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    Clinical Trial Results:
    A Phase 2 open label biomarker study of angiotensin II type 2 receptor antagonist EMA401 for the treatment of pain in patients with chemotherapy-induced peripheral neuropathy. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2011-004033-13
    Trial protocol
    		 GB  
    Global end of trial date
    09 May 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jul 2018
    First version publication date
    05 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EMA401-005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Novartis Pharmaceuticals AG, Novartis Pharmaceuticals AG, 41 613241111 ,
    Scientific contact
    Novartis Pharma AG, Novartis Pharma AG, 41 613241111 ,
    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
    09 May 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy of EMA401 100 mg orally twice daily for 28 days in reducing spontaneous neuropathic pain from baseline to Week 4 in patients with chemotherapy-induced peripheral neuropathy (CIPN).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Sep 2012
    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
    United Kingdom: 31
    Worldwide total number of subjects
    31
    EEA total number of subjects
    31
    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)
    17
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Potential patients were contacted to describe general inclusion criteria, including diagnosis, medical history and current medications.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 EMA401 100 mg BID
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    EMA401
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    EMA401 Sodium Salt was presented as 50 mg capsules. Patients were asked to self-administer 2 capsules, each containing 50 mg EMA401, twice a day (morning and evening) for 28 days (i.e. a dose of 100 mg twice daily for a total daily dose of 200 mg). Capsules were to be taken on an empty stomach at least 1 hour before a meal, with at least 200 mL non-carbonated water.

    Number of subjects in period 1
    		EMA401 100 mg BID
    Started
    31
    Completing the Treatment Period
    28
    Completing the Follow-Up Period
    29
    Completed
    28
    Not completed
    3
         Physician decision
    1
         Consent withdrawn by subject
    1
         Inability or failure to comply with protocol
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    EMA401 100 mg BID
    Reporting group description
    		 -

    Reporting group values
    		 EMA401 100 mg BID Total
    Number of subjects
    		 31 31
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 17 17
        From 65-84 years
    		 14 14
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.3 ( 12.46 ) -
    Gender categorical
    Units: Subjects
        Female
    		 17 17
        Male
    		 14 14

    End points

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    End points reporting groups
    Reporting group title
    EMA401 100 mg BID
    Reporting group description
    		 -

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) included all patients who received EMA401 and for whom at least one post-dosing efficacy assessment was available.

    Primary: Change in Spontaneous Mean Pain Intensity Score from Baseline

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    End point title
    		 Change in Spontaneous Mean Pain Intensity Score from Baseline [1]
    End point description
    Patients evaluated their average pain since their last self-assessment by circling the appropriate corresponding number between 0 ("no pain") and 10 ("pain as bad as you can imagine").
    End point type
    Primary
    End point timeframe
    Baseline and Week 4
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses have not been specified for this primary end point as only one arm is reported.
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    30 [2]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Baseline
    6.5 ( 1.58 )
        Week 1
    6.1 ( 1.87 )
        Change from Baseline at Week 1
    -0.4 ( 0.81 )
        Week 2
    6 ( 2.05 )
        Change from Baseline at Week 2
    -0.7 ( 0.94 )
        Week 3
    5.5 ( 1.98 )
        Change from Baseline at Week 3
    -1 ( 1.04 )
        Week 4
    5.3 ( 2.15 )
        Change from Baseline at Week 4
    -1.3 ( 1.25 )
        Follow-up
    5.7 ( 2.36 )
        Change from Baseline at Follow-up
    -1 ( 1.7 )
    Notes
    [2] - Baseline n=30, Week 1 n=30, Week 2 n=27, Week 3 n=27, Week 4 n= 27, Follow-up n= 28
    No statistical analyses for this end point

    Secondary: Decrease of at Least 30% in Spontaneous Mean Pain Intensity Score over Time

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    End point title
    		 Decrease of at Least 30% in Spontaneous Mean Pain Intensity Score over Time
    End point description
    Patients evaluated their average pain since their last self-assessment by circling the appropriate corresponding number between 0 ("no pain") and 10 ("pain as bad as you can imagine"). Participants with available Week 4 data, can be classified as responders when the mean pain intensity score was at least 30% lower at Week 4 compared to Baseline.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    30
    Units: Percentage of participants
    number (confidence interval 95%)
        Baseline
    0 (0 to 0)
        Week 1 n=30
    6.7 (0.8 to 22.1)
        Week 2 n=27
    7.4 (0.9 to 24.3)
        Week 3 n=27
    7.4 (0.9 to 24.3)
        Week 4 n=27
    29.6 (13.8 to 50.2)
        Follow-Up n=28
    25 (10.7 to 44.9)
    No statistical analyses for this end point

    Secondary: Change in Evoked (Light Touch) Mean Pain Intensity Score from Baseline over Time

