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    Clinical Trial Results:
    Equimolar Mixture of Oxygen and Nitrous Oxide (EMONO) for the Treatment of Peripheral Neuropathic Pain: a Randomised, International, Multicentre, Placebo-Controlled, Phenotype-stratified Phase IIa Study

    Summary
    EudraCT number
    		 2015-004779-64
    Trial protocol
    		 DE   FR  
    Global end of trial date
    30 Aug 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Nov 2019
    First version publication date
    14 Nov 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ALMED-15-C2-054
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02957851
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Air Liquide Santé International
    Sponsor organisation address
    75, quai d'Orsay, Paris, France, 75007
    Public contact
    Healthcare Communication & Public Affairs Director, Air Liquide Santé International, muriel.doucet@airliquide.com
    Scientific contact
    Clinical Development Physician, Air Liquide Santé International, fralsi-ctpublication@airliquide.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
    23 Oct 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of 3 consecutive days of one-hour administration of Nitrous Oxide/Oxygen 50%/50% (EMONO) versus placebo as Oxygen/Nitrogen 22%/78% (synthetic medical air), in add-on therapy to chronic analgesic treatments, on average pain intensity in patients with chronic peripheral neuropathic pain.
    Protection of trial subjects
    The study was conducted in compliance with Good Clinical Practice (GCP) guidelines, and in keeping with the most recent revised version of the Declaration of Helsinki and in the European Directive 2001/20/CE on 4th April 2001 on the approximation of the laws, regulations and administrative provisions of the member states relating to the implementation of GCP in the conduct of the clinical trials on medicinal products for human use. The Protocol and Substantial Amendments were submitted to the Independent Ethics Committee (IEC) and national Competent Authority (CA) for approval in each participating country. The enrolment of the patients in the study started only after the written approvals of the corresponding IEC and national CA.
    Background therapy
    		 Drugs with anti-NMDA mechanism of action such as ketamine were not allowed during the study and within the 4 weeks before the Selection visit (V0). All treatments for chronic neuropathic pain and non drugs therapies such as hypnosis being currently used by the patients at the entry into the study were allowed throughout the study providing these treatments were stable since at least 4 weeks prior the Selection visit V0. Other concomitant treatments prescribed for co-morbidities (hypertension, dyslipidemia...) or associated chronic diseases (such as diabetes, cardiovascular disease, respiratory diseases...) were allowed. Rescue therapy limited to paracetamol was authorised in case the pain intensity increased too much according to the patient during the study.
    Evidence for comparator
    		 The comparator is a placebo, here synthetic medical air (Oxygen/Nitrogen 22%/78%).
    Actual start date of recruitment
    21 Nov 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 270
    Country: Number of subjects enrolled
    Germany: 17
    Worldwide total number of subjects
    287
    EEA total number of subjects
    287
    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)
    213
    From 65 to 84 years
    72
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 287 patients were enrolled (240 met the inclusion criteria) from 22 centres in 2 countries; 2 in Germany and 20 in France First Patient Enrolled: 21 November 2016 Last Patient Completed: 30 August 2018

    Pre-assignment
    Screening details
    		 Adult patients with chronic peripheral neuropathic pain. Diagnosis based on DN4 questionnaire (score ≥ 4) and NeuPSIG criteria (“definite” or “probable” levels). Baseline pain intensity between 4 and 9 on NRS. Analgesic medications had to be stable since at least 4 weeks prior to the study.

    Pre-assignment period milestones
    Number of subjects started
    		 287
    Number of subjects completed
    		 240

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 At least one selection/inclusion criterion not met: 39
    Reason: Number of subjects
    		 Consent withdrawn by subject: 5
    Reason: Number of subjects
    		 Adverse event, non-fatal: 1
    Reason: Number of subjects
    		 Protocol deviation: 1
    Reason: Number of subjects
    		 Subject not available: 1
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Assessor
    Blinding implementation details
    Patient and the physician (Investigator 1) who performed selection, inclusion, stratification and follow-ups visits (including study end) remained blinded as to the nature of study treatment. Only caregiver (Investigator 2) who performed randomisation according to stratification and administered the treatment was unblinded. All information regarding randomisation and administration have been collected in a separate source document.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 EMONO
    Arm description
    		 Equimolar gases mixture of medicinal nitrous oxide 50% and medicinal oxygen 50% (EMONO) from Air Liquide Santé International.
    Arm type
    		 Experimental

    Investigational medicinal product name
    EMONO
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Medicinal gas, compressed
    Routes of administration
    Inhalation use
    Dosage and administration details
    60 min per day during 3 consecutive days.

    Arm title
    		 Placebo
    Arm description
    		 Oxygen/Nitrogen 22%/78% (synthetic medical air)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Medical Air
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Medicinal gas, compressed
    Routes of administration
    Inhalation use
    Dosage and administration details
    60 min per day during 3 consecutive days.

