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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled Parallel Group Study to Investigate the Safety and Efficacy of Arbaclofen Extended-Release Tablets for the Treatment of Spasticity in Patients with Multiple Sclerosis (Study OS440-3004)

    Summary
    EudraCT number
    		 2017-004100-22
    Trial protocol
    		 BG   PL   HR  
    Global end of trial date
    03 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Nov 2020
    First version publication date
    30 Nov 2020
    Other versions
    Summary report(s)
    		 OS440-3004 CSR Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    OS440-3004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03290131
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Osmotica Pharmaceutical US LLC
    Sponsor organisation address
    400 Crossing Boulevard, Bridgewater, United States, NJ 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
    03 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Dec 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate the safety and efficacy of Arbaclofen Extended-Release Tablets (AERT) for treatment of spasticity in patients with Multiple Sclerosis (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. An independent, chartered Data Safety Monitoring Board (DSMB) reviewed all safety data on 4 occasions during the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jan 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 54
    Country: Number of subjects enrolled
    Croatia: 20
    Country: Number of subjects enrolled
    Bulgaria: 57
    Country: Number of subjects enrolled
    Belarus: 33
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 21
    Country: Number of subjects enrolled
    Moldova, Republic of: 12
    Country: Number of subjects enrolled
    Russian Federation: 149
    Country: Number of subjects enrolled
    Serbia: 30
    Country: Number of subjects enrolled
    Ukraine: 135
    Country: Number of subjects enrolled
    United States: 25
    Worldwide total number of subjects
    536
    EEA total number of subjects
    131
    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)
    531
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First subject enrolled on 13 Feb 2018; last subject completed on 03 Dec 2018. Total of 536 subjects were enrolled at 82 sites in the United States and Central and Eastern Europe (Russia, Belarus, Serbia, Bosnia and Herzegovina, Croatia, Bulgaria, Moldova, Poland, and Ukraine).

    Pre-assignment
    Screening details
    		 Eligible subjects underwent up to a 21-day washout period for withdrawal of anti-spasticity and/or muscle relaxation medications before randomization. Eligibility was confirmed before randomization (Visit 2). 594 subjects were screened; 58 subjects were screen failures (39 due to inclusion/exclusion criteria not met); 536 subjects were randomized.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Every effort was made to retain the integrity of the blind. The study medication was identical in appearance for all subjects, regardless of treatment assignment. No premature unblinding occurred during the study. The study blind was broken at study completion once the following were met: 1) Database was locked and 2) the statistical analysis plan (SAP) was finalized.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AERT 40 mg
    Arm description
    		 Experimental therapy arm: arbaclofen extended-release tablets (AERT) 40 mg (20 mg twice daily). Results are presented for the Intent-to-Treat (ITT) population, which includes all 179 subjects who were randomized to the AERT 40 mg arm.
    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 blister card wallets with matching placebo tablets. IMP was administered as follows: - Days 1 to 6: AERT 20 mg/day given as two placebo tablets in the morning and one placebo tablet and one 20-mg AERT in the evening - Days 7 to 84: AERT 40 mg/day given as one placebo tablet and one 20-mg AERT in both the morning and the evening - Days 85 to 88: AERT 20 mg/day given as two placebo tablets in the morning and one placebo tablet and one 20-mg AERT in the evening - Days 89 to 91: AERT 0 mg/day given as two placebo tablets both in the morning and the evening.

