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    Clinical Trial Results:
    A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized Study To Evaluate the Efficacy, Safety and Tolerability of E2027 in Subjects With Dementia With Lewy Bodies

    Summary
    EudraCT number
    		 2017-003728-64
    Trial protocol
    		 DE   GB   ES   IT  
    Global end of trial date
    15 Apr 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jun 2022
    First version publication date
    24 Jun 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    E2027-G000-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03467152
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai Ltd.
    Sponsor organisation address
    European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire, United Kingdom, AL10 9SN
    Public contact
    Eisai Medical Information, Eisai Ltd., +1 888-274-2378, esi_medinfo@eisai.com
    Scientific contact
    Eisai Medical Information, Eisai Ltd., +1 888-274-2378, esi_medinfo@eisai.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
    15 Apr 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This main objective of the trial is to compare E2027 (herein referred to as Irsenontrine) to placebo on the cognitive endpoint of Montreal Cognitive Assessment (MoCA) and the global clinical endpoint of Clinician’s Interview Based Impression of Change Plus (CIBIC-Plus) Caregiver Input in subject with dementia with Lewy bodies after 12 weeks of treatment.
    Protection of trial subjects
    This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - International Council on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 May 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
    European Union: 62
    Country: Number of subjects enrolled
    Japan: 67
    Country: Number of subjects enrolled
    United States: 67
    Worldwide total number of subjects
    196
    EEA total number of subjects
    0
    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)
    17
    From 65 to 84 years
    179
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subject took part in the study at 65 investigative sites in the United States, Japan, United Kingdom, France, Spain, Germany, and Italy from 04 May 2018 to 15 April 2020.

    Pre-assignment
    Screening details
    		 A total of 320 subjects were screened and enrolled (signed informed consent form), of which 120 were screen failures and 200 were randomized out of which 196 were treated. An additional 6 subjects were randomized but were not treated and included in this study due to closure of a site resulting from serious compliance issues.

    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, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received Irsenontrine-matched placebo capsule, orally, once daily for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Irsenontrine-matched placebo capsule, orally, once daily for 12 weeks.

    Arm title
    		 Irsenontrine 50 mg
    Arm description
    		 Subjects received Irsenontrine 50 milligram (mg), capsule, once daily for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Irsenontrine
    Investigational medicinal product code
    Other name
    E2027
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Irsenontrine 50 mg, capsule, once daily for 12 weeks.

    Number of subjects in period 1
    		Placebo Irsenontrine 50 mg
    Started
    97
    99
    Completed
    84
    89
    Not completed
    13
    10
         Consent withdrawn by subject
    5
    5
         Others
    3
    -
         Adverse event, non-fatal
    4
    5
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received Irsenontrine-matched placebo capsule, orally, once daily for 12 weeks.

    Reporting group title
    Irsenontrine 50 mg
    Reporting group description
    		 Subjects received Irsenontrine 50 milligram (mg), capsule, once daily for 12 weeks.

    Reporting group values
    		 Placebo Irsenontrine 50 mg Total
    Number of subjects
    		 97 99 196
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 9 8 17
        From 65-84 years
    		 88 91 179
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 73.8 ± 6.60 75.3 ± 6.44 -
    Gender categorical
    Units: Subjects
        Female
    		 36 37 73
        Male
    		 61 62 123
    Race (NIH/OMB)
    Units: Subjects
        Asian
    		 33 34 67
        Black or African American
    		 1 1 2
        White
    		 48 55 103
        Unknown or Not Reported
    		 15 9 24
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 11 17 28
        Not Hispanic or Latino
    		 73 76 149
        Unknown or Not Reported
    		 13 6 19
    Subject analysis sets

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set included the group of subjects who received at least 1 dose of study drug and had at least 1 post randomization safety assessment.

    Subject analysis sets values
    		 Safety Analysis Set
    Number of subjects
    196
    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 (standard deviation)
    74.5 ± 6.54
    Gender categorical
    Units: Subjects
        Female
    73
        Male
    123
    Race (NIH/OMB)
    Units: Subjects
        Asian
    67
        Black or African American
    2
        White
    103
        Unknown or Not Reported
    24
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    28
        Not Hispanic or Latino
    149
        Unknown or Not Reported
    19

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received Irsenontrine-matched placebo capsule, orally, once daily for 12 weeks.

