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    Clinical Trial Results:
    A double-blind, placebo-controlled, randomized dose ranging trial to determine the safety and efficacy of three dose levels of EMA401 in reducing 24-hour average pain intensity score in patients with post-herpetic neuralgia (EMPHENE)

    Summary
    EudraCT number
    		 2016-000280-16
    Trial protocol
    		 DE   GB   SK   AT   NO   DK   ES   CZ   HU   FR   BE   PT   PL  
    Global end of trial date
    07 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Mar 2020
    First version publication date
    22 Mar 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CEMA401A2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03094195
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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
    07 Mar 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Mar 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To characterize dose-response for change in the weekly mean of 24-hour average pain intensity scores at Week 12.
    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
    27 Jun 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
    Austria: 5
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Czech Republic: 16
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Japan: 29
    Country: Number of subjects enrolled
    Norway: 7
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Slovakia: 12
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United Kingdom: 6
    Worldwide total number of subjects
    129
    EEA total number of subjects
    96
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    19
    From 65 to 84 years
    106
    85 years and over
    4

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Two hundred thirty patients were screened.

    Period 1
    Period 1 title
    Double-Blind Treatment Period (DB)
    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
    Yes

    Arm title
    		 EMA401 25mg BID DB
    Arm description
    		 Ema401 25 mg was administered orally twice a day during double blind (DB) treatment period
    Arm type
    		 Experimental

    Investigational medicinal product name
    EMA401
    Investigational medicinal product code
    EMA401
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 12.5 mg capsules taken twice a day for a total daily dose of 50 mg per day

    Arm title
    		 EMA401 100mg BID DB
    Arm description
    		 Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period
    Arm type
    		 Experimental

    Investigational medicinal product name
    EMA401
    Investigational medicinal product code
    EMA401
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 50 mg capsules taken twice a day for a total daily dose of 200 mg per day

    Arm title
    		 Placebo BID DB
    Arm description
    		 Matching placebo capsules administered orally twice a day during double blind (DB) treatment period
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 matching placebo capsules taken twice a day

    Number of subjects in period 1
    		EMA401 25mg BID DB EMA401 100mg BID DB Placebo BID DB
    Started
    43
    43
    43
    Completed
    28
    30
    29
    Not completed
    15
    13
    14
         Consent withdrawn by subject
    -
    1
    1
         Physician decision
    -
    -
    1
         Adverse event, non-fatal
    3
    2
    1
         Study terminated by sponsor
    12
    10
    11
    Period 2
    Period 2 title
    Treatment withdrawal period (TW)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 EMA401 25mg BID -> EMA401 25mg BID TW
    Arm description
    		 Participants on EMA401 25mg were randomized 1:1 to EMA401 25mg or placebo at end of treatment period (week 12)
    Arm type
    		 Experimental

    Investigational medicinal product name
    EMA401
    Investigational medicinal product code
    EMA401
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 12.5 mg capsules taken twice a day for a total daily dose of 50 mg per day

    Arm title
    		 EMA401 25mg BID -> Placebo BID TW
    Arm description
    		 Participants on EMA401 25mg were randomized 1:1 to EMA401 25mg or placebo at end of treatment period (week 12)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 matching placebo capsules taken twice a day

    Arm title
    		 EMA401 100mg BID -> EMA401 100mg BID TW
    Arm description
    		 Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of treatment period (week 12)
    Arm type
    		 Experimental

    Investigational medicinal product name
    EMA401
    Investigational medicinal product code
    EMA401
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 50 mg capsules taken twice a day for a total daily dose of 200 mg per day

    Arm title
    		 EMA401 100mg BID -> Placebo BID TW
    Arm description
    		 Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of treatment period (week 12)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 matching placebo capsules taken twice a day

    Arm title
    		 Placebo BID -> Placebo BID TW
    Arm description
    		 Participants on placebo remained on placebo at end of treatment period (week 12)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 matching placebo capsules taken twice a day

