment arms
    End point type
    Primary
    End point timeframe
    from Baseline to week 24
    Notes
    [33] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been specified for this primary end point. Only descriptive analyses were planned for
    End point values
    		 Tesofensine/Metoprolol Placebo
    Number of subjects analysed
    14
    8
    Units: counts of participants
        GGT: Baseline - Low
    0
    0
        GGT: Baseline - High
    5
    1
        GGT: Week 12 - Low
    0
    1
        GGT: Week 12 - High
    5
    2
        GGT: Week 24 - Low
    0
    0
        GGT: Week 24 - High
    4
    0
        AST: Baseline - Low
    0
    0
        AST: Baseline - High
    0
    0
        AST: Week 12 - Low
    0
    0
        AST: Week 12 - High
    0
    0
        AST: Week 24 - Low
    0
    0
        AST: Week 24 - High
    0
    0
        ALT: Baseline - Low
    0
    0
        ALT: Baseline - High
    0
    0
        ALT: Week 12 - Low
    0
    0
        ALT: Week 12 - High
    1
    0
        ALT: Week 24 - Low
    0
    0
        ALT: Week 24 - High
    0
    0
        ALP: Baseline - Low
    0
    0
        ALP: Baseline - High
    1
    0
        ALP: Week 12 - Low
    0
    0
        ALP: Week 12 - High
    2
    0
        ALP: Week 24 - Low
    0
    0
        ALP: Week 24 - High
    1
    0
        GFR: Baseline - Low
    0
    0
        GFR: Baseline - High
    0
    0
        GFR: Week 12 - Low
    0
    0
        GFR: Week 12 - High
    0
    0
        GFR: Week 24 - Low
    0
    0
        GFR: Week 24 - High
    0
    0
        Urea: Baseline - Low
    1
    1
        Urea: Baseline - High
    0
    0
        Urea: Week 12 - Low
    2
    0
        Urea: Week 12 - High
    0
    0
        Urea: Week 24 - Low
    1
    0
        Urea: Week 24 - High
    0
    0
    No statistical analyses for this end point

    Secondary: Composite Satiety Score (CSS)

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    End point title
    		 Composite Satiety Score (CSS)
    End point description
    Change in satiety and appetite using the CSS from Baseline to week 24, from Baseline to week 48 and from week 24 to week 48 measured at each visit for each of the two treatment arms Full name of the scale: composite satiety score (CSS), sometimes referred to as “appetite suppression score”. Range of values is 0-100; lower the value, hungrier a person is. CSS = (satiety + fullness + [100 − hunger] + [100 − prospective food consumption]) / 4. The four variables included are measured by visual analog scales (0-100 mm)
    End point type
    Secondary
    End point timeframe
    from baseline to week 24, from baseline to week 48 and from week 24 to week 48
    End point values
    		 Tesofensine/Metoprolol -> Tesofensine/Metoprolol Placebo -> Tesofensine/Metoprolol
    Number of subjects analysed
    12
    6
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline to Week 24
    4.5 ( 20.6 )
    6.5 ( 19.3 )
        Baseline to Week 48
    4.2 ( 15.1 )
    11.2 ( 14.3 )
        Week 24 to Week 48
    -0.3 ( 14.4 )
    4.7 ( 12.5 )
    Statistical analysis title
    		 Statistical Analysis 1 for Composite Satiety Score
    Statistical analysis description
    Baseline to week 24
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7782 [34]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -2.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.23
         upper limit
    		 16.2
    Notes
    [34] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 2 for Composite Satiety Score
    Statistical analysis description
    Baseline to Week 48
    Comparison groups
    Placebo -> Tesofensine/Metoprolol v Tesofensine/Metoprolol -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.313 [35]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -7.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.09
         upper limit
    		 7.56
    Notes
    [35] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 3 for Composite Satiety Score
    Statistical analysis description
    Week 24 to Week 48
    Comparison groups
    Placebo -> Tesofensine/Metoprolol v Tesofensine/Metoprolol -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4033 [36]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -5.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.92
         upper limit
    		 8.47
    Notes
    [36] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.

    Secondary: Body Weight

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    End point title
    		 Body Weight
    End point description
    Change in body weight (kg) from baseline to week 24, from baseline to 48 and from week 24 to week 48 measured at each visit for each of the two treatment arms
    End point type
    Secondary
    End point timeframe
    from baseline to week 24, from baseline to week 48 and from week 24 to week 48
    End point values
    		 Tesofensine/Metoprolol -> Tesofensine/Metoprolol Placebo -> Tesofensine/Metoprolol
    Number of subjects analysed
    12
    6
    Units: kg
    arithmetic mean (standard deviation)
        Baseline to Week 24
    -7.93 ( 6.59 )
    -0.15 ( 4.74 )
        Baseline to Week 48
    -6.53 ( 7.36 )
    -5.65 ( 8.90 )
        Week 24 to Week 48
    1.40 ( 4.05 )
    -5.50 ( 6.20 )
    Statistical analysis title
    		 Statistical Analysis 1 for Body Weight
    Statistical analysis description
    Baseline to Week 24
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0325 [37]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -7.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.29
         upper limit
    		 -0.71
    Notes
    [37] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 2 for Body Weight
    Statistical analysis description
    Baseline to Week 48
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9394 [38]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.04
         upper limit
    		 8.4
    Notes
    [38] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 3 for Body Weight
    Statistical analysis description
    Week 24 to Week 28
    Comparison groups
    Placebo -> Tesofensine/Metoprolol v Tesofensine/Metoprolol -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0135 [39]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    6.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.65
         upper limit
    		 12.18
    Notes
    [39] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.