    Reporting group title
    Irsenontrine 50 mg
    Reporting group description
    		 Subjects received Irsenontrine 50 milligram (mg), capsule, once daily for 12 weeks.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set included the group of subjects who received at least 1 dose of study drug and had at least 1 post randomization safety assessment.

    Primary: Change From Baseline in the Montreal Cognitive Assessment (MoCA) Total Score at Week 12 of Treatment

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    End point title
    		 Change From Baseline in the Montreal Cognitive Assessment (MoCA) Total Score at Week 12 of Treatment
    End point description
    The MoCA scale is used for detecting cognitive impairment, the scores range between 0 to 30 points; a score of 26 or above was considered normal. Higher values represent a better outcome. The full analysis set (FAS) included the group of randomized subjects who received at least 1 dose of study drug, had baseline and at least 1 post randomization coprimary efficacy measurement. Here number of subjects analysed were subjects evaluable for the endpoint and number analysed “n” were the subject who were evaluable for the endpoint for given time points.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Irsenontrine 50 mg
    Number of subjects analysed
    92
    96
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Baseline
    13.9 ± 5.40
    13.8 ± 5.18
        Change at Week12(n=81,87)
    -0.6 ± 2.63
    -0.4 ± 3.41
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Irsenontrine 50 mg
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6909
    Method
    		 Mixed Models for Repeated Measures(MMRM)
    Confidence interval

    Primary: Clinician’s Interview Based Impression of Change Plus Caregiver Input (CIBIC-Plus) Scale at Week 12 of Treatment

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    End point title
    		 Clinician’s Interview Based Impression of Change Plus Caregiver Input (CIBIC-Plus) Scale at Week 12 of Treatment
    End point description
    The CIBIC-Plus scale is designed to measure various domains that describe subject function: general, mental/cognitive state, behavior, and activities of daily living. It is a semi-structured global rating derived from a comprehensive interview with the subject and caregiver or informant by an independent rater who has no access to the source data or other psychometric test scores conducted post-randomization as part of the protocol. The CIBIC-Plus was a 7-point scale and scores were: 1 (marked improvement), 2 (moderate improvement), 3 (minimal improvement), 4 (no change), 5 (minimal worsening), 6 (moderate worsening), and 7 (marked worsening). Higher values represent a worse outcome. The FAS included the group of randomized subjects who received at least 1 dose of study drug, had baseline and at least 1 post randomization coprimary efficacy measurement. Here number of subjects analysed were the subjects who were evaluable for the endpoint.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 Placebo Irsenontrine 50 mg
    Number of subjects analysed
    86
    89
    Units: Subjects
        Marked improvement
    0
    0
        Moderate improvement
    5
    3
        Minimal improvement
    13
    18
        No change
    32
    32
        Minimal worsening
    30
    28
        Moderate worsening
    6
    8
        Marked worsening
    0
    0
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Irsenontrine 50 mg
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8251
    Method
    		 Generalized Linear Mixed Models (GLMM)
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.018
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.695
         upper limit
    		 1.492

    Secondary: Clinician’s Global Impression of Change-In Dementia With Lewy Bodies (CGIC-DLB) Scale at Week 12 of Treatment

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    End point title
    		 Clinician’s Global Impression of Change-In Dementia With Lewy Bodies (CGIC-DLB) Scale at Week 12 of Treatment
    End point description
    The CGIC-DLB scale provided an overall clinician-determined summary measure of change from the subject’s clinical status that takes into account all available information from the efficacy endpoints (which include cognitive function, non-cognitive symptoms, behavior, and the impact of the symptoms on the subject’s ability to function) and safety data. The FAS included the group of randomized subjects who received at least 1 dose of study drug, had baseline and at least 1 post randomization coprimary efficacy measurement. Here number of subjects analysed were the subjects who were evaluable for the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo Irsenontrine 50 mg
    Number of subjects analysed
    83
    90
    Units: Subjects
        Marked improvement
    1
    0
        Moderate improvement
    3
    10
        Minimal improvement
    20
    15
        No change
    36
    30
        Minimal worsening
    22
    27
        Moderate worsening
    1
    8
        Marked worsening
    0
    0
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Irsenontrine 50 mg
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3003
    Method
    		 Generalized Linear Mixed Models (GLMM)
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.853
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.584
         upper limit
    		 1.247

