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    Clinical Trial Results:
    An Open-Label, Randomized, Crossover Trial utilizing a Single-Blinded Rater to evaluate APL-130277 compared to subcutaneous Apomorphine in Levodopa Responsive Subjects with Parkinson’s Disease Complicated by Motor Fluctuations

    Summary
    EudraCT number
    		 2016-003456-70
    Trial protocol
    		 GB   DE   AT   ES   IT  
    Global end of trial date
    11 Aug 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    15 Jun 2023
    First version publication date
    19 Aug 2022
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CTH-302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03391882
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sunovion Pharmaceuticals Inc.
    Sponsor organisation address
    84 Waterford Drive, Marlboro, United States, 01752
    Public contact
    CNS Medical Director, Sunovion Pharmaceuticals Inc., 01 18665036351, clinicaltrialdisclosure@sunovion.com
    Scientific contact
    CNS Medical Director, Sunovion Pharmaceuticals Inc., 01 18665036351, clinicaltrialdisclosure@sunovion.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
    11 Aug 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Aug 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Aug 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to demonstrate the efficacy of sublingual (sl) APL-130277 compared to subcutaneous (sc) apomorphine as a treatment of “OFF” episodes in subjects with Parkinson’s Disease (PD) as measured by the change from pre-dose to 90 minutes post-dose in Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III score.
    Protection of trial subjects
    The study was conducted according to the protocol, ICH Good Clinical Practice (GCP), ICH guidelines, and the ethical principles that have their origin in the Declaration of Helsinki
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Oct 2018
    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
    Germany: 41
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    France: 3
    Worldwide total number of subjects
    112
    EEA total number of subjects
    101
    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)
    52
    From 65 to 84 years
    60
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patients with Parkinson’s disease (PD) complicated by motor fluctuations (‘OFF’ episodes) were recruited for this study Approval was obtained from the Enrollment Adjudication Committee and Sponsor prior to enrollment of each patient.

    Pre-assignment
    Screening details
    		 Screening assessments must be performed within 21 days before Titration Visit 1. If TV1 is required to occur more than 21 days after SV1, Medical Monitor approval is required. Subjects who fail screening process will be allowed to rescreen once if agreed by the Medical Monitor There were 113 subjects randomized, 112 dosed with study drug.

    Period 1
    Period 1 title
    Part A - Titration Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 APL-SC
    Arm description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine); Did not continue in Part B - Treatment Phase.
    Arm type
    		 Experimental/Active comparator

    Investigational medicinal product name
    Subcutaneous Apomorphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2mg, 3mg, 4mg, 5/6mg

    Investigational medicinal product name
    APL-130277
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sublingual film
    Routes of administration
    Oral use
    Dosage and administration details
    10/15 mg, 20mg, 25mg. 30mg