    Secondary: Body Composition - Fat Mass

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    End point title
    		 Body Composition - Fat Mass
    End point description
    Change in body fat mass as measured in kg by DXA scan measured at baseline, week 24 and week 48 for each of the two treatment arms - (mITT observed values).
    End point type
    Secondary
    End point timeframe
    from baseline to week 24, from baseline to week 48 and from week 24 to week 48
    End point values
    		 Tesofensine/Metoprolol -> Tesofensine/Metoprolol Placebo -> Tesofensine/Metoprolol
    Number of subjects analysed
    12 [40]
    6 [41]
    Units: kilogram(s)
    arithmetic mean (standard deviation)
        Baseline to Week 24
    -5.31 ( 5.34 )
    -1.04 ( 3.75 )
        Baseline to Week 48
    -4.87 ( 5.31 )
    -3.77 ( 5.81 )
        Week 24 to Week 48
    0.44 ( 3.50 )
    -2.73 ( 3.37 )
    Notes
    [40] - number of participants at baseline/w24/w48: 13/12/12
    [41] - number of participants at baseline/w24/w48: 13/12/12
    Statistical analysis title
    		 Statistical Analysis 1 for Body Composition - Fat
    Statistical analysis description
    Baseline to Week 24; last observation carried forward (LOCF) approach (mITT observed).
    Comparison groups
    Placebo -> Tesofensine/Metoprolol v Tesofensine/Metoprolol -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1048 [42]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -4.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.31
         upper limit
    		 0.98
    Notes
    [42] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 2 for Body Composition - Fat
    Statistical analysis description
    Baseline to Week 48; last observation carried forward (LOCF) approach (mITT LOCF).
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7189 [43]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.75
         upper limit
    		 4.77
    Notes
    [43] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 3 for Body Composition - Fat
    Statistical analysis description
    Week 24 to Week 48; last observation carried forward (LOCF) approach (mITT LOCF).
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1053 [44]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.73
         upper limit
    		 6.91
    Variability estimate
    Standard deviation
    Notes
    [44] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.

    Secondary: Body Composition - Lean Tissue Mass

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    End point title
    		 Body Composition - Lean Tissue Mass
    End point description
    Change in lean body mass as measured in kg by DXA scan measured at baseline, week 24 and week 48 for each of the two treatment arms (mITT observed values).
    End point type
    Secondary
    End point timeframe
    from baseline to week 24, from baseline to week 48 and from week 24 to week 48
    End point values
    		 Tesofensine/Metoprolol -> Tesofensine/Metoprolol Placebo -> Tesofensine/Metoprolol
    Number of subjects analysed
    12 [45]
    6 [46]
    Units: kilogram(s)
    arithmetic mean (standard deviation)
        Baseline to Week 24
    -2.85 ( 1.88 )
    0.55 ( 1.32 )
        Baseline to Week 48
    -1.81 ( 2.18 )
    -1.87 ( 3.36 )
        Week 24 to Week 48
    1.04 ( 1.18 )
    -2.42 ( 3.51 )
    Notes
    [45] - number of participants at baseline/w24/w48: 13/12/12
    [46] - number of participants at baseline/w24/w48: 8/6/6
    Statistical analysis title
    		 Statistical Analysis 1 for Lean Tissue Mass
    Statistical analysis description
    Baseline to Week 24; mITT observed.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0033 [47]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -3.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.02
         upper limit
    		 -1.21
    Notes
    [47] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 2 for Lean Tissue Mass
    Statistical analysis description
    Baseline to Week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6663 [48]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.24
         upper limit
    		 3.41
    Notes
    [48] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 3 for Lean Tissue Mass
    Statistical analysis description
    Week 24 to Week 48; mITT LOCF
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0058 [49]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    3.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.21
         upper limit
    		 5.98
    Notes
    [49] - P-value from an ANCOVA model with treatment as factor and baseline as covariate

    Secondary: Glycemic Control - HbA1c

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    End point title
    		 Glycemic Control - HbA1c
    End point description
    Change in HbA1c from baseline to week 24, baseline to week 48 and week 24 to week 48 measured at baseline, week 14, week 24, week 36 and week 48 for each of the two treatment arms
    End point type
    Secondary
    End point timeframe
    from baseline to week 24, from baseline to week 48 and from week 24 to week 48 (mITT observed values).
    End point values
    		 Tesofensine/Metoprolol -> Tesofensine/Metoprolol Placebo -> Tesofensine/Metoprolol
    Number of subjects analysed
    12 [50]
    6 [51]
    Units: mmol/mol
    arithmetic mean (standard deviation)
        Baseline to Week 24
    -6.00 ( 15.39 )
    -0.17 ( 2.40 )
        Baseline to Week 48
    -5.33 ( 14.79 )
    -0.17 ( 2.23 )
        Week 24 to Week 48
    0.67 ( 1.30 )
    0.00 ( 0.63 )
    Notes
    [50] - number of participants at baseline/w24/w48: 13/12/12
    [51] - number of participants at baseline/w24/w48: 8/6/6
    Statistical analysis title
    		 Statistical Analysis 1 for Glycemic Control - HbA1
    Statistical analysis description
    Baseline to Week 24; mITT observed
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0713 [52]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -3.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.34
         upper limit
    		 0.3
    Notes
    [52] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 2 for Glycemic Control - HbA1
    Statistical analysis description
    Baseline to Week 48: mITT LOCF
    Comparison groups
    Placebo -> Tesofensine/Metoprolol v Tesofensine/Metoprolol -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1457 [53]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -2.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.92
         upper limit
    		 0.96
    Notes
    [53] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 3 for Glycemic Control - HbA1
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [54]
    P-value
    		 = 0.1837 [55]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.45
         upper limit
    		 2.15
    Variability estimate
    Standard deviation
    Notes
    [54] - Statistical analysis description: Week 24 to Week 48: mITT LOCF
    [55] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.