    Secondary: Mean Change From Baseline in the Cognitive Fluctuation Inventory (CFI) Score at Week 12 of Treatment

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    End point title
    		 Mean Change From Baseline in the Cognitive Fluctuation Inventory (CFI) Score at Week 12 of Treatment
    End point description
    The CFI scale assessed cognitive fluctuation. It evaluates fluctuation in various domains including attention, ability to perform daily functions, orientation, verbal communication and behavior. The score was based on frequency and severity with a score range of 0 to 12. The scale also assessed the degree of caregiver or informant distress engendered by the symptoms. Higher scores indicating greater impairment. The FAS included the group of randomized subjects who received at least 1 dose of study drug, had baseline and at least 1 post randomization coprimary efficacy measurement. Here number of subjects analysed are the subjects who were evaluable for the endpoint and number analysed “n” were the subjects who were evaluable for the endpoint for given time points.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Irsenontrine 50 mg
    Number of subjects analysed
    92
    96
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline
    3.4 ± 2.68
    3.1 ± 2.48
        Change at Week12(n=86,89)
    0.1 ± 3.20
    0.3 ± 3.25
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Irsenontrine 50 mg
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9198
    Method
    		 Mixed Models for Repeated Measures(MMRM)
    Confidence interval

    Secondary: Mean Change From Baseline in the Mini-Mental State Examination (MMSE) Total Score Week 12 of Treatment

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    End point title
    		 Mean Change From Baseline in the Mini-Mental State Examination (MMSE) Total Score Week 12 of Treatment
    End point description
    The MMSE is a 30-point scale that measured orientation to time and place, registration, immediate and delayed recall, attention, language, and drawing. The total score ranges from 0 (most impaired) to 30 (no impairment). The lower score means severe cognitive deficit and higher score indicates better function. The FAS included the group of randomized subjects who received at least 1 dose of study drug, had baseline and at least 1 post randomization coprimary efficacy measurement. Here number of subjects analysed are the subjects who were evaluable for the endpoint and number analysed “n” were the subjects who were evaluable for the endpoint for given time points.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Irsenontrine 50 mg
    Number of subjects analysed
    93
    96
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline
    21.0 ± 3.63
    21.1 ± 3.22
        Change at Week12(n=85,92)
    -1.1 ± 3.63
    -1.7 ± 3.58
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Irsenontrine 50 mg
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2909
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Mean Change from Baseline in the Neuropsychiatric Inventory (NPI-12) Total Score at Week 12 of Treatment

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    End point title
    		 Mean Change from Baseline in the Neuropsychiatric Inventory (NPI-12) Total Score at Week 12 of Treatment
    End point description
    The NPI-12 scale assessed the frequency and severity of 12 neuropsychiatric symptoms commonly described in dementia subjects: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, nighttime behaviors, and appetite/eating changes. The scale also assessed the degree of caregiver or informant distress engendered by each of the symptoms. The sum of the composite scores for the 12 domains yielded the NPI-12 total score. NPI-12 total score ranged from 0 (minimum severity) to 144 (maximum severity); higher score indicates greater neuropsychiatric disturbance. FAS was included. Here number of subjects analysed are the subjects who were evaluable for the endpoint and number analysed “n” were the subjects who were evaluable for the endpoint for given time points.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Irsenontrine 50 mg
    Number of subjects analysed
    93
    96
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    17.6 ± 14.32
    19.1 ± 16.07
        Change at Week12(n=86,89)
    -0.2 ± 11.07
    -2.0 ± 15.36
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Irsenontrine 50 mg
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6127
    Method
    		 Mixed Models for Repeated Measures(MMRM)
    Confidence interval

    Secondary: Change from Baseline in NPI-4 Subscore at Week 12

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    End point title
    		 Change from Baseline in NPI-4 Subscore at Week 12
    End point description
    The NPI scale assesses the frequency and severity of 12 neuropsychiatric symptoms commonly described in dementia subjects: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, nighttime behaviors, and appetite/eating changes. NPI-4 is the subscore covering the domains of delusions, hallucinations, apathy and depression. NPI-4 total subscore ranged from 0 to 48, with higher scores indicating a greater neuropsychiatric disturbance. The FAS included the group of randomized Subjects who received at least 1 dose of study drug, had baseline and at least 1 post randomization coprimary efficacy measurement. Here number of subjects analysed are the subjects who were evaluable for the endpoint and number analysed “n” were the subjects who were evaluable for the endpoint for given time points.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Irsenontrine 50 mg
    Number of subjects analysed
    93
    96
    Units: Score on scale
    arithmetic mean (standard deviation)
        Baseline
    8.2 ± 6.40
    8.6 ± 7.18
        Change at Week 12 (n=86,89)
    -0.4 ± 5.15
    -0.6 ± 6.79
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Irsenontrine 50 mg
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.878
    Method
    		 Mixed Models for Repeated Measures(MMRM)
    Confidence interval

