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    Clinical Trial Results:
    An Open-Label Study to Evaluate the Long-Term Safety of Arbaclofen Extended-Release Tablets in Multiple Sclerosis Patients with Spasticity (Study OS440-3005).

    Summary
    EudraCT number
    		 2017-004101-40
    Trial protocol
    		 BG   PL   HR  
    Global end of trial date
    27 Jan 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jul 2021
    First version publication date
    29 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OS440-3005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03319732
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Osmotica Pharmaceutical US LLC
    Sponsor organisation address
    400 Crossing Boulevard, Bridgewater/NJ, United States, 08807
    Public contact
    Meredith Velasco, Osmotica Pharmaceutical US LLC, +1 908809 1423, mvelasco@osmotica.com
    Scientific contact
    Meredith Velasco, Osmotica Pharmaceutical US LLC, +1 908809 1423, mvelasco@osmotica.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
    11 Jun 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the long-term safety and tolerability of AERT in patients with spasticity due to MS.
    Protection of trial subjects
    This study was performed in accordance with Good Clinical Practice standards. Before undertaking any study-related procedures with subjects, the purpose and nature of the study, as well as possible adverse effects, were explained to them in understandable terms and written informed consent was obtained from each individual.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jan 2018
    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: 25
    Country: Number of subjects enrolled
    Croatia: 13
    Country: Number of subjects enrolled
    Bulgaria: 48
    Country: Number of subjects enrolled
    Belarus: 14
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 14
    Country: Number of subjects enrolled
    Moldova, Republic of: 5
    Country: Number of subjects enrolled
    Russian Federation: 62
    Country: Number of subjects enrolled
    Serbia: 18
    Country: Number of subjects enrolled
    Ukraine: 99
    Country: Number of subjects enrolled
    United States: 25
    Worldwide total number of subjects
    323
    EEA total number of subjects
    86
    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)
    318
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First subject enrolled on 20 Mar 2018; last subject completed on 27 Jan 2020. A total of 323 subjects were enrolled at 67 sites in Poland, Croatia, Bulgaria, Belarus, Bosnia and Herzegovina, Moldova, Russia, Serbia, Ukraine, and the United States.

    Pre-assignment
    Screening details
    		 Subjects from Study OS440-3004 could rollover into this open-label extension study plus de novo subjects, provided. Eligible de novo subjects underwent a 21-day washout period, withdrawing all medications used for anti-spasticity and/or muscle relaxation. 328 subjects screened, 323 enrolled.

    Period 1
    Period 1 title
    overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study

    Arms
    Arm title
    		 open-label long-term follow-up
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    arbaclofen extended-release tablets
    Investigational medicinal product code
    Other name
    AERT, arbaclofen ER tablets
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    AERT was supplied as blue, round biconvex tablets in HDPE white bottles with 60 active 20-mg tablets

    Number of subjects in period 1
    		open-label long-term follow-up
    Started
    323
    Completed
    218
    Not completed
    105
         Physician decision
    1
         Adverse event, non-fatal
    40
         medical condition
    1
         subject request
    50
         unspecified
    3
         relapse
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    open-label long-term follow-up
    Reporting group description
    		 -

    Reporting group values
    		 open-label long-term follow-up Total
    Number of subjects
    		 323 323
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 318 318
        From 65-84 years
    		 5 5
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 47.2 (22 to 66) -
    Gender categorical
    For the Safety population, the majority of subjects were female (58.8%).
    Units: Subjects
        Female
    		 190 190
        Male
    		 133 133
    Race
    For the Safety population, the majority of subjects were white (96.6%). The results for race were generally balanced across treatment groups.
    Units: Subjects
        Black or African American
    		 6 6
        White
    		 312 312
        More than one race
    		 1 1
        Not collected
    		 4 4
    Height
    Units: cm
        arithmetic mean (full range (min-max))
    		 169.6 (148 to 198) -
    weight
    Study subjects' weight was collected at baseline
    Units: kg
        arithmetic mean (full range (min-max))
    		 71.67 (42.0 to 124.4) -
    Body Mass Index
    Body Mass Index was collected for study subjects at baseline
    Units: kg/m2
        arithmetic mean (full range (min-max))
    		 24.825 (16.41 to 43.23) -
    Subject analysis sets

    Subject analysis set title
    AERT 40 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Screened population received 20 mg AERT bid

    Subject analysis set title
    AERT 60 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    screened population received 20 mg in the morning and 40 mg in the evening

    Subject analysis set title
    AERT 80 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    screened population 2 20-mg tablets bid