    Secondary: Glycemic Control - Fasting Plasma Glucose

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    End point title
    		 Glycemic Control - Fasting Plasma Glucose
    End point description
    Change in fasting plasma glucose from baseline to week 24, baseline to week 48 and week 24 to week 48 measured at each visit for each of the two treatments arms
    End point type
    Secondary
    End point timeframe
    from baseline to week 24, from baseline to week 48 and from week 24 to week 48 (mITT observed values).
    End point values
    		 Tesofensine/Metoprolol -> Tesofensine/Metoprolol Placebo -> Tesofensine/Metoprolol
    Number of subjects analysed
    12 [56]
    6 [57]
    Units: mmmol/L
    arithmetic mean (standard deviation)
        Baseline to Week 24
    -0.29 ( 0.64 )
    -0.28 ( 0.57 )
        Baseline to Week 48
    -0.11 ( 0.53 )
    -0.08 ( 0.37 )
        Week 24 to Week 48
    0.18 ( 0.46 )
    0.37 ( 0.59 )
    Notes
    [56] - number of participants at baseline/w24/w48: 13/12/12
    [57] - number of participants at baseline/w24/w48: 6/6/6
    Statistical analysis title
    		 Statistical Analysis 1 for Glycemic Control - Fast
    Statistical analysis description
    Baseline to Week 24; mITT LOCF
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7926 [58]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.42
         upper limit
    		 0.33
    Notes
    [58] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 2 for Glycemic Control - Fast
    Statistical analysis description
    Baseline to Week 48; mITT LOCF
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2124 [59]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.72
         upper limit
    		 0.17
    Variability estimate
    Standard deviation
    Notes
    [59] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 3 for Glycemic Control - Fast
    Statistical analysis description
    Week 24 to Week 48; last observation carried forward (LOCF) approach
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6084 [60]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.72
         upper limit
    		 0.43
    Variability estimate
    Standard deviation
    Notes
    [60] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.

    Secondary: Craving for Something Sweet, Salty, Meat/Fish, or Fatty

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    End point title
    		 Craving for Something Sweet, Salty, Meat/Fish, or Fatty
    End point description
    Change in craving for something sweet, salty, meat/fish, or fatty by the use of visual analogue scales (VAS) from baseline to week 24, from baseline to week 48, and from week 24 to week 48 The VAS consisted of a 100-mm horizontal line; subjects placed a vertical line on the VAS to indicate the level of intensity of their food craving. The VAS value is the distance in mm (0-100 mm) from the left end of the line to the subject's vertical line (higher value represents less craving). (mITT observed values).
    End point type
    Secondary
    End point timeframe
    from baseline to week 24, from baseline to week 48 and from week 24 to week 48
    End point values
    		 Tesofensine/Metoprolol -> Tesofensine/Metoprolol Placebo -> Tesofensine/Metoprolol
    Number of subjects analysed
    12 [61]
    6 [62]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Desire for something sweet from baseline to W 24
    9.0 ( 36.6 )
    16.2 ( 30.8 )
        Desire for something sweet from baseline to W 48
    2.1 ( 35.8 )
    35.3 ( 32.9 )
        Desire for something sweet from week 24 to week 48
    -6.9 ( 20.2 )
    19.2 ( 30.7 )
        Desire for something salty from baseline to W 24
    -2.3 ( 27.9 )
    13.2 ( 21.5 )
        Desire for something salty from baseline to W 48
    -3.4 ( 28.8 )
    33.3 ( 30.9 )
        Desire for something salty from W 24 to W 48
    -1.2 ( 8.5 )
    20.2 ( 22.7 )
        Desire for meat/fish from baseline to week 24
    7.3 ( 42.6 )
    8.8 ( 34.0 )
        Desire for meat/fish from baseline to week 48
    14.0 ( 44.1 )
    35.0 ( 34.6 )
        Desire for meat/fish from week 24 to week 48
    6.8 ( 18.6 )
    26.2 ( 34.2 )
        Desire for something fatty from baseline to W24
    18.2 ( 22.6 )
    2.2 ( 11.3 )
        Desire for something fatty from baseline to W48
    5.2 ( 25.7 )
    22.5 ( 26.3 )
        Desire for something fatty from W24 to W48
    -13.0 ( 15.6 )
    20.3 ( 28.0 )
    Notes
    [61] - number of participants at baseline/w24/w48: 13/12/12
    [62] - number of participants at baseline/w24/w48: 8/6/6
    Statistical analysis title
    		 Statistical Analysis 1 Desire for something fatty
    Statistical analysis description
    Baseline to week 24; mITT observed.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0905 [63]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.85
         upper limit
    		 34.85
    Notes
    [63] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 2 Desire for meat/fish
    Statistical analysis description
    Baseline to Week 24; mITT observed.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6285 [64]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    6.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.05
         upper limit
    		 35.36
    Notes
    [64] - P-value from ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 3 Desire for something salty
    Statistical analysis description
    Baseline to Week 24; mITT observed.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5884 [65]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -6.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.05
         upper limit
    		 19.43
    Notes
    [65] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 4 Desire for something sweet
    Statistical analysis description
    Baseline to Week 24; mITT observed.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8533 [66]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    2.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.73
         upper limit
    		 36.68
    Notes
    [66] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 5 Desire for something fatty
    Statistical analysis description
    Baseline to Week 48; mITT LOCF.
    Comparison groups
    Placebo -> Tesofensine/Metoprolol v Tesofensine/Metoprolol -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1529 [67]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -17.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41.87
         upper limit
    		 7.2
    Notes
    [67] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 6 Desire for meat/fish
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [68]
    P-value
    		 = 0.3399 [69]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -11.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.15
         upper limit
    		 13.65
    Notes
    [68] - Baseline to Week 48; mITT LOCF.
    [69] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 7 Desire for something salty
    Statistical analysis description
    Baseline to Week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0673
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.0673
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -49.84
         upper limit
    		 1.93
    Statistical analysis title
    		 Statistical Analysis 8 Desire for something sweet
    Statistical analysis description
    Baseline to Week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1657 [70]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -22.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -55.65
         upper limit
    		 10.46
    Notes
    [70] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 9 Desire for something fatty
    Statistical analysis description
    Week 24 to week 48; mITT LOCF.
    Comparison groups
    Placebo -> Tesofensine/Metoprolol v Tesofensine/Metoprolol -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0108 [71]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -30.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -52.31
         upper limit
    		 -8.06
    Notes
    [71] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 10 Desire for meat/fish
    Statistical analysis description
    Week 24 to week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.171 [72]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -14.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.71
         upper limit
    		 7.13
    Notes
    [72] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 11 Desire for something salty
    Statistical analysis description
    Week 24 to week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0083 [73]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -19.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.8
         upper limit
    		 -5.93
    Notes
    [73] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 12 Desire for something sweet
    Statistical analysis description
    Week 24 to week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0631 [74]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -22.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -47.39
         upper limit
    		 1.43
    Notes
    [74] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.

