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    Clinical Trial Results:
    A Brain Imaging and Cognition Study to Determine Changes in Cerebral Perfusion and Cognition After Oral Administration of CST-103 or CST-139

    Summary
    EudraCT number
    		 2020-003796-17
    Trial protocol
    		 GB  
    Global end of trial date
    29 Oct 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Oct 2022
    First version publication date
    11 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CST103/CST139-CLIN-010
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CuraSen Therapeutics, Inc.
    Sponsor organisation address
    930 Brittan Avenue, #306, San Carlos, United States, CA94070
    Public contact
    Clinical Trial Information Desk, CuraSen Therapeutics, Inc., +1 650475 2842, clinicaltrials@curasen.com
    Scientific contact
    Clinical Trial Information Desk, CuraSen Therapeutics, Inc., +1 650475 2842, clinicaltrials@curasen.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
    14 Jul 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Oct 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Oct 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objectives of this study are: Part A: To evaluate the effects of CST-139 on cerebral perfusion in healthy subjects. Part B: To evaluate the effects of multiple doses of CST-139 on cerebral perfusion in subjects with Mild Cognitive Impairment (MCI) or Parkinson’s Disease (PD). Part C: To evaluate the effects of multiple doses of CST-103 on cognition in subjects with MCI or PD. Part D: To evaluate the effects of multiple doses of CST-103 on cognition in older healthy subjects (aged 55 to 75 years) Part E: To evaluate the effects of a single dose of CST-103 on cerebral perfusion in subjects who completed Part C or D
    Protection of trial subjects
    Written informed consent was obtained from each subject before any investigation specifically required for the study was performed. The informed consent forms (ICFs) were signed and dated, and were retained by the Principal Investigator as part of the clinical trial records. The terms of the consent and when it was obtained was also documented in the electronic case report form (eCRF). Each subject received a fully signed copy of each ICF that he/she signed for the study. If a protocol amendment had substantially altered the clinical trial design or increased potential risk to the study subjects, the ICF would have been revised and, if applicable, the subject’s consent to continue participation obtained.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Nov 2020
    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
    United Kingdom: 34
    Worldwide total number of subjects
    34
    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)
    29
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects who gave informed consent were screened for the study between Day -21 and Day -1. Subjects who met the eligibility criteria were enrolled and underwent the baseline assessments.

    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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Part A - CST-139 2mg
    Arm description
    		 Healthy volunteers enrolled in Part A who received CST-139 2 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    CST-139
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The study drug was administered as two or four 1-mg CST-139 tablets twice daily (4 hours apart) in the clinical study unit by the Investigator or trained and qualified designee. The first dose of study drug was administered on Day 1 following an overnight fast and light breakfast and the second dose was administered 4 hours after the first dose.

    Arm title
    		 Part A - CST-139 4 mg
    Arm description
    		 Healthy volunteers enrolled to Part A who received 4 mg CST-139.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CST-139
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The study drug was administered as two or four 1-mg CST-139 tablets twice daily (4 hours apart) in the clinical study unit by the Investigator or trained and qualified designee. The first dose of study drug was administered on Day 1 following an overnight fast and light breakfast and the second dose was administered 4 hours after the first dose.

    Arm title
    		 Part C - Placebo
    Arm description
    		 Patients with Parkinson's disease (PD) enrolled into Part C following treatment with placebo.
    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 were randomised to received active vs placebo in a cross-over design involving a 7 day dosing period, followed by a 14 day washout, followed by cross-over to 7 days dosing with the other treatment. The study drug was administered as two 40-μg CST-103 capsules or two matching placebo capsules once daily. Study drug was administered in the clinical study unit by the Investigator or trained and qualified designee following an overnight fast and light breakfast on Days 1 and 7 of each treatment period. On Days 2 to 6, the doses were self-administered by the subjects at home.

    Arm title
    		 Part C - CST-103 80 μg
    Arm description
    		 Patients with Parkinson's Disease enrolled in Part C following treatment with CST-103.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CST-103 80 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were randomised to received active vs placebo in a cross-over design involving a 7 day dosing period, followed by a 14 day washout, followed by cross-over to 7 days dosing with the other treatment. The study drug was administered as two 40-μg CST-103 capsules or two matching placebo capsules once daily. Study drug was administered in the clinical study unit by the Investigator or trained and qualified designee following an overnight fast and light breakfast on Days 1 and 7 of each treatment period. On Days 2 to 6, the doses were self-administered by the subjects at home.

