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    Clinical Trial Results:
    A Phase 2, Double-blind, Randomized, Placebo-controlled, Four-arm, Multicenter, Dose-finding Study to Assess the Safety and Efficacy of Three Dose Levels of AVP-923 (Dextromethorphan/Quinidine) in the Treatment of Central Neuropathic Pain in Patients with Multiple Sclerosis

    Summary
    EudraCT number
    2011-002178-22
    Trial protocol
    ES   CZ   PL   GB  
    Global end of trial date
    26 Sep 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Jan 2021
    First version publication date
    02 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    11-AVR-130
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01324232
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Avanir Pharmaceuticals, Inc.
    Sponsor organisation address
    30 Enterprise, Suite 400, Aliso Viejo, California, United States, 92656
    Public contact
    Clinical Trial Information Desk, Avanir Pharmaceuticals, Inc., 1 949-268-1167, study11AVR130@avanir.com
    Scientific contact
    Clinical Trial Information Desk, Avanir Pharmaceuticals, Inc., 1 949-268-1167, study11AVR130@avanir.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
    01 Nov 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objectives of the study are to evaluate the safety, tolerability, and efficacy of 3 doses of AVP-923 capsules containing either 45 mg DM and 10 mg Q (AVP-923-45) or 30 mg DM 10 mg Q (AVP-923-30) or 20 mg DM and 10 mg Q (AVP-923-20) compared to placebo, for the treatment of central neuropathic pain in a population of patients with multiple sclerosis (MS) over a 12-week period.
    Protection of trial subjects
    Ethics committees met the guidelines set out by the Food and Drug Administration (FDA) and conformed to local laws and customs where appropriate. Written institutional review board (IRB) approval for the protocol and the signed informed consent form (ICF) were obtained and transmitted to Avanir Pharmaceuticals, Inc. or their representative before the study was initiated. The IRB was informed of and approved all protocol amendments. Modifications that eliminated an apparent immediate hazard to patients did not require preapproval by the IRB/IEC. Standards for Good Clinical Practice, as outlined by regional regulations, were adhered to for all study-based procedures. The investigator ensured that this study was conducted in full conformance with the laws and regulations of the United States. Informed consent followed the principles outlined in the current version of the Helsinki Declaration. Each patient found to be eligible for the study was properly informed of the purpose of the study. The patient was alerted to any anticipated adverse event (AE) that may be encountered with the study drug. A signed ICF was obtained from all patients (or their authorized representative if enrolled prior to Amendment 2 of the protocol) prior to patient entry into this study. Patients were provided with a copy of their signed ICF (except for patients enrolled prior to Amendment 1 of the protocol).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Sep 2011
    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
    Poland: 31
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Czech Republic: 48
    Country: Number of subjects enrolled
    United States: 112
    Country: Number of subjects enrolled
    Argentina: 8
    Worldwide total number of subjects
    209
    EEA total number of subjects
    89
    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)
    198
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    After screening procedures, participants underwent a 1-week washout period for all analgesic medications, with the exception of ibuprofen in doses that did not exceed 800 milligrams per day (mg/day).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received one matching placebo capsule in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral capsule; once daily and twice daily

    Arm title
    AVP-923-20
    Arm description
    Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    AVP-923
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral capsule; once daily and twice daily

    Arm title
    AVP-923-30
    Arm description
    Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    AVP-923
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral capsule; once daily and twice daily

    Arm title
    AVP-923-45
    Arm description
    Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    AVP-923
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral capsule; once daily and twice daily

    Number of subjects in period 1
    Placebo AVP-923-20 AVP-923-30 AVP-923-45
    Started
    49
    53
    54
    53
    Completed
    44
    42
    41
    42
    Not completed
    5
    11
    13
    11
         Consent withdrawn by subject
    -
    3
    4
    -
         Adverse event, non-fatal
    2
    5
    6
    6
         Other
    2
    2
    2
    2
         Intercurrent illness
    -
    -
    -
    1
         Patient refused medication
    -
    1
    -
    -
         Lost to follow-up
    1
    -
    -
    -
         Missing
    -
    -
    1
    -
         Protocol deviation
    -
    -
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received one matching placebo capsule in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.

    Reporting group title
    AVP-923-20
    Reporting group description
    Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.

    Reporting group title
    AVP-923-30
    Reporting group description
    Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.

    Reporting group title
    AVP-923-45
    Reporting group description
    Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.

    Reporting group values
    Placebo AVP-923-20 AVP-923-30 AVP-923-45 Total
    Number of subjects
    49 53 54 53 209
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    49.7 ( 8.41 ) 47.2 ( 9.20 ) 49.1 ( 11.21 ) 48.1 ( 13.04 ) -
    Gender categorical
    Units: Subjects
        Female
    40 46 42 41 169
        Male
    9 7 12 12 40
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    43 46 49 48 186
        Black or African American
    3 4 5 4 16
        Asian
    1 0 0 0 1
        Hispanic or Latino
    2 3 0 1 6

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received one matching placebo capsule in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.

    Reporting group title
    AVP-923-20
    Reporting group description
    Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.

    Reporting group title
    AVP-923-30
    Reporting group description
    Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.

    Reporting group title
    AVP-923-45
    Reporting group description
    Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Participants received one matching placebo capsule containing in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.

    Subject analysis set title
    AVP-923-20
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.

    Subject analysis set title
    AVP-923-30
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.

    Subject analysis set title
    AVP-923-45
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.

    Subject analysis set title
    Total
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    All participants receiving placebo, AVP-923-20, AVP-923-30, or AVP-923-45.