    Arm title
    		 SC-APL
    Arm description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then apomorphine hydrochloride APL (APL-130277); Did not continue in Part B - Treatment Phase.
    Arm type
    		 Experimental/Active comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 APL-SC-APL-SC
    Arm description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine) into Part B - Treatment Phase: APL then SC
    Arm type
    		 Experimental/Active comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 APL-SC-SC-APL
    Arm description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine); Randomized into Part B - Treatment Phase: SC then APL
    Arm type
    		 Experimental/Active comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 SC-APL-APL-SC
    Arm description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then APL (APL-130277); Randomized into Part B - Treatment Phase: APL then SC
    Arm type
    		 Experimental/Active comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 SC-APL-SC-APL
    Arm description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then APL (APL-130277); Randomized into Part B - Treatment Phase: SC then APL
    Arm type
    		 Experimental/Active comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		APL-SC SC-APL APL-SC-APL-SC APL-SC-SC-APL SC-APL-APL-SC SC-APL-SC-APL
    Started
    20
    18
    19
    18
    18
    19
    Safety Population Part A
    20
    18
    19
    18
    18
    19
    Mod.Intent-to-Treat Population Part A
    20
    18
    19
    18
    18
    19
    Completed
    2
    3
    19
    18
    18
    19
    Not completed
    18
    15
    0
    0
    0
    0
         Consent withdrawn by subject
    3
    2
    -
    -
    -
    -
         Adverse event, non-fatal
    3
    6
    -
    -
    -
    -
         EARLY TERM AT SPONSOR REQUEST
    -
    1
    -
    -
    -
    -
         Lack of efficacy
    12
    6
    -
    -
    -
    -
    Period 2
    Period 2 title
    Post Part A / Pre Part B
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 APL-SC
    Arm description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine); Did not continue in Part B - Treatment Phase.
    Arm type
    		 Experimental/Active comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 SC-APL
    Arm description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then apomorphine hydrochloride APL (APL-130277); Did not continue in Part B - Treatment Phase.
    Arm type
    		 Experimental/Active comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 APL-SC-APL-SC
    Arm description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine) into Part B - Treatment Phase: APL then SC
    Arm type
    		 Experimental/Active comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 APL-SC-SC-APL
    Arm description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine); Randomized into Part B - Treatment Phase: SC then APL
    Arm type
    		 Experimental/Active comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 SC-APL-APL-SC
    Arm description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then APL (APL-130277); Randomized into Part B - Treatment Phase: APL then SC
    Arm type
    		 Experimental/Active comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 SC-APL-SC-APL
    Arm description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then APL (APL-130277); Randomized into Part B - Treatment Phase: SC then APL
    Arm type
    		 Experimental/Active comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		APL-SC SC-APL APL-SC-APL-SC APL-SC-SC-APL SC-APL-APL-SC SC-APL-SC-APL
    Started
    2
    3
    19
    18
    18
    19
    Completed
    0
    0
    19
    18
    18
    19
    Not completed
    2
    3
    0
    0
    0
    0
         Lack of efficacy
    1
    3
    -
    -
    -
    -
         Protocol deviation
    1
    -
    -
    -
    -
    -
    Period 3
    Period 3 title
    Part B - Treatment Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 APL-SC-APL-SC
    Arm description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine) into Part B - Treatment Phase: APL then SC
    Arm type
    		 Experimental/Active comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 APL-SC-SC-APL
    Arm description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine); Randomized into Part B - Treatment Phase: SC then APL
    Arm type
    		 Experimental/Active comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 SC-APL-APL-SC
    Arm description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then APL (APL-130277); Randomized into Part B - Treatment Phase: APL then SC
    Arm type
    		 Experimental/Active comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 SC-APL-SC-APL
    Arm description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then APL (APL-130277); Randomized into Part B - Treatment Phase: SC then APL
    Arm type
    		 Experimental/Active comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		APL-SC-APL-SC APL-SC-SC-APL SC-APL-APL-SC SC-APL-SC-APL
    Started
    19
    18
    18
    19
    Safety Population Part B
    19
    18
    18
    19
    Mod. Intent-to-Treat Population Part B
    19
    18
    18
    19
    Completed
    16
    15
    14
    15
    Not completed
    3
    3
    4
    4
         Consent withdrawn by subject
    2
    2
    1
    3
         Adverse event, non-fatal
    1
    1
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    APL-SC
    Reporting group description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine); Did not continue in Part B - Treatment Phase.

    Reporting group title
    SC-APL
    Reporting group description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then apomorphine hydrochloride APL (APL-130277); Did not continue in Part B - Treatment Phase.

    Reporting group title
    APL-SC-APL-SC
    Reporting group description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine) into Part B - Treatment Phase: APL then SC

    Reporting group title
    APL-SC-SC-APL
    Reporting group description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine); Randomized into Part B - Treatment Phase: SC then APL

    Reporting group title
    SC-APL-APL-SC
    Reporting group description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then APL (APL-130277); Randomized into Part B - Treatment Phase: APL then SC

    Reporting group title
    SC-APL-SC-APL
    Reporting group description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then APL (APL-130277); Randomized into Part B - Treatment Phase: SC then APL

