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    Clinical Trial Results:
    An Open-label, Randomized 12 Week Study Comparing Efficacy of Levodopa-Carbidopa Intestinal Gel/Carbidopa-Levodopa Enteral Suspension and Optimized Medical Treatment on Dyskinesia in Subjects with Advanced Parkinson's Disease

    Summary
    EudraCT number
    2016-001403-23
    Trial protocol
    FI   SK   GR   ES   HU   IT  
    Global end of trial date
    19 Sep 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Sep 2020
    First version publication date
    03 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M15-535
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02799381
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AbbVie
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6-4UB
    Public contact
    AbbVie, Global Medical Services, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    AbbVie, Global Medical Services, 001 8006339110, abbvieclinicaltrials@abbvie.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
    19 Sep 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this Phase 3b, open-label, randomized, multicenter, 12-week study was to examine the effect of levodopa-carbidopa intestinal gel (LCIG) compared with optimized medical treatment (OMT) on dyskinesia in participants with advanced Parkinson's disease (PD). The study consisted of 3 sequential periods: Screening, Treatment, and Follow-Up. The OMT group had the same schedule of visits/procedures throughout the study as the LCIG treatment group, except for visits related to nasojejunal (NJ)/percutaneous endoscopic gastrostomy (PEG) procedures, titration of LCIG, and follow-up period.
    Protection of trial subjects
    Subject and/or legal guardian read and understood the information provided about the study and gave written permission.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Feb 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
    Finland: 6
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Slovakia: 12
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    United States: 1
    Worldwide total number of subjects
    63
    EEA total number of subjects
    62
    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)
    10
    From 65 to 84 years
    53
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Safety Data Set: all participants randomized to OMT and all participants randomized to LCIG treatment who had a study tube (NJ or PEG-J) placement procedure. Two participants randomized to the LCIG arm did not have device placement for LCIG infusion and were not included in the safety data set.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Optimized Medical Treatment (OMT)
    Arm description
    Participants randomized to OMT continued their current anti Parkinson’s disease (anti-PD) medication regimen for the duration of the study. All anti-PD medications and medications to treat dyskinesia must have remained stable for the duration of the study unless adjustments were medically indicated. The Investigator provided the prescription for continued OMT.
    Arm type
    Active comparator

    Investigational medicinal product name
    Optimized antiparkinsonian treatment
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet, Transdermal patch
    Routes of administration
    Oral use, Transdermal use
    Dosage and administration details
    Dose levels of prescribed antiparkinsonian medications were individually optimized to their maximum therapeutic effect.

    Arm title
    Levodopa-Carbidopa Intestinal Gel (LCIG)
    Arm description
    The total daily dose of infusion LCIG was composed of three components: (i) the morning dose, (ii) continuous maintenance infusion dose and (iii) extra doses. A temporary nasojejunal (NJ) tube may have been used initially with the infusion pump to determine a participant’s response to this method of treatment and to optimize the dose of LCIG before treatment with a permanent percutaneous endoscopic gastrostomy - with jejunal extension (PEG-J) tube was started. Following optional NJ and/or PEG-J placement and, at the investigator's discretion, the participant may have begun initiation and titration of LCIG infusion on Day 1 once tube placement was confirmed. The dose of LCIG was adjusted to obtain the optimal clinical response. The rate of LCIG infusion is typically within the range of 1 to 10 mL/hour (20 to 200 mg of levodopa/hour) in most instances and runs over a period of 16 consecutive hours each day.
    Arm type
    Experimental

    Investigational medicinal product name
    Levodopa-Carbidopa Intestinal Gel (LCIG)
    Investigational medicinal product code
    Other name
    ABT-SLV187, DUOPA (carbidopa and levodopa Enteral Suspension), DUODOPA
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intestinal use
    Dosage and administration details
    Dose levels were individually optimized.

    Number of subjects in period 1 [1]
    Optimized Medical Treatment (OMT) Levodopa-Carbidopa Intestinal Gel (LCIG)
    Started
    33
    28
    Completed
    29
    25
    Not completed
    4
    3
         Participant did not take any study drug
    1
    -
         Adverse event, non-fatal
    -
    1
         Withdrew consent
    3
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Two participants randomized to the LCIG arm did not have device placement for LCIG infusion and were not included in the safety data set.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Optimized Medical Treatment (OMT)
    Reporting group description
    Participants randomized to OMT continued their current anti Parkinson’s disease (anti-PD) medication regimen for the duration of the study. All anti-PD medications and medications to treat dyskinesia must have remained stable for the duration of the study unless adjustments were medically indicated. The Investigator provided the prescription for continued OMT.

