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    Clinical Trial Results:
    Dose finding phase IIb study of Bavisant to evaluate its safety and efficacy in treatment of excessive daytime sleepiness (EDS) in Parkinson’s Disease (PD). CASPAR study.

    Summary
    EudraCT number
    		 2017-000877-35
    Trial protocol
    		 CZ   ES   GB   DE   IT  
    Global end of trial date
    28 May 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Aug 2021
    First version publication date
    27 Aug 2021
    Other versions
    Summary report(s)
    		 BB-2001-201b_Synopsis_v1.0_23Apr2020

    Trial information

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    Trial identification
    Sponsor protocol code
    BB-2001-201b
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03194217
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    BenevolentAI Bio Limited
    Sponsor organisation address
    4-8 Maple Street, London, United Kingdom, W1T 5HD
    Public contact
    Chief Scientific Officer, BenevolentAI Bio, +44 2037819360, anne.phelan@benevolent.ai
    Scientific contact
    Chief Scientific Officer, BenevolentAI Bio, +44 2037819360, anne.phelan@benevolent.ai
    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
    09 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    28 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of Bavisant compared to placebo on excessive daytime sleepiness (EDS) in Parkinson's Disease (PD) after a 6-week treatment period.
    Protection of trial subjects
    Suicide risk was assessed by C-SSRS before and after treatment administration at all study visits (including follow-up) in accordance with FDA Guidance for Industry on Suicidal Ideation and Behavior. BPRS+ was used to monitor psychotic symptoms and HAM-D to monitor depression at all study visits (including follow-up). These assessments were included because subjects with PD are at a higher risk of psychosis and depression than the general population. Vital signs (including blood pressure and heart rate) were assessed at all study visits (including follow-up) because subjects with PD commonly exhibit orthostatism and other cardiovascular changes.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Oct 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 74
    Country: Number of subjects enrolled
    Spain: 44
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Czechia: 21
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Italy: 36
    Country: Number of subjects enrolled
    United States: 47
    Worldwide total number of subjects
    244
    EEA total number of subjects
    197
    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)
    84
    From 65 to 84 years
    160
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 230 subjects were planned for enrollment. 248 subjects were randomised, of which 244 received the double-blind medication. The randomization followed a centralized method, and was stratified by region (US, Western Europe, Eastern Europe) and by whether or not the site performed polysonmography and maintenance of wakefulness test (MWT).

    Pre-assignment
    Screening details
    		 A total of 364 subjects were screened. 116 were screening failures and 248 were randomised. 4 out of the 248 did not receive the study medication. The 244 that received the study medication satisfied the inclusion/exclusion criteria prior to entry in the study.

    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, Assessor
    Blinding implementation details
    IMP administration was blinded; the randomization schedule and the allocation to treatment groups were not known by the investigator, the sponsor, or any other person involved in the conduct of the study, except in the case of an emergency if knowledge of the IMP was necessary to provide optimal treatment to the subject. Bavisant and placebo tablets had identical appearance. Prior consent from sponsor/representative was required where possible before emergency unblinding by the investigator.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bavisant (0.5mg)
    Arm description
    		 Subjects were randomly allocated to 1 of 4 treatment groups at a ratio of 1:1:1:1 to one of the following IMPs: - Bavisant 0.5 mg tablets - Bavisant 1.0 mg tablets - Bavisant 3.0 mg tablets - Placebo tablets
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bavisant
    Investigational medicinal product code
    BEN2001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets containing bavisant dihydrochloride monohydrate equivalent to 0.5 mg of bavisant. Dosage: Once daily administration

    Arm title
    		 Bavisant (1.0mg)
    Arm description
    		 Subjects were randomly allocated to 1 of 4 treatment groups at a ratio of 1:1:1:1 to one of the following IMPs: - Bavisant 0.5 mg tablets - Bavisant 1.0 mg tablets - Bavisant 3.0 mg tablets - Placebo tablets
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bavisant
    Investigational medicinal product code
    BEN2001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets containing bavisant dihydrochloride monohydrate equivalent to 1.0 mg of bavisant. Dosage: Once daily administration

