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    Clinical Trial Results:
    A 12-weeks, multicentre, randomized, double-blind, placebo-controlled, exploratory, pilot study to evaluate the safety and efficacy of safinamide 200 mg once daily, as add-on therapy, in patients with possible or probable parkinsonian variant of multiple system atrophy.

    Summary
    EudraCT number
    		 2018-004145-16
    Trial protocol
    		 ES   IT  
    Global end of trial date
    05 Jan 2021

    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
    Z7219K01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03753763
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Zambon S.p.A.
    Sponsor organisation address
    Via Lillo del Duca 10, Bresso (MI), Italy, 20091
    Public contact
    Clinical Development Manager, Zambon S.p.A., +39 02665241, clinicaltrials@zambongroup.com
    Scientific contact
    Clinical Development Manager, Zambon S.p.A., +39 02665241, clinicaltrials@zambongroup.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
    05 Jan 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Jan 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Safety: To evaluate the safety and tolerability of safinamide 200 mg once daily compared with placebo. Efficacy: To evaluate the potential efficacy of safinamide 200 mg once daily, as add-on therapy, on motor function and/or quality of life.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and its subsequent revisions, Regulation (European Union) No 536/2014, Commission Directive 2005/28/EC, and with all applicable laws and regulations of the locale and country where the study was conducted, and in compliance with International Council for Harmonisation (ICH) E6 Good Clinical Practice Guidelines.
    Background therapy
    		 Oral daily Levodopa alone or in combination with other anti-parkinsonian drugs (such as dopamine agonist, anticholinergic, and/or amantadine) allowed for MSA treatment.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Oct 2019
    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
    Italy: 36
    Country: Number of subjects enrolled
    Spain: 13
    Worldwide total number of subjects
    49
    EEA total number of subjects
    49
    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)
    28
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Approximately 56 participants were planned to be screened in order to achieve 49 participants randomly assigned (2:1) to study drug and 42 evaluable participants, resulting in a planned estimated total of 32 evaluable participants receiving safinamide and 17 evaluable participants receiving matching placebo.

    Pre-assignment
    Screening details
    		 After providing written informed consent to participate in the study, participants entered a Screening period of up to 2 weeks. During the Screening period, participants underwent all of the evaluations necessary to establish their eligibility for the study and were assigned a unique screening number.

    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
    Blinding implementation details
    This was a double-blind study; therefore, the Sponsor, Investigator, and participant did not know the study drugs being administered.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Safinamide
    Arm description
    		 Safinamide methanesulfonate film-coated tablets once daily. During the titration period of 2 weeks (Week 1 to Week 2) participants received 1 tablet (100 mg) safinamide, while during the treatment period (Week 3 to Week 12) they received 2 tablets (200 mg) safinamide once-a-day, taken in the morning, in addition to their daily levodopa dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Safinamide
    Investigational medicinal product code
    Other name
    safinamide methanesulfonate
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During the titration period of 2 weeks (Week 1 to Week 2) participants received 1 tablet (100 mg) safinamide once-daily. During the treatment period (Week 3 to Week 12) they received 2 tablets (200 mg) safinamide once-a-day. Tablets were taken in the morning, along with patients' first levodopa dose of the day. Safinamide was supplied as 100 mg round, orange to copper, biconcave, film-coated tablets.

    Arm title
    		 Placebo
    Arm description
    		 Safinamide methanesulfonate matching placebo film-coated tablets once daily. Safinamide matching placebo was administered both during the titration period of 2 weeks (Week 1 to Week 2) and during the following period (Week 3 to Week 12), once daily, taken in the morning, in addition to their daily levodopa dose.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered both during the titration period of 2 weeks (Week 1 to Week 2) and during the following period (Week 3 to Week 12), once daily, taken in the morning, in addition to their daily levodopa dose. Safinamide matching placebo was supplied as 100 mg round, orange to copper, biconcave, film-coated tablets.

    Number of subjects in period 1
    		Safinamide Placebo
    Started
    32
    17
    Completed
    26
    16
    Not completed
    6
    1
         Consent withdrawn by subject
    3
    1
         Adverse event, non-fatal
    2
    -
         clinical deterioration
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Safinamide
    Reporting group description
    		 Safinamide methanesulfonate film-coated tablets once daily. During the titration period of 2 weeks (Week 1 to Week 2) participants received 1 tablet (100 mg) safinamide, while during the treatment period (Week 3 to Week 12) they received 2 tablets (200 mg) safinamide once-a-day, taken in the morning, in addition to their daily levodopa dose.