    Number of subjects in period 1 [1]
    		EMONO Placebo
    Started
    120
    120
    Completed
    112
    117
    Not completed
    8
    3
         Subject decided not to participate anymore
    1
    -
         Consent withdrawn by subject
    3
    1
         Adverse event, non-fatal
    1
    -
         Subject decision
    1
    -
         Subject non available
    -
    1
         Unavailability of the subject
    1
    -
         Subject could not come on site (personal reason)
    -
    1
         Lost to follow-up
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 287 subjects signed an informed consent. 240 subjects received at least one administration of investigational medicinal product.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    EMONO
    Reporting group description
    		 Equimolar gases mixture of medicinal nitrous oxide 50% and medicinal oxygen 50% (EMONO) from Air Liquide Santé International.

    Reporting group title
    Placebo
    Reporting group description
    		 Oxygen/Nitrogen 22%/78% (synthetic medical air)

    Reporting group values
    		 EMONO Placebo Total
    Number of subjects
    		 120 120 240
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.8 ( 14.8 ) 54.4 ( 14.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 64 67 131
        Male
    		 56 53 109
    Peripheral neuropathy aetiology
    Units: Subjects
        Post-traumatic or post-surgical nerve injury
    		 73 76 149
        Polyneuropathy including diabetic neuropathy
    		 32 33 65
        Post-herpetic neuralgia
    		 14 9 23
        Other
    		 1 2 3
    NPSI Evoked/non Evoked Pain Repartition
    Presence or absence of evoked pain as assessed by the Neuropathic Pain Symptom Inventory (NPSI).
    Units: Subjects
        Subjects with evoked pain
    		 103 108 211
        Subjects without evoked pain
    		 17 12 29
    At least one past or current chronic neuropathic pain treatment
    Units: Subjects
        Yes
    		 118 120 238
        No
    		 2 0 2
    At least one past neuropathic pain treatment failure
    Units: Subjects
        Yes
    		 101 108 209
        No
    		 19 12 31
    At least one chronic neuropathic pain treatment at baseline
    Units: Subjects
        Yes
    		 93 91 184
        No
    		 27 29 56
    At least one anti-epileptic for neuropathic pain ongoing at baseline
    Units: Subjects
        Yes
    		 38 47 85
        No
    		 82 73 155
    At least one antidepressant for neuropathic pain ongoing at baseline
    Units: Subjects
        Yes
    		 43 45 88
        No
    		 77 75 152
    At least one opioid and derivates for neuropathic pain ongoing at baseline
    Units: Subjects
        Yes
    		 48 50 98
        No
    		 72 70 142
    At least one local neuropathic pain treatment ongoing at baseline
    Units: Subjects
        Yes
    		 30 21 51
        No
    		 90 99 189
    At least one other non-drug therapy for neuropathic pain ongoing at baseline
    Units: Subjects
        Yes
    		 5 5 10
        No
    		 115 115 230
    Number of chronic neuropathic pain treatments at baseline
    Units: Subjects
        <2
    		 67 62 129
        ≥2
    		 53 58 111
    HADS-Anxiety
    Units: Subjects
        Normal (Score 0-7)
    		 63 51 114
        Mild (Score 8-10)
    		 24 32 56
        Moderate (Score 11-14)
    		 18 31 49
        Severe (Score 15-21)
    		 12 4 16
        Missing
    		 3 2 5
    HADS-Depression
    Units: Subjects
        Normal (Score 0-7)
    		 62 63 125
        Mild (Score 8-10)
    		 30 28 58
        Moderate (Score 11-14)
    		 17 22 39
        Severe (Score 15-21)
    		 9 5 14
        Missing
    		 2 2 4
    At least one on demand/rescue therapy
    On Demand and/or rescue therapies were reported in the booklets by the patients. Timeframe: during the 7-day baseline period.
    Units: Subjects
        Yes
    		 55 61 116
        No
    		 65 59 124
    At least one on demand/rescue therapy (only opioid treatments)
    On Demand and/or rescue therapies were reported in the booklets by the patients. Timeframe: during the 7-day baseline period.
    Units: Subjects
        Yes
    		 21 33 54
        No
    		 99 87 186
    Disease duration
    Units: months
        arithmetic mean (standard deviation)
    		 52 ( 48 ) 55 ( 34 ) -
    Number of Trts with Past Therapeutic Failure
    Number of treatments (Trts) calculated in patients with at least one past neuropathic pain treatment failure.
    Units: treatments per subject
        arithmetic mean (standard deviation)
    		 4.4 ( 3.1 ) 4.3 ( 2.9 ) -
    Mean 7-day NRS at baseline
    Mean NRS calculated from daily NRS assessments collected from a period of 7 days before randomisation (7-day baseline period).
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 6.42 ( 1.25 ) 6.41 ( 1.08 ) -
    NPSI total score
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 47.4 ( 17.8 ) 46.0 ( 16.6 ) -
    NPSI evoked pain score
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 4.78 ( 2.32 ) 4.79 ( 2.38 ) -
    SF-12 Mental Component Summary
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 41.6 ( 10.5 ) 42.4 ( 9.1 ) -
    SF-12 Physical Component Summary
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 37.1 ( 8.5 ) 35.9 ( 8.1 ) -
    SF-12 Bodily pain
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 33.8 ( 8.8 ) 33.2 ( 8.0 ) -
    Subject analysis sets

    Subject analysis set title
    EMONO - mFAS
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Randomised patients who received three administrations of EMONO (with at least one complete administration) and had at least 4 evaluations of NRS in the first week post-treatment. A complete administration was defined as an administration with an exposure between 55 and 65 minutes with no more than 5 minutes without treatment administration. The mFAS was used for efficacy analyses.