    Secondary: Change from Baseline in NPI-10 Subscore at Week 12

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    End point title
    		 Change from Baseline in NPI-10 Subscore at Week 12
    End point description
    The NPI-10 assessed range of behaviors seen in dementia for both frequency and severity. It is a 10 item questionnaire with the following domains: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/liability and aberrant motor behavior. The total score was a sum of the 10 domains, where the score of each domain was calculated as frequency (scale: 1=occasionally to 4=very frequently)*Severity(scale:1 = Mild to 3 = Severe). Each domain has a maximum score of 12 and all domains were equally weighted for total score, the range for total score is 0 to 120. Higher scores indicating a greater neuropsychiatric disturbance. FAS was included. Here number of subjects analysed are the subjects who were evaluable for the endpoint, “n” were evaluable for given time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Irsenontrine 50 mg
    Number of subjects analysed
    93
    96
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline
    13.5 ± 11.22
    14.9 ± 13.54
        Change at Week 12 (n= 86,89)
    0.6 ± 9.32
    -1.4 ± 12.53
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Irsenontrine 50 mg
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.409
    Method
    		 Mixed Models for Repeated Measures(MMRM)
    Confidence interval

    Secondary: Change From Baseline in NPI-D (Caregiver Distress) Total Score at Week 12

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    End point title
    		 Change From Baseline in NPI-D (Caregiver Distress) Total Score at Week 12
    End point description
    The NPI scale assesses the frequency and severity of 12 neuropsychiatric symptoms commonly described in dementia Subjects:delusions,hallucinations,agitation/aggression,depression/dysphoria,anxiety,elation/euphoria,apathy/indifference, disinhibition,irritability/lability,motor disturbance,nighttime behaviors,and appetite/eating changes. The scale assesses the degree of caregiver distress engendered by each of the symptoms. The NPI-D is rated by caregiver based on his or her own stress on a five point scale from 0 to 5,where: 0(no distress),1(minimal),2(mild),3(moderate),4(moderately severe),5(very severe or extreme). NPI-D total score is calculated by summing the scores of the 12 sub-scale distress scores. The NPI-D total scores ranges from 0 to 60 with higher scores indicating greater distress. The FAS was included. Here number of subjects analysed are the subjects who were evaluable for the endpoint, “n” were evaluable for given time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Irsenontrine 50 mg
    Number of subjects analysed
    93
    96
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    8.8 ± 7.65
    9.4 ± 8.44
        Change at Week12(n=86,89)
    -0.2 ± 6.18
    -0.6 ± 7.28
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Irsenontrine 50 mg
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8736
    Method
    		 Mixed Models for Repeated Measures(MMRM)
    Confidence interval

    Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Severe TEAEs, Serious TEAEs, Adverse Events (AEs) Resulting in Study Discontinuation

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    End point title
    		 Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Severe TEAEs, Serious TEAEs, Adverse Events (AEs) Resulting in Study Discontinuation
    End point description
    TEAE was defined as an AE that emerged or worsened in severity relative to baseline during treatment or within 28 days after the last dose of study drug. ); Severe TEAE was defined as inability to work or to perform normal daily activity; A Serious TEAE is any untoward medical occurrence that at any dose: results in death; is life threatening (that is, the subject was at immediate risk of death from the adverse event as it occurred; this does not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death) requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is medically important due to other reasons than the above mentioned criteria. An adverse event (AE) was defined as any untoward medical occurrence in a subject administered an investigational product. Safety analysis set.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to Week 16
    End point values
    		 Placebo Irsenontrine 50 mg
    Number of subjects analysed
    97
    99
    Units: Subjects
        TEAEs
    67
    70
        Severe TEAEs
    6
    2
        Serious TEAEs
    9
    7
        AE Leading to Discontinuation from Study
    7
    6
    No statistical analyses for this end point