    Reporting group title
    Placebo
    Reporting group description
    		 Safinamide methanesulfonate matching placebo film-coated tablets once daily. Safinamide matching placebo was administered both during the titration period of 2 weeks (Week 1 to Week 2) and during the following period (Week 3 to Week 12), once daily, taken in the morning, in addition to their daily levodopa dose.

    Reporting group values
    		 Safinamide Placebo Total
    Number of subjects
    		 32 17 49
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 17 11 28
        From 65-84 years
    		 15 6 21
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.8 ± 8.23 62.8 ± 10.27 -
    Gender categorical
    Units: Subjects
        Female
    		 20 6 26
        Male
    		 12 11 23
    Subject analysis sets

    Subject analysis set title
    Safinamide - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT Population included all randomized participants. This population was used for describing all the demographic characteristics and all efficacy variables.

    Subject analysis set title
    Safinamide - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Population will include all randomized participants who do not have any entry criteria violations or protocol deviations that could significantly impact the assessment or interpretation of efficacy data.

    Subject analysis set title
    Safinamide - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population included all randomized participants who took at least 1 dose of study drug. This population was used to summarize all safety data; participants were analyzed according to the drug they actually received.

    Subject analysis set title
    Placebo - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT Population included all randomized participants. This population was used for all efficacy variables.

    Subject analysis set title
    Placebo - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per-Protocol (PP) Population included all randomized participants who did not have any entry criteria violations or protocol deviations that significantly impacted the assessment or interpretation of efficacy data.

    Subject analysis set title
    Placebo - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population included all randomized participants who took at least 1 dose of study drug. This population was used to summarize all safety data; participants were analyzed according to the drug they actually received.

    Subject analysis sets values
    		 Safinamide - ITT Safinamide - PP Safinamide - Safety Placebo - ITT Placebo - PP Placebo - Safety
    Number of subjects
    32
    32
    32
    17
    17
    17
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    17
    17
    17
    11
    11
    11
        From 65-84 years
    15
    15
    15
    6
    6
    6
        85 years and over
    0
    0
    0
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    65.8 ± 8.23
    65.8 ± 8.23
    65.8 ± 8.23
    62.8 ± 10.27
    62.8 ± 10.27
    62.8 ± 10.27
    Gender categorical
    Units: Subjects
        Female
    20
    20
    20
    6
    6
    6
        Male
    12
    12
    12
    11
    11
    11

    End points

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    End points reporting groups
    Reporting group title
    Safinamide
    Reporting group description
    		 Safinamide methanesulfonate film-coated tablets once daily. During the titration period of 2 weeks (Week 1 to Week 2) participants received 1 tablet (100 mg) safinamide, while during the treatment period (Week 3 to Week 12) they received 2 tablets (200 mg) safinamide once-a-day, taken in the morning, in addition to their daily levodopa dose.

    Reporting group title
    Placebo
    Reporting group description
    		 Safinamide methanesulfonate matching placebo film-coated tablets once daily. Safinamide matching placebo was administered both during the titration period of 2 weeks (Week 1 to Week 2) and during the following period (Week 3 to Week 12), once daily, taken in the morning, in addition to their daily levodopa dose.

    Subject analysis set title
    Safinamide - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT Population included all randomized participants. This population was used for describing all the demographic characteristics and all efficacy variables.

    Subject analysis set title
    Safinamide - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Population will include all randomized participants who do not have any entry criteria violations or protocol deviations that could significantly impact the assessment or interpretation of efficacy data.

    Subject analysis set title
    Safinamide - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population included all randomized participants who took at least 1 dose of study drug. This population was used to summarize all safety data; participants were analyzed according to the drug they actually received.

    Subject analysis set title
    Placebo - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT Population included all randomized participants. This population was used for all efficacy variables.

    Subject analysis set title
    Placebo - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per-Protocol (PP) Population included all randomized participants who did not have any entry criteria violations or protocol deviations that significantly impacted the assessment or interpretation of efficacy data.

    Subject analysis set title
    Placebo - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population included all randomized participants who took at least 1 dose of study drug. This population was used to summarize all safety data; participants were analyzed according to the drug they actually received.