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    End point title
    		 Change in Evoked (Light Touch) Mean Pain Intensity Score from Baseline over Time
    End point description
    Patients evaluated their average pain since their last self-assessment by circling the appropriate corresponding number between 0 ("no pain") and 10 ("pain as bad as you can imagine").
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    30 [3]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Baseline
    3.8 ( 3.07 )
        Week 1
    3.5 ( 2.92 )
        Change from Baseline at Week 1
    -0.3 ( 1.8 )
        Week 2
    3.3 ( 3.03 )
        Change from Baseline at Week 2
    -0.6 ( 1.52 )
        Week 3
    3.2 ( 3.01 )
        Change from Baseline at Week 3
    -0.6 ( 1.73 )
        Week 4
    3 ( 3.02 )
        Change from Baseline at Week 4
    -0.8 ( 1.62 )
        Follow-up
    3.3 ( 3.24 )
        Change from Baseline at Follow-up
    -0.4 ( 1.55 )
    Notes
    [3] - Baseline n=30, Week 1 n=30, Week 2 n=27, Week 3 n=27, Week 4 n= 27, Follow-up n= 28
    No statistical analyses for this end point

    Secondary: Change in Evoked (Cold Touch) Mean Pain Intensity Score over Time

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    End point title
    		 Change in Evoked (Cold Touch) Mean Pain Intensity Score over Time
    End point description
    Patients evaluated their average pain since their last self-assessment by circling the appropriate corresponding number between 0 ("no pain") and 10 ("pain as bad as you can imagine").
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    30 [4]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Baseline
    3.8 ( 3.42 )
        Week 1
    3.5 ( 3.44 )
        Change from Baseline at Week 1
    -0.4 ( 1.36 )
        Week 2
    3.3 ( 3.29 )
        Change from Baseline at Week 2
    -0.5 ( 1.68 )
        Week 3
    2.9 ( 3.33 )
        Change from Baseline at Week 3
    -0.8 ( 1.72 )
        Week 4
    2.8 ( 3.27 )
        Change from Baseline at Week 4
    -1 ( 1.67 )
        Follow-up
    3.1 ( 3.27 )
        Change from Baseline at Follow-up
    -0.6 ( 2.21 )
    Notes
    [4] - Baseline n=30, Week 1 n=30, Week 2 n=27, Week 3 n=27, Week 4 n= 27, Follow-up n= 28
    No statistical analyses for this end point

    Secondary: Change in Short Form McGill Pain Questionnaire-2 Scores from Baseline

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    End point title
    		 Change in Short Form McGill Pain Questionnaire-2 Scores from Baseline
    End point description
    The SF-MPQ-2 is a 22-item self-administered patient questionnaire that is used to measure the different qualities of pain and related symptoms. The questionnaire provides patients with a list of words that describe some of the different qualities of pain and related symptoms and patients rated the intensity of each type of pain they felt during the past week on a scale from 0 to 10.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4 and Follow-Up visits
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    30 [5]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Total Pain - Baseline
    72.1 ( 43.79 )
        Total Pain - Week 4
    48.7 ( 44.71 )
        Total Pain - Early Withdrawal
    122 ( 57.98 )
        Total Pain - Follow-Up
    57.9 ( 45.39 )
        Continuous Pain - Baseline
    18.9 ( 12.42 )
        Continuous Pain - Week 4
    13.3 ( 13.89 )
        Continuous Pain - Early Withdrawal
    29 ( 16.97 )
        Continuous Pain - Follow-Up
    16.1 ( 12.97 )
        Intermittent Pain - Baseline
    16 ( 15.02 )
        Intermittent Pain - Week 4
    9.8 ( 11.16 )
        Intermittent Pain - Early Withdrawal
    28.5 ( 26.16 )
        Intermittent Pain - Follow-Up
    13 ( 14.77 )
        Neuropathic Pain - Baseline
    25.8 ( 12.87 )
        Neuropathic Pain - Week 4
    18.4 ( 14.95 )
        Neuropathic Pain - Early Withdrawal
    31 ( 18.38 )
        Neuropathic Pain - Follow-Up
    21.1 ( 14.18 )
        Affective Descriptors - Baseline
    11.3 ( 10.67 )
        Affective Descriptors - Week 4
    7.3 ( 9.92 )
        Affective Descriptors - Early Withdrawal
    33.5 ( 3.54 )
        Affective Descriptors - Follow-up
    7.7 ( 9.82 )
        Total Pain - Week 4 Change from Baseline
    -22.8 ( 26.38 )
        Total Pain - Early Withdrawal Change from Baseline
    10 ( 26.87 )
        Total Pain - Follow-Up Change from Baseline
    -14.3 ( 35.62 )
        Continuous Pain - Week 4 Change from Baseline
    -5.9 ( 8.36 )
        Continuous Pain - E W Change from Baseline
    -1 ( 12.73 )
        Continuous Pain - Follow-Up Change from Baseline
    -2.8 ( 10.64 )
        Intermittent Pain - Week 4 Change from Baseline
    -6.1 ( 9.79 )
        Intermittent Pain - E W Change from Baseline
    3.5 ( 3.54 )
        Intermittent Pain - Follow-Up Change from Baseline
    -3.1 ( 14.67 )
        Neuropathic Pain - Week 4 Change from Baseline
    -7.8 ( 9.41 )
        Neuropathic Pain - E W Change from Baseline
    0.5 ( 0.71 )
        Neuropathic Pain - Follow-Up Change from Baseline
    -5.2 ( 9.18 )
        Affective Descriptors - Week 4 Change from BL
    -3 ( 7.51 )
        Affective Descriptors - E W Change from Baseline
    7 ( 9.9 )
        Affective Descriptors - F/U Change from Baseline
    -3.3 ( 10.12 )
    Notes
    [5] - Actual vs Change: Baseline n=29/na Week 4 n=28/27, Early Withdrawal n=2/2, Follow-Up n=29/28
    No statistical analyses for this end point