    Arm title
    		 AERT 80 mg
    Arm description
    		 Experimental therapy arm: arbaclofen extended-release tablets (AERT) 80 mg (40 mg twice daily). Results are presented for the Intent-to-Treat (ITT) population, which includes all 179 subjects who were randomized to the AERT 80 mg arm.
    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 blister card wallets with matching placebo tablets. IMP was administered as follows: - Days 1 to 3: AERT 20 mg/day given as two placebo tablets in the morning and one placebo tablet and one 20-mg AERT in the evening - Days 4 to 6: AERT 40 mg/day given as one placebo tablet and one 20-mg AERT both in the morning and the evening - Days 7 to 9: AERT 60 mg/day was given as one placebo tablet and one 20-mg AERT in the morning and two 20-mg AERT in the evening - Days 10 to 84: AERT 80 mg/day was given as two 20-mg AERT both in the morning and the evening - Days 85 to 88: AERT 40 mg/day was given as one placebo tablet and one 20-mg AERT both in the morning and the evening - Days 89 to 91: AERT 20 mg/day was given as two placebo tablets in the morning and one placebo tablet and one 20-mg AERT in the evening

    Arm title
    		 Placebo
    Arm description
    		 Placebo arm: placebo tablets administered twice daily. Results are presented for the Intent-to-Treat (ITT) population, which includes all 178 subjects who were randomized to the placebo arm.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets were supplied as blue, round biconvex tablets that matched the AERT tablets and were packaged in blister card wallets. From Days 1 to 91, two placebo tablets were administered both in the morning and the evening.

    Number of subjects in period 1
    		AERT 40 mg AERT 80 mg Placebo
    Started
    179
    179
    178
    Completed
    137
    107
    159
    Not completed
    42
    72
    19
         Adverse event, non-fatal
    22
    57
    11
         Subject moved to another city
    -
    1
    -
         Subject request
    18
    13
    8
         MS relapse
    2
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AERT 40 mg
    Reporting group description
    		 Experimental therapy arm: arbaclofen extended-release tablets (AERT) 40 mg (20 mg twice daily). Results are presented for the Intent-to-Treat (ITT) population, which includes all 179 subjects who were randomized to the AERT 40 mg arm.

    Reporting group title
    AERT 80 mg
    Reporting group description
    		 Experimental therapy arm: arbaclofen extended-release tablets (AERT) 80 mg (40 mg twice daily). Results are presented for the Intent-to-Treat (ITT) population, which includes all 179 subjects who were randomized to the AERT 80 mg arm.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo arm: placebo tablets administered twice daily. Results are presented for the Intent-to-Treat (ITT) population, which includes all 178 subjects who were randomized to the placebo arm.

    Reporting group values
    		 AERT 40 mg AERT 80 mg Placebo Total
    Number of subjects
    		 179 179 178 536
    Age categorical
    For the ITT population, the overall mean (SD) age at baseline was 46.5 (9.60) years (range, 21 to 65 years). The results for age were generally balanced across the treatment groups.
    Units: Subjects
        Adults (18-65 years)
    		 179 179 178 536
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 46.0 ± 9.50 46.0 ± 9.71 47.5 ± 9.55 -
    Gender categorical
    For the ITT population, the majority of subjects were female (59.5%). The results for gender were generally balanced across treatment groups.
    Units: Subjects
        Female
    		 108 101 110 319
        Male
    		 71 78 68 217
    Race
    For the ITT population, the majority of subjects were white (97.4%). The results for race were generally balanced across treatment groups.
    Units: Subjects
        Asian
    		 0 0 1 1
        Black or African American
    		 4 0 2 6
        White
    		 171 177 174 522
        More than one race
    		 1 0 1 2
        Missing
    		 3 2 0 5
    MS Subtype
    For the ITT population, the MS subtype at baseline was relapsing-remitting (RR) for the majority of subjects (323 subjects; 60.3%); 186 subjects (34.7%) had secondary progressive (SP) MS and 27 subjects (5.0%) had primary progressive (PP) MS. The results for MS subtype were generally balanced across treatment groups.
    Units: Subjects
        Relapsing remitting
    		 117 100 106 323
        Primary progressive
    		 9 8 10 27
        Secondary progressive
    		 53 71 62 186
    Weight
    For the ITT population, the overall mean (SD) weight at baseline was 70.85 (15.182) kg (range, 36.5 to 126.0 kg). The results for weight were generally balanced across treatment groups.
    Units: kg
        arithmetic mean (standard deviation)
    		 70.38 ± 15.371 71.45 ± 15.405 70.71 ± 14.825 -
    Body Mass Index
    For the ITT population, the overall mean (SD) BMI at baseline was 24.648 (4.6036) kg/m2 (range, 16.23 to 42.52 kg/m2). Results for BMI were generally balanced across treatment groups.
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 24.661 ± 5.1229 24.660 ± 4.2615 24.623 ± 4.4048 -