    Subject analysis set title
    AVP-923-20 and AVP-923-30
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Participants received either AVP-923-20 or AVP-923-30 in the morning during the first 7 days of the study. Participants then received one capsule of AVP-20 or AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.

    Subject analysis set title
    AVP-923-30 and AVP-923-45
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Participants received either AVP-923-30 or AVP-923-45 in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 or AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.

    Subject analysis set title
    All AVP-923
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    All participants receiving AVP-923-20, AVP-923-30, or AVP-923-45.

    Primary: Association between the Dextromethorphan (DM) Plasma Concentration and the Change from Baseline Pain Rating Scale Score to the Average Pain Rating Scale Score during Days 57 through 84

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    End point title
    Association between the Dextromethorphan (DM) Plasma Concentration and the Change from Baseline Pain Rating Scale Score to the Average Pain Rating Scale Score during Days 57 through 84
    End point description
    The association between the DM plasma concentration and the change from Baseline (BL) PRS score to the average PRS score during Days 57 through 84 was measured. The PRS requires participants (par.) to rate their pain over the past 12 hours on a scale of 0 to 10 (0=no pain; 10=worst possible pain) by circling the number that best describes their pain on average over the past 12 hours. Baseline (BL) PRS was defined as the average of the PRS scores in the last 7 days collected prior to the BL visit. Post-BL PRS is the average of the Day 57 through 84 values. For par. who did not have any PRS scores during Days 57 through 84, the average of the last 7 available post-BL PRS scores was used. Change from BL was calculated as the post-BL score minus the BL score. Modified Intention-To-Treat (MITT) Population: all par. in the ITT Population (randomized participants) who received >=1 dose of study drug, provided a BL PRS score, and had >=1 post-BL PRS assessment. 999=data not available.
    End point type
    Primary
    End point timeframe
    Baseline; Days 57 through 84
    End point values
    Placebo AVP-923-20 AVP-923-30 AVP-923-45 Total
    Number of subjects analysed
    49 [1]
    53 [2]
    54 [3]
    53 [4]
    209 [5]
    Units: units on a scale
    median (full range (min-max))
        Change from BL in PRS Scores, n=49,53,54,53,209
    -1.821 (-7.86 to 2.06)
    -2.143 (-7.60 to 5.71)
    -2.650 (-6.54 to 3.00)
    -1.679 (-6.79 to 2.00)
    -2.000 (-7.86 to 5.71)
        DM Plasma Concentration, n=0,43,35,45,133
    999 (999 to 999)
    4.019 (2.38 to 4.84)
    4.493 (3.27 to 5.55)
    4.758 (-1.61 to 5.81)
    4.394 (-1.61 to 5.81)
    Notes
    [1] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [2] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [3] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [4] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [5] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis was that the true correlation between the change from Baseline PRS scores and the DM plasma concentration was equal to zero and was tested using a 2-sided test at the 5% level of significance within active treatment groups.
    Comparison groups
    AVP-923-20 v AVP-923-30 v Placebo v AVP-923-45
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9827
    Method
    t-test, 2-sided
    Confidence interval

    Secondary: Comparison of the Change From Baseline PRS Score to the Average PRS Score During Days 57 Through 84

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    End point title
    Comparison of the Change From Baseline PRS Score to the Average PRS Score During Days 57 Through 84
    End point description
    The PRS requires participants to rate their pain over the past 12 hours on a scale of 0 to 10 (0=no pain; 10=worst possible pain) by circling the number that best describes their pain on average over the past 12 hours. Baseline PRS was defined as the average of the PRS scores in the last 7 days collected prior to the Baseline visit. If participants did not have at least 4 PRS scores during the last 7 days prior to the Baseline visit, then the average of up to 7 of the most recent PRS scores available prior to the Baseline visit was used. Post-Baseline PRS is the average of the Day 57 through 84 values. For participants who did not have any PRS scores during Days 57 through 84, the average of the last 7 available post-Baseline PRS scores was used. Change from Baseline was calculated as the post-Baseline score minus the Baseline score. PRS score change from baseline to Days 57-84 was the dependent variable, treatment group was a fixed effect, and the baseline PRS score was a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline; Days 57 through 84
    End point values
    Placebo AVP-923-20 AVP-923-30 AVP-923-45 AVP-923-20 and AVP-923-30 AVP-923-30 and AVP-923-45 All AVP-923
    Number of subjects analysed
    49 [6]
    53 [7]
    54 [8]
    53 [9]
    107 [10]
    107 [11]
    160 [12]
    Units: units on a scale
        least squares mean (standard error)
    -2.04 ( 0.332 )
    -2.07 ( 0.319 )
    -2.41 ( 0.316 )
    -2.00 ( 0.319 )
    -2.24 ( 0.224 )
    -2.21 ( 0.225 )
    -2.16 ( 0.184 )
    Notes
    [6] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [7] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [8] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [9] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [10] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [11] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [12] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Overall P value tested the hypothesis of no treatment effect.
    Comparison groups
    Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8869
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v AVP-923-20
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9381
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.94
         upper limit
    0.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.46
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Placebo v AVP-923-30
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4128
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.28
         upper limit
    0.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.46
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Placebo v AVP-923-45
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9427
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.88
         upper limit
    0.94
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.461
    Statistical analysis title
    Statistical Analysis 5
    Comparison groups
    Placebo v AVP-923-20 and AVP-923-30
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6075
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    0.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.401
    Statistical analysis title
    Statistical Analysis 6
    Comparison groups
    Placebo v AVP-923-30 and AVP-923-45
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.669
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.96
         upper limit
    0.62
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.402
    Statistical analysis title
    Statistical Analysis 7
    Comparison groups
    Placebo v All AVP-923
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7394
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.88
         upper limit
    0.62
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.38