    Reporting group values
    		 APL-SC SC-APL APL-SC-APL-SC APL-SC-SC-APL SC-APL-APL-SC SC-APL-SC-APL Total
    Number of subjects
    		 20 18 19 18 18 19 112
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0 0 0 0 0 0
        Between 18 and 65 years
    		 9 8 8 10 9 8 52
        >=65 years
    		 11 10 11 8 9 11 60
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 64.9 ± 8.33 63.9 ± 9.99 65.0 ± 9.80 63.2 ± 6.91 63.4 ± 9.71 65.6 ± 8.96 -
    Gender, Male/Female
    Units: Participants
        Female
    		 7 7 6 1 6 7 34
        Male
    		 13 11 13 17 12 12 78
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0
        Asian
    		 0 0 0 0 0 0 0
        Black or African American
    		 0 0 0 0 0 0 0
        More than one race
    		 0 0 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0 0 0
        White
    		 20 18 19 18 18 19 112
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 3 1 1 2 1 8
        Not Hispanic or Latino
    		 19 15 18 16 16 18 102
        Unknown or Not Reported
    		 1 0 0 1 0 0 2
    Country
    Units: Subjects
        Austria
    		 1 0 2 1 1 0 5
        Germany
    		 6 2 8 10 5 10 41
        Spain
    		 7 8 4 3 5 4 31
        France
    		 1 1 0 0 0 1 3
        United Kingdom
    		 1 1 1 3 2 3 11
        Italy
    		 4 6 4 1 5 1 21
    Apomorphine naive at screening
    Units: Subjects
        Not Naive
    		 1 2 5 2 2 1 13
        Yes Naive
    		 19 16 14 16 16 18 99
    Total Daily Levodopa Dose Category (mg)
    Units: Subjects
        < 900 mg
    		 15 13 15 14 15 14 86
        >= 900 mg
    		 5 5 4 4 3 5 26
    Parkinson's disease duration Group
    Units: Subjects
        <=10 years
    		 17 14 11 12 10 11 75
        >10 years
    		 3 4 8 6 8 8 37
    Baseline Height (cm)
    Units: cm
        arithmetic mean (standard deviation)
    		 168.05 ± 12.626 165.62 ± 12.348 171.91 ± 10.260 174.78 ± 6.632 170.94 ± 9.795 171.16 ± 9.929 -
    Baseline Weight (kg)
    Units: kg
        arithmetic mean (standard deviation)
    		 74.25 ± 16.151 70.91 ± 18.624 78.45 ± 21.893 80.31 ± 11.691 83.26 ± 24.383 77.14 ± 15.284 -
    Baseline BMI (kg/m^2)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 26.19 ± 4.436 25.60 ± 4.813 26.36 ± 5.866 26.34 ± 4.013 28.12 ± 6.100 26.30 ± 4.912 -
    Movement Disorders Society Unified Parkinson Part III Score assessed prior to levodopa dosing at SV2
    The summary score used here is Part III motor examination score. Each Part III item has a 0-4 rating, where 0=normal, 1=slight, 2=mild, 3= moderate, and 4=severe. Higher MDS-UPDRS scores reflect worse motor function. MDS-UPDRS III is a total of 18 questions with 33 individual items, each item ranges from 0-4. The MDS-UPDRS III motor score is the summation of all these 33 individual item scores, and hence ranges from 0-132. Score drops over time imply improvement in motor function (higher values represent a worse outcome). SV2= Screening Visit 2
    Units: Units on a scale
        arithmetic mean (standard deviation)
    		 53.6 ± 13.11 50.6 ± 14.74 50.3 ± 12.18 50.1 ± 10.33 53.3 ± 15.20 48.6 ± 13.36 -
    Change in MDS-UPDRS Part III Score from Pre-dose to 30 minutes after levodopa dosing at SV2
    The summary score used here is Part III motor examination score. Each Part III item has a 0-4 rating, where 0=normal, 1=slight, 2=mild, 3= moderate, and 4=severe. Higher MDS-UPDRS scores reflect worse motor function. MDS-UPDRS III is a total of 18 questions with 33 individual items, each item ranges from 0-4. The MDS-UPDRS III motor score is the summation of all these 33 individual item scores, and hence ranges from 0-132. Score drops over time imply improvement in motor function (higher values represent a worse outcome). SV2= Screening Visit 2
    Units: Units on a scale
        arithmetic mean (standard deviation)
    		 -18.0 ± 12.33 -16.2 ± 11.80 -19.8 ± 13.64 -22.9 ± 12.09 -21.9 ± 14.19 -21.8 ± 12.53 -