    Secondary: Number of Subjects With Orthostatic Hypotension

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    End point title
    		 Number of Subjects With Orthostatic Hypotension
    End point description
    Orthostatic hypotension was defined as drop in standing systolic blood pressure greater than or equal to (>=) 20 millimeter of mercury (mmHg) compared to supine, or drop in standing diastolic blood pressure >=10 mmHg compared to supine. The safety analysis set included the group of subjects who received at least 1 dose of study drug and had at least 1 post randomization safety assessment.
    End point type
    Secondary
    End point timeframe
    Week 2, Week 4, Week 6, Week 9, Week 12, and Week 16
    End point values
    		 Placebo Irsenontrine 50 mg
    Number of subjects analysed
    97
    99
    Units: Subjects
        Week 2
    10
    2
        Week 4
    9
    7
        Week 6
    6
    11
        Week 9
    13
    9
        Week 12
    7
    9
    No statistical analyses for this end point

    Secondary: Number of Subjects With Orthostatic Tachycardia

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    End point title
    		 Number of Subjects With Orthostatic Tachycardia
    End point description
    Orthostatic tachycardia by numerical criteria was defined by the following numerical criteria: Standing heart rate (HR) increased by >30 beats/min compared to supine and absolute standing HR was >100 beats/min. The safety analysis set included the group of subjects who received at least 1 dose of study drug and had at least 1 post randomization safety assessment.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to Week 16
    End point values
    		 Placebo Irsenontrine 50 mg
    Number of subjects analysed
    97
    99
    Units: Subjects
        Number of Subjects With Orthostatic Tachycardia
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Markedly Abnormal Laboratory Values

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    End point title
    		 Number of Subjects With Markedly Abnormal Laboratory Values
    End point description
    A laboratory value was determined to be a markedly abnormal value if the postbaseline common toxicity criteria grade increased from baseline and the post-baseline grade was >= 2. The safety analysis set included the group of subjects who received at least 1 dose of study drug and had at least 1 post randomization safety assessment. Here “N” were the subjects who were evaluable for the endpoint. Number analysed “n” were the subjects who were evaluable for the endpoint for given categories.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to Week 16
    End point values
    		 Placebo Irsenontrine 50 mg
    Number of subjects analysed
    94
    97
    Units: Subjects
        Albumin: Markedly Abnormal Low(n=94,96)
    1
    0
        Bilirubin: Markedly Abnormal High(n=94,96)
    1
    0
        Calcium:Markedly Abnormal Low(n=94,96)
    1
    0
        Creatinine:Markedly Abnormal High(n=94,96)
    0
    2
        GlutamylTransferase:MarkedlyAbnormal High(n=94,96)
    2
    0
        Hemoglobin:Markedly Abnormal Low(n=94,96)
    0
    1
        Leukocytes:Markedly Abnormal Low(n=94,96)
    0
    1
        Lymphocytes:Markedly Abnormal Low(n=94,96)
    4
    1
        Neutrophils:Markedly Abnormal Low(n=94,96)
    1
    0
        Phosphate:Markedly Abnormal Low(n=94,96)
    0
    1
        Potassium:Markedly Abnormal Low(n=94,97)
    1
    0
        Potassium:Markedly Abnormal High(n=94,97)
    2
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Abnormal Electrocardiogram (ECG) Findings

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    End point title
    		 Number of Subjects With Abnormal Electrocardiogram (ECG) Findings
    End point description
    The safety analysis set included the group of subjects who received at least 1 dose of study drug and had at least 1 post randomization safety assessment. Here “N” were the subjects who were evaluable for the endpoint.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to Week 16
    End point values
    		 Placebo Irsenontrine 50 mg
    Number of subjects analysed
    96
    98
    Units: Subjects
        QTcF prolongation by >60 milliseconds (ms)
    2
    0
        QTcF prolongation to >500 ms
    2
    0
        Change from baseline of PR >= 25 percent (%)
    1
    1
        Change from baseline of QRS >= 25%
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Suicidal Ideation or Suicidal Behavior as Measured Using Columbia Suicide Severity Rating Scale (C-SSRS)

