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    Clinical Trial Results:
    A Double-Blind, Randomized, Placebo-Controlled, Multiple-Dose, Multi-Center Safety and Efficacy Study of Co-Administration of Tesofensine/Metoprolol for 12 weeks in Adult and Adolescent Patients with Prader-Willi Syndrome (PWS), followed by two open label 12 weeks extension periods for Adolescent Patients.

    Summary
    EudraCT number
    		 2016-003694-18
    Trial protocol
    		 CZ   HU  
    Global end of trial date
    22 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jul 2022
    First version publication date
    20 Jul 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TM002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03149445
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Saniona
    Sponsor organisation address
    Smedeland 26B, Glostrup, Denmark, 2600
    Public contact
    Janus Schreiber Larsen, Chief Develovment Officer, Saniona A/S, +45 70 70 52 25, janus.larsen@saniona.com
    Scientific contact
    Janus Schreiber Larsen, Chief Develovment Officer, 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
    20 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jul 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to investigate the safety and efficacy of co-administration of tesofensine/metoprolol treatment versus placebo in adult and pediatric subjects with Prader-Willi syndrome. The primary objective is to examine the effect of co-administration of tesofensine/metoprolol on body weight in subjects with PWS in a study with an open label extension.
    Protection of trial subjects
    Any records will be kept and handled in compliance with effective legal regulations (Act XLVII of 1997 and CXII of 2011). The patient’s personal data will be processed by administrators who are the sponsor of this study (Saniona, A/S, Smedeland 26B, DK2600 Glostrup) and healthcare service providers, in compliance with Act No 101/2000 Coll., on Personal Data Protection. The protocol, the informed consent document, relevant supporting information, and all types of patient recruitment or advertisement information were approved by the appropriate IEC prior to study start. The protocol was approved by the competent authorities of the Czech Republic and by the competent authorities in Hungary. Amendments to the protocol were approved, as applicable, by the IEC and competent authorities prior to implementation of any changes in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Mar 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    Hungary: 10
    Worldwide total number of subjects
    18
    EEA total number of subjects
    18
    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)
    9
    Adults (18-64 years)
    9
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This study was planned to be conducted in two steps: Step 1 in adult patients and Step 2 in adolescent patients. Step 2 was initiated following an unblinded analysis of data from Step 1. Participation in a 12-week OLE I was offered to patients who completed Step 2. Participation in a 12 week OLE II was offered to all eligible patients of OLE I.

    Pre-assignment
    Screening details
    		 Patients who gave written informed consent were assigned a subject screening number and underwent the screening visit assessments to determine their eligibility for the study, and if found eligible they were randomized on the same day to minimize their travelling to the site.

    Period 1
    Period 1 title
    DB Step 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    It was a double-blind, placebo-controlled study, i.e. investigators, site staff and patients were blinded as to the treatment allocation. This was achieved by the following procedures: The IMP blinding was done by third party The placebo was identical to IMP with regard to size, color, and general appearance

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tesomet 0.50/50 mg
    Arm description
    		 Subjects (adults) were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication Tesomet) once daily for 91 days (+2 days after the final assessments with halfdose of metoprolol) during Step 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tesomet (Tesofensine/Metoprolol)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tesomet (tesofensine/metoprolol): 0.5mg/50mg q.d., per oral

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo matching IMP, q.d.
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching IMP, q.d.

    Number of subjects in period 1 [1]
    		Tesomet 0.50/50 mg Placebo
    Started
    6
    3
    Completed
    2
    2
    Not completed
    4
    1
         Consent withdrawn by subject
    2
    1
         Adverse event, non-fatal
    2
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 9 adult subjects were included in Step 1 (baseline period). After finalization of Step 1, Step 2 was initiated and 9 adolescent subjects were included in Step 2.
    Period 2
    Period 2 title
    DB Step 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    It was a double-blind, placebo-controlled study, i.e. investigators, site staff and patients were blinded as to the treatment allocation. This was achieved by the following procedures: The IMP blinding was done by third party Within Step 2, the placebo matching metoprolol 25 mg was slightly different in size therefore the site staff and CRA were trained in appropriate IMP handling procedures in order to preserve the blinding of the study

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Tesomet 0.125/25 mg
    Arm description
    		 Subjects (adolescents) were randomized to receive co-administration of 0.125 mg tesofensine/25 mg metoprolol (active medication Tesomet) once daily for 91 days: +2days after the final assessments with halfdose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tesomet (Tesofensine/Metoprolol)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tesomet (tesofensione/metoprolol) 0.125mg/25mg, q.d., per oral

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo matching IMP, q.d.
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching IMP, q.d.