    End points

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    End points reporting groups
    Reporting group title
    APL-SC
    Reporting group description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine); Did not continue in Part B - Treatment Phase.

    Reporting group title
    SC-APL
    Reporting group description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then apomorphine hydrochloride APL (APL-130277); Did not continue in Part B - Treatment Phase.

    Reporting group title
    APL-SC-APL-SC
    Reporting group description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine) into Part B - Treatment Phase: APL then SC

    Reporting group title
    APL-SC-SC-APL
    Reporting group description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine); Randomized into Part B - Treatment Phase: SC then APL

    Reporting group title
    SC-APL-APL-SC
    Reporting group description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then APL (APL-130277); Randomized into Part B - Treatment Phase: APL then SC

    Reporting group title
    SC-APL-SC-APL
    Reporting group description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then APL (APL-130277); Randomized into Part B - Treatment Phase: SC then APL
    Reporting group title
    APL-SC
    Reporting group description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine); Did not continue in Part B - Treatment Phase.

    Reporting group title
    SC-APL
    Reporting group description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then apomorphine hydrochloride APL (APL-130277); Did not continue in Part B - Treatment Phase.

    Reporting group title
    APL-SC-APL-SC
    Reporting group description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine) into Part B - Treatment Phase: APL then SC

    Reporting group title
    APL-SC-SC-APL
    Reporting group description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine); Randomized into Part B - Treatment Phase: SC then APL

    Reporting group title
    SC-APL-APL-SC
    Reporting group description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then APL (APL-130277); Randomized into Part B - Treatment Phase: APL then SC

    Reporting group title
    SC-APL-SC-APL
    Reporting group description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then APL (APL-130277); Randomized into Part B - Treatment Phase: SC then APL
    Reporting group title
    APL-SC-APL-SC
    Reporting group description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine) into Part B - Treatment Phase: APL then SC

    Reporting group title
    APL-SC-SC-APL
    Reporting group description
    		 Part A - Titration Phase: APL (APL-130277) then SC (subcutaneous apomorphine); Randomized into Part B - Treatment Phase: SC then APL

    Reporting group title
    SC-APL-APL-SC
    Reporting group description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then APL (APL-130277); Randomized into Part B - Treatment Phase: APL then SC

    Reporting group title
    SC-APL-SC-APL
    Reporting group description
    		 Part A - Titration Phase: SC (subcutaneous apomorphine) then APL (APL-130277); Randomized into Part B - Treatment Phase: SC then APL

    Subject analysis set title
    SC (subcutaneous apomorphine)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    subcutaneous apomorphine

    Subject analysis set title
    APL (APL-130277)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    APL-130277

    Subject analysis set title
    APL (APL-130227)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    APL-130227

    Subject analysis set title
    Overall
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Overall

    Subject analysis set title
    SC (subcutaneous apomorphine)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    subcutaneous apomorphine

    Subject analysis set title
    APL (APL-130277)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    APL-130277

    Primary: Change from pre-dose to 90 mins. post-dose in Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III score after 4 weeks of dosing in each crossover period (assessed by the blinded-rater in-clinic at Visit 3 and Visit 6 of PART B).