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    End point title
    		 Number of Subjects With Suicidal Ideation or Suicidal Behavior as Measured Using Columbia Suicide Severity Rating Scale (C-SSRS)
    End point description
    The C-SSRS (mapped to C-CASA categories); is an interview-based instrument to systematically assess suicidal ideation and suicidal behavior. C-SSRS assess whether subject experience any of the following: completed suicide; suicide attempt; preparatory acts toward imminent suicidal behavior, suicidal ideation, wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent. Here, number of subjects with positive response (yes) to suicidal behavior or/and Ideation, any non-suicidal self-injurious behavior will be reported. The safety analysis set included the group of subjects who received at least 1 dose of study drug and had at least 1 post randomization safety assessment. Here number of subjects analysed were the subjects who were evaluable for the endpoint.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to Week 16
    End point values
    		 Placebo Irsenontrine 50 mg
    Number of subjects analysed
    95
    98
    Units: Subjects
        Completed Suicide
    0
    0
        Suicide Attempt
    0
    0
        Imminent Suicidal Behavior
    0
    2
        Wish to Die
    6
    8
        Actual Suicidal Thoughts; Non-specific
    1
    1
        Actual Suicidal Thoughts with Method; No Intent
    0
    1
        Active Thoughts with Intent
    0
    0
        Active Thoughts with Plan and Intent
    0
    0
        Self-injurious Behavior; No Intent
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Total Score of Unified Parkinson’s Disease Rating Scale Part III: Motor Examination (UPDRS-III)

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    End point title
    		 Change From Baseline in Total Score of Unified Parkinson’s Disease Rating Scale Part III: Motor Examination (UPDRS-III)
    End point description
    The UPDRS scale evaluates extrapyramidal features in motor function in Parkinson’s disease. It contains 33 items in 18 categories:(1)speech,(2)facial expression,(3) rigidity,(4)finger tapping,(5)hand movements,(6)supinational and pronation movements of hands, (7)toe tapping,(8)leg agility,(9)arising from chair,(10) gait,(11)freezing of gait,(12)postural stability,(13) posture,(14)body bradykinesia,(15)postural tremor of hands, (16) kinetic tremor of hands, (17) rest tremor amplitude and (18) constancy of rest tremor. Each item is scored 0 to 4, giving a total score range 0 to 132. Higher scores indicating more severe symptoms. The safety analysis set included the group of subjects who received at least 1 dose of study drug and had at least 1 post randomization safety assessment. Here number analysed “n” were the subjects who were evaluable for the endpoint for given time points.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 16
    End point values
    		 Placebo Irsenontrine 50 mg
    Number of subjects analysed
    97
    99
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline
    31.3 ± 18.51
    34.5 ± 18.12
        Change at Week16(n=81,84)
    -1.2 ± 10.97
    1.0 ± 9.22
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to follow up (Week 16)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received Irsenontrine-matched placebo capsule, orally, once daily for 12 weeks.

    Reporting group title
    Irsenontrine 50 mg
    Reporting group description
    		 Subjects received Irsenontrine 50 mg, capsule, once daily for 12 weeks.

