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    Clinical Trial Results:
    A Phase IIa, Multi-Centre, Randomised, Double-Blind, Cross-Over, Placebo-Controlled Study to Assess the Efficacy, Safety and Tolerability of MT-8554 in Subjects with Painful Diabetic Peripheral Neuropathy Incorporating an Open Label Pilot Arm

    Summary
    EudraCT number
    		 2016-002571-10
    Trial protocol
    		 HU   PL   DE  
    Global end of trial date
    08 Aug 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Aug 2019
    First version publication date
    18 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MT-8554-E06
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03172598
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mitsubishi Tanabe Pharma Corporation
    Sponsor organisation address
    17-10, Nihonbashi-Koamicho, Chuo-ku, Tokyo, Japan, 103-8405
    Public contact
    General Information, Mitsubishi Tanabe Pharma Europe Ltd., regulatory@mt-pharma-eu.com
    Scientific contact
    General Information, Mitsubishi Tanabe Pharma Europe Ltd., regulatory@mt-pharma-eu.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
    08 Aug 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part 1 (Pilot Arm): To evaluate the safety and tolerability of MT-8554 to determine the dose level administered in Part 2. Part 2 (Cross-over Arm): To evaluate the efficacy of MT-8554 in reducing pain intensity in subjects with painful DPN.
    Protection of trial subjects
    Subjects were withdrawn from the study if any of the following scenarios occurred: • The subject wished to withdraw from further participation. • The subject was significantly noncompliant with the Protocol. • Continuing in the study would have been detrimental to the subject’s safety in the opinion of the Investigator, e.g., - The subject experienced intolerable AEs or serious adverse events (SAEs) - The subject became pregnant from the Screening Visit until 3 months after the last dose of IMP - The subject had CS changes in safety parameters at any of the post-dose time points, as confirmed with a repeat assessment performed as soon as possible after the initial out-of-range result - The subject had an increase in QTcF to ≥500 ms or increase of ≥60 ms from baseline (pre-dose on Day 1), as confirmed with 3 consecutive ECGs taken at least 5 minutes apart in a 30-minute period - Development of any CS liver dysfunction, as follows: • ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN, or • ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%), or • ALT or AST >5 × ULN - The subject experienced signs or symptoms of significant hypothermia or a tympanic/oral body temperature <35°C over a 1 hour period (confirmed by repeat assessment performed at least 60 minutes after the original assessment). In addition, a subject may have been withdrawn at any time for reason(s) other than those listed here.
    Background therapy
    		 Prior and concomitant medications which were considered necessary for the safety and well-being of the subject were permitted during the study at the discretion of the Investigator, provided the medication was not listed within the exclusion criteria (Section 9.3.2) or the prohibited medications (Section 9.4.7.2). Every effort was made to keep subjects on stable concomitant medications. Subjects were also permitted to use acetylsalicylic acid up to 325 mg/day post-myocardial infarction or prophylactically at doses ongoing at study entry for prevention of transient ischaemic attack, and zolpidem 5 mg for sleep disorders. Acetaminophen/paracetamol was allowable as rescue medication if dosed at up to 3 g/day, if required for pain relief. Should acetaminophen/paracetamol have provided insufficient relief from pain then use of metamizole in single doses up to 1 g and up to the maximum daily dose of 4 g was allowed. The label restrictions for acetaminophen/paracetamol and metamizole applied.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jul 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
    Poland: 36
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Hungary: 13
    Worldwide total number of subjects
    61
    EEA total number of subjects
    61
    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)
    39
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Potential study subjects were identified using a range of study-specific methods, as appropriate. Subjects were selected from those currently attending clinics for the treatment of DPN or identified from a review of relevant databases. All recruitment material was approved by an Independent Ethics Committee (IEC) prior to implementation.

    Pre-assignment
    Screening details
    		 Eligible subjects were required to complete a washout from any current DPN medications. For part 1, subjects received open label oral dose of MT-8554. For part 2, subjects attended a baseline visit at Day -7 and received a single-blind placebo for a period of a week before being randomised into double-blind cross over treatment sequence.