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    End point title
    		 Change from pre-dose to 90 mins. post-dose in Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III score after 4 weeks of dosing in each crossover period (assessed by the blinded-rater in-clinic at Visit 3 and Visit 6 of PART B).
    End point description
    The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society. The summary score used in this study for the primary objective and primary efficacy endpoint is Part III motor examination score. Each Part III item has a 0-4 rating, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Higher MDS-UPDRS scores reflect worse motor function. MDS-UPDRS III is a total of 18 questions with 33 individual items, each item ranges from 0-4. The MDS-UPDRS III motor score is the summation of all these 33 individual item scores, and hence ranges from 0-132. Score drops over time imply improvement in motor function (higher values represent a worse outcome).
    End point type
    Primary
    End point timeframe
    Pre-dose to 90 minutes post-dose at Week 4 of each treatment period (Visit 3 and 6)
    End point values
    		 SC (subcutaneous apomorphine) APL (APL-130277)
    Number of subjects analysed
    61
    62
    Units: Units on a scale
        least squares mean (confidence interval 95%)
    -13.78 (-16.65 to -10.90)
    -13.55 (-16.39 to -10.70)
    Statistical analysis title
    		 primary outcome analysis
    Comparison groups
    SC (subcutaneous apomorphine) v APL (APL-130277)
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8944
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.16
         upper limit
    		 3.62
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.722

    Secondary: Durability of effect, defined as an Investigator confirmed full “ON” within 30 minutes post dose and at 90 minutes post-dose, after 4 weeks of dosing in each crossover period (assessed by the blinded-rater in-clinic at Visit 3 and Visit 6 of PART B).

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    End point title
    		 Durability of effect, defined as an Investigator confirmed full “ON” within 30 minutes post dose and at 90 minutes post-dose, after 4 weeks of dosing in each crossover period (assessed by the blinded-rater in-clinic at Visit 3 and Visit 6 of PART B).
    End point description
    Investigator will confirm whether subject is “OFF”, Full “ON” or Partial “ON” , and note the time the subject changes from “OFF” to Partial “ON” or Full “ON”. The Investigator will also record the subject “ON”/”OFF” status (binary variable, Yes / No) prior to performing each MDS-UPDRS Part III assessment. Durability of effect is defined as an Investigator confirmed full “ON” within 30 minutes post-dose and at 90 minutes post-dose, after 4 weeks of dosing in each PART B crossover period. Response rate = % of subjects that achived full "ON" within the timeframe
    End point type
    Secondary
    End point timeframe
    Within 30 minutes post-dose and at 90 minutes post-dose at Week 4 of each treatment period (Visit 3 and 6)
    End point values
    		 SC (subcutaneous apomorphine) APL (APL-130227)
    Number of subjects analysed
    61
    62
    Units: Percentage of participants
        number (not applicable)
    18.03
    17.74
    Statistical analysis title
    		 secondary outcome measure analysis
    Comparison groups
    SC (subcutaneous apomorphine) v APL (APL-130227)
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7777
    Method
    		 generalized linear random effects model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.129
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.484
         upper limit
    		 2.637

    Secondary: Patient Global Impression of Change (PGI-C): Subject improvement of “OFF” episodes, defined as very much better, much better or a little better after 4 weeks of dosing in each crossover period (assessed in-clinic at Visit 3 and Visit 6 of PART B).

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    End point title
    		 Patient Global Impression of Change (PGI-C): Subject improvement of “OFF” episodes, defined as very much better, much better or a little better after 4 weeks of dosing in each crossover period (assessed in-clinic at Visit 3 and Visit 6 of PART B).
    End point description
    The PGI-C is the patient reported outcome counterpart to the Clinical Global Impressions scale, (CGI), which was published in 1976 by the National Institute of Mental Health (US). It consists of one item taken from the CGI and adapted to the patient. The PGI-C is based on a 7-point scale, where a lower score is associated with higher symptom improvement. The scale is: Very much better Much better A little better No change A little worse Much worse Very much worse Subject improvement of “OFF” episodes is defined as very much better, much better or a little better at Week 4 in each PART B crossover period. Response rate= % of subjects who achieved improvement of "OFF" episodes
    End point type
    Secondary
    End point timeframe
    At Week 4 of each treatment period (Visit 3 and 6, or Early Termination)
    End point values
    		 SC (subcutaneous apomorphine) APL (APL-130277)
    Number of subjects analysed
    70
    71
    Units: Percentage of participants
        number (not applicable)
    77.14
    83.10
    Statistical analysis title
    		 secondary outcome measure analysis
    Comparison groups
    SC (subcutaneous apomorphine) v APL (APL-130277)
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3922
    Method
    		 generalized linear random effects model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 3.53