    Reporting group title
    Levodopa-Carbidopa Intestinal Gel (LCIG)
    Reporting group description
    The total daily dose of infusion LCIG was composed of three components: (i) the morning dose, (ii) continuous maintenance infusion dose and (iii) extra doses. A temporary nasojejunal (NJ) tube may have been used initially with the infusion pump to determine a participant’s response to this method of treatment and to optimize the dose of LCIG before treatment with a permanent percutaneous endoscopic gastrostomy - with jejunal extension (PEG-J) tube was started. Following optional NJ and/or PEG-J placement and, at the investigator's discretion, the participant may have begun initiation and titration of LCIG infusion on Day 1 once tube placement was confirmed. The dose of LCIG was adjusted to obtain the optimal clinical response. The rate of LCIG infusion is typically within the range of 1 to 10 mL/hour (20 to 200 mg of levodopa/hour) in most instances and runs over a period of 16 consecutive hours each day.

    Reporting group values
    Optimized Medical Treatment (OMT) Levodopa-Carbidopa Intestinal Gel (LCIG) Total
    Number of subjects
    33 28 61
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    68.7 ± 7.20 69.3 ± 6.99 -
    Gender categorical
    Units: Subjects
        Female
    16 16 32
        Male
    17 12 29

    End points

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    End points reporting groups
    Reporting group title
    Optimized Medical Treatment (OMT)
    Reporting group description
    Participants randomized to OMT continued their current anti Parkinson’s disease (anti-PD) medication regimen for the duration of the study. All anti-PD medications and medications to treat dyskinesia must have remained stable for the duration of the study unless adjustments were medically indicated. The Investigator provided the prescription for continued OMT.

    Reporting group title
    Levodopa-Carbidopa Intestinal Gel (LCIG)
    Reporting group description
    The total daily dose of infusion LCIG was composed of three components: (i) the morning dose, (ii) continuous maintenance infusion dose and (iii) extra doses. A temporary nasojejunal (NJ) tube may have been used initially with the infusion pump to determine a participant’s response to this method of treatment and to optimize the dose of LCIG before treatment with a permanent percutaneous endoscopic gastrostomy - with jejunal extension (PEG-J) tube was started. Following optional NJ and/or PEG-J placement and, at the investigator's discretion, the participant may have begun initiation and titration of LCIG infusion on Day 1 once tube placement was confirmed. The dose of LCIG was adjusted to obtain the optimal clinical response. The rate of LCIG infusion is typically within the range of 1 to 10 mL/hour (20 to 200 mg of levodopa/hour) in most instances and runs over a period of 16 consecutive hours each day.

    Primary: Mean Change from Baseline to Week 12 in Unified Dyskinesia Rating Scale (UDysRS) Total Score

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    End point title
    Mean Change from Baseline to Week 12 in Unified Dyskinesia Rating Scale (UDysRS) Total Score
    End point description
    The Unified Dyskinesia Rating Scale (UDysRS) is a tool used to assess dyskinesia in Parkinson’s disease (PD) and contains both self-evaluation questions and items that are assessed directly by the physician to objectively rate the abnormal movements associated with PD. Part 1 contains 11 questions about the ON time dyskinesia and the impact of ON-dyskinesia on experiences of daily living. Part 2 contains 4 questions about OFF-dystonia rating. Part 3 contains 7 questions about objective evaluation of dyskinesia impairment and Part 4 contains 4 questions regarding dyskinesia disability. Each question is scored with respect to severity, which is rated on a scale where 0 = normal, 1 = slight, 2 = mild, 3= moderate and 4 = severe. The UDysRS total score is obtained by summing the item scores, ranging from 0 to 104. Higher scores are associated with more disability. Negative changes from baseline indicate improvement.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    Optimized Medical Treatment (OMT) Levodopa-Carbidopa Intestinal Gel (LCIG)
    Number of subjects analysed
    26 [1]
    24 [2]
    Units: units on a scale
        least squares mean (standard error)
    -2.33 ± 2.56
    -17.37 ± 2.79
    Notes
    [1] - Intent-to-treat (ITT): subjects with available data at Wk 12 who were randomized to the OMT group
    [2] - ITT: randomized w/available data at Wk 12 who rcvd ≥ 1 dose of study drug after PEG-J placement
    Statistical analysis title
    Change from baseline to Week 12
    Statistical analysis description
    The likelihood-based mixed-effects model repeated measures (MMRM) analysis of the change from baseline to Week 12 used all observed data. The model included fixed, categorical effects for treatment, country, visit, and treatment-by-visit interaction, with continuous fixed covariates for baseline score and the baseline score-by-visit interaction.
    Comparison groups
    Optimized Medical Treatment (OMT) v Levodopa-Carbidopa Intestinal Gel (LCIG)
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference (LCIG-OMT) at Week 12
    Point estimate
    -15.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -21.47
         upper limit
    -8.63
    Notes
    [3] - Two-sided p-value