    Number of subjects in period 2 [1]
    		EMA401 25mg BID -> EMA401 25mg BID TW EMA401 25mg BID -> Placebo BID TW EMA401 100mg BID -> EMA401 100mg BID TW EMA401 100mg BID -> Placebo BID TW Placebo BID -> Placebo BID TW
    Started
    13
    13
    15
    13
    26
    Completed
    13
    13
    15
    13
    26
    Notes
    [1] - 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: Not all patients entered second period

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    EMA401 25mg BID DB
    Reporting group description
    		 Ema401 25 mg was administered orally twice a day during double blind (DB) treatment period

    Reporting group title
    EMA401 100mg BID DB
    Reporting group description
    		 Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period

    Reporting group title
    Placebo BID DB
    Reporting group description
    		 Matching placebo capsules administered orally twice a day during double blind (DB) treatment period

    Reporting group values
    		 EMA401 25mg BID DB EMA401 100mg BID DB Placebo BID DB Total
    Number of subjects
    		 43 43 43 129
    Age Categorical
    Units: participants
        18 - 64 years
    		 4 8 7 19
        65 - 84 years
    		 36 34 36 106
        ≥ 85 years
    		 3 1 0 4
    Sex: Female, Male
    Units: participants
        Female
    		 20 15 30 65
        Male
    		 23 28 13 64
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 33 32 32 97
        Asian
    		 9 10 10 29
        Other
    		 1 1 1 3
    Body mass index
    Units: kg/m2
        median (full range (min-max))
    		 25.9 (18.4 to 36.4) 25.2 (17.4 to 33.0) 24.9 (17.9 to 39.4) -

    End points

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    End points reporting groups
    Reporting group title
    EMA401 25mg BID DB
    Reporting group description
    		 Ema401 25 mg was administered orally twice a day during double blind (DB) treatment period

    Reporting group title
    EMA401 100mg BID DB
    Reporting group description
    		 Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period

    Reporting group title
    Placebo BID DB
    Reporting group description
    		 Matching placebo capsules administered orally twice a day during double blind (DB) treatment period
    Reporting group title
    EMA401 25mg BID -> EMA401 25mg BID TW
    Reporting group description
    		 Participants on EMA401 25mg were randomized 1:1 to EMA401 25mg or placebo at end of treatment period (week 12)

    Reporting group title
    EMA401 25mg BID -> Placebo BID TW
    Reporting group description
    		 Participants on EMA401 25mg were randomized 1:1 to EMA401 25mg or placebo at end of treatment period (week 12)

    Reporting group title
    EMA401 100mg BID -> EMA401 100mg BID TW
    Reporting group description
    		 Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of treatment period (week 12)

    Reporting group title
    EMA401 100mg BID -> Placebo BID TW
    Reporting group description
    		 Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of treatment period (week 12)

    Reporting group title
    Placebo BID -> Placebo BID TW
    Reporting group description
    		 Participants on placebo remained on placebo at end of treatment period (week 12)

    Primary: Dose-response in change in weekly mean of the 24-hour average pain score, using an 11-point Numeric Rating Scale (NRS), from Baseline to Week 12

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    End point title
    		 Dose-response in change in weekly mean of the 24-hour average pain score, using an 11-point Numeric Rating Scale (NRS), from Baseline to Week 12 [1]
    End point description
    Since the 300 mg b.i.d. dose of EMA401 could not be initiated in the study due to premature study termination, the dose-response characterization was not performed. Specifically, only the trend test deduced from the set of candidate models was performed but the dose response estimation was not conducted.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 12
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was done because the high dose was never implemented due to study termination
    End point values
    		 EMA401 25mg BID DB EMA401 100mg BID DB Placebo BID DB
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    Units: scores on a scale
        number (not applicable)
    Notes
    [2] - Study was terminated and 300 mg dose was not initiated
    [3] - Study was terminated and 300 mg dose was not initiated
    [4] - Study was terminated and 300 mg dose was not initiated
    No statistical analyses for this end point