    Arm title
    		 Part D - Placebo
    Arm description
    		 Healthy volunteers enrolled in Part D following treatment with placebo.
    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 were randomised to received active vs placebo in a cross-over design involving a 7 day dosing period, followed by a 14 day washout, followed by cross-over to 7 days dosing with the other treatment. The study drug was administered as two 40-μg CST-103 capsules or two matching placebo capsules once daily. Study drug was administered in the clinical study unit by the Investigator or trained and qualified designee following an overnight fast and light breakfast on Days 1 and 7 of each treatment period. On Days 2 to 6, the doses were self-administered by the subjects at home.

    Arm title
    		 Part D - CST-103 80 μg
    Arm description
    		 Healthy volunteers enrolled in Part D following treatment with CST-103.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CST-103 80 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were randomised to received active vs placebo in a cross-over design involving a 7 day dosing period, followed by a 14 day washout, followed by cross-over to 7 days dosing with the other treatment. The study drug was administered as two 40-μg CST-103 capsules or two matching placebo capsules once daily. Study drug was administered in the clinical study unit by the Investigator or trained and qualified designee following an overnight fast and light breakfast on Days 1 and 7 of each treatment period. On Days 2 to 6, the doses were self-administered by the subjects at home.

    Arm title
    		 Part E - CST-103 80 μg
    Arm description
    		 Healthy volunteers who completed Part D, enrolled to Part E and received CST-103.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CST-103 80 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The study drug was administered by the Investigator or trained and qualified designee as two 40-μg CST-103 capsules in the clinical study unit following an overnight fast and light breakfast on Day 1.

    Number of subjects in period 1
    		Part A - CST-139 2mg Part A - CST-139 4 mg Part C - Placebo Part C - CST-103 80 μg Part D - Placebo Part D - CST-103 80 μg Part E - CST-103 80 μg
    Started
    5
    6
    6
    7
    16
    16
    8
    Completed
    5
    5
    6
    6
    16
    16
    8
    Not completed
    0
    1
    0
    1
    0
    0
    0
         Adverse event, non-fatal
    -
    1
    -
    1
    -
    -
    -

    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
    		 34 34
    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)
    		 29 29
        From 65-84 years
    		 5 5
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 14 14
        Male
    		 20 20

    End points

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    End points reporting groups
    Reporting group title
    Part A - CST-139 2mg
    Reporting group description
    		 Healthy volunteers enrolled in Part A who received CST-139 2 mg

    Reporting group title
    Part A - CST-139 4 mg
    Reporting group description
    		 Healthy volunteers enrolled to Part A who received 4 mg CST-139.

    Reporting group title
    Part C - Placebo
    Reporting group description
    		 Patients with Parkinson's disease (PD) enrolled into Part C following treatment with placebo.

    Reporting group title
    Part C - CST-103 80 μg
    Reporting group description
    		 Patients with Parkinson's Disease enrolled in Part C following treatment with CST-103.

    Reporting group title
    Part D - Placebo
    Reporting group description
    		 Healthy volunteers enrolled in Part D following treatment with placebo.

    Reporting group title
    Part D - CST-103 80 μg
    Reporting group description
    		 Healthy volunteers enrolled in Part D following treatment with CST-103.

    Reporting group title
    Part E - CST-103 80 μg
    Reporting group description
    		 Healthy volunteers who completed Part D, enrolled to Part E and received CST-103.

    Primary: Part A: Change in cerebral perfusion (am)