    Arm title
    		 Bavisant (3.0mg)
    Arm description
    		 Subjects were randomly allocated to 1 of 4 treatment groups at a ratio of 1:1:1:1 to one of the following IMPs: - Bavisant 0.5 mg tablets - Bavisant 1.0 mg tablets - Bavisant 3.0 mg tablets - Placebo tablets
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bavisant
    Investigational medicinal product code
    BEN2001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets containing bavisant dihydrochloride monohydrate equivalent to 3.0 mg of bavisant. Dosage: Once daily administration

    Arm title
    		 Placebo
    Arm description
    		 Subjects were randomly allocated to 1 of 4 treatment groups at a ratio of 1:1:1:1 to one of the following IMPs: - Bavisant 0.5 mg tablets - Bavisant 1.0 mg tablets - Bavisant 3.0 mg tablets - Placebo tablets
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablets to the IMP. Dosage: Once daily administration

    Number of subjects in period 1
    		Bavisant (0.5mg) Bavisant (1.0mg) Bavisant (3.0mg) Placebo
    Started
    60
    60
    64
    60
    Completed
    57
    56
    60
    60
    Not completed
    3
    4
    4
    0
         Selection criteria
    -
    -
    1
    -
         Patient decision
    1
    1
    -
    -
         Adverse event, non-fatal
    2
    3
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 244 244
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 84 84
        From 65-84 years
    		 160 160
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 81 81
        Male
    		 163 163
    Subject analysis sets

    Subject analysis set title
    Efficacy
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Efficacy Set consisted of all patients in the intent-to-treat (ITT) population and supportive analyses in the per-protocol (PP) population.

    Subject analysis sets values
    		 Efficacy
    Number of subjects
    244
    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)
    84
        From 65-84 years
    160
        85 years and over
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
    81
        Male
    163

    End points

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    End points reporting groups
    Reporting group title
    Bavisant (0.5mg)
    Reporting group description
    		 Subjects were randomly allocated to 1 of 4 treatment groups at a ratio of 1:1:1:1 to one of the following IMPs: - Bavisant 0.5 mg tablets - Bavisant 1.0 mg tablets - Bavisant 3.0 mg tablets - Placebo tablets

    Reporting group title
    Bavisant (1.0mg)
    Reporting group description
    		 Subjects were randomly allocated to 1 of 4 treatment groups at a ratio of 1:1:1:1 to one of the following IMPs: - Bavisant 0.5 mg tablets - Bavisant 1.0 mg tablets - Bavisant 3.0 mg tablets - Placebo tablets

    Reporting group title
    Bavisant (3.0mg)
    Reporting group description
    		 Subjects were randomly allocated to 1 of 4 treatment groups at a ratio of 1:1:1:1 to one of the following IMPs: - Bavisant 0.5 mg tablets - Bavisant 1.0 mg tablets - Bavisant 3.0 mg tablets - Placebo tablets

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were randomly allocated to 1 of 4 treatment groups at a ratio of 1:1:1:1 to one of the following IMPs: - Bavisant 0.5 mg tablets - Bavisant 1.0 mg tablets - Bavisant 3.0 mg tablets - Placebo tablets

    Subject analysis set title
    Efficacy
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Efficacy Set consisted of all patients in the intent-to-treat (ITT) population and supportive analyses in the per-protocol (PP) population.

    Primary: Efficacy: Mean Absolute Change in the Epworth Sleepiness Scale (ESS) from baseline to the end of the 6-week treatment period