    Primary: TEAEs (treatment emergent adverse events) and SAEs (serious adverse events)

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    End point title
    		 TEAEs (treatment emergent adverse events) and SAEs (serious adverse events) [1]
    End point description
    While evaluating safety and tolerability of safinamide, 200 mg od, compared with placebo, severity of TEAEs, their relationship to study drug, their seriousness and their consequences were assessed. TEAEs were defined as adverse events (AEs) that started after the first dose of study drug.
    End point type
    Primary
    End point timeframe
    Throughout the study, from baseline (and at each interim visit) to telephone follow-up visit at 14 week.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Measure type "Number" related to adverse events can't have a statistical analysis
    End point values
    		 Safinamide - Safety Placebo - Safety
    Number of subjects analysed
    32
    17
    Units: events
        Any TEAEs
    52
    28
        Mild TEAEs
    49
    21
        Moderate TEAEs
    4
    5
        Severe TEAEs
    3
    4
        Serious TEAEs
    2
    0
        Study drug-related TEAEs
    15
    11
        TEAEs leading to study drug withdrawal
    1
    0
        AEs leading to death
    1
    0
    No statistical analyses for this end point

    Secondary: Change from baseline to week 12 in the goniometric measurement for anterior displacement

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    End point title
    		 Change from baseline to week 12 in the goniometric measurement for anterior displacement
    End point description
    To evaluate the potential efficacy of safinamide 200 mg od, as add-on therapy, on quality of life (change in anterior displacement). The goniometric measurement consists in the posture evaluation of the patient, measuring through a goniometer the angle of the flexion of the trunk. Goniometric measurement of “anterior” displacement was determined using a wall goniometer and expressing the value in degrees in the range of 0 to 90.
    End point type
    Secondary
    End point timeframe
    From baseline to week 12
    End point values
    		 Safinamide - ITT Placebo - ITT
    Number of subjects analysed
    32
    17
    Units: degrees
        arithmetic mean (standard deviation)
    1.3 ± 9.46
    0.9 ± 8.01
    Statistical analysis title
    		 Safinamide vs placebo
    Comparison groups
    Safinamide - ITT v Placebo - ITT
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.9697 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 least square mean difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.3
         upper limit
    		 6.5
    Notes
    [2] - The model included treatment, week of visit, and treatment-by-visit interaction as fixed effects and baseline score as a covariate.
    [3] - A mixed-model repeated measures (MMRM) was used to analyze the change in anterior displacement from baseline.

    Secondary: Change From Baseline to Week 12 in the Goniometric Measurement for lateral Displacement

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    End point title
    		 Change From Baseline to Week 12 in the Goniometric Measurement for lateral Displacement
    End point description
    To evaluate the potential efficacy of safinamide 200 mg od, as add-on therapy, on quality of life (change in anterior displacement). The goniometric measurement consists in the posture evaluation of the patient, measuring through a goniometer the angle of the flexion of the trunk. Goniometric measurement of “lateral” displacement was determined using a wall goniometer and expressing the value in degrees in the range of 0 to 90.
    End point type
    Secondary
    End point timeframe
    From baseline to week 12
    End point values
    		 Safinamide - ITT Placebo - ITT
    Number of subjects analysed
    32
    17
    Units: degrees
        arithmetic mean (standard deviation)
    1.3 ± 5.08
    -0.2 ± 4.47
    Statistical analysis title
    		 Safinamide vs placebo
    Comparison groups
    Safinamide - ITT v Placebo - ITT
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.7751 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 least square mean difference
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 4.1
    Notes
    [4] - The model included treatment, week of visit, and treatment-by-visit interaction as fixed effects and baseline score as a covariate.
    [5] - A mixed-model repeated measures (MMRM) was used to analyze the change in lateral displacement from baseline.

    Secondary: Change From Baseline to Week 12 in Unified Multiple System Atrophy Rating Scale (UMSARS), Part II (ITT Population)

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    End point title
    		 Change From Baseline to Week 12 in Unified Multiple System Atrophy Rating Scale (UMSARS), Part II (ITT Population)
    End point description
    UMSARS is a validated, disease-specific scale representing the diverse signs and symptoms in MSA. Higher scores on the UMSARS scales mean poorer health. UMSARS has the following domains: Part I - Activities of Daily Living score (12 questions ranged in 0-4 [total score 0-48]) that evaluates motor including autonomic activities Part II - Motor Examination score (14 questions, [total score 0-56]) Part III - Autonomic Examination Part IV - Global disability scale ((1=completely independent; 2=not completely independent; 3=more dependent; 4=very dependent; 5=total dependent and helpless). Only UMSARS Part II total score is reported, which was obtained as the sum of the 14 items in the scale. If any of the items were missing, then the total score was considered missing. Higher scores indicate worse functional situation.
    End point type
    Secondary
    End point timeframe
    From baseline to week 12
    End point values
    		 Safinamide - ITT Placebo - ITT
    Number of subjects analysed
    32
    17
    Units: score on a scale
        arithmetic mean (standard deviation)
    -0.1 ± 5.40
    -0.4 ± 5.85
    Statistical analysis title
    		 Safinamide vs placebo
    Comparison groups
    Safinamide - ITT v Placebo - ITT
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.9076 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 least square mean difference
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 3.7
    Notes
    [6] - The model included treatment, week of visit, and treatment-by-visit interaction as fixed effects and baseline score as a covariate.
    [7] - The MMRM analysis, specified in Section Goniometric measurement, was used to analyze the change in Part II total scores from baseline.