    Subject analysis set title
    Placebo - mFAS
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Randomised patients who received three administrations of Placebo (with at least one complete administration) and had at least 4 evaluations of NRS in the first week post-treatment. A complete administration was defined as an administration with an exposure between 55 and 65 minutes with no more than 5 minutes without treatment administration. The mFAS was used for efficacy analyses.

    Subject analysis sets values
    		 EMONO - mFAS Placebo - mFAS
    Number of subjects
    103
    118
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    52.4 ( 14.6 )
    54.6 ( 14.6 )
    Gender categorical
    Units: Subjects
        Female
    54
    66
        Male
    49
    52
    Peripheral neuropathy aetiology
    Units: Subjects
        Post-traumatic or post-surgical nerve injury
    61
    74
        Polyneuropathy including diabetic neuropathy
    28
    33
        Post-herpetic neuralgia
    13
    9
        Other
    1
    2
    NPSI Evoked/non Evoked Pain Repartition
    Presence or absence of evoked pain as assessed by the Neuropathic Pain Symptom Inventory (NPSI).
    Units: Subjects
        Subjects with evoked pain
    91
    106
        Subjects without evoked pain
    12
    12
    At least one past or current chronic neuropathic pain treatment
    Units: Subjects
        Yes
    102
    118
        No
    1
    0
    At least one past neuropathic pain treatment failure
    Units: Subjects
        Yes
    89
    106
        No
    14
    12
    At least one chronic neuropathic pain treatment at baseline
    Units: Subjects
        Yes
    82
    90
        No
    21
    28
    At least one anti-epileptic for neuropathic pain ongoing at baseline
    Units: Subjects
        Yes
    32
    46
        No
    88
    74
    At least one antidepressant for neuropathic pain ongoing at baseline
    Units: Subjects
        Yes
    38
    44
        No
    65
    74
    At least one opioid and derivates for neuropathic pain ongoing at baseline
    Units: Subjects
        Yes
    43
    49
        No
    60
    69
    At least one local neuropathic pain treatment ongoing at baseline
    Units: Subjects
        Yes
    25
    21
        No
    78
    97
    At least one other non-drug therapy for neuropathic pain ongoing at baseline
    Units: Subjects
        Yes
    4
    5
        No
    99
    113
    Number of chronic neuropathic pain treatments at baseline
    Units: Subjects
        <2
    57
    61
        ≥2
    46
    57
    HADS-Anxiety
    Units: Subjects
        Normal (Score 0-7)
    54
    51
        Mild (Score 8-10)
    20
    31
        Moderate (Score 11-14)
    18
    30
        Severe (Score 15-21)
    9
    4
        Missing
    2
    2
    HADS-Depression
    Units: Subjects
        Normal (Score 0-7)
    52
    62
        Mild (Score 8-10)
    26
    28
        Moderate (Score 11-14)
    15
    21
        Severe (Score 15-21)
    9
    5
        Missing
    1
    2
    At least one on demand/rescue therapy
    On Demand and/or rescue therapies were reported in the booklets by the patients. Timeframe: during the 7-day baseline period.
    Units: Subjects
        Yes
    46
    60
        No
    57
    58
    At least one on demand/rescue therapy (only opioid treatments)
    On Demand and/or rescue therapies were reported in the booklets by the patients. Timeframe: during the 7-day baseline period.
    Units: Subjects
        Yes
    21
    32
        No
    82
    86
    Disease duration
    Units: months
        arithmetic mean (standard deviation)
    54 ( 50 )
    55 ( 34 )
    Number of Trts with Past Therapeutic Failure
    Number of treatments (Trts) calculated in patients with at least one past neuropathic pain treatment failure.
    Units: treatments per subject
        arithmetic mean (standard deviation)
    4.4 ( 2.7 )
    4.2 ( 2.8 )
    Mean 7-day NRS at baseline
    Mean NRS calculated from daily NRS assessments collected from a period of 7 days before randomisation (7-day baseline period).
    Units: units on a scale
        arithmetic mean (standard deviation)
    6.42 ( 1.27 )
    6.43 ( 1.07 )
    NPSI total score
    Units: units on a scale
        arithmetic mean (standard deviation)
    47.2 ( 17.5 )
    46.0 ( 16.6 )
    NPSI evoked pain score
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.92 ( 2.25 )
    4.80 ( 2.39 )
    SF-12 Mental Component Summary
    Units: units on a scale
        arithmetic mean (standard deviation)
    41.5 ( 10.3 )
    42.5 ( 9.2 )
    SF-12 Physical Component Summary
    Units: units on a scale
        arithmetic mean (standard deviation)
    36.9 ( 8.5 )
    35.9 ( 8.1 )
    SF-12 Bodily pain
    Units: units on a scale
        arithmetic mean (standard deviation)
    33.2 ( 8.3 )
    33.3 ( 8.0 )

    End points

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    End points reporting groups
    Reporting group title
    EMONO
    Reporting group description
    		 Equimolar gases mixture of medicinal nitrous oxide 50% and medicinal oxygen 50% (EMONO) from Air Liquide Santé International.