    Subject analysis sets values
    		 AERT 40 mg AERT 60 mg AERT 80 mg
    Number of subjects
    44
    39
    239
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    48.4 (26 to 65)
    48.4 (27 to 65)
    46.7 (22 to 66)
    Gender categorical
    For the Safety population, the majority of subjects were female (58.8%).
    Units: Subjects
        Female
    30
    24
    136
        Male
    14
    15
    103
    Race
    For the Safety population, the majority of subjects were white (96.6%). The results for race were generally balanced across treatment groups.
    Units: Subjects
        Black or African American
    1
    3
    2
        White
    43
    35
    233
        More than one race
    0
    0
    1
        Not collected
    0
    1
    3
    Height
    Units: cm
        arithmetic mean (full range (min-max))
    168.0 (155 to 189)
    169.0 (150 to 196)
    170.0 (148 to 198)
    weight
    Study subjects' weight was collected at baseline
    Units: kg
        arithmetic mean (full range (min-max))
    72.23 (48.0 to 97.0)
    68.10 (45.0 to 96.0)
    72.16 (42.0 to 124.4)
    Body Mass Index
    Body Mass Index was collected for study subjects at baseline
    Units: kg/m2
        arithmetic mean (full range (min-max))
    25.547 (18.37 to 38.86)
    23.811 (16.94 to 37.08)
    24.860 (16.41 to 43.23)

    End points

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    End points reporting groups
    Reporting group title
    open-label long-term follow-up
    Reporting group description
    		 -

    Subject analysis set title
    AERT 40 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Screened population received 20 mg AERT bid

    Subject analysis set title
    AERT 60 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    screened population received 20 mg in the morning and 40 mg in the evening

    Subject analysis set title
    AERT 80 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    screened population 2 20-mg tablets bid

    Primary: Co-primary Efficacy Endpoint: Patient Global Impression of Change (PGIC) in the Safety population

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    End point title
    		 Co-primary Efficacy Endpoint: Patient Global Impression of Change (PGIC) in the Safety population
    End point description
    The PGIC is a standard instrument that is a well-validated outcome measure. The 7-point PGIC measures the change in the subject’s overall status. PGIC Scores of 2.0 corresponded to “almost the same,” scores of 3.0 corresponded to “a little better,” and scores of 4.0 corresponded to “somewhat better.” Note: In the AERT <40 mg group, there is only 1 patient. At baseline and at Visit 8, no confidence intervals are provided with the mean values.
    End point type
    Primary
    End point timeframe
    The PGIC was recorded at Baseline and at Visit 8 (Week 60).
    End point values
    		 open-label long-term follow-up AERT 40 mg AERT 60 mg AERT 80 mg
    Number of subjects analysed
    323
    44
    39
    232
    Units: score
    least squares mean (confidence interval 95%)
        Baseline
    3.3 (3.1 to 3.5)
    2.7 (2.2 to 3.2)
    3.3 (2.6 to 3.9)
    3.3 (3.1 to 3.5)
        Viait 8 (Week 60)
    2.7 (2.5 to 2.9)
    2.0 (1.5 to 2.4)
    2.4 (1.9 to 3.0)
    2.7 (2.5 to 2.9)
    Statistical analysis title
    		 PGIC
    Statistical analysis description
    The PGIC categories were summarized by frequencies and percentages by study visit. The PGIC values were also summarized by study visit using descriptive statistics.
    Comparison groups
    AERT 40 mg v AERT 60 mg v AERT 80 mg
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.5
         upper limit
    		 2.9
    Variability estimate
    Standard deviation
    Dispersion value
    2
    Notes
    [1] - descriptive statistics