    Number of subjects in period 2
    		Tesomet 0.125/25 mg Placebo
    Started
    5
    4
    Completed
    5
    4
    Period 3
    Period 3 title
    OLE I
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg
    Arm description
    		 Participation in a 12-week OLE I was offered to patients who completed Step 2. Patients were receiving co-administration of 0.125 mg tesofensine/25 mg metoprolol (active medication Tesomet) once daily for 12 weeks during OLE I.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tesomet (Tesofensine/Metoprolol)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tesomet (tesofensione/metoprolol) 0.125mg/25mg, q.d., per oral

    Arm title
    		 Placebo -> Tesomet 0.125/25 mg
    Arm description
    		 Participation in a 12-week OLE I was offered to patients who completed Step 2. Patients were receiving co-administration of 0.125 mg tesofensine/25 mg metoprolol (active medication Tesomet) once daily for 12 weeks during OLE I.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tesomet (Tesofensine/Metoprolol)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tesomet (tesofensine/metoprolol): 0.125mg/25mg q.d., per oral

    Number of subjects in period 3
    		Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg Placebo -> Tesomet 0.125/25 mg
    Started
    4
    4
    Completed
    4
    3
    Not completed
    0
    1
         Lost to follow-up
    -
    1
    Period 4
    Period 4 title
    OLE II
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tesomet 0.25/25 mg
    Arm description
    		 Participation in a 12 week OLE II was offered to all eligible patients of OLE I. Patients were receiving co-administration of 0.25 mg tesofensine/25 mg metoprolol (active medication Tesomet) once daily for 12 weeks during OLE II.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tesomet (Tesofensine/Metoprolol)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tesomet (tesofensine/metoprolol): 0.25mg/25mg q.d., per oral

    Arm title
    		 Tesomet 0.125/25 mg
    Arm description
    		 Participation in a 12 week OLE II was offered to all eligible patients of OLE I. Patients were receiving co-administration of 0.125 mg tesofensine/25 mg metoprolol (active medication) once daily for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tesomet (Tesofensine/Metoprolol)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tesomet (tesofensione/metoprolol) 0.125mg/25mg, q.d., per oral

    Number of subjects in period 4 [2]
    		Tesomet 0.25/25 mg Tesomet 0.125/25 mg
    Started
    5
    1
    Completed
    3
    1
    Not completed
    2
    0
         Adverse event, non-fatal
    2
    -
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Participation in a 12 week OLE II was offered to all patients who completed OLE I. 7 patients completed OLE I and 6 patients continued to OLE II. The numbers completing OLE I and the numbers starting OLE II are therefore not identical.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tesomet 0.50/50 mg
    Reporting group description
    		 Subjects (adults) were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication Tesomet) once daily for 91 days (+2 days after the final assessments with halfdose of metoprolol) during Step 1.

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Tesomet 0.50/50 mg Placebo Total
    Number of subjects
    		 6 3 9
    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
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
        Adults aged (18-30)
    		 6 3 9
    Gender categorical
    Units: Subjects
        Female
    		 4 2 6
        Male
    		 2 1 3

    End points

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    End points reporting groups
    Reporting group title
    Tesomet 0.50/50 mg
    Reporting group description
    		 Subjects (adults) were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication Tesomet) once daily for 91 days (+2 days after the final assessments with halfdose of metoprolol) during Step 1.

    Reporting group title
    Placebo
    Reporting group description
    		 -
    Reporting group title
    Tesomet 0.125/25 mg
    Reporting group description
    		 Subjects (adolescents) were randomized to receive co-administration of 0.125 mg tesofensine/25 mg metoprolol (active medication Tesomet) once daily for 91 days: +2days after the final assessments with halfdose.

    Reporting group title
    Placebo
    Reporting group description
    		 -
    Reporting group title
    Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg
    Reporting group description
    		 Participation in a 12-week OLE I was offered to patients who completed Step 2. Patients were receiving co-administration of 0.125 mg tesofensine/25 mg metoprolol (active medication Tesomet) once daily for 12 weeks during OLE I.

    Reporting group title
    Placebo -> Tesomet 0.125/25 mg
    Reporting group description
    		 Participation in a 12-week OLE I was offered to patients who completed Step 2. Patients were receiving co-administration of 0.125 mg tesofensine/25 mg metoprolol (active medication Tesomet) once daily for 12 weeks during OLE I.
    Reporting group title
    Tesomet 0.25/25 mg
    Reporting group description
    		 Participation in a 12 week OLE II was offered to all eligible patients of OLE I. Patients were receiving co-administration of 0.25 mg tesofensine/25 mg metoprolol (active medication Tesomet) once daily for 12 weeks during OLE II.

    Reporting group title
    Tesomet 0.125/25 mg
    Reporting group description
    		 Participation in a 12 week OLE II was offered to all eligible patients of OLE I. Patients were receiving co-administration of 0.125 mg tesofensine/25 mg metoprolol (active medication) once daily for 12 weeks.