    Secondary: Change From Baseline in Fatigue Severity Scale (FSS) Scores

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    End point title
    Change From Baseline in Fatigue Severity Scale (FSS) Scores
    End point description
    The FSS questionnaire contains 9 statements that attempt to explore the severity of fatigue symptoms in participants with MS and other conditions, including chronic fatigue immune dysfunction syndrome and systemic lupus erythematosus, and is designed to differentiate fatigue from clinical depression because both share some of the same symptoms. Participants were asked to respond to each statement on a scale of 1 to 7, with 1 indicating “Strongly Disagree” and 7 indicating “Strongly Agree.” The total score is computed as the sum of the sub-scores for all 9 statements; a higher score indicates increasing fatigue. Baseline (BL) is defined as last non-missing measurement prior to dosing. Change from BL is calculated as the post-BL value minus the BL value. Only participants with a value at both the BL visit and the specific post-BL visit have been included in the analysis. FSS change from BL was the dependent variable, treatment group was a fixed effect, and the BL FSS was a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline; Days 57 through 84
    End point values
    Placebo AVP-923-20 AVP-923-30 AVP-923-45
    Number of subjects analysed
    48 [13]
    52 [14]
    54 [15]
    53 [16]
    Units: units on a scale
        least squares mean (standard error)
    -3.32 ( 1.742 )
    -2.00 ( 1.680 )
    -6.32 ( 1.642 )
    -2.12 ( 1.662 )
    Notes
    [13] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [14] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [15] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [16] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.
    Comparison groups
    Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9731
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v AVP-923-20
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    1.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.45
         upper limit
    6.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.42
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Placebo v AVP-923-30
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.72
         upper limit
    1.72
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.394
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Placebo v AVP-923-45
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.54
         upper limit
    5.95
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.408

    Secondary: Change From Baseline in Expanded Disability Status Scale (EDSS) Scores

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    End point title
    Change From Baseline in Expanded Disability Status Scale (EDSS) Scores
    End point description
    The EDSS is a method of quantifying disability in participants with MS. It is based on neurological examination of 8 functional systems (FS) (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral, and other) that allows neurologists to assign a FS score to each of these systems. Neurological findings in each FS are scored on a scale of 0 (low level of problems) to 5 (high level of problems). The “other” category is not rated numerically but measures disability related to a particular issue, like motor loss. A total EDSS score is then calculated on a scale of 0 (normal) to 10 (death from MS). The total EDSS score is determined by 2 factors: gait and FS scores. A higher score indicates greater disability. Baseline (BL) is defined as last non-missing measurement prior to dosing. Change from BL is calculated as the post-BL value minus the BL value. Only participants with a value at both the BL visit and the specific post-BL visit were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline; Days 22 and 85
    End point values
    Placebo AVP-923-20 AVP-923-30 AVP-923-45 Total
    Number of subjects analysed
    49 [17]
    54 [18]
    53 [19]
    53 [20]
    209 [21]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Day 22, n=46, 41, 42, 45, 174
    -0.1 ( 0.35 )
    -0.1 ( 0.56 )
    -0.2 ( 0.67 )
    -0.0 ( 0.63 )
    -0.1 ( 0.56 )
        Day 85, n=48, 51, 49, 52, 200
    -0.1 ( 0.75 )
    -0.1 ( 0.67 )
    -0.1 ( 0.46 )
    0.0 ( 0.58 )
    -0.1 ( 0.62 )
    Notes
    [17] - Safety Population: all participants who received at least 1 dose of study drug
    [18] - Safety Population: all participants who received at least 1 dose of study drug
    [19] - Safety Population: all participants who received at least 1 dose of study drug
    [20] - Safety Population: all participants who received at least 1 dose of study drug
    [21] - Safety Population: all participants who received at least 1 dose of study drug
    No statistical analyses for this end point

    Secondary: Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Scores

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    End point title
    Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Scores
    End point description
    The MSIS-29 is an instrument measuring the physical (20 items) and psychological (9 items) impact of MS from the participant' perspective and is used to evaluate therapeutic effectiveness from the participants' perspective. Participants were asked to circle the response that best described the impact of MS on daily life on a scale of 0 (not at all) to 5 (extremely). The total MSIS-29 score is calculated as the sum of the sub-scores for all 29 questions, with lower scores indicating better quality of life. Baseline is defined as last non-missing measurement prior to dosing. Change from Baseline is calculated as the post-Baseline value minus the Baseline value. For participants with missing data at Day 85, the last available value has been used. MSIS change from Baseline to Day 85 was the dependent variable, treatment group was a fixed effect, and the Baseline MSIS was a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline; Day 85
    End point values
    Placebo AVP-923-20 AVP-923-30 AVP-923-45
    Number of subjects analysed
    49 [22]
    53 [23]
    54 [24]
    53 [25]
    Units: units on a scale
        least squares mean (standard error)
    -4.84 ( 2.651 )
    -4.34 ( 2.551 )
    -6.50 ( 2.526 )
    -1.41 ( 2.550 )
    Notes
    [22] - mITT Population: Analysis was based on the randomized treatment assigned
    [23] - mITT Population: Analysis was based on the randomized treatment assigned
    [24] - mITT Population: Analysis was based on the randomized treatment assigned
    [25] - mITT Population: Analysis was based on the randomized treatment assigned
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.
    Comparison groups
    Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4778
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v AVP-923-20
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.76
         upper limit
    7.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.676
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Placebo v AVP-923-30
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.89
         upper limit
    5.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.663
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Placebo v AVP-923-45
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    3.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.83
         upper limit
    10.68
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.681