    End points

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    End points reporting groups
    Reporting group title
    AERT 40 mg
    Reporting group description
    		 Experimental therapy arm: arbaclofen extended-release tablets (AERT) 40 mg (20 mg twice daily). Results are presented for the Intent-to-Treat (ITT) population, which includes all 179 subjects who were randomized to the AERT 40 mg arm.

    Reporting group title
    AERT 80 mg
    Reporting group description
    		 Experimental therapy arm: arbaclofen extended-release tablets (AERT) 80 mg (40 mg twice daily). Results are presented for the Intent-to-Treat (ITT) population, which includes all 179 subjects who were randomized to the AERT 80 mg arm.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo arm: placebo tablets administered twice daily. Results are presented for the Intent-to-Treat (ITT) population, which includes all 178 subjects who were randomized to the placebo arm.

    Primary: Co-primary Efficacy Endpoint: TNmAS-MAL in the ITT Population

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    End point title
    		 Co-primary Efficacy Endpoint: TNmAS-MAL in the ITT Population
    End point description
    The Total Numeric-transformed modified Ashworth Scale (TNmAS) is considered the primary clinical measure of muscle spasticity in subjects with neurological conditions. It consists of a 6-point rating scale to measure abnormality in tone or the resistance to passive movements. The TNmAS assessment was to be performed by the study evaluator (someone other than the Investigator) who had been appropriately trained to perform and assess the TNmAS, and when possible all TNmAS assessments were performed for a particular subject by the same study evaluator throughout the study. The outcome variable for TNmAS-MAL was least-squares (LS) mean change from baseline (and 95% confidence interval [CI]) to Day 84 in the ITT population by treatment group. AERT 40 mg was compared with placebo first (for both co-primary endpoints, TNmAS-MAL and CGIC). Both co-primary endpoints had to meet the 0.05 level for AERT 40 mg vs placebo for the study to be considered a success.
    End point type
    Primary
    End point timeframe
    TNmAS score of the most affected limb (TNmAS-MAL) was recorded at screening (Visit 1), baseline (Visit 2), Day 42 (Visit 4), Day 84 (Visit 5), and Day 92 (final visit or early termination).
    End point values
    		 AERT 40 mg AERT 80 mg Placebo
    Number of subjects analysed
    139
    115
    164
    Units: Change from baseline to Day 84
        least squares mean (confidence interval 95%)
    -1.67 (-1.97 to -1.36)
    -1.79 (-2.12 to -1.46)
    -1.28 (-1.57 to -0.99)
    Statistical analysis title
    		 LS mean difference for AERT 40 mg vs placebo
    Statistical analysis description
    Least-squares mean were used to compare AERT 40 mg vs placebo. The TNmAS-MAL was analyzed using a restricted maximum likelihood (REML)-based mixed model for repeated measures (MMRM) with fixed effects for treatment, visit, country, and the treatment-by-visit interaction; and with baseline score as a covariate. There was statistically significant greater improvement from baseline to Day 84 in TNmAS-MAL scores in the AERT 40 mg group compared to the placebo group.
    Comparison groups
    AERT 40 mg v Placebo
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0482 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.77
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.196
    Notes
    [1] - p-value calculated for AERT 40 mg LS mean - placebo LS mean.
    Statistical analysis title
    		 LS mean difference for AERT 80 mg vs placebo
    Statistical analysis description
    Least-squares mean were used to compare AERT 80 mg versus placebo. The TNmAS-MAL was analyzed using a restricted maximum likelihood (REML)-based mixed model for repeated measures (MMRM) with fixed effects for treatment, visit, country, and the treatment-by-visit interaction; and with baseline score as a covariate. There was statistically significant greater improvement from baseline to Day 84 in TNmAS-MAL scores in the AERT 80 mg group compared to the placebo group.
    Comparison groups
    AERT 80 mg v Placebo
    Number of subjects included in analysis
    279
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0118 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.91
         upper limit
    		 -0.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.203
    Notes
    [2] - p-value calculated for AERT 80 mg LS mean - placebo LS mean.