    Primary: Percent change from baseline to end of treatment in mean body weight

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    End point title
    		 Percent change from baseline to end of treatment in mean body weight
    End point description
    Percent change from baseline to end of treatment in body weight. LOCF.
    End point type
    Primary
    End point timeframe
    DB Step 1: Day 1 to Day 91 DB Step 2: Day 1 to Day 91 OLE I: Day 91 to Day 181 OLE II: Day 181 to Day 271
    End point values
    		 Tesomet 0.50/50 mg Placebo Tesomet 0.125/25 mg Placebo Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg Placebo -> Tesomet 0.125/25 mg Tesomet 0.25/25 mg Tesomet 0.125/25 mg
    Number of subjects analysed
    6
    3
    5
    4
    4
    4
    4
    1
    Units: percent
        arithmetic mean (standard deviation)
    -4.09 ± 3.73
    -0.38 ± 2.05
    3.56 ± 2.73
    3.00 ± 2.35
    5.79 ± 2.08
    0.33 ± 3.26
    -1.20 ± 3.80
    -5.51 ± 0
    Statistical analysis title
    		 Step 1: Percent change in body weight
    Comparison groups
    Placebo v Tesomet 0.50/50 mg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1045 [1]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -5.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.3
         upper limit
    		 1.5
    Notes
    [1] - P-value from an ANCOVA with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Step 2: Percent change in body weight
    Comparison groups
    Tesomet 0.125/25 mg v Placebo
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7422 [2]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 5.3
    Notes
    [2] - P-value from an ANCOVA with treatment as factor and baseline as covariate
    Statistical analysis title
    		 OLE I: Percent change in body weight
    Comparison groups
    Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg v Placebo -> Tesomet 0.125/25 mg
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.046 [3]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    5.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 11
    Notes
    [3] - P-value from an ANCOVA with treatment as factor and baseline as covariate
    Statistical analysis title
    		 OLE II: Percent change in body weight
    Comparison groups
    Tesomet 0.25/25 mg v Tesomet 0.125/25 mg
    Number of subjects included in analysis
    5
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3847 [4]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    4.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.2
         upper limit
    		 17.8
    Notes
    [4] - P-value from an ANCOVA with treatment as factor and baseline as covariate

    Secondary: Change from baseline to end of treatment in mean body weight

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    End point title
    		 Change from baseline to end of treatment in mean body weight
    End point description
    Change from baseline to end of treatment in body weight [kg]. LOCF.
    End point type
    Secondary
    End point timeframe
    DB Step 1: Day 1 to Day 91 DB Step 2: Day 1 to Day 91 OLE I: Day 91 to Day 181 OLE II: Day 181 to Day 271
    End point values
    		 Tesomet 0.50/50 mg Placebo Tesomet 0.125/25 mg Placebo Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg Placebo -> Tesomet 0.125/25 mg Tesomet 0.25/25 mg Tesomet 0.125/25 mg
    Number of subjects analysed
    6
    3
    5
    4
    4
    4
    4
    1
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    -4.15 ± 4.82
    -0.77 ± 3.23
    3.10 ± 2.85
    2.25 ± 1.71
    4.75 ± 2.41
    0.45 ± 2.82
    -0.90 ± 3.20
    -3.50 ± 0
    Statistical analysis title
    		 Step 1: Change in body weight
    Comparison groups
    Tesomet 0.50/50 mg v Placebo
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1326 [5]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -6.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.9
         upper limit
    		 2.5
    Notes
    [5] - P-value from an ANCOVA with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Step 2: Change in body weight
    Comparison groups
    Tesomet 0.125/25 mg v Placebo
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5148 [6]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 5.3
    Notes
    [6] - P-value from an ANCOVA with treatment as factor and baseline as covariate
    Statistical analysis title
    		 OLE I: Change in body weight
    Comparison groups
    Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg v Placebo -> Tesomet 0.125/25 mg
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0605 [7]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    4.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 9.4
    Notes
    [7] - P-value from an ANCOVA with treatment as factor and baseline as covariate
    Statistical analysis title
    		 OLE II: Change in body weight
    Comparison groups
    Tesomet 0.25/25 mg v Tesomet 0.125/25 mg
    Number of subjects included in analysis
    5
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5198 [8]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.8
         upper limit
    		 14
    Notes
    [8] - P-value from an ANCOVA with treatment as factor and baseline as covariate