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    End point title
    		 Part A: Change in cerebral perfusion (am) [1] [2]
    End point description
    The change in cerebral perfusion after oral administration of CST-139 as measured by arterial spin labeling magnetic resonance imaging (ALD MRI) in healthy subjects.
    End point type
    Primary
    End point timeframe
    Change from Baseline to 3 hours (± 30-minute window) after administration of the morning dose.
    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: As per protocol, no statistical analyses were performed.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this end point was relevant to Part A only.
    End point values
    		 Part A - CST-139 2mg Part A - CST-139 4 mg
    Number of subjects analysed
    5
    2
    Units: Percentage
    arithmetic mean (standard deviation)
        Whole grey matter
    0.95 ( 3.77 )
    -4.05 ( 3.13 )
        Cortex
    0.48 ( 3.93 )
    -3.95 ( 2.99 )
        Subcortical
    6.04 ( 5.55 )
    4.26 ( 3.82 )
        Striatum
    6.03 ( 5.73 )
    7.06 ( 3.61 )
        Thalamus
    6.38 ( 6.02 )
    -2.44 ( 3.67 )
        Amygdala
    6.47 ( 10.69 )
    4.84 ( 10.90 )
        Hippocampus
    7.29 ( 7.34 )
    5.95 ( 4.46 )
        Cerebellum
    2.26 ( 4.26 )
    -6.89 ( 4.45 )
        Whole white matter
    0.37 ( 3.87 )
    -4.59 ( 2.95 )
    No statistical analyses for this end point

    Primary: Part A: Change in cerebral perfusion (pm)

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    End point title
    		 Part A: Change in cerebral perfusion (pm) [3] [4]
    End point description
    The change in cerebral perfusion after oral administration of CST-139 as measured by arterial spin labeling magnetic resonance imaging (ALD MRI) in healthy subjects.
    End point type
    Primary
    End point timeframe
    Change from Baseline to 3 hours (± 30-minute window) after administration of the afternoon dose.
    Notes
    [3] - 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: As per protocol, no statistical analyses were performed.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this end point was relevant to Part A only.
    End point values
    		 Part A - CST-139 2mg Part A - CST-139 4 mg
    Number of subjects analysed
    5
    2
    Units: Percentage
    arithmetic mean (standard deviation)
        Whole grey matter
    5.18 ( 7.06 )
    3.01 ( 4.44 )
        Cortex
    4.12 ( 7.38 )
    2.09 ( 4.45 )
        Subcortical
    11.20 ( 7.38 )
    6.45 ( 4.00 )
        Striatum
    9.61 ( 7.76 )
    4.78 ( 3.39 )
        Thalamus
    14.18 ( 7.86 )
    9.00 ( 5.12 )
        Amygdala
    10.66 ( 8.02 )
    8.07 ( 2.08 )
        Hippocampus
    13.11 ( 5.48 )
    11.69 ( 2.85 )
        Cerebellum
    9.42 ( 7.51 )
    7.28 ( 3.82 )
        Whole white matter
    4.72 ( 4.94 )
    1.79 ( 3.58 )
    No statistical analyses for this end point

