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    Clinical Trial Results:
    A double-blind, placebo-controlled, randomized trial to determine the safety and efficacy of EMA401 100 mg b.i.d. in reducing 24-hour average pain intensity score in patients with painful diabetic neuropathy (EMPADINE)

    Summary
    EudraCT number
    		 2016-000281-39
    Trial protocol
    		 NO   GB   HU   ES   DK   BE   SK   FI   DE   AT   PT   BG  
    Global end of trial date
    25 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Apr 2020
    First version publication date
    06 Apr 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CEMA401A2202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03297294
    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
    25 Mar 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Mar 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare the efficacy of EMA401 vs. placebo in 24-hour average pain intensity score at Week 12, using an 11-point Numeric Rating Scale (NRS) by testing the superiority of EMA401 100 mg b.i.d. vs. placebo
    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
    14 Mar 2018
    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
    Australia: 6
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Bulgaria: 4
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    Finland: 6
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 31
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Slovakia: 11
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 5
    Worldwide total number of subjects
    137
    EEA total number of subjects
    123
    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)
    67
    From 65 to 84 years
    69
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Three hundred six patients were screened and 137 randomized

    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, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    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
    olodanrigan
    Investigational medicinal product code
    EMA401
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 50 mg capsules b.i.d taken orally

    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 b.i.d.

    Number of subjects in period 1
    		EMA401 100mg BID DB Placebo BID DB
    Started
    70
    67
    Completed
    32
    30
    Not completed
    38
    37
         Consent withdrawn by subject
    4
    4
         Physician decision
    1
    1
         Adverse event, non-fatal
    3
    1
         Study Terminated by Sponsor
    30
    31
    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 100mg BID -> EMA401 100mg BID TW
    Arm description
    		 Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of DB treatment period (week 12)
    Arm type
    		 Experimental

    Investigational medicinal product name
    olodanrigan
    Investigational medicinal product code
    EMA401
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 50 mg capsules b.i.d taken orally

    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 DB 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 b.i.d.

    Arm title
    		 Placebo BID -> Placebo BID TW
    Arm description
    		 Participants on placebo remained on placebo at end of DB 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 b.i.d.

    Number of subjects in period 2 [1]
    		EMA401 100mg BID -> EMA401 100mg BID TW EMA401 100mg BID -> Placebo BID TW Placebo BID -> Placebo BID TW
    Started
    14
    12
    27
    Completed
    14
    11
    27
    Not completed
    0
    1
    0
         Study Terminated by Sponsor
    -
    1
    -
    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: All subjects who completed the double-blind treatment period did not enter the treatment withdrawal period

    Baseline characteristics

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    Baseline characteristics reporting groups
    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 100mg BID DB Placebo BID DB Total
    Number of subjects
    		 70 67 137
    Age Categorical
    Units:
        18 - 64 years
    		 34 33 67
        65 - 84 years
    		 36 33 69
        ≥ 85 years
    		 0 1 1
    Sex: Female, Male
    Units: participants
        Female
    		 20 24 44
        Male
    		 50 43 93
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 70 63 133
        Asian
    		 0 1 1
        Other
    		 0 3 3
    Body mass index
    Units: kg/m2
        median (full range (min-max))
    		 30.8 (22.7 to 43.2) 30.2 (19.5 to 48.2) -

    End points

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    End points reporting groups
    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 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 DB 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 DB treatment period (week 12)

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

    Primary: 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
    Primary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 EMA401 100mg BID DB Placebo BID DB
    Number of subjects analysed
    70
    67
    Units: scores on a scale
    least squares mean (standard error)
        Week 4
    -1.0 ( 0.21 )
    -0.8 ( 0.18 )
        Week 8
    -1.7 ( 0.29 )
    -1.1 ( 0.26 )
        Week 12
    -1.9 ( 0.31 )
    -1.3 ( 0.27 )
    Statistical analysis title
    		 EMA401 vs placebo at week 12
    Comparison groups
    Placebo BID DB v EMA401 100mg BID DB
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.101
    Method
    		 ANCOVA
    Parameter type
    		 least squares mean
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.39