    Secondary: Mean Change from Baseline to Week 12 in ON time without troublesome dyskinesia

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    End point title
    Mean Change from Baseline to Week 12 in ON time without troublesome dyskinesia
    End point description
    The Parkinson’s Disease (PD) Symptom Diary is completed every 30 minutes for the full 24 hours of each of 3 days prior to selected study visits. It reflects both time awake and time asleep. Daily totals are normalized to a 16-hour scale (i.e., 16 hours of awake time). The normalized totals for the 3 days prior to the visit are averaged for the analysis. ON time is when PD symptoms are well controlled by the drug, and OFF time is when PD symptoms are not adequately controlled by the drug. Positive change from baseline for ON time without troublesome dyskinesia indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Optimized Medical Treatment (OMT) Levodopa-Carbidopa Intestinal Gel (LCIG)
    Number of subjects analysed
    28 [4]
    25 [5]
    Units: hours
        least squares mean (standard error)
    -0.12 ± 0.63
    3.15 ± 0.69
    Notes
    [4] - Intent-to-treat (ITT): subjects with available data at Wk 12 who were randomized to the OMT group
    [5] - ITT: randomized w/available data at Wk 12 who rcvd ≥ 1 dose of study drug after PEG-J placement
    Statistical analysis title
    Change from baseline to Week 12
    Statistical analysis description
    If the primary efficacy variable was statistically significant, each of the secondary variables were to be tested using a fixed sequence as a gatekeeping procedure and at α level of 0.050. Testing was to cease at the point that a secondary variable failed to demonstrate statistical significance.
    Comparison groups
    Optimized Medical Treatment (OMT) v Levodopa-Carbidopa Intestinal Gel (LCIG)
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    < 0.0001 [7]
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference (LCIG-OMT) at Week 12
    Point estimate
    3.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.71
         upper limit
    4.83
    Notes
    [6] - The likelihood-based mixed-effects model repeated measures (MMRM) analysis of the change from baseline to Week 12 used all observed data. The model included fixed, categorical effects for treatment, country, visit, and treatment-by-visit interaction, with continuous fixed covariates for baseline score and the baseline score-by-visit interaction.
    [7] - Two-sided p-value

    Secondary: Mean Change from Baseline to Week 12 in Parkinson's Disease Questionnaire-8 (PDQ-8) Summary Index