    Reporting group title
    Placebo
    Reporting group description
    		 Oxygen/Nitrogen 22%/78% (synthetic medical air)

    Subject analysis set title
    EMONO - mFAS
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Randomised patients who received three administrations of EMONO (with at least one complete administration) and had at least 4 evaluations of NRS in the first week post-treatment. A complete administration was defined as an administration with an exposure between 55 and 65 minutes with no more than 5 minutes without treatment administration. The mFAS was used for efficacy analyses.

    Subject analysis set title
    Placebo - mFAS
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Randomised patients who received three administrations of Placebo (with at least one complete administration) and had at least 4 evaluations of NRS in the first week post-treatment. A complete administration was defined as an administration with an exposure between 55 and 65 minutes with no more than 5 minutes without treatment administration. The mFAS was used for efficacy analyses.

    Primary: Change in mean pain intensity (assessed by NRS)

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    End point title
    		 Change in mean pain intensity (assessed by NRS)
    End point description
    Change was calculated between the mean of the daily NRS records from the first week after last treatment administration and the mean of the daily NRS records from the 7-day baseline period.
    End point type
    Primary
    End point timeframe
    Between the 7-day baseline period and the first 7-day after the last administration of treatment.
    End point values
    		 EMONO - mFAS Placebo - mFAS
    Number of subjects analysed
    103
    118
    Units: units on a scale
        arithmetic mean (standard deviation)
    -1.02 ( 1.50 )
    -0.81 ( 1.30 )
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    ANCOVA with mean 7-day baseline pain intensity score, sensory phenotype at baseline (presence or absence of evoked pain) and treatment group as factors.
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2465
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean difference
    Point estimate
    -0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.59
         upper limit
    		 0.15

    Secondary: Weekly Change in mean pain intensity (assessed by NRS) up to 28 days

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    End point title
    		 Weekly Change in mean pain intensity (assessed by NRS) up to 28 days
    End point description
    Weekly pain intensity scores were calculated as the mean of the daily NRS records for each week. Changes were calculated from the 7-day baseline period.
    End point type
    Secondary
    End point timeframe
    Between the 7-day baseline period and each week after the last administration of treatment up to 28 days.
    End point values
    		 EMONO - mFAS Placebo - mFAS
    Number of subjects analysed
    103 [1]
    118 [2]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Week 1
    -1.02 ( 1.50 )
    -0.81 ( 1.30 )
        Week 2
    -0.93 ( 1.56 )
    -0.68 ( 1.35 )
        Week 3
    -0.90 ( 1.53 )
    -0.67 ( 1.45 )
        Week 4
    -0.83 ( 1.41 )
    -0.67 ( 1.47 )
    Notes
    [1] - mFAS: 3 administrations with at least one complete Week 1=103; Week 2=101; Week 3=100; Week 4=99
    [2] - mFAS: 3 administrations with at least one complete Week 1=118; Week 2=117; Week 3=117; Week 4=116
    Statistical analysis title
    		 ANCOVA Week 1 - mFAS
    Statistical analysis description
    ANCOVA comparing EMONO and Placebo at Week 1 in the mFAS, with mean 7-day baseline pain intensity score, sensory phenotype at baseline (presence or absence of evoked pain) and treatment group as factors.
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2465
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean difference
    Point estimate
    -0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.59
         upper limit
    		 0.15
    Statistical analysis title
    		 ANCOVA Week 2 - mFAS
    Statistical analysis description
    ANCOVA comparing EMONO and Placebo at Week 2 in the mFAS, with mean 7-day baseline pain intensity score, sensory phenotype at baseline (presence or absence of evoked pain) and treatment group as factors. Number of subjects included in analysis = 218
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2227
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean difference
    Point estimate
    -0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.63
         upper limit
    		 0.15
    Statistical analysis title
    		 ANCOVA Week 3 - mFAS
    Statistical analysis description
    ANCOVA comparing EMONO and Placebo at Week 3 in the mFAS, with mean 7-day baseline pain intensity score, sensory phenotype at baseline (presence or absence of evoked pain) and treatment group as factors. Number of subjects included in analysis = 217
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2624
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean difference
    Point estimate
    -0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.63
         upper limit
    		 0.17
    Statistical analysis title
    		 ANCOVA Week 4 - mFAS
    Statistical analysis description
    ANCOVA comparing EMONO and Placebo at Week 4 in the mFAS, with mean 7-day baseline pain intensity score, sensory phenotype at baseline (presence or absence of evoked pain) and treatment group as factors. Number of subjects included in analysis = 215
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3949
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean difference
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 0.22