    Secondary: Subject preference for APL treatment as measured by the Subject Treatment Preference Questionnaire (TPQ), planned after the subject had completed both APL-130277 and sc apomorphine treatment regimens (assessed in-clinic at Visit 6 of PART B)

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    End point title
    		 Subject preference for APL treatment as measured by the Subject Treatment Preference Questionnaire (TPQ), planned after the subject had completed both APL-130277 and sc apomorphine treatment regimens (assessed in-clinic at Visit 6 of PART B)
    End point description
    The TPQ assessment of subject treatment preference was changed from being based on a visual analogue scale or VAS (Q9b)) to a 5-point Likert scale (Q9a). Subject reported preference for APL or SC was based on question Q9a or Q9b combined. For Q9a, responses were dichotomized as follows for statistical analysis: preference for APL (responses of either definitely or somewhat prefer APL) versus no preference for APL (responses of no preference, or somewhat/definitely prefer sc apomorphine). The VAS score was similarly dichotomized as preference for APL (score of >0 to 50) versus no preference for APL (-50 to 0). If a subject responded to both Q9a and Q9b, then Q9a only was used.
    End point type
    Secondary
    End point timeframe
    After 8 weeks of treatment (Visit 6)
    End point values
    		 Overall
    Number of subjects analysed
    72
    Units: % of participants
        number (confidence interval 95%)
    72.2 (61.9 to 82.6)
    No statistical analyses for this end point

    Secondary: Subject confirmed durability of effect, defined as subject confirmed full “ON” within 30 minutes post-dose and at 90 minutes post-dose, after 4 weeks of dosing in each crossover period (assessed in-clinic at Visit 3 and Visit 6 of PART B).

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    End point title
    		 Subject confirmed durability of effect, defined as subject confirmed full “ON” within 30 minutes post-dose and at 90 minutes post-dose, after 4 weeks of dosing in each crossover period (assessed in-clinic at Visit 3 and Visit 6 of PART B).
    End point description
    Patients will confirm whether he/she is “OFF”, Full “ON” or Partial “ON”, and the staff will ask the subject to notify the staff when he/she changes from “OFF” to Partial “ON” or Full “ON” (binary variable, Yes / No) . Subject confirmed durability of effect is defined as subject confirmed full “ON” within 30 minutes post-dose and at 90 minutes post-dose, after 4 weeks of dosing in each crossover period (assessed in-clinic at V3 and V6 of PART B). Response rate = % subjects that achived full ON within the timeframe
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 SC (subcutaneous apomorphine) APL (APL-130227)
    Number of subjects analysed
    61
    62
    Units: Percentage of participants
        number (not applicable)
    14.75
    19.36
    Statistical analysis title
    		 secondary outcome measure analysis
    Comparison groups
    SC (subcutaneous apomorphine) v APL (APL-130227)
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1769
    Method
    		 generalized linear random effects model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.835
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.759
         upper limit
    		 4.438

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    10 weeks (from first dose of study drug to last study visit)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Part A Dose Titration: SC (Subcutaneous Apomorphine)
    Reporting group description
    		 Part A Dose Titration: SC (Subcutaneous Apomorphine)

    Reporting group title
    Part B Treatment: SC (Subcutaneous Apomorphine)
    Reporting group description
    		 Part B Treatment: SC (Subcutaneous Apomorphine)

    Reporting group title
    Part B Treatment: APL (APL-130277)
    Reporting group description
    		 Part B Treatment: APL (APL-130277)

    Reporting group title
    Part A Dose Titration: APL (APL-130277)
    Reporting group description
    		 Part A Dose Titration: APL (APL-130277)