    Primary: Co-primary endpoint: TNmAS-MAL in the Safety population

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    End point title
    		 Co-primary endpoint: TNmAS-MAL in the Safety population
    End point description
    The TNmAS is considered the primary clinical measure of muscle spasticity in subjects with neurological conditions. It is a useful 6-point rating scale to measure abnormality in tone or the resistance to passive movements, since there is no clinically direct method for measuring spasticity. Although there are no standardized guidelines for its use, it can be applied to muscles of both the upper or lower body. The TNmAS assessment was performed by the Investigator who had been appropriately trained to perform and assess the TNmAS. When possible, all TNmAS assessments were to be performed for a particular subject by the same person throughout the study and always prior to any scheduled laboratory sample draw. The most affected limb was determined by the Investigator. Note: in the AERT <40 mg group, there is only 1 patient. Confidence intervals are not provided with the mean values at baseline and Visit 4. There is no mean value provided at Visit 8.
    End point type
    Primary
    End point timeframe
    From baseline to Week 60
    End point values
    		 open-label long-term follow-up AERT 40 mg AERT 60 mg AERT 80 mg
    Number of subjects analysed
    323
    44
    39
    239
    Units: score
    least squares mean (confidence interval 95%)
        Baseline
    6.3 (5.9 to 6.6)
    5.6 (4.5 to 6.6)
    5.9 (4.9 to 7.0)
    6.5 (6.1 to 6.9)
        Visit 4 (Week 28)
    5.6 (5.2 to 5.9)
    4.9 (3.8 to 5.9)
    5.6 (4.4 to 6.7)
    5.7 (5.3 to 6.1)
        Visit 4 (Week 28) change from Baseline
    -0.7 (-0.9 to -0.5)
    -0.6 (-1.2 to 0)
    -0.4 (-0.9 to 0.1)
    -0.7 (-1.0 to -0.5)
        Visit 8 (Week 60)
    6.0 (5.6 to 6.5)
    5.1 (3.9 to 6.3)
    5.5 (3.8 to 7.1)
    6.3 (5.8 to 6.7)
        Visit 8 (Week 60) change from Baseline
    -0.1 (-0.3 to 0.1)
    0 (-0.7 to 0.7)
    -0.2 (-0.9 to 0.6)
    -0.1 (-0.3 to 0.1)
    Statistical analysis title
    		 TNmAS-MAL
    Statistical analysis description
    Results from TNmAS-MAL were summarized descriptively by study visit in terms of actual values and change from baseline values.
    Comparison groups
    AERT 40 mg v AERT 80 mg v AERT 60 mg
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.1
    Variability estimate
    Standard deviation
    Dispersion value
    1.7
    Notes
    [2] - Descriptive statistics

    Primary: Co-primary Endpoint: Expanded Disability Status Scale (EDSS) in the Safety population

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    End point title
    		 Co-primary Endpoint: Expanded Disability Status Scale (EDSS) in the Safety population
    End point description
    The EDSS is a method of quantifying disability in MS and monitoring changes in the level of disability over time. It is widely used in clinical studies and in the assessment of people with MS. The EDSS scale ranges from 0 to 10 in 0.5-unit increments that represent higher levels of disability. EDSS steps 1.0 to 4.5 refer to people with MS who are able to walk without any aid and is based on measures of impairment in 8 functional systems (FS): pyramidal (weakness or difficulty moving limbs), cerebellar (ataxia, loss of coordination, or tremor), brainstem (problems with speech, swallowing, and nystagmus), sensory (numbness or loss of sensations), bowel and bladder function, visual function, cerebral (or mental) functions, and other. Each FS is scored on a scale of 0 (no disability) to 5 or 6 (more severe disability). EDSS steps 5.0 to 9.5 are defined by the impairment to walking. Note: in the AERT <40 mg group, there is only 1 patient, causing lack of confidence intervals.
    End point type
    Primary
    End point timeframe
    Baseline to Visit 8 (Week 60)
    End point values
    		 open-label long-term follow-up AERT 40 mg AERT 60 mg AERT 80 mg
    Number of subjects analysed
    323
    44
    39
    323
    Units: score
    least squares mean (confidence interval 95%)
        Baseline
    4.98 (4.84 to 5.12)
    4.90 (4.45 to 5.34)
    5.21 (4.79 to 5.62)
    4.98 (4.84 to 5.12)
        Visit 4 (Week 28)
    4.98 (4.82 to 5.15)
    4.77 (4.22 to 5.31)
    5.03 (4.42 to 5.63)
    4.98 (4.82 to 5.15)
        Visit 4 (Week 28) change from baseline
    0.06 (0.02 to 0.11)
    0.03 (-0.08 to 0.14)
    0.15 (-0.15 to 0.45)
    0.06 (0.02 to 0.11)
        Visit 8 (Week 60)
    5.01 (4.87 to 5.16)
    4.83 (4.39 to 5.27)
    5.47 (5.06 to 5.89)
    5.01 (4.87 to 5.16)
        Visit 8 (Week 60) change from baseline
    0.08 (0.04 to 0.12)
    0.07 (-0.02 to 0.17)
    0.32 (0.10 to 0.54)
    0.08 (0.04 to 0.12)
    Statistical analysis title
    		 EDSS
    Statistical analysis description
    Results from EDSS were summarized descriptively by study visit in terms of actual values and change from baseline values.
    Comparison groups
    AERT 40 mg v AERT 60 mg v AERT 80 mg
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.12
    Variability estimate
    Standard deviation
    Dispersion value
    0.351
    Notes
    [3] - Descriptive statistics