    Secondary: Change From Baseline to Week 12 in Unified Multiple System Atrophy Rating Scale (UMSARS), Part II (PP Population)

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    End point title
    		 Change From Baseline to Week 12 in Unified Multiple System Atrophy Rating Scale (UMSARS), Part II (PP Population)
    End point description
    UMSARS is a validated, disease-specific scale representing the diverse signs and symptoms in MSA. Higher scores on the UMSARS scales mean poorer health. UMSARS has the following domains: Part I - Activities of Daily Living score (12 questions ranged in 0-4 [total score 0-48]) that evaluates motor including autonomic activities Part II - Motor Examination score (14 questions, [total score 0-56]) Part III - Autonomic Examination Part IV - Global disability scale ((1=completely independent; 2=not completely independent; 3=more dependent; 4=very dependent; 5=total dependent and helpless). Only UMSARS Part II total score is reported, which was obtained as the sum of the 14 items in the scale. If any of the items were missing, then the total score was considered missing. Higher scores indicate worse functional situation.
    End point type
    Secondary
    End point timeframe
    From baseline to week 12
    End point values
    		 Safinamide - PP Placebo - PP
    Number of subjects analysed
    21
    13
    Units: score on a scale
        arithmetic mean (standard deviation)
    -1.1 ± 4.66
    -0.6 ± 6.17
    Statistical analysis title
    		 Safinamide vs placebo
    Comparison groups
    Placebo - PP v Safinamide - PP
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.5386 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 least square mean difference
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.8
         upper limit
    		 2.6
    Notes
    [8] - The model included treatment, week of visit, and treatment-by-visit interaction as fixed effects and baseline score as a covariate.
    [9] - A mixed-model repeated measures (MMRM) was used to analyze the change in from baseline in UMSARS Part II.

    Secondary: Change From Baseline to Week 12 in Multiple System Atrophy Health-Related Quality of Life (MSA-QoL) Scale

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    End point title
    		 Change From Baseline to Week 12 in Multiple System Atrophy Health-Related Quality of Life (MSA-QoL) Scale
    End point description
    The MSA-QoL is a self-reported questionnaire focusing on MSA-specific symptoms and has a scale ranging from 0 to 160, with 0= 'no problem' and 160= "extreme problem".
    End point type
    Secondary
    End point timeframe
    From baseline to week 12
    End point values
    		 Safinamide - ITT Placebo - ITT
    Number of subjects analysed
    32
    17
    Units: units on a scale
        arithmetic mean (standard deviation)
    5.6 ± 25.57
    -2.9 ± 14.37
    Statistical analysis title
    		 Safinamide vs placebo
    Comparison groups
    Safinamide - ITT v Placebo - ITT
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.3364 [11]
    Method
    		 Mixed models analysis
    Parameter type
    		 least square mean difference
    Point estimate
    6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.5
         upper limit
    		 18.6
    Notes
    [10] - The model included treatment, week of visit, and treatment-by-visit interaction as fixed effects and baseline score as a covariate.
    [11] - A mixed-model repeated measures (MMRM) was used to analyze the change in from baseline in MSA-QoL scale.

    Secondary: Change From Baseline to Week 12 in Montreal Cognitive Assessment (MoCA) Scale

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    End point title
    		 Change From Baseline to Week 12 in Montreal Cognitive Assessment (MoCA) Scale
    End point description
    The Montreal Cognitive Assessment (MoCA) was designed as a tool for rapid screening for mild cognitive impairment. It evaluates different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructive skills, abstraction, calculation and orientation. The administration time of the MoCa is 10 minutes. The MoCA scale ranges from 0 to 30, with higher scores indicating better cognitive functioning.
    End point type
    Secondary
    End point timeframe
    From baseline to week 12
    End point values
    		 Safinamide - ITT Placebo - ITT
    Number of subjects analysed
    32
    17
    Units: score on a scale
        arithmetic mean (standard deviation)
    0.0 ± 2.01
    -0.3 ± 2.09
    Statistical analysis title
    		 Safinamide vs placebo
    Comparison groups
    Safinamide - ITT v Placebo - ITT
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.7574
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 1.5
    Notes
    [12] - Change from Screening at Week 12 was analyzed by an analysis of covariance (ANCOVA). The ANCOVA included change from baseline as the response variable, treatment group as a factor, and baseline score as a covariate.