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    End point title
    Mean Change from Baseline to Week 12 in Parkinson's Disease Questionnaire-8 (PDQ-8) Summary Index
    End point description
    The Parkinson's Disease Questionnaire-8 (PDQ-8) is a disease-specific instrument designed to measure aspects of health that are relevant to participants with PD, and which may not be included in general health status questionnaires. The PDQ-8 is a self-administered questionnaire. Each item is scored on the following 5-point scale: 0 = Never, 1 = Occasionally, 2 = Sometimes, 3 = Often, 4 = Always (or cannot do at all, if applicable). Higher scores are consistently associated with the more severe symptoms of the disease such as tremors and stiffness. The results are presented as a summary index. The PDQ-8 summary index ranges from 0 to 100, where lower scores indicate a better perceived health status. Negative changes from baseline indicate improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Optimized Medical Treatment (OMT) Levodopa-Carbidopa Intestinal Gel (LCIG)
    Number of subjects analysed
    29 [8]
    25 [9]
    Units: units on a scale
        least squares mean (standard error)
    -4.95 ± 3.11
    -21.62 ± 3.47
    Notes
    [8] - Intent-to-treat (ITT): subjects with available data at Wk 12 who were randomized to the OMT group
    [9] - ITT: randomized w/available data at Wk 12 who rcvd ≥ 1 dose of study drug after PEG-J placement
    Statistical analysis title
    Change from baseline to Week 12
    Statistical analysis description
    If the primary efficacy variable was statistically significant, each of the secondary variables were to be tested using a fixed sequence as a gatekeeping procedure and at α level of 0.050. Testing was to cease at the point that a secondary variable failed to demonstrate statistical significance.
    Comparison groups
    Optimized Medical Treatment (OMT) v Levodopa-Carbidopa Intestinal Gel (LCIG)
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    < 0.0001 [11]
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference (LCIG-OMT) at Week 12
    Point estimate
    -16.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -24.48
         upper limit
    -8.85
    Notes
    [10] - The likelihood-based mixed-effects model repeated measures (MMRM) analysis of the change from baseline to Week 12 used all observed data. The model included fixed, categorical effects for treatment, country, visit, and treatment-by-visit interaction, with continuous fixed covariates for baseline score and the baseline score-by-visit interaction.
    [11] - Two-sided p-value

    Secondary: Mean Clinical Global Impression of Change (CGI-C) Score at Week 12

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    End point title
    Mean Clinical Global Impression of Change (CGI-C) Score at Week 12
    End point description
    The Clinical Global Impression of Change (CGI-C) score is a clinician's rating scale for assessing Global Improvement of Change. The CGI-C rates improvement by 7 categories: very much improved (1), much improved (2), minimally improved (3), no change (4), minimally worse (5), much worse (6), very much worse (7). The CGI-C score ranges from 1 to 7, with lower scores indicating improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Optimized Medical Treatment (OMT) Levodopa-Carbidopa Intestinal Gel (LCIG)
    Number of subjects analysed
    29 [12]
    25 [13]
    Units: units on a scale
        least squares mean (standard error)
    4.58 ± 0.25
    2.48 ± 0.28
    Notes
    [12] - Intent-to-treat (ITT): subjects with available data at Wk 12 who were randomized to the OMT group
    [13] - ITT: randomized w/available data at Wk 12 who rcvd ≥ 1 dose of study drug after PEG-J placement
    Statistical analysis title
    CGI-C Score at Week 12
    Statistical analysis description
    If the primary efficacy variable was statistically significant, each of the secondary variables were to be tested using a fixed sequence as a gatekeeping procedure and at α level of 0.050. Testing was to cease at the point that a secondary variable failed to demonstrate statistical significance.
    Comparison groups
    Optimized Medical Treatment (OMT) v Levodopa-Carbidopa Intestinal Gel (LCIG)
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    superiority [14]
    P-value
    < 0.0001 [15]
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference (LCIG-OMT) at Week 12
    Point estimate
    -2.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.78
         upper limit
    -1.44
    Notes
    [14] - The likelihood-based mixed-effects model repeated measures (MMRM) analysis of the change from baseline to Week 12 used all observed data. The model included fixed, categorical effects for treatment, country, visit, and treatment-by-visit interaction, with continuous fixed covariates for baseline score and the baseline score-by-visit interaction.
    [15] - Two-sided p-value

    Secondary: Mean Change From Baseline to Week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II Score (Activities of Daily Living)