    Primary: Co-primary Endpoint: TNmAS-TL in the Safety population

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    End point title
    		 Co-primary Endpoint: TNmAS-TL in the Safety population
    End point description
    The TNmAS is considered the primary clinical measure of muscle spasticity in subjects with neurological conditions. It is a useful 6-point rating scale to measure abnormality in tone or the resistance to passive movements, since there is no clinically direct method for measuring spasticity. The TNmAS-TL score is the sum of the 3 main joint muscular group scores for all 4 limbs. The TNmAS assessment was performed by the Investigator who had been appropriately trained to perform and assess the TNmAS. When possible, all TNmAS assessments were to be performed for a particular subject by the same person throughout the study and always prior to any scheduled laboratory sample draw. Note: in the AERT <40 mg group, there is only 1 patient. Confidence intervals are not provided with the mean values at baseline and Visit 4. There is no mean value provided at Visit 8.
    End point type
    Primary
    End point timeframe
    From baseline to Week 60
    End point values
    		 open-label long-term follow-up AERT 40 mg AERT 60 mg AERT 80 mg
    Number of subjects analysed
    323
    44
    39
    239
    Units: score
    least squares mean (confidence interval 95%)
        Baseline
    13.0 (12.2 to 13.9)
    11.1 (8.3 to 13.9)
    11.3 (8.6 to 14.0)
    13.7 (12.7 to 14.6)
        Visit 4 (Week 28)
    11.5 (10.7 to 12.4)
    9.5 (6.8 to 12.1)
    11.0 (8.1 to 13.9)
    12.0 (11.1 to 13.0)
        Visit 4 (Week 28) change from baseline
    -1.3 (-1.7 to -0.9)
    -1.4 (-2.9 to 0.1)
    -0.4 (-1.3 to 0.5)
    -1.4 (-1.9 to -1.0)
        Visit 8 (Week 60)
    12.8 (11.7 to 13.9)
    11.0 (7.1 to 14.8)
    10.2 (6.6 to 13.7)
    13.4 (12.2 to 14.6)
        Visit 8 (Week 60) change from baseline
    0.3 (-0.2 to 0.9)
    0.3 (-1.9 to 2.5)
    0.4 (-0.9 to 1.7)
    0.3 (-0.2 to 0.9)
    Statistical analysis title
    		 TNm-AS-TL
    Statistical analysis description
    Results from TNmAS-TL were summarized descriptively by study visit in terms of actual values and change from baseline values.
    Comparison groups
    AERT 40 mg v AERT 60 mg v AERT 80 mg
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.9
    Variability estimate
    Standard deviation
    Dispersion value
    4.18
    Notes
    [4] - Descriptive statistics

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from time of informed consent through completion of the last study visit. A treatment-emergent AE was any AE with onset or worsening on or after the first dose of study drug up until 30 days after the last dose of study drug
    Adverse event reporting additional description
    Adverse events could have been reported spontaneously by the subject or observed by the Investigator. Within each preferred term, subjects were counted only once if they had more than 1 event reported during the treatment period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    AERT <40 mg
    Reporting group description
    		 Adverse event results are presented for the Safety population, which includes all subjects who received at least 1 dose of open-label study treatment and had at least 1 postdose visit. All serious TEAEs that occurred are reported. Non-serious TEAEs that occurred in 5% or more of subjects in any treatment group are reported. No deaths occurred during the study.

    Reporting group title
    AERT 40 mg
    Reporting group description
    		 The safety population included all subjects who received at least 1 dose of open-label study treatment and had at least 1 postdose visit. All serious TEAEs that occurred are reported. Non-serious TEAEs that occurred in 5% or more of subjects in any treatment group are reported. No deaths occurred during the study.

    Reporting group title
    AERT 60 mg
    Reporting group description
    		 The safety population included all subjects who received at least 1 dose of open-label study treatment and had at least 1 postdose visit. All serious TEAEs that occurred are reported. Non-serious TEAEs that occurred in 5% or more of subjects in any treatment group are reported. No deaths occurred during the study.

    Reporting group title
    AERT 80 mg
    Reporting group description
    		 The safety population included all subjects who received at least 1 dose of open-label study treatment and had at least 1 postdose visit. All serious TEAEs that occurred are reported. Non-serious TEAEs that occurred in 5% or more of subjects in any treatment group are reported. One death occurred during the study.