    Secondary: Change from baseline to end of treatment in HQ-CT score

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    End point title
    		 Change from baseline to end of treatment in HQ-CT score
    End point description
    Change from baseline to end of treatment in HQ-CT score. LOCF.
    End point type
    Secondary
    End point timeframe
    DB Step 1: Day 1 to Day 91 DB Step 2: Day 1 to Day 91 OLE I: Day 91 to Day 181 OLE II: Day 181 to Day 271
    End point values
    		 Tesomet 0.50/50 mg Placebo Tesomet 0.125/25 mg Placebo Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg Placebo -> Tesomet 0.125/25 mg Tesomet 0.25/25 mg Tesomet 0.125/25 mg
    Number of subjects analysed
    6
    2
    5
    4
    4
    4
    4
    1
    Units: score on a scale
        arithmetic mean (standard deviation)
    -8.50 ± 9.25
    -4.00 ± 7.07
    -3.30 ± 6.82
    -6.75 ± 3.69
    1.25 ± 5.68
    -1.75 ± 1.50
    -1.00 ± 2.00
    -2.00 ± 0
    Statistical analysis title
    		 Step 1: Change in HQ-CT score
    Comparison groups
    Tesomet 0.50/50 mg v Placebo
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0058 [9]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -8.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.5
         upper limit
    		 -3.6
    Notes
    [9] - P-value from an ANCOVA with treatment as factor and baseline as covariate
    Statistical analysis title
    		 Step 2: Change in HQ-CT score
    Comparison groups
    Tesomet 0.125/25 mg v Placebo
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5142 [10]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.3
         upper limit
    		 9.5
    Notes
    [10] - P-value from an ANCOVA with treatment as factor and baseline as covariate
    Statistical analysis title
    		 OLE I: Change in HQ-CT score
    Comparison groups
    Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg v Placebo -> Tesomet 0.125/25 mg
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3794 [11]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.1
         upper limit
    		 11.3
    Notes
    [11] - P-value from an ANCOVA with treatment as factor and baseline as covariate
    Statistical analysis title
    		 OLE II: Change in HQ-CT score
    Comparison groups
    Tesomet 0.25/25 mg v Tesomet 0.125/25 mg
    Number of subjects included in analysis
    5
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.685 [12]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.1
         upper limit
    		 8.1
    Notes
    [12] - P-value from an ANCOVA with treatment as factor and baseline as covariate

    Secondary: Steady state concentrations of tesofensine and metoprolol as measured by trough values

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    End point title
    		 Steady state concentrations of tesofensine and metoprolol as measured by trough values [13]
    End point description
    Steady state concentrations of tesofensine and metoprolol as measured by trough values. Observed values.
    End point type
    Secondary
    End point timeframe
    DB Step 1: Day 29 DB Step 2: Day 29 OLE I: Day 120 OLE II: Day 210
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive statistics were planned for.
    End point values
    		 Tesomet 0.50/50 mg Tesomet 0.125/25 mg Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg Placebo -> Tesomet 0.125/25 mg Tesomet 0.25/25 mg Tesomet 0.125/25 mg
    Number of subjects analysed
    6
    5
    4
    3
    4
    1
    Units: μg/L
    geometric mean (geometric coefficient of variation)
        Tesofensine
    16.29 ± 49.8
    3.34 ± 32.2
    4.14 ± 17.3
    5.06 ± 18.0
    4.13 ± 137.5
    6.43 ± 0
        Teso. metab.
    2.97 ± 52.6
    0.79 ± 17.1
    1.45 ± 23.3
    1.00 ± 41.9
    1.56 ± 49.1
    1.98 ± 0
        Metoprolol
    1.61 ± 903.7
    1.97 ± 285.5
    2.81 ± 119.0
    3.32 ± 32.0
    1.76 ± 242.5
    14.50 ± 0
    No statistical analyses for this end point

    Secondary: Change from baseline to end of treatment in fat- and fat free mass (%) by dual X-ray absorptiometry (DEXA)

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    End point title
    		 Change from baseline to end of treatment in fat- and fat free mass (%) by dual X-ray absorptiometry (DEXA) [14]
    End point description
    Change from baseline to end of treatment in fat- and fat free mass (%) by dual X-ray absorptiometry (DEXA). Observed values.
    End point type
    Secondary
    End point timeframe
    DB Step 1: Day 1 to Day 91 DB Step 2: Day 1 to Day 91 OLE I: Day 91 to Day 181 OLE II: Day 181 to Day 271
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive statistics were planned for.
    End point values
    		 Tesomet 0.50/50 mg Tesomet 0.125/25 mg Placebo Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg Placebo -> Tesomet 0.125/25 mg Tesomet 0.25/25 mg Tesomet 0.125/25 mg
    Number of subjects analysed
    3
    3
    2
    3
    2
    2
    1
    Units: percent
    arithmetic mean (standard deviation)
        Fat mass
    -1.27 ± 1.07
    -0.13 ± 0.25
    -0.50 ± 0.85
    1.20 ± 1.74
    -0.05 ± 0.21
    -1.70 ± 0.1
    -1.50 ± 0
        Fat free mass
    1.19 ± 1.11
    0.137 ± 0.217
    -2.080 ± 4.511
    0.053 ± 2.559
    4.290 ± 3.974
    0.000 ± 0.1
    1.470 ± 0
    No statistical analyses for this end point