    Secondary: Change in weekly mean 24-hour average pain score using the 11 point Numerical Rating Scale (NRS) from Baseline to Week 12

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    End point title
    		 Change in weekly mean 24-hour average pain score using the 11 point Numerical Rating Scale (NRS) from Baseline to Week 12
    End point description
    The NRS is an 11–point scale ranging from zero ("no pain") to ten ("pain as bad as you can imagine") for self-reporting of pain by patients. The following parameters were evaluated using the 11-point NRS: 24-hour Average Pain Score and 24-hour Worst Pain Score Patients evaluated their “average pain” and “worst pain” during the past 24 hours in the evening prior to sleep by touching the appropriate corresponding number between zero and ten on a eDiary device.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 EMA401 25mg BID DB EMA401 100mg BID DB Placebo BID DB
    Number of subjects analysed
    43
    43
    43
    Units: scores on a scale
    least squares mean (standard error)
        Week 4
    -0.4 ± 0.23
    -0.9 ± 0.25
    -0.5 ± 0.23
        Week 8
    -1.0 ± 0.29
    -1.0 ± 0.29
    -0.7 ± 0.30
        Week 12
    -0.9 ± 0.40
    -1.2 ± 0.38
    -0.7 ± 0.40
    Statistical analysis title
    		 EMA401 25mg BID vs Placebo
    Comparison groups
    EMA401 25mg BID DB v Placebo BID DB
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.689
    Method
    		 ANCOVA
    Parameter type
    		 least squares mean
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 0.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.56
    Statistical analysis title
    		 EMA401 100mg BID vs Placebo
    Comparison groups
    EMA401 100mg BID DB v Placebo BID DB
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.35
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.54

    Secondary: Change in Brief Pain Inventory-Short Form interference (BPI-SF) mean total score from Baseline to Week 12

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    End point title
    		 Change in Brief Pain Inventory-Short Form interference (BPI-SF) mean total score from Baseline to Week 12
    End point description
    The BPI-SF is a validated, self-administered (at clinic) questionnaire that assesses pain severity and its mpact on daily functions. Patients were asked to complete the 7-item pain interference scale that assessed the degree to which pain interfered with walking and other physical activity, work, mood, relations with others and sleep using a zero to ten numeric rating scale (NRS) with zero being "does not interfere" and ten being "completely interferes". A reduction in mean indicates improvement
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 EMA401 25mg BID DB EMA401 100mg BID DB Placebo BID DB
    Number of subjects analysed
    43
    43
    43
    Units: scores on a numeric rating scale
        arithmetic mean (standard deviation)
    -8.24 ± 12.994
    -15.03 ± 13.280
    -14.07 ± 12.535
    No statistical analyses for this end point

    Secondary: Change in weekly mean of the 24-hour worst pain score, using an 11-point NRS, from Baseline to Week 12

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    End point title
    		 Change in weekly mean of the 24-hour worst pain score, using an 11-point NRS, from Baseline to Week 12
    End point description
    The NRS is an 11–point scale ranging from zero ("no pain") to ten ("pain as bad as you can imagine") for self-reporting of pain by patients. The following parameters were evaluated using the 11-point NRS: 24-hour Average Pain Score and 24-hour Worst Pain Score Patients evaluated their “average pain” and “worst pain” during the past 24 hours in the evening prior to sleep by touching the appropriate corresponding number between zero and ten on a eDiary device.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 EMA401 25mg BID DB EMA401 100mg BID DB Placebo BID DB
    Number of subjects analysed
    43
    43
    43
    Units: scores on numeric rating scale
        arithmetic mean (standard deviation)
    -1.04 ± 1.851
    -1.96 ± 2.365
    -1.49 ± 2.215
    No statistical analyses for this end point

    Secondary: Number of participants per Patient Global Impression of Change category at Week 12