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Part 1 MT-8554 20mg Open Label
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    MT-8554
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg BID

    Arm title
    		 Part 1 MT-8554 50mg Open Label
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    MT-8554
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg BID

    Arm title
    		 Part 2 Overall
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    MT-8554
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    20mg BID during one of two treatment periods.

    Investigational medicinal product name
    MT-8554 matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    20mg BID during two baselines, washout and one of two treatment periods.

    Number of subjects in period 1
    		Part 1 MT-8554 20mg Open Label Part 1 MT-8554 50mg Open Label Part 2 Overall
    Started
    5
    4
    52
    Completed
    4
    2
    34
    Not completed
    1
    2
    18
         Consent withdrawn by subject
    -
    -
    3
         Adverse event, non-fatal
    -
    1
    14
         protocol specific reason
    -
    1
    1
         Protocol deviation
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1 MT-8554 20mg Open Label
    Reporting group description
    		 -

    Reporting group title
    Part 1 MT-8554 50mg Open Label
    Reporting group description
    		 -

    Reporting group title
    Part 2 Overall
    Reporting group description
    		 -

    Reporting group values
    		 Part 1 MT-8554 20mg Open Label Part 1 MT-8554 50mg Open Label Part 2 Overall Total
    Number of subjects
    		 5 4 52 61
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 3 3 33 39
        From 65-84 years
    		 2 1 19 22
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.8 ( 6.4 ) 63.3 ( 6.8 ) 60.1 ( 9.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 1 19 23
        Male
    		 2 3 33 38

    End points

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    End points reporting groups
    Reporting group title
    Part 1 MT-8554 20mg Open Label
    Reporting group description
    		 -

    Reporting group title
    Part 1 MT-8554 50mg Open Label
    Reporting group description
    		 -

    Reporting group title
    Part 2 Overall
    Reporting group description
    		 -

    Subject analysis set title
    Part 2 Placebo Week 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Includes all randomised subjects who receive at least 1 dose of IMP and who have at least 1 post-baseline efficacy assessment.

    Subject analysis set title
    Part 2 MT-8554 20mg week 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Includes all randomised subjects who receive at least 1 dose of IMP and who have at least 1 post-baseline efficacy assessment.

    Subject analysis set title
    Part 2 Placebo Week 2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Includes all randomised subjects who receive at least 1 dose of IMP and who have at least 1 post-baseline efficacy assessment.

    Subject analysis set title
    Part 2 MT-8554 20mg week 2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Includes all randomised subjects who receive at least 1 dose of IMP and who have at least 1 post-baseline efficacy assessment.

    Primary: Change from baseline in the weekly median 24-hour API score

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    End point title
    		 Change from baseline in the weekly median 24-hour API score
    End point description
    End point type
    Primary
    End point timeframe
    week 1 and 2
    End point values
    		 Part 2 Placebo Week 1 Part 2 MT-8554 20mg week 1 Part 2 Placebo Week 2 Part 2 MT-8554 20mg week 2
    Number of subjects analysed
    42
    45
    42
    40
    Units: no unit
        least squares mean (standard error)
    -0.37 ( 0.18 )
    -0.67 ( 0.16 )
    -0.58 ( 0.20 )
    -0.95 ( 0.20 )
    Statistical analysis title
    		 Change from Baseline Weekly API Score at week 1
    Statistical analysis description
    The 'number of subjects included in analysis' is not correct because of the cross-over study design (subject analysis sets were not mutually exclusive). The 'number of subjects included in analysis' for the comparison is equivalent to the 'number of subjects analysed'.
    Comparison groups
    Part 2 Placebo Week 1 v Part 2 MT-8554 20mg week 1
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.202 [1]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - Difference MT-8554 20mg - Placebo
    Statistical analysis title
    		 Change from Baseline Weekly API Score at week 2
    Statistical analysis description
    The 'number of subjects included in analysis' is not correct because of the cross-over study design (subject analysis sets were not mutually exclusive). The 'number of subjects included in analysis' for the comparison is equivalent to the 'number of subjects analysed'.
    Comparison groups
    Part 2 Placebo Week 2 v Part 2 MT-8554 20mg week 2
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.155 [2]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [2] - Difference MT-8554 20mg - Placebo