    Secondary: Thirst

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    End point title
    		 Thirst
    End point description
    Change in thirst by the use of a visual analog scale (VAS) from baseline to week 24, from baseline to week 48, and from week 24 to week 48 The VAS consisted of a 100-mm horizontal line; subjects placed a vertical line on the VAS to indicate the level of intensity of their thirst. The VAS value is the distance in mm (0-100 mm) from the left end of the line to the subject's vertical line (higher value represents an increase in perception of thirst). mITT observed values
    End point type
    Secondary
    End point timeframe
    from baseline to week 24, from baseline to week 48 and from week 24 to week 48
    End point values
    		 Tesofensine/Metoprolol -> Tesofensine/Metoprolol Placebo -> Tesofensine/Metoprolol
    Number of subjects analysed
    12 [75]
    6 [76]
    Units: score on a scale
    arithmetic mean (standard deviation)
        From baseline to week 24
    -2.4 ( 28.9 )
    -18.8 ( 23.2 )
        From baseline to week 48
    -6.3 ( 25.8 )
    -16.7 ( 18.8 )
        From week 24 to week 48
    -3.8 ( 16.5 )
    2.2 ( 20.5 )
    Notes
    [75] - number of participants at baseline/w24/w48: 13/12/12
    [76] - number of participants at baseline/w24/w48: 8/6/6
    Statistical analysis title
    		 Statistical Analysis 1 for Thirst
    Statistical analysis description
    Baseline to Week 24; mITT observed.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8082 [77]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -2.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.65
         upper limit
    		 19.53
    Notes
    [77] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 2 for Thirst
    Statistical analysis description
    Baseline to Week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9034 [78]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.94
         upper limit
    		 23.1
    Notes
    [78] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 3 for Thirst
    Statistical analysis description
    Week 24 to week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4658 [79]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.93
         upper limit
    		 12.93
    Variability estimate
    Standard deviation
    Notes
    [79] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.

    Secondary: Waist Circumference

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    End point title
    		 Waist Circumference
    End point description
    Change in waist circumference from baseline to week 24, from baseline to week 48, and from week 24 to week 48. mITT observed values
    End point type
    Secondary
    End point timeframe
    from baseline to week 24, from baseline to week 48 and from week 24 to week 48
    End point values
    		 Tesofensine/Metoprolol -> Tesofensine/Metoprolol Placebo -> Tesofensine/Metoprolol
    Number of subjects analysed
    12 [80]
    6 [81]
    Units: cm
        arithmetic mean (standard deviation)
    -7.08 ( 6.93 )
    -1.17 ( 4.40 )
    Notes
    [80] - number of participants at baseline/w24/w48: 13/12/12
    [81] - number of participants at baseline/w24/w48: 8/6/6
    Statistical analysis title
    		 Statistical Analysis 1 for Waist Circumference
    Statistical analysis description
    Baseline to Week 24; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0537 [82]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -5.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.46
         upper limit
    		 0.1
    Notes
    [82] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 2 for Waist Circumference
    Statistical analysis description
    Baseline to Week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3772 [83]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -2.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.98
         upper limit
    		 3.61
    Notes
    [83] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 3 for Waist Circumference
    Statistical analysis description
    Week 24 to week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1171 [84]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    3.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.85
         upper limit
    		 6.91
    Notes
    [84] - P-value from an ANCOVA model with treatment as factor and baseline as covariate