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    End point title
    		 Efficacy: Mean Absolute Change in the Epworth Sleepiness Scale (ESS) from baseline to the end of the 6-week treatment period
    End point description
    Mean Absolute Change in Epworth Sleepiness Scale Score from Baseline to the End of the 6-week Treatment Period (Analysis of Covariance Model, Multiple Imputation) (Intent-to-Treat Population)
    End point type
    Primary
    End point timeframe
    From baseline to the end of the 6-week treatment period.
    End point values
    		 Bavisant (0.5mg) Bavisant (1.0mg) Bavisant (3.0mg) Placebo
    Number of subjects analysed
    60
    60
    64
    60
    Units: Epworth Sleepiness Scale
    arithmetic mean (standard deviation)
        Baseline Mean
    15.50 ± 2.17
    15.60 ± 2.51
    15.44 ± 2.46
    15.75 ± 2.53
        6-week Mean
    10.86 ± 4.57
    12.05 ± 4.54
    10.87 ± 3.97
    11.37 ± 5.09
        Absolute change from baseline Mean
    -4.66 ± 3.80
    -3.49 ± 4.31
    -4.62 ± 3.68
    -4.38 ± 4.23
    Statistical analysis title
    		 Primary Endpoint Analysis (0.5mg)
    Comparison groups
    Bavisant (0.5mg) v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Least-squared Mean
    Point estimate
    -4.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.64
         upper limit
    		 -3.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.51
    Notes
    [1] - Statistical significance was assessed as two-sided P value < 0.05
    Statistical analysis title
    		 Primary Endpoint Analysis (1.0mg)
    Comparison groups
    Bavisant (1.0mg) v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Least-squared Mean
    Point estimate
    -3.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.46
         upper limit
    		 -2.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.51
    Notes
    [2] - Statistical significance was assessed as two-sided P value < 0.05
    Statistical analysis title
    		 Primary Endpoint Analysis (3.0mg)
    Comparison groups
    Bavisant (3.0mg) v Placebo
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [3]
    Method
    		 ANCOVA
    Parameter type
    		 Least-squared Mean
    Point estimate
    -4.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.72
         upper limit
    		 -3.75
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5
    Notes
    [3] - Statistical significance was assessed as two-sided P value < 0.05

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to the 4-week follow-up period (post-dose).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Related Treatment-emergent Adverse Events
    Reporting group description
    		 Total for all participants randomised in the study

    Reporting group title
    Subjects affected by SAEs
    Reporting group description
    		 Total for all participants randomised for the study

    Serious adverse events
    		 Related Treatment-emergent Adverse Events Subjects affected by SAEs
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 244 (0.00%)
    3 / 244 (1.23%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Surgical and medical procedures
    Cholecystectomy
    Additional description: assessed as unrelated to the IMP, occuring in the placebo group
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
    Additional description: Occured in the 3.0mg treatment group and considered unrelated to the IMP by the investigator
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
    Additional description: Occured in the 3.0mg group and was considered unrelated to the IMP by the investigator
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Related Treatment-emergent Adverse Events Subjects affected by SAEs
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 244 (18.85%)
    0 / 244 (0.00%)
    Investigations
    Blood triglycerides increased
         subjects affected / exposed
    5 / 244 (2.05%)
    0 / 244 (0.00%)
         occurrences all number
    5
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 244 (1.23%)
    0 / 244 (0.00%)
         occurrences all number
    3
    0
    Tremor
         subjects affected / exposed
    2 / 244 (0.82%)
    0 / 244 (0.00%)
         occurrences all number
    2
    0
    Somnolence
         subjects affected / exposed
    4 / 244 (1.64%)
    0 / 244 (0.00%)
         occurrences all number
    4
    0
    Eye disorders
    Cataract nuclear
         subjects affected / exposed
    2 / 244 (0.82%)
    0 / 244 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    7 / 244 (2.87%)
    0 / 244 (0.00%)
         occurrences all number
    7
    0
    Dry mouth
         subjects affected / exposed
    3 / 244 (1.23%)
    0 / 244 (0.00%)
         occurrences all number
    3
    0
    Psychiatric disorders
    Initial insomnia
         subjects affected / exposed
    9 / 244 (3.69%)
    0 / 244 (0.00%)
         occurrences all number
    9
    0
    Middle insomnia
         subjects affected / exposed
    5 / 244 (2.05%)
    0 / 244 (0.00%)
         occurrences all number
    5
    0
    Insomnia
         subjects affected / exposed
    3 / 244 (1.23%)
    0 / 244 (0.00%)
         occurrences all number
    3
    0
    Nightmare
         subjects affected / exposed
    3 / 244 (1.23%)
    0 / 244 (0.00%)
         occurrences all number
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    The secondary endpoints were not reported however, the synopsis (which includes description of the study endpoints) has been included as part of this CSR.
    For support, Contact us.
    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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