    Serious adverse events
    		 AERT <40 mg AERT 40 mg AERT 60 mg AERT 80 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 44 (4.55%)
    6 / 39 (15.38%)
    18 / 239 (7.53%)
         number of deaths (all causes)
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    0 / 39 (0.00%)
    1 / 239 (0.42%)
         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
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    0 / 39 (0.00%)
    1 / 239 (0.42%)
         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
    Acute myocardial infarction
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    0 / 39 (0.00%)
    1 / 239 (0.42%)
         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
    Death
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    0 / 39 (0.00%)
    1 / 239 (0.42%)
         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 / 1
    Surgical and medical procedures
    Hypertension
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    0 / 39 (0.00%)
    1 / 239 (0.42%)
         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
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 44 (2.27%)
    4 / 39 (10.26%)
    5 / 239 (2.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Restless legs syndrome
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    0 / 39 (0.00%)
    1 / 239 (0.42%)
         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
    Paraparesis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    0 / 39 (0.00%)
    1 / 239 (0.42%)
         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
    Meningioma
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    0 / 39 (0.00%)
    1 / 239 (0.42%)
         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
    General disorders and administration site conditions
    Somnolence
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    1 / 39 (2.56%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Withdrawal syndrome
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    1 / 39 (2.56%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    0 / 39 (0.00%)
    1 / 239 (0.42%)
         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
    Drug withdrawal syndrome
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    0 / 39 (0.00%)
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    1 / 39 (2.56%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    0 / 39 (0.00%)
    1 / 239 (0.42%)
         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
    Constipation
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    0 / 39 (0.00%)
    1 / 239 (0.42%)
         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
    Cholecystitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    0 / 39 (0.00%)
    1 / 239 (0.42%)
         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
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 44 (2.27%)
    0 / 39 (0.00%)
    0 / 239 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decubitus ulcer
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    0 / 39 (0.00%)
    1 / 239 (0.42%)
         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
    Renal and urinary disorders
    Atonic urinary bladder
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    0 / 39 (0.00%)
    1 / 239 (0.42%)
         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
    Musculoskeletal and connective tissue disorders
    Osteomyelitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 44 (0.00%)
    0 / 39 (0.00%)
    1 / 239 (0.42%)
         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: 5%
    Non-serious adverse events
    		 AERT <40 mg AERT 40 mg AERT 60 mg AERT 80 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    42 / 44 (95.45%)
    36 / 39 (92.31%)
    197 / 239 (82.43%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 44 (9.09%)
    7 / 39 (17.95%)
    40 / 239 (16.74%)
         occurrences all number
    0
    4
    7
    40
    Somnolence
         subjects affected / exposed
    1 / 1 (100.00%)
    7 / 44 (15.91%)
    4 / 39 (10.26%)
    28 / 239 (11.72%)
         occurrences all number
    1
    7
    4
    28
    Headache
         subjects affected / exposed
    0 / 1 (0.00%)
    7 / 44 (15.91%)
    1 / 39 (2.56%)
    16 / 239 (6.69%)
         occurrences all number
    0
    7
    1
    16
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 44 (9.09%)
    11 / 39 (28.21%)
    46 / 239 (19.25%)
         occurrences all number
    0
    4
    11
    46
    Gait disturbance
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 44 (9.09%)
    4 / 39 (10.26%)
    12 / 239 (5.02%)
         occurrences all number
    0
    4
    4
    12
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 1 (100.00%)
    25 / 44 (56.82%)
    11 / 39 (28.21%)
    29 / 239 (12.13%)
         occurrences all number
    1
    25
    11
    29
    Vomiting
         subjects affected / exposed
    0 / 1 (0.00%)
    10 / 44 (22.73%)
    7 / 39 (17.95%)
    10 / 239 (4.18%)
         occurrences all number
    0
    10
    7
    10
    Renal and urinary disorders
    Urinary tract disorder
         subjects affected / exposed
    0 / 1 (0.00%)
    16 / 44 (36.36%)
    13 / 39 (33.33%)
    82 / 239 (34.31%)
         occurrences all number
    0
    16
    13
    82
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 1 (0.00%)
    28 / 44 (63.64%)
    14 / 39 (35.90%)
    35 / 239 (14.64%)
         occurrences all number
    0
    28
    14
    35

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Nov 2017
    Entire protocol: editorial corrections and clarifications, added revised protocol number, added hyperlinks. Title page: added protocol version history. Section 9.6.2: Corrected the mistake in the original protocol regarding a 4-point change in total USP score by replacing “A reduction of 4 points…” with “An increase of 4 points….” Appendix 8: Added new Appendix 8 Summary of Changes to summarize the changes made to the original protocol with Amendment 1.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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