    Secondary: Change From Baseline to Week 12 in Unified Dystonia Rating Scale (UDRS)

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    End point title
    		 Change From Baseline to Week 12 in Unified Dystonia Rating Scale (UDRS)
    End point description
    UDRS consists of a Historical Section, divided into questionnaires about 1) on-dyskinesia and 2) off -dystonia, and an Objective Section, divided into 3) impairment and 4) disability scales. The Historical Section is scored from 0-60, and the Objective section is scored 0-44, where higher scores reflect greater difficulty or impairment. The Unified Dystonia Rating Scale (UDRS) assesses the motor severity and duration of dystonia in 14 body areas. The total score, obtained as the sum of the severity and duration factors, ranges from 0 to 112. Higher scores indicate worse dystonia.
    End point type
    Secondary
    End point timeframe
    From baseline to week 12
    End point values
    		 Safinamide - ITT Placebo - ITT
    Number of subjects analysed
    32
    17
    Units: units on a scale
        arithmetic mean (standard deviation)
    1.0 ± 4.82
    0.3 ± 5.60
    Statistical analysis title
    		 Safinamide vs placebo
    Comparison groups
    Safinamide - ITT v Placebo - ITT
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.6393 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 least square mean difference
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 4
    Notes
    [13] - The model included treatment, week of visit, and treatment-by-visit interaction as fixed effects and baseline score as a covariate.
    [14] - A mixed-model repeated measures (MMRM) was used to analyze the change from baseline in UDRS.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    At baseline, at interim visits (Weeks 2 - 8, and more precisely at days 14 ± 3, 28 ± 3, 56 ± 3), at End of Treatment visit (EOT) at Week 12 (84 ± 3 days), and at follow-up call at week 14 ( 98 ± 3).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Safinamide - safety
    Reporting group description
    		 Safinamide methanesulfonate film-coated tablets once daily. During the titration period of 2 weeks (Week 1 to Week 2) participants received 1 tablet (100 mg) safinamide, while during the treatment period (Week 3 to Week 12) they received 2 tablets (200 mg) safinamide once-a-day, taken in the morning, in addition to their daily levodopa dose.

    Reporting group title
    Placebo - safety
    Reporting group description
    		 Safinamide methanesulfonate matching placebo film-coated tablets once daily. Safinamide matching placebo was administered both during the titration period of 2 weeks (Week 1 to Week 2) and during the following period (Week 3 to Week 12), once daily, taken in the morning, in addition to their daily levodopa dose.

    Serious adverse events
    		 Safinamide - safety Placebo - safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 17 (0.00%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Cardiac respiratory arrest
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Safinamide - safety Placebo - safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 32 (65.63%)
    11 / 17 (64.71%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    5 / 32 (15.63%)
    7 / 17 (41.18%)
         occurrences all number
    5
    5
    Wound
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Chest injury
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Head injury
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Rib fracture
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Tooth fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 17 (11.76%)
         occurrences all number
    2
    4
    Dependent rubor
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Dyskinesia
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorder
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Parkinsonian gait
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Parkinsonism
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Somnolence
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Oedema peripheral
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Pyrexia
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Gait disturbance
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Influenza like illness
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Pain
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Peripheral swelling
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Salivar hypersecretion
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    2
    Abdominal discomfort
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Hallucination
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Irritability
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Nervousness
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 32 (9.38%)
    2 / 17 (11.76%)
         occurrences all number
    3
    2
    Cystitis
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Escherichia infection
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Oral fungal infection
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Pseudomonas infection
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jul 2020
    This amendment was developed to formally incorporate the administrative letter, to add details of measures taken during the COVID-19 pandemic, to clarify and correct inconsistencies in the original Protocol raised from the Italian Health Authority and/or Italian Coordinating Site, to address an inconsistency within the Protocol in regard to the number of evaluable participants, to provide additional clarifications on the sample size determination background, and to provide information on the benefit/risk assessment as outlined in the 09 August 2019 administrative letter.

    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.
    No limitations or caveats were applicable to this summary of the results
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