    Serious adverse events
    		 Placebo Irsenontrine 50 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 97 (9.28%)
    7 / 99 (7.07%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dementia with Lewy bodies
         subjects affected / exposed
    1 / 97 (1.03%)
    2 / 99 (2.02%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal perforation
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (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
    		 Placebo Irsenontrine 50 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    65 / 97 (67.01%)
    68 / 99 (68.69%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lipoma
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Prostate cancer
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Haematoma
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Orthostatic hypotension
         subjects affected / exposed
    0 / 97 (0.00%)
    3 / 99 (3.03%)
         occurrences all number
    0
    4
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    2 / 97 (2.06%)
    1 / 99 (1.01%)
         occurrences all number
    2
    1
    Malaise
         subjects affected / exposed
    1 / 97 (1.03%)
    2 / 99 (2.02%)
         occurrences all number
    1
    2
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    2 / 97 (2.06%)
    3 / 99 (3.03%)
         occurrences all number
    2
    4
    Pyrexia
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 99 (1.01%)
         occurrences all number
    1
    1
    Atelectasis
         subjects affected / exposed
    0 / 97 (0.00%)
    2 / 99 (2.02%)
         occurrences all number
    0
    2
    Alveolar lung disease
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Dyspnoea
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 99 (1.01%)
         occurrences all number
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 97 (2.06%)
    0 / 99 (0.00%)
         occurrences all number
    2
    0
    Orthopnoea
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Rales
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Pulmonary mass
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Aggression
         subjects affected / exposed
    0 / 97 (0.00%)
    2 / 99 (2.02%)
         occurrences all number
    0
    2
    Confusional state
         subjects affected / exposed
    2 / 97 (2.06%)
    3 / 99 (3.03%)
         occurrences all number
    2
    3
    Behaviour disorder
         subjects affected / exposed
    0 / 97 (0.00%)
    2 / 99 (2.02%)
         occurrences all number
    0
    3
    Delirium
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 99 (1.01%)
         occurrences all number
    1
    1
    Delusion
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Depressed mood
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 99 (1.01%)
         occurrences all number
    1
    1
    Depression
         subjects affected / exposed
    2 / 97 (2.06%)
    0 / 99 (0.00%)
         occurrences all number
    2
    0
    Euphoric mood
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Hallucination, auditory
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Hallucination, visual
         subjects affected / exposed
    9 / 97 (9.28%)
    7 / 99 (7.07%)
         occurrences all number
    11
    8
    Irritability
         subjects affected / exposed
    2 / 97 (2.06%)
    0 / 99 (0.00%)
         occurrences all number
    2
    0
    Libido increased
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Neuropsychiatric symptoms
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Nightmare
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Panic attack
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Paranoia
         subjects affected / exposed
    2 / 97 (2.06%)
    0 / 99 (0.00%)
         occurrences all number
    2
    0
    Sexually inappropriate behaviour
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Rapid eye movement sleep behaviour disorder
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Sleep disorder
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Suicidal ideation
         subjects affected / exposed
    2 / 97 (2.06%)
    2 / 99 (2.02%)
         occurrences all number
    2
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Blood triglycerides increased
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Blood pressure decreased
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 97 (2.06%)
    2 / 99 (2.02%)
         occurrences all number
    2
    2
    Haemoglobin decreased
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Liver function test increased
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    2
    0
    Norovirus test positive
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Prostatic specific antigen increased
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Red blood cell count decreased
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Weight decreased
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    3 / 97 (3.09%)
    1 / 99 (1.01%)
         occurrences all number
    4
    1
    Facial bones fracture
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    15 / 97 (15.46%)
    10 / 99 (10.10%)
         occurrences all number
    15
    14
    Femur fracture
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    2
    0
    Foot fracture
         subjects affected / exposed
    2 / 97 (2.06%)
    0 / 99 (0.00%)
         occurrences all number
    2
    0
    Joint dislocation
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Ligament sprain
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Skin abrasion
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Rib fracture
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 99 (1.01%)
         occurrences all number
    1
    1
    Skin laceration
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 99 (1.01%)
         occurrences all number
    1
    1
    Spinal compression fracture
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Thermal burn
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Upper limb fracture
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Wound
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 99 (1.01%)
         occurrences all number
    2
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 97 (2.06%)
    0 / 99 (0.00%)
         occurrences all number
    2
    0
    Palpitations
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Dementia with Lewy bodies
         subjects affected / exposed
    0 / 97 (0.00%)
    4 / 99 (4.04%)
         occurrences all number
    0
    4
    Cognitive disorder
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 99 (1.01%)
         occurrences all number
    1
    1
    Dizziness
         subjects affected / exposed
    1 / 97 (1.03%)
    5 / 99 (5.05%)
         occurrences all number
    4
    5
    Dizziness postural
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    1 / 97 (1.03%)
    2 / 99 (2.02%)
         occurrences all number
    1
    2
    Hypersomnia
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Loss of consciousness
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 99 (1.01%)
         occurrences all number
    1
    2