    Secondary: Proportion of subjects with 30% reduction in pain intensity (assessed by NRS) up to 28 days

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    End point title
    		 Proportion of subjects with 30% reduction in pain intensity (assessed by NRS) up to 28 days
    End point description
    Weekly pain intensity scores were calculated as the mean of the pain intensity score records for each week. A patient was considered as a responder to a 30% reduction of pain intensity score at a given week if there was a decrease in the weekly mean NRS score equal or greater than 30%
    End point type
    Secondary
    End point timeframe
    Between the 7-day baseline period and each week after the last administration of treatment up to 28 days.
    End point values
    		 EMONO - mFAS Placebo - mFAS
    Number of subjects analysed
    103 [3]
    118 [4]
    Units: subjects
        Week 1
    28
    23
        Week 2
    26
    20
        Week 3
    30
    19
        Week 4
    25
    23
    Notes
    [3] - mFAS: 3 administrations with at least one complete Week 1=103; Week 2=101; Week 3=100; Week 4=99
    [4] - mFAS: 3 administrations with at least one complete Week 1=118; Week 2=117; Week 3=117; Week 4=116
    Statistical analysis title
    		 Chi-Square test - Week 1
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1757
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Chi-Square test - Week 2
    Statistical analysis description
    Number of subjects included in analysis = 218
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1186
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Chi-Square test - Week 3
    Statistical analysis description
    Number of subjects included in analysis = 217
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0157
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Chi-Square test - Week 4
    Statistical analysis description
    Number of subjects included in analysis = 215
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.341
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Weekly Evolution of NPSI Total Score up to 28 days

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    End point title
    		 Weekly Evolution of NPSI Total Score up to 28 days
    End point description
    Evolution assessed using percent change score from baseline.
    End point type
    Secondary
    End point timeframe
    Between baseline and the end of each week after the last administration of treatment (Day 10, Day 17, Day 24, Day 31).
    End point values
    		 EMONO - mFAS Placebo - mFAS
    Number of subjects analysed
    103 [5]
    118 [6]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Day 10
    -20.8 ( 32.0 )
    -17.1 ( 38.6 )
        Day 17
    -22.1 ( 28.6 )
    -14.8 ( 31.3 )
        Day 24
    -17.9 ( 31.7 )
    -9.9 ( 36.2 )
        Day 31
    -17.6 ( 36.4 )
    -12.0 ( 37.7 )
    Notes
    [5] - mFAS: 3 administrations with at least one complete Day 10=90; Day 17=92; Day 24=93; Day 31=89
    [6] - mFAS: 3 administrations with at least one complete Day 10=104; Day 17=108; Day 24=106; Day 31=106
    Statistical analysis title
    		 ANCOVA Day 10 - mFAS
    Statistical analysis description
    ANCOVA comparing EMONO and Placebo at Day 10 in the mFAS, with baseline score, sensory phenotype at baseline (presence or absence of evoked pain) and treatment group as factors. Number of subjects included in analysis = 194
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4149
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean difference
    Point estimate
    -4.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.24
         upper limit
    		 5.9
    Statistical analysis title
    		 ANCOVA Day 17 - mFAS
    Statistical analysis description
    ANCOVA comparing EMONO and Placebo at Day 17 in the mFAS, with baseline score, sensory phenotype at baseline (presence or absence of evoked pain) and treatment group as factors. Number of subjects included in analysis = 200
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0795
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean difference
    Point estimate
    -7.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.99
         upper limit
    		 0.9
    Statistical analysis title
    		 ANCOVA Day 24 - mFAS
    Statistical analysis description
    ANCOVA comparing EMONO and Placebo at Day 24 in the mFAS, with baseline score, sensory phenotype at baseline (presence or absence of evoked pain) and treatment group as factors. Number of subjects included in analysis = 199
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0985
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean difference
    Point estimate
    -8.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.64
         upper limit
    		 1.52
    Statistical analysis title
    		 ANCOVA Day 31 - mFAS
    Statistical analysis description
    ANCOVA comparing EMONO and Placebo at Day 31 in the mFAS, with baseline score, sensory phenotype at baseline (presence or absence of evoked pain) and treatment group as factors. Number of subjects included in analysis = 195
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2808
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean difference
    Point estimate
    -5.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.37
         upper limit
    		 4.78

