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    Clinical Trial Results:
    A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTIPLE-DOSE, TWO-CENTRE, SAFETY AND EFFICACY STUDY OF CO-ADMINISTRATION OF TESOFENSINE/METOPROLOL TREATMENT IN SUBJECTS WITH TYPE 2 DIABETES MELLITUS

    Summary
    EudraCT number
    		 2015-005522-19
    Trial protocol
    		 DE  
    Global end of trial date
    22 Nov 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Dec 2017
    First version publication date
    30 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TM001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02737891
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Saniona A/S
    Sponsor organisation address
    Baltorpvej 154 , Ballerup , Denmark, 2750
    Public contact
    Jørgen Drejer, PhD CEO and founder, Saniona, A/S, +45 20289705, jd@saniona.com
    Scientific contact
    Roman V Dovrak, Saniona, A/S, +45 70705225, rdv@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
    24 Aug 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effects of co-administration of tesofensine/ metoprolol treatment vs. placebo on 24-hour mean heart rate
    Protection of trial subjects
    All available measures were implemented per local EC.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Mar 2016
    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
    Germany: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    60
    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)
    54
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects from general population in Neuss and Mainz were recruited for the study.

    Pre-assignment
    Screening details
    		 Subjects who gave the written informed consent were screened for the study. For subjects on any anti-diabetic medications, treatment with all anti-diabetic medications except metformin was washed out. The subjects returned for a baseline visit at the end of the washout period (1-4 weeks).

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    Randomization and blinding was used in order to avoid bias introduced through an association between allocation order of IMP and subject characteristics. Subjects were also stratified based on their background anti-diabetic therapy – on metformin vs. metformin + further anti-diabetic agent.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo tesofensine/metoprolol
    Arm description
    		 Each subject was randomly allocated to one of two treatment arms. Treatment arm 1 was tesofensine 0.5 mg + metoprolol 100 mg administered once a day, in the morning with a meal (the first 2 days a loading dose of 1.0 mg/d of tesofensine was given) and treatment arm 2 was placebo tablets matching oral tesofensine + metoprolol administered once a day, in the morning with meal (the first 2 days a loading dose of 1.0 mg/d of placebo tesofensine was given). Each tablet was formulated separately; a currently available commercial formulation of metoprolol, MetoHEXAL® 100 mg retard, was used.
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo Tesofensine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5mg placebo

    Investigational medicinal product name
    placebo metoprolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg placebo

    Arm title
    		 Tesofensine/Metoprolol
    Arm description
    		 Each subject was randomly allocated to one of two treatment arms. Treatment arm 1 was tesofensine 0.5 mg + metoprolol 100 mg administered once a day, in the morning with a meal (the first 2 days a loading dose of 1.0 mg/d of tesofensine was given) and treatment arm 2 was placebo tablets matching oral tesofensine + metoprolol administered once a day, in the morning with meal (the first 2 days a loading dose of 1.0 mg/d of placebo tesofensine was given). Each tablet was formulated separately; a currently available commercial formulation of metoprolol, MetoHEXAL® 100 mg retard, was used.
    Arm type
    		 Experimental

    Investigational medicinal product name
    tesofensine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5mg

    Investigational medicinal product name
    metoprolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg

    Number of subjects in period 1
    		Placebo tesofensine/metoprolol Tesofensine/Metoprolol
    Started
    30
    30
    Completed
    28
    30
    Not completed
    2
    0
         one withdrawn consent and second SAE
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 60 60
    Age categorical
    inclusion criteria: 18-70 years of age
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 54 54
        From 65-84 years
    		 6 6
        85 years and over
    		 0 0
        Adult
    		 0 0
    Gender categorical
    Randomisation
    Units: Subjects
        Female
    		 21 21
        Male
    		 39 39
    Subject analysis sets

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) was based on the intention-to-treat principle and it included all randomized subjects

    Subject analysis sets values
    		 FAS
    Number of subjects
    60
    Age categorical
    inclusion criteria: 18-70 years of age
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    54
        From 65-84 years
    6
        85 years and over
    0
        Adult
    0
    Age continuous
    Units:
        
    ( )
    Gender categorical
    Randomisation
    Units: Subjects
        Female
    21
        Male
    39

    End points

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    End points reporting groups
    Reporting group title
    Placebo tesofensine/metoprolol
    Reporting group description
    		 Each subject was randomly allocated to one of two treatment arms. Treatment arm 1 was tesofensine 0.5 mg + metoprolol 100 mg administered once a day, in the morning with a meal (the first 2 days a loading dose of 1.0 mg/d of tesofensine was given) and treatment arm 2 was placebo tablets matching oral tesofensine + metoprolol administered once a day, in the morning with meal (the first 2 days a loading dose of 1.0 mg/d of placebo tesofensine was given). Each tablet was formulated separately; a currently available commercial formulation of metoprolol, MetoHEXAL® 100 mg retard, was used.