    Secondary: Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Scores

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    End point title
    Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Scores
    End point description
    The PSQI is a self-rated questionnaire that assesses sleep quality and disturbances over a 1-month time interval. A total of 19 individual items generate 7 component scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. Each component is scored from 0 (no difficulty) to 3 (severe difficulty). The sum of the scores for the 7 components yields 1 global score (from 0 to 21). A higher PSQI score indicates worse quality of sleep. Baseline (BL) is defined as last non-missing measurement prior to dosing. Change from BL is calculated as the post-BL value minus the BL value. Only participants with a value at both the BL visit and the specific post-BL visit were included in the analysis. For participants with missing data at Day 85, the last available value was used. PSQI change from BL was the dependent variable, treatment group was a fixed effect, and the BL PQIS was a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline; Day 85
    End point values
    Placebo AVP-923-20 AVP-923-30 AVP-923-45
    Number of subjects analysed
    49 [26]
    53 [27]
    54 [28]
    53 [29]
    Units: units on a scale
        least squares mean (standard error)
    -0.51 ( 0.490 )
    -1.02 ( 0.471 )
    -1.36 ( 0.467 )
    -1.71 ( 0.472 )
    Notes
    [26] - mITT Population: Analysis was based on the randomized treatment assigned
    [27] - mITT Population: Analysis was based on the randomized treatment assigned
    [28] - mITT Population: Analysis was based on the randomized treatment assigned
    [29] - mITT Population: Analysis was based on the randomized treatment assigned
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.
    Comparison groups
    Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0685
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v AVP-923-20
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.85
         upper limit
    0.83
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.68
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Placebo v AVP-923-30
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.19
         upper limit
    0.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.677
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Placebo v AVP-923-45
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.54
         upper limit
    0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.681

    Secondary: Change From Baseline in MS Neuropsychological Screening Questionnaire (MSNQ) Scores

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    End point title
    Change From Baseline in MS Neuropsychological Screening Questionnaire (MSNQ) Scores
    End point description
    The MSNQ is a self-reporting, 15-item questionnaire developed to screen for cognitive impairment in participants with MS. Participants (or their informants) scored each item on a scale from 0 (not at all) to 4 (often and greatly interferes with life). The total MSNQ score is calculated as the sum of the sub-scores for all 15 questions and thus ranges from 0 to 60. A higher score indicates greater impairment. Baseline is defined as last non-missing measurement prior to dosing. Change from Baseline is calculated as the post-Baseline value minus the Baseline value. Only participants with a value at both the Baseline visit and the specific post-Baseline visit have been included in the analysis. For participants with missing data at Day 85, the last available value has been used. MSNQ change from Baseline to Day 85 was the dependent variable, treatment group was a fixed effect, and the Baseline MSNQ was a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline; Day 85
    End point values
    Placebo AVP-923-20 AVP-923-30 AVP-923-45
    Number of subjects analysed
    48 [30]
    52 [31]
    54 [32]
    53 [33]
    Units: units on a scale
        least squares mean (standard error)
    -0.99 ( 1.058 )
    -1.48 ( 1.020 )
    -1.88 ( 0.998 )
    0.47 ( 1.006 )
    Notes
    [30] - mITT Population: Analysis was based on the randomized treatment assigned
    [31] - mITT Population: Analysis was based on the randomized treatment assigned
    [32] - mITT Population: Analysis was based on the randomized treatment assigned
    [33] - mITT Population: Analysis was based on the randomized treatment assigned
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.
    Comparison groups
    AVP-923-20 v Placebo v AVP-923-30 v AVP-923-45
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4201
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v AVP-923-20
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.4
         upper limit
    2.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.473
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Placebo v AVP-923-30
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.76
         upper limit
    1.97
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.454
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Placebo v AVP-923-45
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    1.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.42
         upper limit
    4.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.46

    Secondary: Change From Baseline in Beck Depression Inventory (BDI-II) Scores

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    End point title
    Change From Baseline in Beck Depression Inventory (BDI-II) Scores
    End point description
    The BDI-II is a 21-item, self-reported instrument intended to assess the existence and severity of symptoms of depression. Each item corresponds to a symptom of depression and is scored on a 4-point scale, ranging from 0 to 3. Participants are asked to consider each statement as it relates to the way they have felt for the past 2 weeks. Each of the 21 items is summed to give a single score (ranging from 0 to 63). A total score of 0 to 13 indicates minimal depression, a score of 14 to 19 indicates mild depression, a score of 20 to 28 indicates moderate depression, and a score of 29 to 63 indicates severe depression. Baseline (BL) is defined as last non-missing measurement prior to dosing. Change from BL is calculated as the post-BL value minus the BL value. Only participants with a value at both the BL visit and the specific post-BL visit have been included in the analysis. For participants with missing data at Day 85, the last available value has been used.
    End point type
    Secondary
    End point timeframe
    Baseline; Day 85
    End point values
    Placebo AVP-923-20 AVP-923-30 AVP-923-45
    Number of subjects analysed
    49 [34]
    53 [35]
    54 [36]
    53 [37]
    Units: units on a scale
        least squares mean (standard error)
    0.83 ( 0.868 )
    -0.26 ( 0.835 )
    0.21 ( 0.828 )
    1.15 ( 0.837 )
    Notes
    [34] - mITT Population: Analysis was based on the randomized treatment assigned
    [35] - mITT Population: Analysis was based on the randomized treatment assigned
    [36] - mITT Population: Analysis was based on the randomized treatment assigned
    [37] - mITT Population: Analysis was based on the randomized treatment assigned
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.
    Comparison groups
    Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8068
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v AVP-923-20
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.47
         upper limit
    1.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.205
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Placebo v AVP-923-30
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.99
         upper limit
    1.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.2
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Placebo v AVP-923-45
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.07
         upper limit
    2.69
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.207