    Serious adverse events
    		 Part A Dose Titration: SC (Subcutaneous Apomorphine) Part B Treatment: SC (Subcutaneous Apomorphine) Part B Treatment: APL (APL-130277) Part A Dose Titration: APL (APL-130277)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 70 (1.43%)
    1 / 71 (1.41%)
    0 / 102 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Foot fracture
    alternative dictionary used: MedDRA 21.0
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 70 (1.43%)
    0 / 71 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal ischaemia
    alternative dictionary used: MedDRA 21.0
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 70 (0.00%)
    0 / 71 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
    alternative dictionary used: MedDRA 21.0
         subjects affected / exposed
    0 / 97 (0.00%)
    0 / 70 (0.00%)
    1 / 71 (1.41%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part A Dose Titration: SC (Subcutaneous Apomorphine) Part B Treatment: SC (Subcutaneous Apomorphine) Part B Treatment: APL (APL-130277) Part A Dose Titration: APL (APL-130277)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 97 (45.36%)
    37 / 70 (52.86%)
    23 / 71 (32.39%)
    52 / 102 (50.98%)
    Injury, poisoning and procedural complications
    Fall
    alternative dictionary used: MedDRA 21.0
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 70 (1.43%)
    4 / 71 (5.63%)
    1 / 102 (0.98%)
         occurrences all number
    1
    3
    5
    2
    Vascular disorders
    Orthostatic hypotension
    alternative dictionary used: MedDRA 21.0
         subjects affected / exposed
    5 / 97 (5.15%)
    4 / 70 (5.71%)
    3 / 71 (4.23%)
    4 / 102 (3.92%)
         occurrences all number
    5
    5
    4
    5
    Nervous system disorders
    Dizziness
    alternative dictionary used: MedDRA 21.0
         subjects affected / exposed
    4 / 97 (4.12%)
    3 / 70 (4.29%)
    2 / 71 (2.82%)
    10 / 102 (9.80%)
         occurrences all number
    4
    3
    2
    15
    Dyskinesia
    alternative dictionary used: MedDRA 21.0
         subjects affected / exposed
    7 / 97 (7.22%)
    14 / 70 (20.00%)
    8 / 71 (11.27%)
    8 / 102 (7.84%)
         occurrences all number
    13
    20
    11
    10
    Somnolence
    alternative dictionary used: MedDRA 21.0
         subjects affected / exposed
    13 / 97 (13.40%)
    4 / 70 (5.71%)
    3 / 71 (4.23%)
    9 / 102 (8.82%)
         occurrences all number
    18
    4
    3
    9
    General disorders and administration site conditions
    Fatigue
    alternative dictionary used: MedDRA 21.0
         subjects affected / exposed
    10 / 97 (10.31%)
    4 / 70 (5.71%)
    4 / 71 (5.63%)
    6 / 102 (5.88%)
         occurrences all number
    10
    5
    4
    6
    Injection site erythema
    alternative dictionary used: MedDRA 21.0
         subjects affected / exposed
    6 / 97 (6.19%)
    5 / 70 (7.14%)
    1 / 71 (1.41%)
    0 / 102 (0.00%)
         occurrences all number
    9
    5
    1
    0
    Injection site haematoma
    alternative dictionary used: MedDRA 21.0
         subjects affected / exposed
    2 / 97 (2.06%)
    19 / 70 (27.14%)
    0 / 71 (0.00%)
    0 / 102 (0.00%)
         occurrences all number
    2
    23
    0
    0
    Gastrointestinal disorders
    Nausea
    alternative dictionary used: MedDRA 21.0
         subjects affected / exposed
    22 / 97 (22.68%)
    11 / 70 (15.71%)
    10 / 71 (14.08%)
    32 / 102 (31.37%)
         occurrences all number
    31
    21
    25
    53
    Respiratory, thoracic and mediastinal disorders
    Yawning
    alternative dictionary used: MedDRA 21.0
         subjects affected / exposed
    5 / 97 (5.15%)
    1 / 70 (1.43%)
    0 / 71 (0.00%)
    3 / 102 (2.94%)
         occurrences all number
    8
    1
    0
    3

    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
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