    Secondary: Change from baseline to end of treatment in BMD by dual X-ray absorptiometry (DEXA)

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    End point title
    		 Change from baseline to end of treatment in BMD by dual X-ray absorptiometry (DEXA) [15]
    End point description
    Change from baseline to end of treatment in BMD by dual X-ray absorptiometry (DEXA). Observed values.
    End point type
    Secondary
    End point timeframe
    DB Step 1: Day 1 to Day 91 DB Step 2: Day 1 to Day 91 OLE I: Day 91 to Day 181 OLE II: Day 181 to Day 271
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive statistics were planned for.
    End point values
    		 Tesomet 0.50/50 mg Tesomet 0.125/25 mg Placebo Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg Placebo -> Tesomet 0.125/25 mg Tesomet 0.25/25 mg Tesomet 0.125/25 mg
    Number of subjects analysed
    3
    3
    2
    3
    2
    2
    1
    Units: g/cm2
        arithmetic mean (standard deviation)
    0.002 ± 0.017
    0.019 ± 0.009
    0.035 ± 0.008
    -0.006 ± 0.008
    -0.007 ± 0.009
    0.023 ± 0.0
    0.009 ± 0
    No statistical analyses for this end point

    Secondary: Change from baseline to end of treatment in BMC by dual X-ray absorptiometry (DEXA)

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    End point title
    		 Change from baseline to end of treatment in BMC by dual X-ray absorptiometry (DEXA) [16]
    End point description
    Change from baseline to end of treatment in BMC by dual X-ray absorptiometry (DEXA). Observed values.
    End point type
    Secondary
    End point timeframe
    DB Step 1: Day 1 to Day 91 DB Step 2: Day 1 to Day 91 OLE I: Day 91 to Day 181 OLE II: Day 181 to Day 271
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive statistics were planned for.
    End point values
    		 Tesomet 0.50/50 mg Tesomet 0.125/25 mg Placebo Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg Placebo -> Tesomet 0.125/25 mg Tesomet 0.25/25 mg Tesomet 0.125/25 mg
    Number of subjects analysed
    3
    3
    2
    3
    2
    2
    1
    Units: gram(s)
        arithmetic mean (standard deviation)
    9.5 ± 63.8
    74.77 ± 22.46
    35.53 ± 55.37
    -1.12 ± 17.86
    5.69 ± 66.33
    22.51 ± 46.6
    -21.90 ± 0
    No statistical analyses for this end point

    Secondary: Change from baseline to end of treatment in HR

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    End point title
    		 Change from baseline to end of treatment in HR
    End point description
    Change from baseline to end of treatment in HR (bpm). LOCF.
    End point type
    Secondary
    End point timeframe
    DB Step 1: Day 1 to Day 91 DB Step 2: Day 1 to Day 91 OLE I: Day 91 to Day 181 OLE II: Day 181 to Day 271
    End point values
    		 Tesomet 0.50/50 mg Placebo Tesomet 0.125/25 mg Placebo Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg Placebo -> Tesomet 0.125/25 mg Tesomet 0.25/25 mg Tesomet 0.125/25 mg
    Number of subjects analysed
    6
    3
    5
    4
    4
    4
    4
    1
    Units: bpm
        arithmetic mean (standard deviation)
    8.22 ± 4.26
    7.89 ± 7.88
    5.87 ± 11.01
    2.75 ± 8.96
    2.42 ± 15.14
    0.33 ± 8.65
    -9.50 ± 10.86
    -5.67 ± 0
    No statistical analyses for this end point

    Secondary: Change from baseline to end of treatment in SBP and DBP

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    End point title
    		 Change from baseline to end of treatment in SBP and DBP
    End point description
    Change from baseline to end of treatment in SBP (mmHg) and DBP (mmHg). LOCF.
    End point type
    Secondary
    End point timeframe
    DB Step 1: Day 1 to Day 91 DB Step 2: Day 1 to Day 91 OLE I: Day 91 to Day 181 OLE II: Day 181 to Day 271
    End point values
    		 Tesomet 0.50/50 mg Placebo Tesomet 0.125/25 mg Placebo Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg Placebo -> Tesomet 0.125/25 mg Tesomet 0.25/25 mg Tesomet 0.125/25 mg
    Number of subjects analysed
    6
    3
    5
    4
    4
    4
    4
    1
    Units: mmHg
    arithmetic mean (standard deviation)
        Change in SBP
    -2.72 ± 9.96
    0.11 ± 15.22
    -0.13 ± 15.79
    -5.00 ± 9.26
    5.67 ± 11.30
    8.08 ± 6.45
    -5.33 ± 2.60
    -9.67 ± 0
        Change in DBP
    0.94 ± 10.72
    -8.89 ± 8.00
    -1.07 ± 7.06
    0.33 ± 2.54
    2.92 ± 10.22
    4.00 ± 5.40
    -6.42 ± 3.95
    1.33 ± 0
    No statistical analyses for this end point