    Secondary: Change From Baseline in Symbol Digit Modalities Test (SDMT) Scores

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    End point title
    Change From Baseline in Symbol Digit Modalities Test (SDMT) Scores
    End point description
    The SDMT assesses organic cerebral dysfunction in both children (8 years and older) and adults. The SDMT involves a simple substitution task that normal participants can easily perform. Using a reference key, the examinee has 90 seconds to pair specific numbers with given geometric figures. The SDMT score is the total correct response (not counting errors) in 90 seconds and ranges from 0 to 110. Lower scores indicate increased dysfunction. Baseline is defined as last non-missing measurement prior to dosing. Change from Baseline is calculated as the post-Baseline value minus the Baseline value. Only participants with a value at both the Baseline visit and the specific post-Baseline visit have been included in the analysis. For participants with missing data at Day 85, the last available value has been used. SDMT change from Baseline to Day 85 was the dependent variable, treatment group was a fixed effect, and the Baseline SDMT was a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline; Day 85
    End point values
    Placebo AVP-923-20 AVP-923-30 AVP-923-45
    Number of subjects analysed
    48 [38]
    52 [39]
    54 [40]
    53 [41]
    Units: units on a scale
    least squares mean (standard error)
        Total correct responses, oral; n=11, 13, 20, 14
    0.59 ( 2.045 )
    2.96 ( 1.881 )
    1.91 ( 1.525 )
    2.06 ( 1.809 )
        Total correct responses, written; n=37, 39, 34, 39
    1.85 ( 1.111 )
    3.62 ( 1.086 )
    0.16 ( 1.158 )
    0.20 ( 1.083 )
    Notes
    [38] - mITT Population: Analysis was based on the randomized treatment assigned
    [39] - mITT Population: Analysis was based on the randomized treatment assigned
    [40] - mITT Population: Analysis was based on the randomized treatment assigned
    [41] - mITT Population: Analysis was based on the randomized treatment assigned
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect. Oral responses.
    Comparison groups
    Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6315
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Oral responses
    Comparison groups
    Placebo v AVP-923-20
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    2.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.19
         upper limit
    7.93
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.772
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Oral responses
    Comparison groups
    Placebo v AVP-923-30
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    1.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.83
         upper limit
    6.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.562
    Statistical analysis title
    Statistical Analysis 4
    Comparison groups
    Placebo v AVP-923-45
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    1.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.01
         upper limit
    6.94
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.728
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    P-value presented tests the hypothesis for overall treatment effect versus no treatment effect. Written responses.
    Comparison groups
    Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1485
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Statistical Analysis 6
    Statistical analysis description
    Written responses
    Comparison groups
    Placebo v AVP-923-20
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    1.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.31
         upper limit
    4.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.558
    Statistical analysis title
    Statistical Analysis 7
    Statistical analysis description
    Written responses
    Comparison groups
    Placebo v AVP-923-30
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.86
         upper limit
    1.49
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.605
    Statistical analysis title
    Statistical Analysis 8
    Statistical analysis description
    Written responses
    Comparison groups
    Placebo v AVP-923-45
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.71
         upper limit
    1.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.549

    Secondary: Mean Numerical Rating Scale (NRS) Scores

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    End point title
    Mean Numerical Rating Scale (NRS) Scores
    End point description
    The NRS is an 11-point scale for participant self-reporting of pain. Scores range from 0 (no spasticity) to 10 (worst possible spasticity). Only participants with a value at both the Baseline visit and the specific post-Baseline visit have been included in the analysis. For participants with missing data at Day 85, the last available value has been used.
    End point type
    Secondary
    End point timeframe
    Baseline; Days 22, 50, and 85
    End point values
    Placebo AVP-923-20 AVP-923-30 AVP-923-45 Total
    Number of subjects analysed
    45 [42]
    49 [43]
    49 [44]
    47 [45]
    190 [46]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Day 22, n=42, 39, 37, 40, 158
    3.29 ( 2.717 )
    3.56 ( 3.016 )
    3.41 ( 2.723 )
    3.90 ( 2.649 )
    3.54 ( 2.762 )
        Day 50, n=42, 37, 36, 37, 152
    3.24 ( 2.721 )
    2.89 ( 2.633 )
    4.06 ( 2.888 )
    3.54 ( 2.364 )
    3.42 ( 2.666 )
        Day 85, n=44, 48, 46, 47, 185
    3.66 ( 2.869 )
    3.13 ( 3.085 )
    3.87 ( 2.825 )
    3.36 ( 2.666 )
    3.50 ( 2.857 )
    Notes
    [42] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [43] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [44] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [45] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [46] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis is that the true correlation between NRS scores and DM plasma concentration is equal to zero. Only 158 of the 209 participants in the mITT Population were analyzed at Day 22.
    Comparison groups
    Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1404 [47]
    Method
    t-test, 2-sided
    Confidence interval
    Notes
    [47] - Day 22
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The null hypothesis that the true correlation between NRS scores and DM plasma concentration is equal to zero. Only 152 of the 209 participants in the mITT Population were analyzed at Day 50.
    Comparison groups
    Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0805 [48]
    Method
    t-test, 2-sided
    Confidence interval
    Notes
    [48] - Day 50
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The null hypothesis that the true correlation between NRS scores and DM plasma concentration is equal to zero. Only 185 of the 209 participants in the mITT Population were analyzed at Day 85.
    Comparison groups
    Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0551 [49]
    Method
    t-test, 2-sided
    Confidence interval
    Notes
    [49] - Day 85