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    End point title
    		 Number of participants per Patient Global Impression of Change category at Week 12
    End point description
    The Patient Global Impression of Change (PGIC) is a patient-reported instrument that measures change in overall status on a scale ranging from one ("very much improved") to seven ("very much worse"). The PGIC is based on the validated Clinical Global Impression of Change scale. The PGIC was to be completed by patients using the electronic tablet at the site
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 EMA401 25mg BID DB EMA401 100mg BID DB Placebo BID DB
    Number of subjects analysed
    43
    43
    43
    Units: participants
        Very much improved
    1
    0
    2
        Much improved
    2
    5
    7
        Minimally improved
    9
    12
    9
        No change
    20
    18
    12
        Minimally worse
    3
    2
    1
        Much worse
    1
    0
    3
        Very much worse
    0
    0
    0
        Missing
    7
    6
    9
    No statistical analyses for this end point

    Secondary: Percentage of patients achieving at least 30% pain reduction at Week 12 on NRS 11 point scale

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    End point title
    		 Percentage of patients achieving at least 30% pain reduction at Week 12 on NRS 11 point scale
    End point description
    The NRS is an 11–point scale ranging from zero ("no pain") to ten ("pain as bad as you can imagine") for self-reporting of pain by patients. The number of patients with observed response, i.e. a decrease of 30% /50% units in weekly mean of the 24-hour average pain score NRS. Logistic regression model with region, treatment, sex, use of PHN medications (yes/no) as factors and age and baseline NRS as covariates. An odds ratio >1 = higher chance of a clinically important improvement.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 EMA401 25mg BID DB EMA401 100mg BID DB Placebo BID DB
    Number of subjects analysed
    43
    43
    43
    Units: % of participants - model adjusted rate
    number (not applicable)
        Week 4 - at least 30% pain reduction
    7.5
    15.6
    12.6
        Week 12 - at least 30% pain reduction
    22.3
    29.6
    23.6
    Statistical analysis title
    		 EMA401 25mg BID vs Placebo
    Comparison groups
    EMA401 25mg BID DB v Placebo BID DB
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.908
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 3.2
    Statistical analysis title
    		 EMA401 100mg BID vs Placebo
    Comparison groups
    EMA401 100mg BID DB v Placebo BID DB
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.609
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 4.5

    Secondary: Percentage of patients achieving at least 50% pain reduction at Week 12 on NRS 11 point scale

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    End point title
    		 Percentage of patients achieving at least 50% pain reduction at Week 12 on NRS 11 point scale
    End point description
    The NRS is an 11–point scale ranging from zero ("no pain") to ten ("pain as bad as you can imagine") for self-reporting of pain by patients. The number of patients with observed response, i.e. a decrease of 50% units in weekly mean of the 24-hour average pain score NRS. Logistic regression model with region, treatment, sex, use of PHN medications (yes/no) as factors and age and baseline NRS as covariates. An odds ratio >1 = higher chance of a clinically important improvement.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 EMA401 25mg BID DB EMA401 100mg BID DB Placebo BID DB
    Number of subjects analysed
    43
    43
    43
    Units: % of participants - model adjusted rate
        number (not applicable)
    12.0
    13.4
    10.3
    Statistical analysis title
    		 EMA401 25mg BID vs Placebo
    Comparison groups
    EMA401 25mg BID DB v Placebo BID DB
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 3.2
    Statistical analysis title
    		 EMA401 100mg BID vs Placebo
    Comparison groups
    EMA401 100mg BID DB v Placebo BID DB
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.653
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 4.5