    Secondary: Adverse events

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    End point title
    		 Adverse events
    End point description
    Incidence of AEs
    End point type
    Secondary
    End point timeframe
    DB Step 1: Day 1 to Day 91 DB Step 2: Day 1 to Day 91 OLE I: Day 91 to Day 181 OLE II: Day 181 to Day 271
    End point values
    		 Tesomet 0.50/50 mg Placebo Tesomet 0.125/25 mg Placebo Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg Placebo -> Tesomet 0.125/25 mg Tesomet 0.25/25 mg Tesomet 0.125/25 mg
    Number of subjects analysed
    6
    3
    5
    4
    4
    4
    5
    1
    Units: Number of AE/Number of subjects
        Total number of AE
    23
    10
    19
    9
    11
    12
    14
    5
        Subjects with at least one AE
    6
    3
    5
    3
    4
    4
    5
    1
        Subjects with at least one SAE
    3
    0
    0
    0
    0
    0
    2
    0
    No statistical analyses for this end point

    Secondary: Change from baseline to end of treatment in ECG parameters

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    End point title
    		 Change from baseline to end of treatment in ECG parameters
    End point description
    Change from baseline to end of treatment in ECG parameters. Observed values
    End point type
    Secondary
    End point timeframe
    DB Step 1: Day 1 to Day 91 DB Step 2: Day 1 to Day 91 OLE I: Day 91 to Day 181 OLE II: Day 181 to Day 271
    End point values
    		 Tesomet 0.50/50 mg Placebo Tesomet 0.125/25 mg Placebo Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg Placebo -> Tesomet 0.125/25 mg Tesomet 0.25/25 mg Tesomet 0.125/25 mg
    Number of subjects analysed
    2 [17]
    2 [18]
    4 [19]
    4 [20]
    4 [21]
    3 [22]
    2 [23]
    1
    Units: ms
    arithmetic mean (standard deviation)
        PR interval
    -20.0 ± 0
    0 ± 0
    0.0 ± 0
    20.0 ± 0.0
    0.0 ± 0
    -20.0 ± 0
    0 ± 0
    10.0 ± 0
        QRS duration
    -4.0 ± 8.5
    4.0 ± 0.0
    2.0 ± 2.3
    2.0 ± 8.5
    -1.5 ± 3.0
    0.7 ± 5.0
    -4.0 ± 5.7
    0.0 ± 0
        QT interval
    -7.0 ± 18.4
    19.0 ± 9.9
    -5.5 ± 27.2
    5.5 ± 27.2
    -5.0 ± 19.2
    -13.3 ± 16.2
    7.0 ± 7.1
    -20.0 ± 0
        QTcF
    -12.9 ± 4.4
    12.8 ± 19.8
    0.1 ± 24.4
    11.0 ± 20.4
    -3.7 ± 14.5
    -10.3 ± 29.3
    17.1 ± 4.5
    -2.9 ± 0
        QTcB
    -16.0 ± 2.8
    9.0 ± 25.5
    3.5 ± 31.8
    13.9 ± 21.4
    -2.6 ± 22.8
    -8.2 ± 37.3
    23.0 ± 2.9
    8.2 ± 0
    Notes
    [17] - 2 subjects in all categories except PR interval. 1 subject in PR interval.
    [18] - 2 subjects in all categories except PR interval. 0 subjects in PR interval.
    [19] - 4 subjects in all categories except PR interval. 1 subject in PR interval.
    [20] - 4 subjects in all categories except PR interval. 2 subjects in PR interval.
    [21] - 4 subjects in all categories except PR interval. 1 subject in PR interval.
    [22] - 3 subjects in all categories except PR interval. 1 subject in PR interval.
    [23] - 2 subjects in all categories except PR interval. 0 subjects in PR interval.
    No statistical analyses for this end point

    Secondary: Change from baseline to end of treatment in HbA1c

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    End point title
    		 Change from baseline to end of treatment in HbA1c
    End point description
    Change from baseline to end of treatment in HbA1c (%). LOCF.
    End point type
    Secondary
    End point timeframe
    DB Step 1: Day 1 to Day 91 DB Step 2: Day 1 to Day 91 OLE I: Day 91 to Day 181 OLE II: Day 181 to Day 271
    End point values
    		 Tesomet 0.50/50 mg Placebo Tesomet 0.125/25 mg Placebo Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg Placebo -> Tesomet 0.125/25 mg Tesomet 0.25/25 mg Tesomet 0.125/25 mg
    Number of subjects analysed
    6
    2
    5
    4
    4
    3
    4
    1
    Units: percent
        arithmetic mean (standard deviation)
    0.11 ± 0.13
    0.15 ± 0.21
    0.06 ± 0.05
    0.15 ± 0.24
    0.12 ± 0.26
    0.10 ± 0.17
    0.00 ± 0.12
    0.00 ± 0
    No statistical analyses for this end point