    Primary: Part C: Change in CANTAB cognitive assessments

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    End point title
    		 Part C: Change in CANTAB cognitive assessments [5] [6]
    End point description
    CANTAB Connect is a standardised and automated administration of cognitive testing via touch tablet, which includes the following assessments: - Reaction Time (RTI) task - Immediate and delayed Verbal Recognition Memory (VRM) recall and recognition tests - Adaptive Tracking Task (ATT) - Paired Associates Learning (PAL) task
    End point type
    Primary
    End point timeframe
    Change from Baseline to Day 7, 3 hrs post-dose.
    Notes
    [5] - 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: As per protocol, no statistical analyses were performed.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this end point was relevant to Part C only.
    End point values
    		 Part C - Placebo Part C - CST-103 80 μg Part D - Placebo Part D - CST-103 80 μg
    Number of subjects analysed
    6
    6
    16
    16
    Units: Counts
    arithmetic mean (standard deviation)
        ATT Euclidean Distance Mean
    -1.37 ( 3.390 )
    0.16 ( 6.717 )
    -0.16 ( 1.384 )
    -1.67 ( 1.561 )
        ATT Euclidean Distance Standard Deviation
    2.47 ( 1.956 )
    6.80 ( 10.165 )
    2.62 ( 4.013 )
    1.88 ( 3.406 )
        ATT Difficulty Multiplier Mean
    0.22 ( 0.317 )
    0.20 ( 0.397 )
    0.19 ( 0.165 )
    0.27 ( 0.115 )
        ATT Difficulty Multiplier Standard Deviation
    0.04 ( 0.026 )
    0.07 ( 0.124 )
    0.04 ( 0.055 )
    0.05 ( 0.054 )
        RTI Median 5-Choice Movement Time
    -24.08 ( 51.868 )
    -18.00 ( 57.546 )
    -11.06 ( 27.919 )
    -11.16 ( 42.054 )
        RTI Median 5-Choice Reaction Time
    -15.92 ( 43.496 )
    -9.08 ( 24.824 )
    -13.66 ( 36.870 )
    -22.94 ( 36.446 )
        PAL First Attempt Memory Score
    1.5 ( 2.07 )
    1.5 ( 4.04 )
    0.6 ( 4.23 )
    0.1 ( 4.77 )
        PAL Number of Patterns Reached
    0.3 ( 0.82 )
    0.3 ( 0.82 )
    0.3 ( 1.24 )
    0.3 ( 1.00 )
        PAL Total Errors (Adjusted)
    -3.5 ( 11.33 )
    -4.5 ( 11.24 )
    -4.1 ( 12.15 )
    -4.0 ( 11.45 )
        VRM Free Recall Distinct Stimuli - P1.1
    0.2 ( 3.06 )
    -0.2 ( 2.56 )
    -0.1 ( 3.19 )
    -0.6 ( 3.41 )
        VRM Free Recall Distinct Stimuli - P1.2
    0.5 ( 3.39 )
    -0.8 ( 2.23 )
    -0.6 ( 2.45 )
    0.1 ( 2.43 )
        VRM Free Recall Distinct Stimuli - P1.3
    -0.7 ( 1.86 )
    0.2 ( 1.47 )
    -1.3 ( 2.98 )
    -0.9 ( 2.77 )
        VRM Delayed Free Recall Distinct Stimuli - P2.1
    0.6 ( 3.36 )
    0.2 ( 3.31 )
    -1.5 ( 2.50 )
    -1.1 ( 3.10 )
        VRM Delayed Recognition Total Correct - P2.2
    -0.6 ( 2.30 )
    0.0 ( 2.10 )
    -1.0 ( 1.83 )
    -0.5 ( 1.59 )
    No statistical analyses for this end point

    Primary: Part E: Change in cerebral perfusion

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    End point title
    		 Part E: Change in cerebral perfusion [7] [8]
    End point description
    The change in cerebral perfusion after oral administration of CST-103 as measured by arterial spin labeling magnetic resonance imaging (ALD MRI) in healthy subjects.
    End point type
    Primary
    End point timeframe
    Change from Baseline to 3 hours (± 60-minute window) post-dose.
    Notes
    [7] - 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: As per protocol, no statistical analyses were performed.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this end point was relevant to Part E only.
    End point values
    		 Part E - CST-103 80 μg
    Number of subjects analysed
    8
    Units: Percentage
    arithmetic mean (standard deviation)
        Whole grey matter
    4.76 ( 5.44 )
        Cortex
    3.86 ( 5.03 )
        Subcortical
    8.90 ( 4.81 )
        Striatum
    5.83 ( 6.41 )
        Thalamus
    15.24 ( 8.00 )
        Amygdala
    9.96 ( 6.96 )
        Hippocampus
    21.73 ( 8.89 )
        Cerebellum
    8.46 ( 9.83 )
        Whole white matter
    5.67 ( 6.42 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose until completion of end of study visit.
    Adverse event reporting additional description
    It is noted that the number of occurrences of each adverse event was not reported in the Clinical Study Report. Therefore the number of occurrences presented below is the same as the number of subjects experiencing each event.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Part A - CST-139 2mg
    Reporting group description
    		 Healthy volunteers enrolled in Part A who received CST-139 2 mg

    Reporting group title
    Part A - CST-139 4 mg
    Reporting group description
    		 Healthy volunteers enrolled to Part A who received 4 mg CST-139.

    Reporting group title
    Part C - Placebo
    Reporting group description
    		 Patients with Parkinson's disease (PD) enrolled into Part C and randomised to receive placebo.

    Reporting group title
    Part C - CST-103
    Reporting group description
    		 Patients with Parkinson's Disease enrolled in Part C and randomised to receive CST-103

    Reporting group title
    Part D - Placebo
    Reporting group description
    		 Healthy volunteers enrolled in Part D and randomised to receive placebo.

    Reporting group title
    Part D - CST-103
    Reporting group description
    		 Healthy volunteers enrolled in Part D randomised to receive CST-103.

