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    Clinical Trial Results:
    A Phase IIa study to assess the safety, tolerability, plasma pharmacokinetics and efficacy of intermittent oral administration of standard levodopa/carbidopa vs. semi-continuous intra-oral administration of levodopa/carbidopa in patients with advanced Parkinson’s disease who suffer motor fluctuations.

    Summary
    EudraCT number
    		 2014-002295-87
    Trial protocol
    		 IT  
    Global end of trial date
    07 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 May 2021
    First version publication date
    19 May 2021
    Other versions
    Summary report(s)
    		 SynAgileConInfusionPrimaryManuscript

    Trial information

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    Trial identification
    Sponsor protocol code
    LDCD-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    SynAgile Corporation
    Sponsor organisation address
    3465 N. Pines Way, Suite 104, PMB218, Wilson, United States, 83014
    Public contact
    Jennifer Harmon, SynAgile, 65 8182 3942, jharmon@synagile.com
    Scientific contact
    Jennifer Harmon, SynAgile, 65 8182 3942, jharmon@synagile.com
    Sponsor organisation name
    SynAgile Corporation
    Sponsor organisation address
    3465 N. Pines Way, Suite 104, PMB 218, Wilson, United States, 83014
    Public contact
    Jennifer Harmon, SynAgile Corporation, +65 8742 8832, jharmon@synagile.com
    Scientific contact
    Jennifer Harmon, SynAgile Corporation, +65 8742 8832, jharmon@synagile.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
    08 Oct 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the plasma pharmacokinetics of continuous intra-oral administration of LD/CD vs. intermittent administration of standard oral LD/CD
    Protection of trial subjects
    EC approval was obtained prior to the start of the study and all subjects were required to sign the EC approved consent prior to the start of the study. An enrollment authorization committee approved all subjects for participation to ensure all inclusion/exclusion criteria had been met and subjects were suitable for participation. A blinded medical monitor reviewed accumulating data during the conduct of the study to ensure that no safety trends were emerging.
    Background therapy
    		 3Stable doses of levodopa plus/minus other dopaminergic therapy (minimum of 4 weeks for each drug). Subjects were excluded if ythey were receiving duodopa, apomorphine infusion or DBS.
    Evidence for comparator
    		 Comparator on Day 1 was usual oral L-dopa/carbidopa dose; day 2 was the investigational dose of L-dopa/carbidopa by "continuous" oral administration and Day3 subjects received a single oral L-dopa/carbidopa dose followed by "continuous" oral administration of L-dopa/carbidopa
    Actual start date of recruitment
    07 Jul 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 18
    Worldwide total number of subjects
    18
    EEA total number of subjects
    18
    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)
    6
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited directly from one clinical site in Italy from the investigators own patient population

    Pre-assignment
    Screening details
    		 Male and female PD subjects of any race aged 35 to 75 years who sign an EC/IRB-approved informed consent. PD diagnosis consistent with UK Brain Bank Criteria. Good response to levodopa with at least 2 hours of wearing off episodes in judgment of investigator Stable doses of levodopa plus/minus other dopaminergic therapy. MMSE>26

    Pre-assignment period milestones
    Number of subjects started
    		 18
    Number of subjects completed
    		 18

    Period 1
    Period 1 title
    Overal Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Day 1
    Arm description
    		 Subjects received their usual oral L-dopa/carbidopa doses
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Standard oral L-dopa/carbidopa
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects took their standard oral L-dopa/carbidopa tablets at their individual usual dosage and time

    Arm title
    		 Day 2
    Arm description
    		 Subjects received L-dopa/carbidopa by "continuous" oral administration
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sinemet 25/100 include: 25 mg carbidopa and 100 mg levodopa administered as a dispersion - chopped and mixed in 50 ml of neutral pH water w/out buffer
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    At the clinic, investigators will prepare suspensions of LD/CD in distilled or deionized water. Fresh suspensions will be prepared every hour. One tablet of Sinemet 25/100 (each tablet containing 100 mg LD and 25 mg CD) will be chopped up by placing the tablet in a pill cuter and chopping the tablet in half, and mixed or shaken in 50 mL of water in a small glass flask with a stopper. Formulas for the volume to be taken every 5 minutes were provided to the site as part of the dosing manual.

    Arm title
    		 Day 3
    Arm description
    		 Subjects received a single dose of oral L-dopa/carbidopa followed by "continuous" oral administration of L-dopa/carbidopa
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sinemet 25/100 include: 25 mg carbidopa and 100 mg levodopa administered as a dispersion - chopped and mixed in 50 ml of neutral pH water w/out buffer
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Initial sinemet tablet of 25/100 given as the initial morning dose and then at the clinic, investigators will prepare suspensions of LD/CD in distilled or deionized water. Fresh suspensions will be prepared every hour. One tablet of Sinemet 25/100 (each tablet containing 100 mg LD and 25 mg CD) will be chopped up by placing the tablet in a pill cuter and chopping the tablet in half, and mixed or shaken in 50 mL of water in a small glass flask with a stopper. Formulas for the volume to be taken every 5 minutes were provided to the site as part of the dosing manual.

    Number of subjects in period 1
    		Day 1 Day 2 Day 3
    Started
    18
    18
    18
    Completed
    18
    18
    18

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overal Trial
    Reporting group description
    		 -

    Reporting group values
    		 Overal Trial Total
    Number of subjects
    		 18 18
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68 ( 8.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 11 11

    End points

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    End points reporting groups
    Reporting group title
    Day 1
    Reporting group description
    		 Subjects received their usual oral L-dopa/carbidopa doses

    Reporting group title
    Day 2
    Reporting group description
    		 Subjects received L-dopa/carbidopa by "continuous" oral administration

    Reporting group title
    Day 3
    Reporting group description
    		 Subjects received a single dose of oral L-dopa/carbidopa followed by "continuous" oral administration of L-dopa/carbidopa

    Primary: Levodopa concentration (ng/ml), fluctuation index (PK set) 4.5-8 hours

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    End point title
    		 Levodopa concentration (ng/ml), fluctuation index (PK set) 4.5-8 hours
    End point description
    Fluctuation index is calculated from all concentrations within the time interval difference between Day 2 and Day 3 is tested with t-test.
    End point type
    Primary
    End point timeframe
    4.5 to 8 hours post dose on Days 2 and 3
    End point values
    		 Day 1 Day 2 Day 3
    Number of subjects analysed
    18 [1]
    18
    18
    Units: ng/ml
    18
    18
    18
    Notes
    [1] - Day 1 was not included in the primary endpoint
    Statistical analysis title
    		 Levodopa concentration (ng/ml), fluctuation index
    Statistical analysis description
    Fluctuation index is calculated from all concentrations within the time interval difference between Day 2 and Day 3 is tested with t-test
    Comparison groups
    Day 2 v Day 3
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.0147 [3]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [2] - fluctuation index
    [3] - Mean on Day 2 is 1.38, SD of 0.51. On Day 3 mean = 0.99 with SD 0.39

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From the time of signing informed consent through last study visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Frequency threshold for reporting non-serious adverse events: 1%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: A total of 3 non-serious adverse events occurred in 2 subjects. All were determined to be mild in severity and not related. Reported terms are accidental fall, pelvic contusion, and fever.

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30653246
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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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