    Reporting group title
    Tesofensine/Metoprolol
    Reporting group description
    		 Each subject was randomly allocated to one of two treatment arms. Treatment arm 1 was tesofensine 0.5 mg + metoprolol 100 mg administered once a day, in the morning with a meal (the first 2 days a loading dose of 1.0 mg/d of tesofensine was given) and treatment arm 2 was placebo tablets matching oral tesofensine + metoprolol administered once a day, in the morning with meal (the first 2 days a loading dose of 1.0 mg/d of placebo tesofensine was given). Each tablet was formulated separately; a currently available commercial formulation of metoprolol, MetoHEXAL® 100 mg retard, was used.

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) was based on the intention-to-treat principle and it included all randomized subjects

    Primary: 24-hour heart rate

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    End point title
    		 24-hour heart rate
    End point description
    In the FAS, the primary endpoint, mean 24-hour heart rate, was reduced on average by 4.3 beats/minute in subjects treated with tesofensine/metoprolol compared to an average decline of 0.2 beats/minute in subjects dosed with placebo. The reduction was statistically significant for treatment with tesofensine/metoprolol compared with placebo (LSM difference -3.8 beats/minute, 95% CI (-6.36; -1.29), p=0.004). The result was confirmed by the analysis based on the PPP (LSM difference -4.1 beats/minute, 95% CI (-6.66; -1.54), p=0.002).
    End point type
    Primary
    End point timeframe
    from the baseline to Week 12
    End point values
    		 Placebo tesofensine/metoprolol Tesofensine/Metoprolol FAS
    Number of subjects analysed
    30
    30
    60
    Units: beats/min
        arithmetic mean (standard deviation)
    70.08 ( 9.115 )
    67.70 ( 7.186 )
    0 ( 0 )
    Statistical analysis title
    		 Repeated measures ANCOVA
    Statistical analysis description
    Efficacy endpoints (primary, secondary and exploratory endpoints apart from PHQ scores) were analysed with a parametric model, i.e. compared between treatment arms by means of an analysis of covariance (ANCOVA) model (proc MIXED) using change from baseline to the end of treatment as dependent variable, treatment and study site as fixed effects and the value from baseline as covariate. The residual errors were assumed independent and identically distributed (i.i.d.) and normally distributed.
    Comparison groups
    Placebo tesofensine/metoprolol v Tesofensine/Metoprolol
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 < 0.05 [2]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - Efficacy endpoints were checked for normal distribution via a Shapiro-Wilk test. In case of normally distributed parameter, an additional analysis was performed without study site as fixed effect, if this effect was not significant (24-hour heart rate, waist circumference).
    [2] - Within the model least square mean (LS-mean) for each treatment as well as the difference of the means between the treatment arms, the corresponding 95% confidence intervals (CIs) and p-values were calculated.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization to Day 91
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Gastrointestinal disorders
    Reporting group description
    		 -

    Serious adverse events
    		 Gastrointestinal disorders
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 60 (1.67%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Gastrointestinal disorders
    cholelithiasis
    Additional description: One not treatment-emergent SAE occurred in a subject of the placebo arm, a cholelithiasis of moderate intensity not reported as medical history that led to repeated hospitalization (removal of a gallstone in the distal hepatic duct and cholecystectom
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Gastrointestinal disorders
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 60 (26.67%)
    Gastrointestinal disorders
    Dry mouth
    Additional description: Dry mouth
         subjects affected / exposed
    5 / 60 (8.33%)
         occurrences all number
    5
    Abdominal pain upper
    Additional description: Abdominal pain upper
         subjects affected / exposed
    2 / 60 (3.33%)
         occurrences all number
    2
    Abnormal faeces
    Additional description: Abnormal faeces
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences all number
    1
    Dental caries
    Additional description: Dental caries
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences all number
    1
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    2 / 60 (3.33%)
         occurrences all number
    2
    Gastric disorder
    Additional description: Gastric disorder
         subjects affected / exposed
    2 / 60 (3.33%)
         occurrences all number
    2
    Impaired gastric emptying
    Additional description: Impaired gastric emptying
         subjects affected / exposed
    4 / 60 (6.67%)
         occurrences all number
    4
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    9 / 60 (15.00%)
         occurrences all number
    9
    Toothache
    Additional description: Toothache
         subjects affected / exposed
    2 / 60 (3.33%)
         occurrences all number
    2
    Vomiting
    Additional description: Vomiting
         subjects affected / exposed
    4 / 60 (6.67%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Mar 2016
    Two amendments to the study documentation were generated. Amendment 1 was generated because of the conditional approval of the clinical study by the Competent Authority, German Federal Institute for Drugs and Medical Devices, [Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM)] and entailed a change of the study protocol (final version 4.0, dated 09 Mar 2016, Appendix 16.1.1), the IB, the SI/IC Form and the subject diary. This amendment was substantial for the IEC. On 29 Mar 2016, the leading IEC approved amendment 1 and the corresponding study documents prior to study start.
    29 Mar 2016
    T Amendment 2 concerned minor corrections of the study protocol and was non-substantial for the IEC. Non-substantial amendments did not require a favourable opinion by the IEC and the respective IEC was not to be notified according to local requirements.

    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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