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time written informed consent was obtained until the end of the Follow-up Period or the withdrawal of the subject from the study
    Adverse event reporting additional description
    Part 1 reported all AEs and frequency threshold was only applied to part 2. Following AEs were reported in part1, but did not meet the 5% threshold in part 2: Headache, Peripheral sensory neuropathy, hot flush, dry skin, back pain. Due to the design of the database, these AEs were also reported for part 2 despite not meeting threshold.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Part 1 20mg MT-8554
    Reporting group description
    		 -

    Reporting group title
    Part 1 50mg MT-8554
    Reporting group description
    		 -

    Reporting group title
    Part 2 Placebo
    Reporting group description
    		 -

    Reporting group title
    Part 2 MT-8554 20mg
    Reporting group description
    		 -

    Serious adverse events
    		 Part 1 20mg MT-8554 Part 1 50mg MT-8554 Part 2 Placebo Part 2 MT-8554 20mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 43 (0.00%)
    3 / 52 (5.77%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Autonomic nervous system imbalance
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 43 (0.00%)
    3 / 52 (5.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    4 / 4
         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
    		 Part 1 20mg MT-8554 Part 1 50mg MT-8554 Part 2 Placebo Part 2 MT-8554 20mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 5 (80.00%)
    4 / 4 (100.00%)
    16 / 43 (37.21%)
    39 / 52 (75.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 43 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    1
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 4 (0.00%)
    2 / 43 (4.65%)
    2 / 52 (3.85%)
         occurrences all number
    3
    0
    6
    2
    Hypoaesthesia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    1 / 43 (2.33%)
    5 / 52 (9.62%)
         occurrences all number
    1
    0
    1
    12
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 43 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 43 (2.33%)
    7 / 52 (13.46%)
         occurrences all number
    0
    0
    1
    8
    Burning sensation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 43 (4.65%)
    5 / 52 (9.62%)
         occurrences all number
    0
    0
    2
    9
    Autonomic nervous system imbalance
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 43 (0.00%)
    5 / 52 (9.62%)
         occurrences all number
    0
    0
    0
    6
    Dizziness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 43 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    0
    0
    4
    Dysgeusia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 43 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    0
    0
    3
    General disorders and administration site conditions
    Feeling hot
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    2 / 43 (4.65%)
    15 / 52 (28.85%)
         occurrences all number
    1
    1
    4
    85
    Hypothermia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 43 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    1
    0
    4
    Asthenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    3 / 43 (6.98%)
    2 / 52 (3.85%)
         occurrences all number
    0
    0
    4
    3
    Feeling cold
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 43 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    0
    0
    3
    Gastrointestinal disorders
    Hypoaesthesia oral
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 4 (0.00%)
    0 / 43 (0.00%)
    5 / 52 (9.62%)
         occurrences all number
    2
    0
    0
    32
    Diarrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    3 / 43 (6.98%)
    1 / 52 (1.92%)
         occurrences all number
    0
    0
    7
    1
    Dry mouth
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 43 (4.65%)
    3 / 52 (5.77%)
         occurrences all number
    0
    0
    3
    4
    Paraesthesia oral
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 43 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    0
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 43 (2.33%)
    9 / 52 (17.31%)
         occurrences all number
    0
    0
    1
    40
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 43 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin burning sensation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 43 (0.00%)
    5 / 52 (9.62%)
         occurrences all number
    0
    0
    0
    38
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 43 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Dec 2017
    Protocol v3.0 (06 October 2017)

    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.
    There was a limitation for reporting some data within the EudraCT database in AEs and primary endpoint due to study being a two parts study and only second part with a cross-over design. Further information can be found in relevant section.
    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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