    Secondary: Summary of Patient Global Impression of Change (PGIC) Scores

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    End point title
    Summary of Patient Global Impression of Change (PGIC) Scores
    End point description
    The PGIC is a standard, validated 7-point categorical scale. The participant was asked to assess the overall change in his or her central neuropathic pain symptoms since entry into the study on a scale of 0 to 7 (0=much better; 7=much worse). Only participants with a value at the specific post-Baseline visit have been included in the analysis. For participants with missing data at Day 85, the last available value has been used.
    End point type
    Secondary
    End point timeframe
    Day 85
    End point values
    Placebo AVP-923-20 AVP-923-30 AVP-923-45 Total
    Number of subjects analysed
    43 [50]
    45 [51]
    46 [52]
    45 [53]
    179 [54]
    Units: units on a scale
        arithmetic mean (standard deviation)
    3.58 ( 1.842 )
    4.42 ( 2.398 )
    3.70 ( 2.346 )
    3.64 ( 2.298 )
    3.84 ( 2.244 )
    Notes
    [50] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [51] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [52] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [53] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    [54] - mITT Population: Analysis was based on the randomized treatment assigned (not treatment received)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The p-value presented tests the hypothesis for overall treatment effect versus no treatment effect.
    Comparison groups
    Placebo v AVP-923-20 v AVP-923-30 v AVP-923-45
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9207
    Method
    ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (AEs) are defined as those events with an onset that was anytime during the study and while on treatment, following the first dose of study drug on Day 1. AEs were collected up to Week 12.
    Adverse event reporting additional description
    AEs are reported for members of the Safety Population, comprising all participants who received at least one dose of study drug. Safety analyses were performed based on the treatment participants actually received.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received one matching placebo capsule containing in the morning during the first 7 days of the study. Participants then received one matching placebo capsule twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.

    Reporting group title
    AVP-923-20
    Reporting group description
    Participants received one capsule containing 20 milligrams (mg) dextromethorphan (DM) and 10 mg quinidine (Q) (AVP-923-20) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-20 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.

    Reporting group title
    AVP-923-30
    Reporting group description
    Participants received one capsule containing 30 mg DM and 10 mg Q (AVP-923-30) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-30 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.

    Reporting group title
    AVP-923-45
    Reporting group description
    Participants received one capsule containing 45 mg DM and 10 mg Q (AVP-923-45) in the morning during the first 7 days of the study. Participants then received one capsule of AVP-923-45 twice daily (approximately every 12 hours) during the remaining 11 weeks of the study to complete 12 weeks of treatment.