    Secondary: Change from baseline to end of treatment in insulin

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    End point title
    		 Change from baseline to end of treatment in insulin
    End point description
    Change from baseline to end of treatment in insulin (mIU/L). LOCF.
    End point type
    Secondary
    End point timeframe
    DB Step 1: Day 1 to Day 91 DB Step 2: Day 1 to Day 91 OLE I: Day 91 to Day 181 OLE II: Day 181 to Day 271
    End point values
    		 Tesomet 0.50/50 mg Placebo Tesomet 0.125/25 mg Placebo Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg Placebo -> Tesomet 0.125/25 mg Tesomet 0.25/25 mg Tesomet 0.125/25 mg
    Number of subjects analysed
    6
    2
    5
    4
    4
    3
    4
    1
    Units: mIU/L
        arithmetic mean (standard deviation)
    2.67 ± 10.93
    1.50 ± 10.61
    1.95 ± 13.85
    -10.32 ± 17.20
    13.14 ± 22.15
    4.93 ± 5.25
    -1.35 ± 24.56
    -5.90 ± 0
    No statistical analyses for this end point

    Secondary: Change from baseline to end of treatment in fasting pl. glucose, triglycerides, LDL and HDL cholesterol

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    End point title
    		 Change from baseline to end of treatment in fasting pl. glucose, triglycerides, LDL and HDL cholesterol
    End point description
    Change from baseline to end of treatment in fasting pl. glucose (mmol/L), triglycerides (mmol/L), LDL and HDL cholesterol (mmol/L). LOCF.
    End point type
    Secondary
    End point timeframe
    DB Step 1: Day 1 to Day 91 DB Step 2: Day 1 to Day 91 OLE I: Day 91 to Day 181 OLE II: Day 181 to Day 271
    End point values
    		 Tesomet 0.50/50 mg Placebo Tesomet 0.125/25 mg Placebo Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg Placebo -> Tesomet 0.125/25 mg Tesomet 0.25/25 mg Tesomet 0.125/25 mg
    Number of subjects analysed
    6
    2
    5
    4
    4
    3
    4
    1
    Units: mmol/L
    arithmetic mean (standard deviation)
        Fasting pl. glucose
    0.27 ± 0.59
    0.30 ± 0.14
    -0.20 ± 0.58
    -0.30 ± 0.29
    1.07 ± 1.19
    0.37 ± 0.31
    0.60 ± 0.35
    -0.40 ± 0
        Triglycerides
    -0.07 ± 0.29
    -0.02 ± 0.06
    0.56 ± 1.32
    -1.33 ± 1.54
    -0.54 ± 1.23
    0.38 ± 0.14
    -0.13 ± 0.26
    0.13 ± 0
        LDL cholesterol
    -0.16 ± 0.44
    -0.12 ± 0.32
    0.16 ± 0.21
    -0.32 ± 0.99
    -0.02 ± 0.43
    -0.01 ± 0.43
    0.10 ± 0.32
    -0.25 ± 0
        HDL cholesterol
    -0.10 ± 0.20
    -0.17 ± 0.01
    -0.03 ± 0.18
    -0.03 ± 0.17
    0.16 ± 0.22
    0.22 ± 0.11
    -0.05 ± 0.05
    -0.14 ± 0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomisation to end of study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Step 1 - Tesomet 0.50/50 mg
    Reporting group description
    		 Subjects (adults) were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication Tesomet) once daily for 91 days (+2 days after the final assessments with halfdose of metoprolol) during Step 1.

    Reporting group title
    Step 1 - Placebo
    Reporting group description
    		 -

    Reporting group title
    Step 2- Tesomet 0.125/25 mg
    Reporting group description
    		 Subjects (adolescents) were randomized to receive co-administration of 0.125 mg tesofensine/25 mg metoprolol (active medication Tesomet) once daily for 91 days: +2days after the final assessments with halfdose.

    Reporting group title
    Step 2 - Placebo
    Reporting group description
    		 -

    Reporting group title
    OLE I - Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg
    Reporting group description
    		 Participation in a 12-week OLE I was offered to patients who completed Step 2. Patients were receiving co-administration of 0.125 mg tesofensine/25 mg metoprolol (active medication Tesomet) once daily for 12 weeks during OLE I.

    Reporting group title
    OLE I - Placebo -> Tesomet 0.125/25 mg
    Reporting group description
    		 Participation in a 12-week OLE I was offered to patients who completed Step 2. Patients were receiving co-administration of 0.125 mg tesofensine/25 mg metoprolol (active medication Tesomet) once daily for 12 weeks during OLE I.