    Secondary: Patient Global Impression of Change (PGIC)

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    End point title
    		 Patient Global Impression of Change (PGIC)
    End point description
    The PGIC is a patient-reported instrument that measures change in overall status on a scale ranging from 1 ("very much improved") to 7 ("very much worse").
    End point type
    Secondary
    End point timeframe
    Week 4 and Follow-Up Visits
    End point values
    		 EMA401 100 mg BID
    Number of subjects analysed
    28
    Units: percentage of participants
    number (not applicable)
        Week 4 - Very much improved
    7.1
        Week 4 - Much improved
    28.6
        Week 4 - Minimally improved
    39.3
        Week 4 - No change
    25
        Week 4 - Minimally worse
    0
        Week 4 - Much worse
    0
        Week 4 - Very much worse
    0
        Follow-up - Very much improved
    10.3
        Follow-up - Much improved
    24.1
        Follow-up - Minimally improved
    27.6
        Follow-up - No change
    20.7
        Follow-up - Minimally worse
    10.3
        Follow-up - Much worse
    6.9
        Follow-up - Very much worse
    0
    No statistical analyses for this end point

    Secondary: Change from Baseline in Skin Biopsy Parameters

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    End point title
    		 Change from Baseline in Skin Biopsy Parameters
    End point description
    Two 3mm skin punch biopsies were to be taken from the lateral distal calf for quantitative analyses using immunostaining for nerve fibres, as well as antibodies to other key factors in nerve degeneration/regeneration and pain, including: o sensory ion channels and receptors; o neuropeptide markers of sub-sets of sensory and autonomic fibres: substance P, Calcitonin gene-related peptide, Neuropeptide Y; o neurotrophic factors and GAP-43; o Further antibodies as appropriate.
    End point type
    Secondary
    End point timeframe
    Change from Baseline at Week 4 and Early Withdrawal visits
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    30 [6]
    Units: mm
    arithmetic mean (standard deviation)
        PGP9.5 (IEF) IENF/mm-Week 4
    -0.1 ( 1.32 )
        PGP9.5 (IEF) IENF/mm-Early Withdrawal
    1.9 ( 0.999 )
        TRPV1 (IEF) IENF/mm-Week 4
    0.3 ( 0.93 )
        TRPV1 (IEF) IENF/mm-Early Withdrawal
    -4.1 ( 0.999 )
        SNSR (IEF) IENF/mm-Week 4
    0.1 ( 1.01 )
        SNSR (IEF) IENF/mm-Early Withdrawal
    0.6 ( 0.999 )
        GAP43 (IEF) IENF/mm-Week 4
    0.3 ( 0.85 )
        GAP43 (IEF) IENF/mm-Early Withdrawal
    -0.5 ( 0.999 )
    Notes
    [6] - Week 4 n=12; Early Withdrawal n=1 Note: value 0.999 indicates no value reported
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious Adverse Events are monitored from date of First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All other adverse events are monitored from First Patient First Treatment until Last Patient Last Visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    EMA401 100 mg BID
    Reporting group description
    		 -

    Serious adverse events
    		 EMA401 100 mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 31 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 EMA401 100 mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 31 (38.71%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 31 (9.68%)
         occurrences all number
    3
    Dizziness
         subjects affected / exposed
    3 / 31 (9.68%)
         occurrences all number
    5
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 31 (9.68%)
         occurrences all number
    4
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    2 / 31 (6.45%)
         occurrences all number
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 31 (6.45%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
    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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