    Serious adverse events
    Placebo AVP-923-20 AVP-923-30 AVP-923-45
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    2 / 53 (3.77%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenitis
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Placebo AVP-923-20 AVP-923-30 AVP-923-45
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 49 (67.35%)
    40 / 54 (74.07%)
    43 / 53 (81.13%)
    40 / 53 (75.47%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Fibroadenoma of breast
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Haematoma
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    4
    Hot flush
         subjects affected / exposed
    2 / 49 (4.08%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Peripheral coldness
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Venous insufficiency
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 49 (2.04%)
    2 / 54 (3.70%)
    1 / 53 (1.89%)
    2 / 53 (3.77%)
         occurrences all number
    1
    3
    1
    2
    Chest discomfort
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Chills
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    3 / 49 (6.12%)
    3 / 54 (5.56%)
    3 / 53 (5.66%)
    3 / 53 (5.66%)
         occurrences all number
    3
    3
    4
    4
    Feeling cold
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Feeling jittery
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gait disturbance
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Malaise
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    2 / 53 (3.77%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences all number
    1
    1
    1
    1
    Pain
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences all number
    0
    1
    1
    1
    Product taste abnormal
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metrorrhagia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    1
    1
    Ovarian cyst
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cough
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    2 / 53 (3.77%)
         occurrences all number
    0
    0
    0
    2
    Dyspnoea
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    1
    1
    3
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sinus congestion
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    1
    0
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Anxiety
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 54 (1.85%)
    3 / 53 (5.66%)
    0 / 53 (0.00%)
         occurrences all number
    1
    1
    4
    0
    Bruxism
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Confusional state
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Depression
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    3 / 53 (5.66%)
    2 / 53 (3.77%)
         occurrences all number
    1
    0
    3
    2
    Hallucination
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 54 (5.56%)
    2 / 53 (3.77%)
    2 / 53 (3.77%)
         occurrences all number
    1
    3
    2
    2
    Libido decreased
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Stress
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences all number
    1
    1
    1
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences all number
    1
    1
    1
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 49 (0.00%)
    2 / 54 (3.70%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    2 / 53 (3.77%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Blood sodium decreased
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    2 / 53 (3.77%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    2
    1
    Electrocardiogram ST segment depression
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 49 (2.04%)
    2 / 54 (3.70%)
    2 / 53 (3.77%)
    1 / 53 (1.89%)
         occurrences all number
    1
    2
    2
    1
    Heart rate irregular
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Urine analysis abnormal
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Weight increased
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    0
    White blood cells urine positive
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Burns second degree
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Contusion
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    2
    0
    0
    1
    Excoriation
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    2 / 53 (3.77%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Fall
         subjects affected / exposed
    2 / 49 (4.08%)
    2 / 54 (3.70%)
    2 / 53 (3.77%)
    0 / 53 (0.00%)
         occurrences all number
    2
    2
    3
    0
    Hand fracture
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Joint injury
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Laceration
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    1
    1
    Ligament sprain
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Overdose
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Post-traumatic pain
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    1
    1
    Sunburn
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tooth fracture
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bradycardia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bundle branch block left
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Balance disorder
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    1
    1
    Burning sensation
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Cervical cord compression
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Clumsiness
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cognitive disorder
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Demyelination
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Disturbance in attention
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dizziness
         subjects affected / exposed
    4 / 49 (8.16%)
    4 / 54 (7.41%)
    9 / 53 (16.98%)
    13 / 53 (24.53%)
         occurrences all number
    4
    6
    13
    22
    Dysgeusia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    1
    1
    Extensor plantar response
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    6 / 49 (12.24%)
    11 / 54 (20.37%)
    14 / 53 (26.42%)
    8 / 53 (15.09%)
         occurrences all number
    9
    20
    22
    23
    Hemiparesis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hyperreflexia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypertonia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 49 (0.00%)
    2 / 54 (3.70%)
    2 / 53 (3.77%)
    1 / 53 (1.89%)
         occurrences all number
    0
    2
    2
    2
    Lethargy
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Loss of consciousness
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Memory impairment
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Mental impairment
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Migraine
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    2 / 53 (3.77%)
         occurrences all number
    1
    0
    0
    3
    Multiple sclerosis relapse
         subjects affected / exposed
    0 / 49 (0.00%)
    2 / 54 (3.70%)
    3 / 53 (5.66%)
    3 / 53 (5.66%)
         occurrences all number
    0
    2
    3
    3
    Muscle spasticity
         subjects affected / exposed
    2 / 49 (4.08%)
    1 / 54 (1.85%)
    2 / 53 (3.77%)
    3 / 53 (5.66%)
         occurrences all number
    3
    1
    2
    4
    Neuralgia
         subjects affected / exposed
    4 / 49 (8.16%)
    2 / 54 (3.70%)
    3 / 53 (5.66%)
    0 / 53 (0.00%)
         occurrences all number
    5
    2
    3
    0
    Paraesthesia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Restless legs syndrome
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Sinus headache
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Somnolence
         subjects affected / exposed
    2 / 49 (4.08%)
    5 / 54 (9.26%)
    3 / 53 (5.66%)
    5 / 53 (9.43%)
         occurrences all number
    2
    6
    3
    5
    Syncope
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tremor
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    2 / 53 (3.77%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    2
    2
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Uhthoff's phenomenon
         subjects affected / exposed
    2 / 49 (4.08%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Lymphopenia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 49 (0.00%)
    2 / 54 (3.70%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Tinnitus
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    3 / 53 (5.66%)
         occurrences all number
    0
    0
    1
    3
    Vertigo
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    5 / 53 (9.43%)
         occurrences all number
    0
    1
    2
    5
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    2 / 53 (3.77%)
         occurrences all number
    0
    0
    1
    2
    Dry eye
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye irritation
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye pain
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eyelid oedema
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Uveitis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    3 / 53 (5.66%)
    2 / 53 (3.77%)
         occurrences all number
    0
    0
    3
    3
    Vitreous floaters
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    2 / 53 (3.77%)
    3 / 53 (5.66%)
         occurrences all number
    1
    0
    2
    3
    Abdominal distension
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    1
    1
    Constipation
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 54 (5.56%)
    0 / 53 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    1
    3
    0
    4
    Crohn's disease
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 49 (2.04%)
    2 / 54 (3.70%)
    2 / 53 (3.77%)
    3 / 53 (5.66%)
         occurrences all number
    1
    2
    3
    4
    Dry mouth
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    2 / 53 (3.77%)
         occurrences all number
    1
    1
    1
    2
    Duodenitis
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences all number
    1
    1
    1
    1
    Dysphagia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Faecal incontinence