    Secondary: Lipid Profile

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    End point title
    		 Lipid Profile
    End point description
    Change in lipid profile from baseline to week 24, from baseline to week 48, and from week 24 to week 48. mITT observed values
    End point type
    Secondary
    End point timeframe
    from baseline to week 24, from baseline to week 48 and from week 24 to week 48
    End point values
    		 Tesofensine/Metoprolol -> Tesofensine/Metoprolol Placebo -> Tesofensine/Metoprolol
    Number of subjects analysed
    12 [85]
    6 [86]
    Units: mmol/L
    arithmetic mean (standard deviation)
        Change in total cholesterol from baseline to W24
    -0.17 ( 0.46 )
    -0.17 ( 0.45 )
        Change in total cholesterol from baseline to W48
    -0.01 ( 0.60 )
    -0.22 ( 0.75 )
        Change in total cholesterol from W24 to W48
    0.16 ( 0.48 )
    -0.05 ( 0.69 )
        Change in HDL cholesterol from baseline to week 24
    0.04 ( 0.21 )
    -0.02 ( 0.37 )
        Change in HDL cholesterol from baseline to week 48
    0.09 ( 0.26 )
    0.03 ( 0.25 )
        Change in HDL cholesterol from week 24 to week 48
    0.05 ( 0.24 )
    0.05 ( 0.16 )
        Change in LDL cholesterol from baseline to week 24
    -0.23 ( 0.39 )
    -0.20 ( 0.43 )
        Change in LDL cholesterol from baseline to week 48
    -0.15 ( 0.38 )
    -0.32 ( 0.53 )
        Change in LDL cholesterol from week 24 to week 48
    0.08 ( 0.28 )
    -0.12 ( 0.45 )
        Change in triglycerides from baseline to week 24
    -0.08 ( 0.77 )
    -0.30 ( 0.76 )
        Change in triglycerides from baseline to week 48
    -0.07 ( 0.77 )
    -0.48 ( 0.28 )
        Change in triglycerides from week 24 to week 48
    0.01 ( 0.69 )
    -0.18 ( 0.66 )
    Notes
    [85] - number of participants at baseline/w24/w48: 13/12/12
    [86] - number of participants at baseline/w24/w48: 8/6/6
    Statistical analysis title
    		 Statistical Analysis 1 Change in total cholesterol
    Statistical analysis description
    Baseline to Week 24; mITT observed.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8623 [87]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.59
         upper limit
    		 0.5
    Notes
    [87] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 2 Change in HDL cholesterol
    Statistical analysis description
    Baseline to Week 24; mITT observed.
    Comparison groups
    Placebo -> Tesofensine/Metoprolol v Tesofensine/Metoprolol -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8327 [88]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.25
         upper limit
    		 0.3
    Notes
    [88] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 3 Change in LDL cholesterol
    Statistical analysis description
    Baseline to Week 24; mITT observed.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.808 [89]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.53
         upper limit
    		 0.42
    Notes
    [89] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 4 Change in triglycerides
    Statistical analysis description
    Baseline to Week 24; mITT observed.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5791
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.62
         upper limit
    		 1.07
    Statistical analysis title
    		 Statistical Analysis 5 Change in cholesterol
    Statistical analysis description
    Baseline to Week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9337 [90]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.71
         upper limit
    		 0.77
    Notes
    [90] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 6 Change in HDL cholesterol
    Statistical analysis description
    Baseline to Week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9305 [91]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 0.23
    Notes
    [91] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 7 Change in LDL cholesterol
    Statistical analysis description
    Baseline to Week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.691 [92]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 0.59
    Notes
    [92] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 8 Change in triglycerides
    Statistical analysis description
    Baseline to Week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2688 [93]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 1.01
    Notes
    [93] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 9 Change in cholesterol
    Statistical analysis description
    Week 24 to week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8262 [94]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.54
         upper limit
    		 0.67
    Notes
    [94] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 10 Change in HDL cholesterol
    Statistical analysis description
    Week 24 to week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8293 [95]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.17
    Notes
    [95] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 11 Change in LDL cholesterol
    Statistical analysis description
    Week 24 to week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5486 [96]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 0.49
    Notes
    [96] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 12 Change in triglycerides
    Statistical analysis description
    Week 24 to week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3226 [97]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 0.75
    Notes
    [97] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.

    Secondary: Quality of Life - SF-36

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    End point title
    		 Quality of Life - SF-36
    End point description
    Change in quality of life by use of the Short Form 36 Health Survey (SF-36) scores from baseline to week 24, from baseline to week 48, and from week 24 to week 48 The physical component summary score includes the aggregated scores for scales of physical functioning, rolephysical, bodily pain, and general health. The mental health component summary score includes the aggregated scores for scales of vitality, social functioning, role-emotional, and mental health. Scores range from 0 to 100; higher score indicates better health. mITT observed values
    End point type
    Secondary
    End point timeframe
    from baseline to week 24, from baseline to week 48 and from week 24 to week 48
    End point values
    		 Tesofensine/Metoprolol -> Tesofensine/Metoprolol Placebo -> Tesofensine/Metoprolol
    Number of subjects analysed
    12 [98]
    6 [99]
    Units: score on scale
    arithmetic mean (standard deviation)
        Physical component from baseline to week 24
    0.90 ( 7.59 )
    1.36 ( 3.74 )
        Physical component from baseline to week 48
    0.70 ( 5.98 )
    2.41 ( 4.82 )
        Physical component from week 24 to week 48
    -0.21 ( 6.80 )
    1.05 ( 3.64 )
        Mental component from baseline to week 24
    -3.08 ( 11.44 )
    -0.49 ( 2.02 )
        Mental component from baseline to week 48
    -1.46 ( 7.74 )
    0.49 ( 1.74 )
        Mental component from week 24 to week 48
    1.62 ( 11.46 )
    0.98 ( 2.29 )
    Notes
    [98] - number of participants at baseline/w24/w48: 13/12/12
    [99] - number of participants at baseline/w24/w48: 8/6/6
    Statistical analysis title
    		 Statistical Analysis 1 for Physical component sco
    Statistical analysis description
    From baseline to week 24; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.842
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.55
         upper limit
    		 6.73
    Statistical analysis title
    		 Statistical Analysis 2 for Mental component score
    Statistical analysis description
    From baseline to week 24; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6693 [100]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -1.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.15
         upper limit
    		 6.67
    Notes
    [100] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 3 for Physical component scor
    Statistical analysis description
    From baseline to week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5444 [101]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -1.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.12
         upper limit
    		 4.46
    Notes
    [101] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 4 for Mental component score
    Statistical analysis description
    From baseline to week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5595 [102]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -1.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.47
         upper limit
    		 4.76
    Notes
    [102] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 5 for Physical component scor
    Statistical analysis description
    Week 24 to week 48; mITT LOCF.
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4331 [103]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -2.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.54
         upper limit
    		 3.41
    Notes
    [103] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 6 for Mental component score
    Statistical analysis description
    Week 24 to week 48; mITT LOCF.
    Comparison groups
    Placebo -> Tesofensine/Metoprolol v Tesofensine/Metoprolol -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6427 [104]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -1.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.9
         upper limit
    		 5.03
    Notes
    [104] - P-value from an ANCOVA model with treatment as factor and baseline as covar