    Secondary: Mean change in Insomnia Severity Index (ISI) from Baseline to Week 12

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    End point title
    		 Mean change in Insomnia Severity Index (ISI) from Baseline to Week 12
    End point description
    Patients were asked to complete the ISI using five-point Likert-style scale as a measure of perceived sleep difficulties. Scores ranged from zero to 28, with a cut-off score of eight suggesting the presence of sub-threshold insomnia. The questionnaire assessed the severity of insomnia, satisfaction with current sleep pattern, sleep interference, "noticeability" of sleeping problem to others and concern about sleeping problems.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 EMA401 25mg BID DB EMA401 100mg BID DB Placebo BID DB
    Number of subjects analysed
    43
    43
    43
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -1.29 ± 4.529
    -4.14 ± 5.146
    -3.44 ± 4.228
    No statistical analyses for this end point

    Secondary: Change in Neuropathic Pain Symptom Inventory (NPSI) from Baseline to Week 12

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    End point title
    		 Change in Neuropathic Pain Symptom Inventory (NPSI) from Baseline to Week 12
    End point description
    The NPSI is a 12-item patient reported outcome measure that contains 10 descriptors representing 5 dimensions of pain (burning pain, deep/pressing pain, paroxysmal pain, evoked pain and paraesthesia/dysesthesia) and 2 temporal items designed to assess pain duration and the number of pain paroxysms. The NPSI was to be completed by patients using the electronic tablet at the site
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 EMA401 25mg BID DB EMA401 100mg BID DB Placebo BID DB
    Number of subjects analysed
    43
    43
    43
    Units: scores on a scale
        least squares mean (standard error)
    -0.4 ± 0.35
    -1.0 ± 0.37
    -1.0 ± 0.38
    Statistical analysis title
    		 EMA401 25mg BID vs Placebo
    Comparison groups
    EMA401 25mg BID DB v Placebo BID DB
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.225
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 1.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.49
    Statistical analysis title
    		 EMA401 100mg BID vs Placebo
    Comparison groups
    EMA401 100mg BID DB v Placebo BID DB
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.914
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 1.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.53

    Secondary: Plasma Pharmacokinetic (PK) Concentrations at Weeks 8 and 12

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    End point title
    		 Plasma Pharmacokinetic (PK) Concentrations at Weeks 8 and 12 [5]
    End point description
    Due to the premature termination of the study, the number of patients and observations providing PK data was much smaller than planned, and no PK model was developed. As a consequence, no PK parameters (Cmax, Tmax, AUC) were derived for this study. Only, summary statistics of the plasma concentrations were calculated
    End point type
    Secondary
    End point timeframe
    Week 8, Week 12
    Notes
    [5] - 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: Pharmacokinetics only done on EMA401 arms
    End point values
    		 EMA401 25mg BID DB EMA401 100mg BID DB
    Number of subjects analysed
    28
    31
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 8 Prior dose n=26,31
    6.4 ± 6.13
    27.2 ± 37.88
        Week 8 1-3 hours n=26,31
    120.7 ± 110.47
    356.3 ± 336.49
        Week 8 4-6 hours n= n=28,31
    16.6 ± 13.21
    62.5 ± 50.53
        Week 12 Prior dose n=25,28
    5.4 ± 3.94
    16.4 ± 10.93
        Week 12 1-3 hours n=25,27
    108.9 ± 88.57
    289.6 ± 241.92
        Week 12 4-6 hours n=25,28
    22.8 ± 37.63
    89.9 ± 88.25
    No statistical analyses for this end point

    Secondary: Exposure-response (decrease in pain intensity) via Evaluation of effect of EMA401 exposure on efficacy variables (e.g. change from baseline of pain score), via descriptive Pharmacokinetics/ Pharmacodynamics (PK/PD)

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    End point title
    		 Exposure-response (decrease in pain intensity) via Evaluation of effect of EMA401 exposure on efficacy variables (e.g. change from baseline of pain score), via descriptive Pharmacokinetics/ Pharmacodynamics (PK/PD) [6]
    End point description
    Due to the premature termination of the study, the number of patients providing data for PKPD analysis data was much smaller than planned and no model to correlate drug exposure (PK) with the change in the pain score (PD) was developed
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8, Week 12
    Notes
    [6] - 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: No statistical analysis was done
    End point values
    		 EMA401 25mg BID DB EMA401 100mg BID DB
    Number of subjects analysed
    43
    43
    Units: scores on a scale
        arithmetic mean (standard deviation)
    10 ± 1
    10 ± 1
    No statistical analyses for this end point