    Reporting group title
    OLE II - Tesomet 0.25/25 mg
    Reporting group description
    		 Participation in a 12 week OLE was offered to all eligible patients of OLE I. Patients were receiving coadministration of 0.25 mg tesofensine/25 mg metoprolol (active medication Tesomet) once daily for 12 weeks during OLE II.

    Reporting group title
    OLE II - Tesomet 0.125/25 mg
    Reporting group description
    		 Participation in a 12 week OLE was offered to all eligible patients of OLE I. Patients were receiving coadministration of 0.125 mg tesofensine/25 mg metoprolol (active medication) once daily for 12 weeks.

    Serious adverse events
    		 Step 1 - Tesomet 0.50/50 mg Step 1 - Placebo Step 2- Tesomet 0.125/25 mg Step 2 - Placebo OLE I - Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg OLE I - Placebo -> Tesomet 0.125/25 mg OLE II - Tesomet 0.25/25 mg OLE II - Tesomet 0.125/25 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 5 (40.00%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Anger
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abnormal behaviour
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Retroperitoneal abscess
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Step 1 - Tesomet 0.50/50 mg Step 1 - Placebo Step 2- Tesomet 0.125/25 mg Step 2 - Placebo OLE I - Tesomet 0.125/25 mg -> Tesomet 0.125/25 mg OLE I - Placebo -> Tesomet 0.125/25 mg OLE II - Tesomet 0.25/25 mg OLE II - Tesomet 0.125/25 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    3 / 3 (100.00%)
    5 / 5 (100.00%)
    3 / 4 (75.00%)
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    5 / 5 (100.00%)
    1 / 1 (100.00%)
    Injury, poisoning and procedural complications
    Joint injury
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Arthropod sting
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    0
    0
    Feeling cold
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 3 (66.67%)
    2 / 5 (40.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    2
    2
    0
    0
    1
    1
    1
    Nausea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Sneezing
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Cough
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 3 (0.00%)
    2 / 5 (40.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    3
    0
    2
    1
    1
    0
    0
    1
    Affect lability
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Aggression
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    2
    0
    0
    2
    0
    1
    0
    1
    Delusion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Illusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    Depression
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Restlessness
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Abnormal behaviour
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    2 / 5 (40.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    2
    0
    Mood swings
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    Dermatillomania
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Hallucination
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Panic attack
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Depressed mood
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Mood altered
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Negativism
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Sleep disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Nervousness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Osteoporosis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    3 / 5 (60.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    2
    1
    2
    3
    0
    Pain in extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Arthralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Osteopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Otitis externa
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Cystitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Tonsillitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Oct 2016
    N/A
    04 Jan 2017
    For Czech Republic only. SUKL as a Czech RA was added to paragraphs where information about SUKL oversight/approval is needed Dietary instructions for patient suffered from diabetes were added Wording of paragraph „UNBLINDING“ was updated
    22 Mar 2017
    HQCT questionnaire added, Update of timelines of the clinical trial
    10 Aug 2017
    Decrease of dose of tesofensin to 0,25mg Maximum number of randomized patients was increased to 20 Wording of inclusion criteria No.7 was changed to „Growth hormone is allowed; but subject must be on a stable dose of growth hormone “>2 months“ Update of timelines of the clinical trial Address of central laboratories was added
    04 Dec 2017
    An unblinded interim analysis after Step 1 will be performed by Sponsor and interim analysis will be done, SUKL will be given all the unblided data for review Step 2 will start only after SUKL positive opinion regarding to interim analysis and unblinded dat
    28 Mar 2018
    Dose reduction of tesofensine and metoprolol in pediatric patients. Psychiatric examinations are added to each patient visit. Change in Follow up, V15. Data on the duration of the clinical trial were updated. Exclusion criterium No. 7 was extended. The minimum number of patients was adjusted to 5.
    10 Oct 2018
    Open Label Phase was added. Visit V14 (last visit of step II) will be simultaneously first visit of OLE Phase for participated patient. To the Protocol Name was added „A 12 Weeks Open Label Extension. New exclusion and inclusion criteria were created. Overall study description was extended. Study procedure for V14-V18 are described in this Protocol. End of OLE was predicted to be in April/May 2019. Manufacture of IMP was changed. Unblinding is not applicable in OLE. For patient in OLE remain the same screening number as in step 2.
    06 Feb 2019
    Second Open Label Phase was added. Last visit V17 of OLE will be first visit of OLE II. To the Protocol Name was added „Second 12 Weeks Open Label Extension. Inclusion and exclusion criteria were updated. Estimated end of study is on Jun 2019.

    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.
    The administration of tesofensine 0.5mg/metoprolol 50 mg led to unintendedly high plasma levels of tesofensine exceeding efficacious levels by a factor two to three.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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