    Secondary: Frequency of Adverse Events and Serious Adverse Events - Open-label Extension

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    End point title
    		 Frequency of Adverse Events and Serious Adverse Events - Open-label Extension
    End point description
    Number and frequency of adverse events and serious adverse events reported from week 24 to week 48
    End point type
    Secondary
    End point timeframe
    from week 24 to week 48
    End point values
    		 Tesofensine/Metoprolol -> Tesofensine/Metoprolol Placebo -> Tesofensine/Metoprolol
    Number of subjects analysed
    11
    6
    Units: counts of participants
        Infections and infestations
    6
    4
        Gastrointestinal disorders
    5
    3
        Musculoskeletal and connective tissue disorders
    7
    1
        Nervous system disorders
    3
    4
        General disorders and administration site conditio
    4
    0
        Psychiatric disorders
    2
    2
        Cardiac disorders
    0
    3
        Injury, poisoning and procedural complicati
    1
    1
        Vascular disorders
    0
    2
        Blood and lymphatic system disorders
    1
    0
        Investigations
    1
    0
        Respiratory, thoracic and mediastinal disorders
    1
    0
    No statistical analyses for this end point

    Secondary: Heart Rate and Blood Pressure (Change)

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    End point title
    		 Heart Rate and Blood Pressure (Change)
    End point description
    Change in heart rate and blood pressure from baseline to week 24, from baseline to week 48, and from week 24 to week 48
    End point type
    Secondary
    End point timeframe
    from baseline to week 24, from baseline to week 48 and from week 24 to week 48
    End point values
    		 Tesofensine/Metoprolol -> Tesofensine/Metoprolol Placebo -> Tesofensine/Metoprolol
    Number of subjects analysed
    12
    6
    Units: mmHg (BP) / bpm (HR)
    arithmetic mean (standard deviation)
        Change in Systolic BP from baseline to week 24
    2.0 ( 13 )
    -4.2 ( 8 )
        Change in Systolic BP from baseline to week 48
    5.8 ( 14 )
    9.7 ( 13 )
        Change in Systolic BP from week 24 to wek 48
    5.0 ( 11 )
    -5.5 ( 14 )
        Change in Diastolic BP from baseline to week 24
    2.8 ( 11 )
    -2.0 ( 11 )
        Change in Diastolic BP from baseline to week 48
    6.5 ( 12 )
    -1.0 ( 13 )
        Change in Diastolic BP from week 24 to week 48
    4.2 ( 9 )
    1.0 ( 10 )
        Change in Heart Rate from baseline to week 24
    -2.4 ( 11 )
    -7.0 ( 12 )
        Change in Heart Rate from baseline to week 48
    0.1 ( 7 )
    0.7 ( 20 )
        Change in Heart Rate from week 24 to week 48
    4.2 ( 8 )
    7.7 ( 10 )
    Statistical analysis title
    		 Statistical Analysis 1 for Heart Rate and Blood Pr
    Statistical analysis description
    From baseline to week 24; safety set LOCF. (Change in systolic blood pressure)
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3037 [105]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    5.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.76
         upper limit
    		 17.48
    Variability estimate
    Standard deviation
    Notes
    [105] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 2 for Heart Rate and Blood Pr
    Statistical analysis description
    From baseline to week 48; safety set LOCF. (Change in systolic blood pressure)
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7912 [106]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.85
         upper limit
    		 10.16
    Variability estimate
    Standard deviation
    Notes
    [106] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 3 for Heart Rate and Blood Pr
    Statistical analysis description
    From baseline to week 24; safety set LOCF. (Change in heart rate)
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.551 [107]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.72
         upper limit
    		 12.12
    Variability estimate
    Standard deviation
    Notes
    [107] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 4 for Heart Rate and Blood Pr
    Statistical analysis description
    From baseline to week 48; safety set LOCF. (Change in systolic blood pressure)
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1773 [108]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    10.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.25
         upper limit
    		 25.83
    Variability estimate
    Standard deviation
    Notes
    [108] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 5 for Heart Rate and Blood Pr
    Statistical analysis description
    From baseline to week 48; safety set LOCF. (Change in diastolic blood pressure)
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.798 [109]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.55
         upper limit
    		 12.2
    Variability estimate
    Standard deviation
    Notes
    [109] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 6 for Heart Rate and Blood Pr
    Statistical analysis description
    From baseline to week 48; safety set LOCF. (Change in heart rate)
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7256 [110]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -2.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.88
         upper limit
    		 10.63
    Variability estimate
    Standard deviation
    Notes
    [110] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 7 for Heart Rate and Blood Pr
    Statistical analysis description
    From week 24 to week 48; safety set LOCF. (Change in systolic blood pressure)
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.158 [111]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    7.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 18.94
    Variability estimate
    Standard deviation
    Notes
    [111] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 8 for Heart Rate and Blood Pr
    Statistical analysis description
    From week 24 to week 48; safety set LOCF. (Change in diastolic blood pressure)
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7021 [112]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    1.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.36
         upper limit
    		 10.64
    Variability estimate
    Standard deviation
    Notes
    [112] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 9 for Heart Rate and Blood Pr
    Statistical analysis description
    From week 24 to week 48; safety set LOCF. (Change in heart rate)
    Comparison groups
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol v Placebo -> Tesofensine/Metoprolol
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4822 [113]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -3.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.05
         upper limit
    		 6.48
    Variability estimate
    Standard deviation
    Notes
    [113] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.