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    2 / 53 (3.77%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    2
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    7 / 49 (14.29%)
    12 / 54 (22.22%)
    10 / 53 (18.87%)
    8 / 53 (15.09%)
         occurrences all number
    7
    16
    10
    11
    Periodontitis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Toothache
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 49 (0.00%)
    5 / 54 (9.26%)
    2 / 53 (3.77%)
    2 / 53 (3.77%)
         occurrences all number
    0
    6
    2
    3
    Chest pain
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Cold sweat
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Decubitus ulcer
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ecchymosis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eczema
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences all number
    0
    1
    2
    2
    Pruritus
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Rash
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    1
    1
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal pain
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Urinary retention
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Endocrine disorders
    Early menarche
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 49 (4.08%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences all number
    3
    1
    1
    1
    Back pain
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    2 / 53 (3.77%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Bone pain
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Costochondritis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Muscle spasms
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 54 (1.85%)
    5 / 53 (9.43%)
    0 / 53 (0.00%)
         occurrences all number
    4
    1
    6
    0
    Muscle tightness
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    2 / 53 (3.77%)
    2 / 53 (3.77%)
         occurrences all number
    0
    0
    2
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    2 / 53 (3.77%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    2
    1
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    0
    0
    3
    Myalgia
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences all number
    1
    0
    4
    1
    Neck pain
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    3 / 53 (5.66%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Pain in extremity
         subjects affected / exposed
    4 / 49 (8.16%)
    0 / 54 (0.00%)
    2 / 53 (3.77%)
    0 / 53 (0.00%)
         occurrences all number
    4
    0
    2
    0
    Pain in jaw
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Plantar fasciitis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sensation of heaviness
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    2 / 53 (3.77%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Infections and infestations
    Asymptomatic bacteriuria
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences all number
    0
    1
    1
    1
    Cellulitis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cystitis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear infection
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Fungal infection
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    1
    1
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Herpes zoster
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 54 (1.85%)
    3 / 53 (5.66%)
    2 / 53 (3.77%)
         occurrences all number
    0
    1
    3
    2
    Laryngitis
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 49 (4.08%)
    1 / 54 (1.85%)
    7 / 53 (13.21%)
    4 / 53 (7.55%)
         occurrences all number
    2
    1
    7
    4
    Oral candidiasis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Oral herpes
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    1
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Sinusitis
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    1
    0
    0
    1
    Subcutaneous abscess
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Tooth infection
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    2
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 54 (1.85%)
    2 / 53 (3.77%)
    2 / 53 (3.77%)
         occurrences all number
    3
    1
    2
    2
    Urinary tract infection
         subjects affected / exposed
    3 / 49 (6.12%)
    4 / 54 (7.41%)
    5 / 53 (9.43%)
    3 / 53 (5.66%)
         occurrences all number
    3
    5
    5
    3
    Viral infection
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    1
    0
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    1
    0
    0
    1
    Increased appetite
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jun 2011
    •Text was added to further clarify the diagnosis of and the eligibility criteria for central neuropathic pain. • Participants with a resting respiratory rate of >20 breaths/minute were ineligible for the study. • A posttreatment, safety follow-up visit was added to the study at Week 13 (Visit 6 [Day 92]). • Early termination was added as 1 of the time points when participants were to return unused study drug to the clinic. • Text was added to clarify the timing, calculation, and review of Pain Rating Scale (PRS) scores in the participants’ diaries. • It was clarified that patient diaries would be reviewed to determine eligibility. • The Expanded Disability Status Scale (EDSS) was changed from an efficacy assessment to a safety assessment. • The Symbol Digit Modalities Test (SDMT) was added as an efficacy assessment. • It was clarified that participants must complete a 1-week washout period for analgesic medications (when applicable), except for acetaminophen in doses up to 2600 milligrams per day. • Text was added to inclusion criteria to specify that dose adjustment may be needed for selective serotonin reuptake inhibitors SSRIs that are CYP2D6 substrates when coadministered with quinidine. • “Physical, psychological, and behavioral” were added as descriptors of unintended change to the definition of an adverse event. • Text was added specifying that any newly reported adverse experience, after receiving the last dose of study drug and up until 30 days after receiving the last dose of study drug, would be followed up until resolved. • Pregnancy was added to the list of reasons why participants may be withdrawn from the study. • It was specified that follow-up of laboratory test results should continue until test values return to the participant’s normal baseline (pretreatment) range. • The process and procedures for monitoring compliance with the study protocol and the overall quality of data collected was clarified.
    15 Dec 2011
    • The total number of sites was increased from approximately 65 sites to approximately 90 sites. • Eligibility criteria were updated. • Text was added stating that a sponsor may withdraw a participant from the study for administrative reasons. • The Modified Ashworth Scale (MAS), Patient Global Impression of Change (PGIC), and Numerical Rating Scale (NRS) were added as efficacy assessments. • A definition for compliance was added. • A modified Intent-to-Treat (MITT) population was added to the analysis populations. • An additional pharmacokinetic sample collection was added to Visit 4 (Day 50). • Text was removed stating that the study drug could be administered by the caregiver and that the caregiver could complete the participant’s diaries. • The stabilization period for multiple sclerosis (MS) disease-modifying therapy was reduced to at least 2 months before randomization from at least 3 months before randomization. • Text was added stating that oral steroids at a stable dose prior to randomization were allowed as long as the dose remained unchanged during the study. • Acetaminophen up to 2600 mg/day was replaced with ibuprofen up to 800 mg/day as a permitted rescue pain medication. • It was clarified that participants should not begin recording their daily pain score until the 1-week washout period was completed, if applicable. • Informants (i.e., a person having contact with the participant at least 3 times a week) could not complete the Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ). • It was clarified that an MS relapse or acute exacerbation was defined as symptoms causing significant change in functional ability or in sensory function. • Randomization was stratified by geographic region instead of by center. Dynamic allocation was handled by interactive voice response system (IVRS). • Text in the introduction was reorganized, deleted, and added. • Records of all investigational product dispensing were in the eCRF.
    24 Apr 2013
    • The sample size was updated to 200 patients from 400 participants. • Due to the decreased sample size, the primary efficacy endpoint was updated from the change from baseline PRS scores to an assessment of the correlation between DM Cmax and change from baseline PRS scores. The key secondary efficacy endpoint changed from change in Fatigue Severity Scores (FSS) to the change from baseline PRS scores. The change in FSS scores was still included as an additional secondary endpoint. • Participants who participated in an interventional clinical study within the past 30 days were excluded from participating in the study; the previous version stated that participating in any clinical study was exclusionary. • Participants with evidence of uncontrolled diabetes based on HbA1c >53 millimoles/mole (mmol/mol) (>7.0%) were excluded from the study; in previous versions, participants with HbA1c <53 mmol/mol (>7.0%) were excluded from participating. • Height and weight were added to the vital sign measurements. • It was clarified that AEs reported after receiving the last dose of study drug would be followed up until resolution or until stabilization of the event had occurred. • Text stating that participant instructions would be reviewed in person and that written instructions would be provided to the participant or their caregiver was removed. • It was clarified that concomitant medication use should not be entered in the patient diary card, as this information was captured in the electronic Case Report Form.

    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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