    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 100mg BID DB Placebo BID DB
    Number of subjects analysed
    70
    67
    Units: scores on a scale
    least squares mean (standard error)
        Week 4
    -1.2 ( 0.19 )
    -1.0 ( 0.18 )
        Week 8
    -1.3 ( 0.25 )
    -0.9 ( 0.22 )
        Week 12
    -1.6 ( 0.32 )
    -1.1 ( 0.26 )
    Statistical analysis title
    		 EMA401 vs placebo at week 12
    Comparison groups
    EMA401 100mg BID DB v Placebo BID DB
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.168
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.38

    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 100mg BID DB Placebo BID DB
    Number of subjects analysed
    70
    67
    Units: scores on a numeric rating scale
        arithmetic mean (standard deviation)
    -12.03 ( 13.336 )
    -10.83 ( 14.602 )
    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 100mg BID DB Placebo BID DB
    Number of subjects analysed
    70
    67
    Units: scores on numeric rating scale
        arithmetic mean (standard deviation)
    -1.63 ( 1.837 )
    -1.28 ( 1.577 )
    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 100mg BID DB Placebo BID DB
    Number of subjects analysed
    70
    67
    Units: participants
        Very much improved
    4
    2
        Much improved
    7
    11
        Minimally improved
    17
    18
        No change
    18
    14
        Minimally worse
    3
    2
        Much worse
    0
    0
        Very much worse
    0
    0
        Missing
    21
    20
    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% 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 100mg BID DB Placebo BID DB
    Number of subjects analysed
    70
    67
    Units: % of participants - model adjusted rate
    number (not applicable)
        Week 4 - at least 30% pain reduction n=18,14
    34.0
    24.7
        Week 12 - at least 30% pain reduction n=14,12
    52.7
    40.4
    Statistical analysis title
    		 EMA401 vs placebo
    Comparison groups
    EMA401 100mg BID DB v Placebo BID DB
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.255
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 3.9

    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 100mg BID DB Placebo BID DB
    Number of subjects analysed
    70 [1]
    67 [2]
    Units: % of participants - model adjusted rate
        number (not applicable)
    31.4
    14.1
    Notes
    [1] - Responders n=8
    [2] - Responders n=4
    Statistical analysis title
    		 EMA401 vs placebo
    Comparison groups
    EMA401 100mg BID DB v Placebo BID DB
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 9.6

    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 100mg BID DB Placebo BID DB
    Number of subjects analysed
    70
    67
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -4.00 ( 4.854 )
    -1.03 ( 6.312 )
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK) Concentrations at Week 8 and 12

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    End point title
    		 Plasma Pharmacokinetics (PK) Concentrations at Week 8 and 12 [3]
    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
    [3] - 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 analysis was performed
    End point values
    		 EMA401 100mg BID DB
    Number of subjects analysed
    32
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Week 8 Prior dose n=32
    30.5 ( 126.6 )
        Week 8 1-3 hours n=32
    205.1 ( 212.8 )
        Week 8 4-6 hours n=32
    72.8 ( 115.2 )
        Week 12 Prior dose n=25
    29.5 ( 209.3 )
        Week 12 1-3 hours n=26
    118.4 ( 278.3 )
        Week 12 4-6 hours n=26
    89.8 ( 117.0 )
    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
    From 3 weeks after end of study up to 16 weeks after end of study
    End point values
    		 EMA401 100mg BID -> EMA401 100mg BID TW EMA401 100mg BID -> Placebo BID TW Placebo BID -> Placebo BID TW
    Number of subjects analysed
    14
    12
    27
    Units: participants
        Peritoneal adhesions
    1
    0
    0
        Cholelithiasis
    1
    0
    0
        Liver abscess
    1
    0
    0
        Blood creatinine increased
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Percentage of patients who required rescue medication in double-blind treatment period