    Secondary: Treatment Emergent Adverse Events during Urgent Safety Measure (USM) Follow-Up

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    End point title
    		 Treatment Emergent Adverse Events during Urgent Safety Measure (USM) Follow-Up
    End point description
    Participants were instructed to stop taking drug immediately upon termination of study and asked to come in for two unscheduled visits for follow up safety assessments
    End point type
    Secondary
    End point timeframe
    Approximately from 3 weeks after end of study up to 16 weeks
    End point values
    		 EMA401 25mg BID -> EMA401 25mg BID TW EMA401 25mg BID -> Placebo BID TW EMA401 100mg BID -> EMA401 100mg BID TW EMA401 100mg BID -> Placebo BID TW Placebo BID -> Placebo BID TW
    Number of subjects analysed
    13
    13
    15
    13
    26
    Units: participants
        Blood creatinine increased
    0
    1
    0
    0
    0
        Blood potassium increased
    0
    1
    0
    0
    0
        Glomerular filtration rate decreased
    0
    1
    0
    1
    0
        Alanine aminotransferase increased
    0
    0
    0
    1
    0
        Blood creatine phosphokinase increased
    0
    0
    0
    1
    0
        Blood glucose increased
    0
    0
    1
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment until end of study treatment plus 28 days post treatment, up to maximum duration of 123 days
    Adverse event reporting additional description
    Any sign or symptom that occurs during the study treatment plus the 28 days post treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    EMA401 25 mg b.i.d. DB
    Reporting group description
    		 Ema401 25 mg was administered orally twice a day during double blind (DB) treatment period

    Reporting group title
    EMA401 100 mg b.i.d. DB
    Reporting group description
    		 Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period

    Reporting group title
    Placebo b.i.d. DB
    Reporting group description
    		 Matching placebo capsules administered orally twice a day during double blind (DB) treatment period

    Reporting group title
    EMA401 25 mg b.i.d. - EMA401 25 mg b.i.d. TW
    Reporting group description
    		 Participants on EMA401 25mg were randomized 1:1 to EMA401 25mg or placebo at end of treatment period (week 12)

    Reporting group title
    EMA401 25 mg b.i.d. - Placebo b.i.d. TW
    Reporting group description
    		 Participants on EMA401 25mg were randomized 1:1 to EMA401 25mg or placebo at end of treatment period (week 12)

    Reporting group title
    EMA401 100 mg b.i.d. - EMA401 100 mg b.i.d.
    Reporting group description
    		 Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of treatment period (week 12)

    Reporting group title
    EMA401 100 mg b.i.d. - Placebo b.i.d. TW
    Reporting group description
    		 Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of treatment period (week 12)

    Reporting group title
    Placebo b.i.d. - Placebo b.i.d. TW
    Reporting group description
    		 Participants on placebo remained on placebo at end of treatment period (week 12)