    Primary: Co-primary Efficacy Endpoint: CGIC in the ITT Population

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    End point title
    		 Co-primary Efficacy Endpoint: CGIC in the ITT Population
    End point description
    For the CGIC, the Investigator rated the change in overall global functional performance (not limited to spasticity) the subject was experiencing (based on assessment of the subject since Visit 2). The Investigator evaluated the subject’s status on a -3 to +3 scale judging whether there had been a change from significantly worse (-3) to significantly improved (+3) relative to baseline (Visit 2) and had to have access to the TNmAS. The outcome variable was LS mean CGIC score (and 95% CI) at Day 84 in the ITT population by treatment group. AERT 40 mg was compared with placebo first (for both co-primary endpoints, TNmAS-MAL and CGIC). Both co-primary endpoints had to meet the 0.05 level for AERT 40 mg vs placebo for the study to be considered a success.
    End point type
    Primary
    End point timeframe
    The CGIC was recorded at Day 42 (Visit 4), Day 84 (Visit 5), and Day 92 (final visit or early termination).
    End point values
    		 AERT 40 mg AERT 80 mg Placebo
    Number of subjects analysed
    140
    115
    164
    Units: Score
        least squares mean (confidence interval 95%)
    0.36 (0.17 to 0.54)
    0.01 (-0.19 to 0.22)
    0.45 (0.27 to 0.63)
    Statistical analysis title
    		 LS mean difference for AERT 40 mg vs placebo
    Statistical analysis description
    Least-squares mean were used to compare AERT 40 mg versus placebo. The CGIC was analyzed using a REML-based MMRM with fixed effects for treatment, visit, country, and the treatment-by-visit interaction. Because the CGIC is a change score, no value was measured at baseline. No statistically significant difference in the mean CGIC score was observed between the placebo group and the AERT 40 mg group.
    Comparison groups
    AERT 40 mg v Placebo
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4272 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.121
    Notes
    [3] - p-value calculated for AERT 40 mg LS mean - placebo LS mean.
    Statistical analysis title
    		 LS mean difference for AERT 80 mg vs placebo
    Statistical analysis description
    Least-squares mean were used to compare AERT 80 mg versus placebo. The CGIC was analyzed using a REML-based MMRM with fixed effects for treatment, visit, country, and the treatment-by-visit interaction. Because the CGIC is a change score, no value was measured at baseline. A statistically significant difference in the mean CGIC score was observed between the placebo group and the AERT 80 mg group.
    Comparison groups
    AERT 80 mg v Placebo
    Number of subjects included in analysis
    279
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.69
         upper limit
    		 -0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.126
    Notes
    [4] - p-value calculated for AERT 80 mg LS mean - placebo LS mean.

    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 one AE 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 double-blind study treatment and had at least 1 postdose visit. The Safety population includes all 179 subjects who were randomized to the AERT 40 mg arm. 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
    		 Adverse event results are presented for the Safety population, which includes all subjects who received at least 1 dose of double-blind study treatment and had at least 1 postdose visit. The Safety population includes all 179 subjects who were randomized to the AERT 80 mg arm. 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
    Placebo
    Reporting group description
    		 Adverse event results are presented for the Safety population, which includes all subjects who received at least 1 dose of double-blind study treatment and had at least 1 postdose visit. The Safety population includes all 178 subjects who were randomized to the placebo arm. 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.