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    End point title
    		 Percentage of patients who required rescue medication in double-blind treatment period
    End point description
    Patients were allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily (divided into 4 times/day) for unacceptable pain due to any reason during the study. This medication use was to be recorded in eDiary prior to use. Percentages of patients presented are those who required rescue meds within 7 days prior to visit.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 EMA401 100mg BID DB Placebo BID DB
    Number of subjects analysed
    70
    67
    Units: Percentage of participants
    number (not applicable)
        Week 1
    13.0
    10.6
        Week 2
    7.7
    9.5
        Week 4
    8.6
    7.0
        Week 6
    7.8
    7.5
        Week 8
    9.3
    9.5
        Week 10
    5.3
    13.2
        Week 12
    2.9
    8.6
        At least once during double-blind period
    20.0
    19.4
    No statistical analyses for this end point

    Secondary: Percentage of patients who required rescue medication in treatment withdrawal period

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    End point title
    		 Percentage of patients who required rescue medication in treatment withdrawal period
    End point description
    Patients were allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily (divided into 4 times/day) for unacceptable pain due to any reason during the study. This medication use was to be recorded in eDiary prior to use. Percentages of patients presented are those who required rescue meds within 7 days prior to visit.
    End point type
    Secondary
    End point timeframe
    Week 12 to Week 13
    End point values
    		 EMA401 100mg BID -> EMA401 100mg BID TW EMA401 100mg BID -> Placebo BID TW Placebo BID -> Placebo BID TW
    Number of subjects analysed
    14
    12
    27
    Units: Percentage of patients
        number (not applicable)
    14.3
    8.3
    7.4
    No statistical analyses for this end point

    Secondary: Time to first rescue medication intake

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    End point title
    		 Time to first rescue medication intake
    End point description
    Patients were allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily (divided into 4 times/day) for unacceptable pain due to any reason during the study. This medication use was to be recorded in eDiary prior to use. Patients who did not take any rescue medication were censored at the last date of double-blind treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 12
    End point values
    		 EMA401 100mg BID DB Placebo BID DB
    Number of subjects analysed
    70 [4]
    67 [5]
    Units: days
        median (full range (min-max))
    44.0 (2 to 90)
    56.5 (2 to 92)
    Notes
    [4] - 14 required rescue medication
    [5] - 13 required rescue medication
    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 21 days post treatment, up to maximum duration of 111 days
    Adverse event reporting additional description
    Any sign or symptom that occurs during the study treatment plus the 21 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 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 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 DB 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 DB treatment period (week 12)

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

    Serious adverse events
    		 EMA401 100mg BID DB Placebo BID DB EMA401 100mg BID -> EMA401 100mg BID TW EMA401 100mg BID -> Placebo BID TW Placebo BID -> Placebo BID TW
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 69 (7.25%)
    3 / 66 (4.55%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Product intolerance
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    2 / 69 (2.90%)
    0 / 66 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 EMA401 100mg BID DB Placebo BID DB EMA401 100mg BID -> EMA401 100mg BID TW EMA401 100mg BID -> Placebo BID TW Placebo BID -> Placebo BID TW
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 69 (33.33%)
    10 / 66 (15.15%)
    1 / 14 (7.14%)
    2 / 12 (16.67%)
    0 / 26 (0.00%)
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 69 (5.80%)
    1 / 66 (1.52%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    4
    1
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    6 / 69 (8.70%)
    0 / 66 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    6
    0
    1
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 69 (1.45%)
    2 / 66 (3.03%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    1
    2
    0
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 69 (5.80%)
    4 / 66 (6.06%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    4
    5
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    5 / 69 (7.25%)
    0 / 66 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    5
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    4 / 69 (5.80%)
    1 / 66 (1.52%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    4
    1
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 69 (5.80%)
    6 / 66 (9.09%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    4
    7
    0
    0
    0

    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.
    None reported
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