    Serious adverse events
    		 EMA401 25 mg b.i.d. DB EMA401 100 mg b.i.d. DB Placebo b.i.d. DB EMA401 25 mg b.i.d. - EMA401 25 mg b.i.d. TW EMA401 25 mg b.i.d. - Placebo b.i.d. TW EMA401 100 mg b.i.d. - EMA401 100 mg b.i.d. EMA401 100 mg b.i.d. - Placebo b.i.d. TW Placebo b.i.d. - Placebo b.i.d. TW
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 43 (6.98%)
    3 / 43 (6.98%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 26 (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
    Investigations
    Electrocardiogram ST segment elevation
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 43 (2.33%)
    0 / 43 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Central nervous system lymphoma
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 43 (0.00%)
    1 / 43 (2.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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
    Injury, poisoning and procedural complications
    Traumatic haematoma
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 43 (2.33%)
    0 / 43 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 43 (0.00%)
    0 / 43 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    Nervous system disorders
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 43 (0.00%)
    1 / 43 (2.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 43 (0.00%)
    1 / 43 (2.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 43 (0.00%)
    1 / 43 (2.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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
    Osteoarthritis
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 43 (0.00%)
    1 / 43 (2.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 43 (2.33%)
    0 / 43 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 EMA401 25 mg b.i.d. DB EMA401 100 mg b.i.d. DB Placebo b.i.d. DB EMA401 25 mg b.i.d. - EMA401 25 mg b.i.d. TW EMA401 25 mg b.i.d. - Placebo b.i.d. TW EMA401 100 mg b.i.d. - EMA401 100 mg b.i.d. EMA401 100 mg b.i.d. - Placebo b.i.d. TW Placebo b.i.d. - Placebo b.i.d. TW
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 43 (18.60%)
    12 / 43 (27.91%)
    14 / 43 (32.56%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    2 / 15 (13.33%)
    1 / 13 (7.69%)
    1 / 26 (3.85%)
    Investigations
    Amylase increased
         subjects affected / exposed
    1 / 43 (2.33%)
    2 / 43 (4.65%)
    0 / 43 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
    0 / 26 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 43 (4.65%)
    0 / 43 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    0
    0
    Lipase increased
         subjects affected / exposed
    1 / 43 (2.33%)
    3 / 43 (6.98%)
    0 / 43 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
    0 / 26 (0.00%)
         occurrences all number
    1
    3
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Tongue injury
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 43 (0.00%)
    0 / 43 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 43 (2.33%)
    3 / 43 (6.98%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    3
    0
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 43 (4.65%)
    3 / 43 (6.98%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    4
    0
    0
    0
    0
    0
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 43 (0.00%)
    1 / 43 (2.33%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    1
    0
    1
    0
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 43 (6.98%)
    2 / 43 (4.65%)
    3 / 43 (6.98%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    3
    2
    3
    0
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 43 (6.98%)
    1 / 43 (2.33%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 43 (6.98%)
    2 / 43 (4.65%)
    4 / 43 (9.30%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    3
    2
    4
    0
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 43 (4.65%)
    3 / 43 (6.98%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    3
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 May 2018
    - Update of Inclusion criteria #5 to modify the wording related to inadequate treatment response to at least two different therapies of PHN for more clarity: two previous therapies with inadequate treatment response also include analgesics prescribed for the treatment of PHN by general practitioners and other treating physicians. - Update of Inclusion criteria #6 to include the patient’s willingness to complete eDiary. - Update of Exclusion criteria #3 to clarify the comorbid ECG abnormalities. - Update of Exclusion criteria #6 considering the total study duration of only 13 weeks, the medical history of malignancy of any organ system in the past 2 years before screening was considered to be sufficient for the study. - Update of Exclusion criteria #10 on Women of Child Bearing Potential (WOCBP) was based on the latest toxicity data. - Deletion of Exclusion criteria #11 based on the data from genotoxic studies, as well as from the recently completed reproductive toxicity studies. - Update of Exclusion criteria #14 to include positive urine drug screen at Screening. - Update of Exclusion criteria #15 to clarify that patients with only active gallbladder or bile duct disease were not considered for the study. - Deletion of Exclusion criteria #21 to consider for enrolment patients who had previously taken herpes zoster vaccine (HZV). - The patients who needed to come off the prohibited concomitant medication after Screening visit had to take last dose of prohibited concomitant medication at least 2 weeks (14 days) prior to V101 (i.e. Baseline visit)

    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.
    Study was terminated early due to preclinical toxicity data. Novartis discontinued study treatment immediately and patients were instructed to return for additional laboratory due to Urgent Safety Measure. Related AE data was reported in separate End
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