    Secondary: Weekly Evolution of NPSI Evoked Pain Score up to 28 days

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    End point title
    		 Weekly Evolution of NPSI Evoked Pain Score up to 28 days
    End point description
    Evolution assessed using percent change score from baseline. For patients with a baseline score of 0, no percent change was calculable.
    End point type
    Secondary
    End point timeframe
    Between baseline and the end of each week after the last administration of treatment (Day 10, Day 17, Day 24, Day 31).
    End point values
    		 EMONO - mFAS Placebo - mFAS
    Number of subjects analysed
    103 [7]
    118 [8]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Day 10
    -24.9 ( 44.4 )
    -19.8 ( 41.3 )
        Day 17
    -23.3 ( 42.0 )
    -12.9 ( 48.0 )
        Day 24
    -23.3 ( 42.6 )
    -7.4 ( 58.9 )
        Day 31
    -22.5 ( 44.2 )
    -13.1 ( 43.8 )
    Notes
    [7] - mFAS: 3 administrations with at least one complete Day 10=93; Day 17=95; Day 24=95; Day 31=92
    [8] - mFAS: 3 administrations with at least one complete Day 10=103; Day 17=111; Day 24=112; Day 31=107
    Statistical analysis title
    		 ANCOVA Day 10 - mFAS
    Statistical analysis description
    ANCOVA comparing EMONO and Placebo at Day 10 in the mFAS, with baseline score, sensory phenotype at baseline (presence or absence of evoked pain) and treatment group as factors. Number of subjects included in analysis = 196
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3236
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean difference
    Point estimate
    -6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.95
         upper limit
    		 5.96
    Statistical analysis title
    		 ANCOVA Day 17 - mFAS
    Statistical analysis description
    ANCOVA comparing EMONO and Placebo at Day 17 in the mFAS, with baseline score, sensory phenotype at baseline (presence or absence of evoked pain) and treatment group as factors. Number of subjects included in analysis = 206
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.045
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean difference
    Point estimate
    -12.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.21
         upper limit
    		 -0.28
    Statistical analysis title
    		 ANCOVA Day 24 - mFAS
    Statistical analysis description
    ANCOVA comparing EMONO and Placebo at Day 24 in the mFAS, with baseline score, sensory phenotype at baseline (presence or absence of evoked pain) and treatment group as factors. Number of subjects included in analysis = 207
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0124
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean difference
    Point estimate
    -17.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.5
         upper limit
    		 -3.87
    Statistical analysis title
    		 ANCOVA Day 31 - mFAS
    Statistical analysis description
    ANCOVA comparing EMONO and Placebo at Day 31 in the mFAS, with baseline score, sensory phenotype at baseline (presence or absence of evoked pain) and treatment group as factors. Number of subjects included in analysis = 199
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0802
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean difference
    Point estimate
    -10.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23
         upper limit
    		 1.32

    Secondary: Evolution of Quality of Life, assessed by SF-12

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    End point title
    		 Evolution of Quality of Life, assessed by SF-12
    End point description
    Evolution assessed using change from baseline in SF-12 Mental Component Summary, SF-12 Physical Component Summary and SF-12 bodily-pain. SF-12v2® Health Survey was used for the study. Scoring was performed using the QualityMetric Health OutcomesTM Scoring Software 4.5.
    End point type
    Secondary
    End point timeframe
    Between baseline and 28 days after last treatment administration (study end).
    End point values
    		 EMONO - mFAS Placebo - mFAS
    Number of subjects analysed
    97
    114
    Units: units on a scale
    arithmetic mean (standard deviation)
        Mental Component Summary (MCS)
    2.01 ( 7.64 )
    1.30 ( 7.79 )
        Physical Component Summary (PCS)
    0.26 ( 6.15 )
    -0.13 ( 6.60 )
        Bodily pain
    3.35 ( 8.27 )
    1.19 ( 7.35 )
    Statistical analysis title
    		 ANCOVA MCS - mFAS
    Statistical analysis description
    ANCOVA comparing EMONO and Placebo MCS change from baseline in the mFAS, with baseline score, sensory phenotype at baseline (presence or absence of evoked pain) and treatment group as factors.
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7181
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean difference
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.57
         upper limit
    		 2.28
    Statistical analysis title
    		 ANCOVA PCS - mFAS
    Statistical analysis description
    ANCOVA comparing EMONO and Placebo PCS change from baseline in the mFAS, with baseline score, sensory phenotype at baseline (presence or absence of evoked pain) and treatment group as factors.
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3848
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean difference
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.91
         upper limit
    		 2.35
    Statistical analysis title
    		 ANCOVA Bodily pain - mFAS
    Statistical analysis description
    ANCOVA comparing EMONO and Placebo bodily pain change from baseline in the mFAS, with baseline score, sensory phenotype at baseline (presence or absence of evoked pain) and treatment group as factors.
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0346
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean difference
    Point estimate
    2.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 4.06