    Serious adverse events
    		 AERT 40 mg AERT 80 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 179 (3.35%)
    6 / 179 (3.35%)
    6 / 178 (3.37%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Schwannoma
         subjects affected / exposed
    0 / 179 (0.00%)
    0 / 179 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 179 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 179 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 179 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    2 / 179 (1.12%)
    3 / 179 (1.68%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Restless legs syndrome
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 179 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 179 (0.00%)
    0 / 179 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 179 (0.00%)
    0 / 179 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 179 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Withdrawal syndrome
         subjects affected / exposed
    0 / 179 (0.00%)
    0 / 179 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 179 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 179 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 179 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Toxic skin eruption
         subjects affected / exposed
    0 / 179 (0.00%)
    0 / 179 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 179 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression suicidal
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 179 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somatic symptom disorder
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 179 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urosepsis
         subjects affected / exposed
    0 / 179 (0.00%)
    0 / 179 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 AERT 40 mg AERT 80 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    137 / 179 (76.54%)
    146 / 179 (81.56%)
    126 / 178 (70.79%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    25 / 179 (13.97%)
    33 / 179 (18.44%)
    19 / 178 (10.67%)
         occurrences all number
    25
    33
    19
    Somnolence
         subjects affected / exposed
    18 / 179 (10.06%)
    26 / 179 (14.53%)
    17 / 178 (9.55%)
         occurrences all number
    18
    26
    17
    Headache
         subjects affected / exposed
    2 / 179 (1.12%)
    6 / 179 (3.35%)
    12 / 178 (6.74%)
         occurrences all number
    2
    6
    12
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    23 / 179 (12.85%)
    33 / 179 (18.44%)
    27 / 178 (15.17%)
         occurrences all number
    23
    33
    27
    Gait disturbance
         subjects affected / exposed
    2 / 179 (1.12%)
    14 / 179 (7.82%)
    6 / 178 (3.37%)
         occurrences all number
    2
    14
    6
    Fatigue
         subjects affected / exposed
    4 / 179 (2.23%)
    9 / 179 (5.03%)
    6 / 178 (3.37%)
         occurrences all number
    4
    9
    6
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    39 / 179 (21.79%)
    27 / 179 (15.08%)
    28 / 178 (15.73%)
         occurrences all number
    39
    27
    28
    Vomiting
         subjects affected / exposed
    13 / 179 (7.26%)
    18 / 179 (10.06%)
    16 / 178 (8.99%)
         occurrences all number
    13
    18
    16
    Renal and urinary disorders
    Urinary tract disorder
         subjects affected / exposed
    48 / 179 (26.82%)
    54 / 179 (30.17%)
    61 / 178 (34.27%)
         occurrences all number
    48
    54
    61
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    39 / 179 (21.79%)
    39 / 179 (21.79%)
    27 / 178 (15.17%)
         occurrences all number
    39
    39
    27

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Sep 2017
    The following changes were made to Protocol CLN.OS440-3004.PR.A01 as Amendment 1 dated 19 September 2017: - Clarified birth control requirements for subjects and partners of subjects. - Clarified that “high dose (120 mg daily)” oral or intravenous methylprednisolone or equivalent within 3 months before Visit 1 (Screening) would be exclusionary. - Added a criterion excluding subjects with clinically significant abnormal laboratory values at Screening. - Added taper and washout periods for specific anti-spasticity and/or muscle relaxation medications. - 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...” - In the sample size calculation, specified that the determination of sample size should be based on the AERT 40 mg/day dose, as the AERT 40 mg/day dose will be analyzed first versus placebo.
    09 Nov 2017
    The following changes were made to Protocol CLN.OS440-3004.PR.A02 as Amendment 2 dated 09 November 2017: - Disallowed subjects who experienced an acute MS exacerbation/relapse during study OS440-3004 from enrolling in study OS440-3005.

    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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