    Reporting group title
    Part E - CST-103
    Reporting group description
    		 Patients with Parkinson's disease who completed Part C or Part D, enrolled to Part E and received CST-103.

    Serious adverse events
    		 Part A - CST-139 2mg Part A - CST-139 4 mg Part C - Placebo Part C - CST-103 Part D - Placebo Part D - CST-103 Part E - CST-103
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Part A - CST-139 2mg Part A - CST-139 4 mg Part C - Placebo Part C - CST-103 Part D - Placebo Part D - CST-103 Part E - CST-103
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 5 (80.00%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    5 / 7 (71.43%)
    5 / 16 (31.25%)
    13 / 16 (81.25%)
    4 / 8 (50.00%)
    Investigations
    Electrocardiogram ST segment depression
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    0
    Palpitations
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    2
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 5 (60.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    3 / 7 (42.86%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    3
    2
    0
    3
    1
    0
    1
    Tremor
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 7 (57.14%)
    0 / 16 (0.00%)
    9 / 16 (56.25%)
    2 / 8 (25.00%)
         occurrences all number
    1
    0
    0
    4
    0
    9
    2
    Dizziness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    General disorders and administration site conditions
    Feeling jittery
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    2 / 16 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    0
    Fatigue
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Feeling abnormal
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Ear and labyrinth disorders
    Otorrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Toothache
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Psychiatric disorders
    Nervousness
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
    4 / 16 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    4
    0
    Muscle tightness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
    2 / 16 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Oct 2020
    The major changes in Version 2.0 (Amendment 1, 07 October 2020) were: • Added a section describing the Dose Level Review Meetings (DLRMs). • Revised the contraceptive inclusion criteria to reference the added Section 5.5, Contraception based on comments from the Medicines and Healthcare products Regulatory Agency (MHRA). Changes were inclusion of a definition of sexual abstinence, removal of period abstinence and withdrawal as acceptable methods of contraception, and removal of tubal ligation as a surgical sterilization procedure. • Added the exclusion criterion regarding uncontrolled hypertension based on comments from the MHRA because β-AR agonists are known to be associated with hypertension risk. • For clarity, revised terminology “Q4 hours” to specify that twice-daily doses were to be given 4 hours apart.
    26 Jan 2021
    The major changes in Versions 3.0, 3.1 and 3.2 (Amendment 2, 20 January 2021, 21 January 2021 and 26 January 2021, respectively) were: • Changed the primary objective of Part C to evaluating the effects of multiple doses of CST-103 on cognition (it was previously cerebral perfusion based on imaging) and changed the design so that the same randomized, double-blind, placebo-controlled, 2-way crossover design would be used in Parts C and D. Part C was originally designed to provide both imaging and cognition data on the same subjects. However, to minimize potential COVID-19 exposure that may have occurred during the imaging procedure, the protocol was amended to remove imaging during the worst of the COVID-19 pandemic. • Added Part D to evaluate the effects of multiple doses of CST-103 on cognition in older healthy subjects. • Deleted the exclusion criterion for subjects on monoamine oxidase type B inhibitors, dopamine agonists, or catechol-O-methyltransferase inhibitors. Those medications are commonly used by Parkinson's Disease (PD) subjects and were not excluded in other CuraSen studies in a similar study population.
    26 Apr 2021
    The major changes in Versions 4.0 and 4.1 (Amendment 3, 22 April 2021 and 26 April 2021, respectively), which was the final version of the protocol, were: • Deleted Part B that was to evaluate the effects of multiple doses of CST-139 on cerebral perfusion in subjects with Mild Cognitive Impairment (MCI) or PD. A DLRM meeting after the conclusion of Part A determined that due to the drug-related Treatment-Emergent Adverse Events (TEAEs) and variability in the CST-139 plasma concentrations and pharmacokinetics results further investigation of CST-139 in Part B was not warranted. • Added Part E to evaluate the effects of a single dose of CST-103 on cerebral perfusion in subjects who completed Parts C or D.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    02 Sep 2021
    The study was placed on temporary hold and then subsequently terminated early due to a high screen failure rate, challenges due to the COVID-19 pandemic, and a competing CuraSen study enrolling subjects at the same site. There were no safety concerns with the program.
    -

    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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