    Hypoaesthesia
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Nystagmus
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Parkinsonism
         subjects affected / exposed
    2 / 97 (2.06%)
    1 / 99 (1.01%)
         occurrences all number
    2
    1
    Paraesthesia
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Petit mal epilepsy
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Restless legs syndrome
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Somnolence
         subjects affected / exposed
    1 / 97 (1.03%)
    3 / 99 (3.03%)
         occurrences all number
    1
    3
    Syncope
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Visuospatial deficit
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Tremor
         subjects affected / exposed
    2 / 97 (2.06%)
    1 / 99 (1.01%)
         occurrences all number
    2
    1
    Blood and lymphatic system disorders
    Blood loss anaemia
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Lymphopenia
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Neutropenia
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear haemorrhage
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Dry eye
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Eye discharge
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Lacrimation increased
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Anal incontinence
         subjects affected / exposed
    2 / 97 (2.06%)
    0 / 99 (0.00%)
         occurrences all number
    2
    0
    Constipation
         subjects affected / exposed
    4 / 97 (4.12%)
    1 / 99 (1.01%)
         occurrences all number
    4
    1
    Dental caries
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    3 / 97 (3.09%)
    4 / 99 (4.04%)
         occurrences all number
    3
    4
    Dry mouth
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    3 / 97 (3.09%)
    1 / 99 (1.01%)
         occurrences all number
    3
    1
    Stomatitis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    2 / 97 (2.06%)
    2 / 99 (2.02%)
         occurrences all number
    2
    2
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 97 (0.00%)
    2 / 99 (2.02%)
         occurrences all number
    0
    2
    Dermatitis bullous
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Eczema asteatotic
         subjects affected / exposed
    2 / 97 (2.06%)
    0 / 99 (0.00%)
         occurrences all number
    2
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Papule
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    2 / 97 (2.06%)
    0 / 99 (0.00%)
         occurrences all number
    2
    0
    Rash macular
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Skin lesion
         subjects affected / exposed
    0 / 97 (0.00%)
    2 / 99 (2.02%)
         occurrences all number
    0
    4
    Skin ulcer
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Xeroderma
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Dysuria
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 99 (1.01%)
         occurrences all number
    1
    1
    Pollakiuria
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 99 (1.01%)
         occurrences all number
    1
    1
    Urinary incontinence
         subjects affected / exposed
    2 / 97 (2.06%)
    2 / 99 (2.02%)
         occurrences all number
    2
    2
    Urinary retention
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 99 (1.01%)
         occurrences all number
    1
    1
    Back pain
         subjects affected / exposed
    2 / 97 (2.06%)
    0 / 99 (0.00%)
         occurrences all number
    2
    0
    Flank pain
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Joint range of motion decreased
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Mobility decreased
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Muscular weakness
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 99 (1.01%)
         occurrences all number
    1
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Neck pain
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Periarthritis
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Infections and infestations
    Cystitis
         subjects affected / exposed
    2 / 97 (2.06%)
    1 / 99 (1.01%)
         occurrences all number
    2
    1
    Bronchitis
         subjects affected / exposed
    2 / 97 (2.06%)
    1 / 99 (1.01%)
         occurrences all number
    2
    1
    Folliculitis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Herpes zoster
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 97 (3.09%)
    5 / 99 (5.05%)
         occurrences all number
    3
    5
    Pharyngitis
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Tinea pedis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 99 (1.01%)
         occurrences all number
    1
    1
    Tooth abscess
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Tooth infection
         subjects affected / exposed
    0 / 97 (0.00%)
    2 / 99 (2.02%)
         occurrences all number
    0
    3
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 97 (1.03%)
    2 / 99 (2.02%)
         occurrences all number
    1
    2
    Urinary tract infection
         subjects affected / exposed
    5 / 97 (5.15%)
    4 / 99 (4.04%)
         occurrences all number
    5
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Dehydration
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Folate deficiency
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Diabetes mellitus
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 99 (1.01%)
         occurrences all number
    1
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 97 (0.00%)
    2 / 99 (2.02%)
         occurrences all number
    0
    2
    Hypophosphataemia
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 99 (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
    29 Jan 2018
    Amendments 1: Addition inclusion criterion was added, Estimated blood volume collected during the study was updated, Description of the MDS-UPDRS was corrected, Instructions were added to recommend that subjects avoided prolonged exposure to the sun or exposure to artificial ultra-violet light, the criterion for pulse increase was removed from the definition of orthostatic hypotension.
    15 Jun 2018
    Amendment 2: Secondary endpoints for safety and tolerability were added, the information regarding breaking of blind was corrected, the “Capacity Rule” was added, CSF substudy criteria and description were added,
    10 Jul 2019
    Amendment 3: Restriction on the use of memantine prior to and during study participation was removed, The number of sites was increased from 60 to 70.
    03 Sep 2019
    Amendment 4: The percentage of randomized subjects who would be on memantine was specified.
    03 Jan 2020
    Amendment 5: Results of a nonclinical toxicology study were added, the requirement for male subjects to use highly effective contraception and the requirement to report pregnancy in female partners of male subjects were added, the order of the secondary efficacy endpoints was revised.

    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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