    Secondary: Proportion of subjects PGIC responders

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    End point title
    		 Proportion of subjects PGIC responders
    End point description
    A patient was considered as a responder in PGIC if the patient improved, i.e. answered one of the following item: minimally improved, much improved or very much improved.
    End point type
    Secondary
    End point timeframe
    At the end of each week after the last administration of treatment (Day 10, Day 17, Day 24, Day 31).
    End point values
    		 EMONO - mFAS Placebo - mFAS
    Number of subjects analysed
    103 [9]
    118 [10]
    Units: subjects
        Day 10
    45
    37
        Day 17
    50
    34
        Day 24
    44
    35
        Day 31
    44
    37
    Notes
    [9] - mFAS: 3 administrations with at least one complete Day 10=102; Day 17=96; Day 24=94; Day 31=93
    [10] - mFAS: 3 administrations with at least one complete Day 10=115; Day 17=113; Day 24=113; Day 31=112
    Statistical analysis title
    		 Chi-Square test - Day 10
    Statistical analysis description
    Number of subjects included in analysis = 217
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0701
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Chi-Square test - Day 17
    Statistical analysis description
    Number of subjects included in analysis = 209
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0012
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Chi-Square test - Day 24
    Statistical analysis description
    Number of subjects included in analysis = 207
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0195
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Chi-Square test - Day 31
    Statistical analysis description
    Number of subjects included in analysis = 205
    Comparison groups
    EMONO - mFAS v Placebo - mFAS
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0374
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Weekly Evolution of HADS-Anxiety up to 28 days

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    End point title
    		 Weekly Evolution of HADS-Anxiety up to 28 days
    End point description
    At each timepoint, the HADS-Anxiety score was categorised as Normal (Score 0-7), Mild (Score 8-10), Moderate (Score 11-14) or Severe (Score 15-21).
    End point type
    Secondary
    End point timeframe
    At the end of each week after the last administration of treatment (Day 10, Day 17, Day 24, Day 31).
    End point values
    		 EMONO - mFAS Placebo - mFAS
    Number of subjects analysed
    103
    118
    Units: subjects
        Day 10 - Normal (score 0-7)
    56
    59
        Day 10 - Mild (score 8-10)
    19
    31
        Day 10 - Moderate (score 11-14)
    20
    19
        Day 10 - Severe (score 15-21)
    5
    5
        Day 17 - Normal (score 0-7)
    60
    67
        Day 17 - Mild (score 8-10)
    17
    22
        Day 17 - Moderate (score 11-14)
    11
    19
        Day 17 - Severe (score 15-21)
    6
    5
        Day 24 - Normal (score 0-7)
    59
    67
        Day 24 - Mild (score 8-10)
    16
    23
        Day 24 - Moderate (score 11-14)
    15
    15
        Day 24 - Severe (score 15-21)
    6
    7
        Day 31 - Normal (score 0-7)
    56
    62
        Day 31 - Mild (score 8-10)
    18
    28
        Day 31 - Moderate (score 11-14)
    17
    14
        Day 31 - Severe (score 15-21)
    3
    8
    No statistical analyses for this end point

    Secondary: Weekly Evolution of HADS-Depression up to 28 days

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    End point title
    		 Weekly Evolution of HADS-Depression up to 28 days
    End point description
    At each timepoint, the HADS-Depression score was categorised as Normal (Score 0-7), Mild (Score 8-10), Moderate (Score 11-14) or Severe (Score 15-21).
    End point type
    Secondary
    End point timeframe
    At the end of each week after the last administration of treatment (Day 10, Day 17, Day 24, Day 31).
    End point values
    		 EMONO - mFAS Placebo - mFAS
    Number of subjects analysed
    103
    118
    Units: subjects
        Day 10 - Normal (score 0-7)
    51
    59
        Day 10 - Mild (score 8-10)
    23
    33
        Day 10 - Moderate (score 11-14)
    18
    20
        Day 10 - Severe (score 15-21)
    8
    2
        Day 17 - Normal (score 0-7)
    52
    60
        Day 17 - Mild (score 8-10)
    21
    30
        Day 17 - Moderate (score 11-14)
    17
    22
        Day 17 - Severe (score 15-21)
    4
    3
        Day 24 - Normal (score 0-7)
    52
    56
        Day 24 - Mild (score 8-10)
    24
    34
        Day 24 - Moderate (score 11-14)
    15
    20
        Day 24 - Severe (score 15-21)
    5
    3
        Day 31 - Normal (score 0-7)
    49
    55
        Day 31 - Mild (score 8-10)
    25
    30
        Day 31 - Moderate (score 11-14)
    13
    25
        Day 31 - Severe (score 15-21)
    7
    2
    No statistical analyses for this end point

    Secondary: On demand/rescue Therapies Post-Baseline

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    End point title
    		 On demand/rescue Therapies Post-Baseline
    End point description
    On Demand and/or rescue therapies were reported in the booklets by the patients.
    End point type
    Secondary
    End point timeframe
    Between the first day after last treatment administration and 28 days after last treatment administration (study end).
    End point values
    		 EMONO - mFAS Placebo - mFAS
    Number of subjects analysed
    103
    118
    Units: subject
        At least 1 on demand/rescue therapy
    57
    72
        At least 1 on demand/rescue therapy (only opioids)
    24
    34
    No statistical analyses for this end point