    Secondary: 24 Hours Blood Pressure

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    End point title
    		 24 Hours Blood Pressure
    End point description
    Changes in 24 hours blood pressure from baseline to week 12 and baseline to week 24
    End point type
    Secondary
    End point timeframe
    from baseline to week 12 and baseline to week 24
    End point values
    		 Tesofensine/Metoprolol Placebo
    Number of subjects analysed
    12
    6
    Units: mmHg
    arithmetic mean (standard deviation)
        Systolic BP mean change from baseline to week 12
    -8.0 ( 20 )
    0.7 ( 14 )
        Systolic BP mean change from baseline to week 24
    2.3 ( 20 )
    -8.4 ( 17 )
        Diastolic BP mean change from baseline to W12
    0.2 ( 9 )
    3.7 ( 8 )
        Diastolic BP mean change from baseline to W24
    3.7 ( 8 )
    -2.8 ( 9 )
    Statistical analysis title
    		 Statistical Analysis 1 for 24 Hours Blood Pressure
    Statistical analysis description
    From baseline to week 24; mITT LOCF. (Change in systolic blood pressure mean)
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8728 [114]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.17
         upper limit
    		 21.18
    Variability estimate
    Standard deviation
    Notes
    [114] - P-value from an ANCOVA model with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Statistical Analysis 2 for 24 Hours Blood Pressure
    Statistical analysis description
    From baseline to week 24; mITT LOCF. (Change in diastolic blood pressure mean)
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5714 [115]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    2.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.61
         upper limit
    		 11.54
    Variability estimate
    Standard deviation
    Notes
    [115] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 3 for 24 Hours Blood Pressure
    Statistical analysis description
    From baseline to week 12; mITT LOCF. (Change in systolic blood pressure mean)
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2322 [116]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -10.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.51
         upper limit
    		 7.22
    Variability estimate
    Standard deviation
    Notes
    [116] - P-value from an ANCOVA model with treatment as factor and baseline as covariate.
    Statistical analysis title
    		 Statistical Analysis 4 for 24 Hours Blood Pressure
    Statistical analysis description
    From baseline to week 12; mITT LOCF. (Change in diastolic blood pressure mean)
    Comparison groups
    Tesofensine/Metoprolol v Placebo
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4321 [117]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -3.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.61
         upper limit
    		 5.68
    Variability estimate
    Standard deviation
    Notes
    [117] - P-value from an ANCOVA model with treatment as factor and baseline as covariate

    Secondary: Plasma Trough Concentrations

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    End point title
    		 Plasma Trough Concentrations
    End point description
    Plasma trough concentrations of tesofensine, metabolite NS2360 and metoprolol for the active arm (the first 24 weeks and then continuously up to week 48) and placebo arm (start of treatment at week 25 and then continuously up to week 48) The placebo arm did not start treatment before week 25 and values are therefore 0 for week 12 and week 24
    End point type
    Secondary
    End point timeframe
    baseline to week 48
    End point values
    		 Tesofensine/Metoprolol -> Tesofensine/Metoprolol Placebo -> Tesofensine/Metoprolol
    Number of subjects analysed
    11
    6
    Units: μg/L
    geometric mean (geometric coefficient of variation)
        Tesofensine Week 12
    12.03 ( 38.6 )
    0 ( 0 )
        Tesofensine Week 24
    12.34 ( 55.4 )
    0 ( 0 )
        Tesofensine Week 36
    11.01 ( 54.4 )
    19.10 ( 56.1 )
        Tesofensine Week 48
    6.78 ( 394.7 )
    15.11 ( 70.2 )
        NS2360 metab. Week 12
    3.39 ( 48.5 )
    0 ( 0 )
        NS2360 metab. Week 24
    3.96 ( 71.9 )
    0 ( 0 )
        NS2360 metab. Week 36
    3.39 ( 57.1 )
    6.51 ( 56.3 )
        NS2360 metab. Week 48
    2.44 ( 157.3 )
    6.02 ( 67.7 )
        Metoprolol Week 12
    10.83 ( 120.8 )
    0 ( 0 )
        Metoprolol Week 24
    9.07 ( 281.4 )
    0 ( 0 )
        Metoprolol Week 36
    8.97 ( 309.6 )
    10.62 ( 206.0 )
        Metoprolol Week 48
    7.29 ( 156.9 )
    7.30 ( 578.8 )
    No statistical analyses for this end point