    Post-hoc: Total number of adverse events by timing of occurrence

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    End point title
    		 Total number of adverse events by timing of occurrence
    End point description
    Treatment Emergent Adverse Events (TEAEs) were categorised according to their timing of occurrence: *Category 1: TEAEs started and ended on or before Study Day 3 *Category 2: TEAEs started or ended after Study Day 3 In case of multiple occurrences of a same preferred term for a same patient, one in category 1 (TEAEs started and ended on or before Study Day 3) and one in category 2 (TEAEs started or ended after Study Day 3), the TEAE was counted in category 2. If study day of start of adverse event was between Day 1 and Day 3 and study day of end of adverse event was missing or if study day of start of adverse event was missing then the TEAE was classified as category 2.
    End point type
    Post-hoc
    End point timeframe
    Between the start of first study treatment administration and study end.
    End point values
    		 EMONO Placebo
    Number of subjects analysed
    120
    120
    Units: adverse event
        Treatment-emergent adverse events (TEAE)
    984
    414
        TEAEs started and ended on or before Study Day 3
    812
    318
        TEAEs started or ended after Study Day 3
    172
    96
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events observed from the start of study treatment until end of follow-up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    EMONO
    Reporting group description
    		 Subjects randomised in Emono arm.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects randomised in Placebo arm.

    Serious adverse events
    		 EMONO Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 120 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Loss of consciousness
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 EMONO Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    120 / 120 (100.00%)
    104 / 120 (86.67%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    99 / 120 (82.50%)
    68 / 120 (56.67%)
         occurrences all number
    230
    131
    Paraesthesia
         subjects affected / exposed
    68 / 120 (56.67%)
    28 / 120 (23.33%)
         occurrences all number
    158
    40
    Depressed level of consciousness
         subjects affected / exposed
    70 / 120 (58.33%)
    21 / 120 (17.50%)
         occurrences all number
    144
    35
    Dizziness
         subjects affected / exposed
    68 / 120 (56.67%)
    22 / 120 (18.33%)
         occurrences all number
    169
    37
    Sensory disturbance
         subjects affected / exposed
    59 / 120 (49.17%)
    8 / 120 (6.67%)
         occurrences all number
    130
    13
    Headache
         subjects affected / exposed
    35 / 120 (29.17%)
    25 / 120 (20.83%)
         occurrences all number
    61
    34
    Sedation
         subjects affected / exposed
    48 / 120 (40.00%)
    8 / 120 (6.67%)
         occurrences all number
    90
    12
    Amnesia
         subjects affected / exposed
    21 / 120 (17.50%)
    0 / 120 (0.00%)
         occurrences all number
    37
    0
    General disorders and administration site conditions
    Feeling drunk
         subjects affected / exposed
    46 / 120 (38.33%)
    3 / 120 (2.50%)
         occurrences all number
    100
    3
    Fatigue
         subjects affected / exposed
    14 / 120 (11.67%)
    17 / 120 (14.17%)
         occurrences all number
    17
    18
    Asthenia
         subjects affected / exposed
    7 / 120 (5.83%)
    9 / 120 (7.50%)
         occurrences all number
    7
    9
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    6 / 120 (5.00%)
    1 / 120 (0.83%)
         occurrences all number
    8
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    37 / 120 (30.83%)
    17 / 120 (14.17%)
         occurrences all number
    53
    19
    Diarrhoea
         subjects affected / exposed
    9 / 120 (7.50%)
    0 / 120 (0.00%)
         occurrences all number
    11
    0
    Vomiting
         subjects affected / exposed
    7 / 120 (5.83%)
    0 / 120 (0.00%)
         occurrences all number
    8
    0
    Dry mouth
         subjects affected / exposed
    6 / 120 (5.00%)
    0 / 120 (0.00%)
         occurrences all number
    9
    0
    Psychiatric disorders
    Euphoric mood
         subjects affected / exposed
    98 / 120 (81.67%)
    64 / 120 (53.33%)
         occurrences all number
    274
    145
    Anxiety
         subjects affected / exposed
    62 / 120 (51.67%)
    34 / 120 (28.33%)
         occurrences all number
    151
    61
    Confusional state
         subjects affected / exposed
    36 / 120 (30.00%)
    3 / 120 (2.50%)
         occurrences all number
    65
    3
    Agitation
         subjects affected / exposed
    21 / 120 (17.50%)
    7 / 120 (5.83%)
         occurrences all number
    38
    7
    Affect lability
         subjects affected / exposed
    21 / 120 (17.50%)
    3 / 120 (2.50%)
         occurrences all number
    29
    3
    Hallucination
         subjects affected / exposed
    16 / 120 (13.33%)
    1 / 120 (0.83%)
         occurrences all number
    19
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 May 2017
    - Authorisation of visit dates flexibility without impacting the dates of filling of the questionnaires in patient booklets, - Possibility to perform follow-up visits V5 and V6 by phone, - Addition of one non selection criterion and modification of three other non selection criteria, - Clarification about the inclusion criterion and one of the secondary objectives, - Addition of three secondary analysis criteria.
    13 Jun 2018
    - Integration of new safety data further to the update of the KALINOX TM SmPC, - Prolongation of study recruitment period to September 2018 for LPI and November 2018 for LPLV.

    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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