    Secondary: 48 Hours Heart Rate and QT Interval at Baseline, Week 12 and Week 24

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    End point title
    		 48 Hours Heart Rate and QT Interval at Baseline, Week 12 and Week 24
    End point description
    For Part 1, 48 hours HR and QT interval from week 12 to week 24 were not recorded in the database and analysis of changes not evaluated. Instead, abnormal findings over visits were summarized. An abnormal ECG assessment at any post-baseline time point was recorded for 3 subjects (23% of 13) treated with Tesomet and for none (0% of 8) receiving Placebo. Abnormal ECG findings detected in the three Tesomet treated subjects are: • QTc prolongation (466 ms) • Bradycardia (56 bpm) • QTc prolongation (460 ms) All were considered not clinically significant.
    End point type
    Secondary
    End point timeframe
    baseline, week 12 and week 24
    End point values
    		 Tesofensine/Metoprolol Placebo
    Number of subjects analysed
    14
    8
    Units: counts of participants
        ECG interretation baseline
    14
    8
        ECG interretation at week 12
    12
    6
        ECG interretation at week 24
    12
    6
        48 hour heart rate at baseline
    13
    8
        48 hour heart rate at week 12
    12
    6
        48 hour heart rate at week 24
    12
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Part 1 (DB): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 W duration). Part 2 (OLE): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 W duration)
    Adverse event reporting additional description
    Safety Analysis Set incl. all subjects receiving at least one dose of study drug (active or placebo). For Part 2 (OLE I and OLE II) only new events staring in Part 2 are reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Tesofensine/Metoprolol
    Reporting group description
    		 Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.

    Reporting group title
    Tesofensine/Metoprolol -> Tesofensine/Metoprolol
    Reporting group description
    		 Subjects who received co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1 continued to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol once daily for an additional 24 weeks in Part 2.

    Reporting group title
    Placebo -> Tesofensine/Metoprolol
    Reporting group description
    		 Subjects who received matching placebo tablets once daily for 24 weeks during Part 1 were switched to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol once daily for an additional 24 weeks in Part 2.

    Serious adverse events
    		 Tesofensine/Metoprolol Placebo Tesofensine/Metoprolol -> Tesofensine/Metoprolol Placebo -> Tesofensine/Metoprolol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 8 (12.50%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Craniopharyngioma
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (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
    Injury, poisoning and procedural complications
    Post procedural complication
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (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
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (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
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 6 (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
    		 Tesofensine/Metoprolol Placebo Tesofensine/Metoprolol -> Tesofensine/Metoprolol Placebo -> Tesofensine/Metoprolol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 14 (85.71%)
    7 / 8 (87.50%)
    11 / 11 (100.00%)
    6 / 6 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Orthostatic hypotension
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    2
    General disorders and administration site conditions
    Energy increased
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 8 (12.50%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 8 (12.50%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nasal discomfort
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Hallucination, auditory
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Paranoia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sleep disorder
         subjects affected / exposed
    7 / 14 (50.00%)
    1 / 8 (12.50%)
    2 / 11 (18.18%)
    1 / 6 (16.67%)
         occurrences all number
    7
    1
    2
    1
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Wound
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    0
    1
    0
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 14 (42.86%)
    3 / 8 (37.50%)
    1 / 11 (9.09%)
    1 / 6 (16.67%)
         occurrences all number
    6
    6
    1
    1
    Dyskinesia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Headace
         subjects affected / exposed
    5 / 14 (35.71%)
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    2 / 6 (33.33%)
         occurrences all number
    6
    0
    1
    2
    Paraesthesia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Presyncope
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Restless legs syndrome
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    lymphadenopathy
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    3 / 14 (21.43%)
    3 / 8 (37.50%)
    0 / 11 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    5
    0
    1
    Constipation
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 8 (0.00%)
    2 / 11 (18.18%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    2
    1
    Diarrhoea
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 8 (25.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Dry mouth
         subjects affected / exposed
    6 / 14 (42.86%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    6
    0
    0
    2
    Faeces hard
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 8 (25.00%)
    2 / 11 (18.18%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    3
    0
    Vomiting
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 8 (25.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Hyperhydrosis
         subjects affected / exposed
    3 / 14 (21.43%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    4 / 11 (36.36%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Back pain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Joint stiffness
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    2
    Myalgia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Neck pain
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infections and infestations
    Eye infection
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 8 (12.50%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 8 (12.50%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Gingivitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 8 (12.50%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Onychomycosis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sinusitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    0 / 11 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    1
    Viral tonsillitis
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 8 (25.00%)
    0 / 11 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 8 (0.00%)
    1 / 11 (9.09%)
    2 / 6 (33.33%)
         occurrences all number
    2
    0
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jun 2019
    Exclusion criterion 23 was original included to ensure that no subjects with depression are included into the study, and read as follows: PHQ-9 (Patient Health Questionnaire) score ≥ 10 or any score > 0 on question 9 at screening and baseline. In connection with the recruitment of subjects to the TM005 study it became evident, that a high proportion of the subjects was classified as screening failures due to a high score in the PHQ-9. This was due to an overlap between the terms and scoring in the questionnaire, and frequent symptoms of the HIO disease.
    05 Sep 2019
    Saniona wishes to also analyse for the trough value of the Tesofensine metabolite N-desmethylmetabolite NS2360. This analysis can be done on samples already taken for analysis of Tesofensine and metoprolol. Analysis of N-desmethyl-metabolite NS2360 has not previous been included in the protocol. BP values to be used for evaluation of exclusion criteria 1 has been clarified.
    10 Dec 2019
    Saniona wish to add Adverse Events of Special Interest to the protocol. Further a section regarding Water Retention and/or Hyponatremia has been added. The section regarding water retention and/or hyponatremia is added based on mechanism of action of Tesofensine, as a non-selective inhibitor of serotonin reuptake. Hence, it may be anticipated that an additive antidiuretic effect of Tensofensine may lead to increased risk of water retention and/or hyponatremia.

    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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