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    End point title
    Mean Change From Baseline to Week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II Score (Activities of Daily Living)
    End point description
    The Unified Parkinson's Disease Rating Scale (UPDRS) is an Investigator-used rating tool to follow the longitudinal course of Parkinson's disease. The Part II score is the sum of the answers to the 13 questions related to Activities of Daily Living, and ranges from 0-52. Higher scores are associated with more disability. Negative values indicate improvement from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Optimized Medical Treatment (OMT) Levodopa-Carbidopa Intestinal Gel (LCIG)
    Number of subjects analysed
    29 [16]
    24 [17]
    Units: units on a scale
        least squares mean (standard error)
    0.21 ± 1.16
    -5.33 ± 1.28
    Notes
    [16] - Intent-to-treat (ITT): subjects with available data at Wk 12 who were randomized to the OMT group
    [17] - ITT: randomized w/available data at Wk 12 who rcvd ≥ 1 dose of study drug after PEG-J placement
    Statistical analysis title
    Change from baseline to Week 12
    Statistical analysis description
    If the primary efficacy variable was statistically significant, each of the secondary variables were to be tested using a fixed sequence as a gatekeeping procedure and at α level of 0.050. Testing was to cease at the point that a secondary variable failed to demonstrate statistical significance.
    Comparison groups
    Optimized Medical Treatment (OMT) v Levodopa-Carbidopa Intestinal Gel (LCIG)
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    superiority [18]
    P-value
    = 0.0006 [19]
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference (LCIG-OMT) at Week 12
    Point estimate
    -5.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.59
         upper limit
    -2.49
    Notes
    [18] - The likelihood-based mixed-effects model repeated measures (MMRM) analysis of the change from baseline to Week 12 used all observed data. The model included fixed, categorical effects for treatment, country, visit, and treatment-by-visit interaction, with continuous fixed covariates for baseline score and the baseline score-by-visit interaction.
    [19] - Two-sided p-value

    Secondary: Mean Change from Baseline to Week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) Part III Score (Motor Examination)

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    End point title
    Mean Change from Baseline to Week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) Part III Score (Motor Examination)
    End point description
    The Unified Parkinson's Disease Rating Scale (UPDRS) is an Investigator-used rating tool to follow the longitudinal course of Parkinson's disease. The Part III score is the sum of the 27 answers related to Motor Examination, and ranges from 0-108. Higher scores are associated with more disability. Negative values indicate improvement from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Optimized Medical Treatment (OMT) Levodopa-Carbidopa Intestinal Gel (LCIG)
    Number of subjects analysed
    29 [20]
    25 [21]
    Units: units on a scale
        least squares mean (standard error)
    -0.87 ± 1.89
    -4.93 ± 2.08
    Notes
    [20] - Intent-to-treat (ITT): subjects with available data at Wk 12 who were randomized to the OMT group
    [21] - ITT: randomized w/available data at Wk 12 who rcvd ≥ 1 dose of study drug after PEG-J placement
    Statistical analysis title
    Change from baseline to Week 12
    Statistical analysis description
    If the primary efficacy variable was statistically significant, each of the secondary variables were to be tested using a fixed sequence as a gatekeeping procedure and at α level of 0.050. Testing was to cease at the point that a secondary variable failed to demonstrate statistical significance.
    Comparison groups
    Optimized Medical Treatment (OMT) v Levodopa-Carbidopa Intestinal Gel (LCIG)
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    superiority [22]
    P-value
    = 0.0762 [23]
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference (LCIG-OMT) at Week 12
    Point estimate
    -4.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.55
         upper limit
    0.44
    Notes
    [22] - The likelihood-based mixed-effects model repeated measures (MMRM) analysis of the change from baseline to Week 12 used all observed data. The model included fixed, categorical effects for treatment, country, visit, and treatment-by-visit interaction, with continuous fixed covariates for baseline score and the baseline score-by-visit interaction.
    [23] - Two-sided p-value

    Secondary: Mean Change from Baseline to Week 12 in OFF time

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    End point title
    Mean Change from Baseline to Week 12 in OFF time
    End point description
    The Parkinson’s Disease (PD) Symptom Diary is completed every 30 minutes for the full 24 hours of each of 3 days prior to selected study visits. It reflects both time awake and time asleep. Daily totals are normalized to a 16-hour scale (i.e., 16 hours of awake time). The normalized totals for the 3 days prior to the visit are averaged for the analysis. ON time is when PD symptoms are well controlled by the drug, and OFF time is when PD symptoms are not adequately controlled by the drug. Negative change from baseline for OFF time indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Optimized Medical Treatment (OMT) Levodopa-Carbidopa Intestinal Gel (LCIG)
    Number of subjects analysed
    28 [24]
    25 [25]
    Units: hours
        least squares mean (standard error)
    0.18 ± 0.49
    -2.17 ± 0.53
    Notes
    [24] - Intent-to-treat (ITT): subjects with available data at Wk 12 who were randomized to the OMT group
    [25] - ITT: randomized w/available data at Wk 12 who rcvd ≥ 1 dose of study drug after PEG-J placement
    Statistical analysis title
    Change from baseline to Week 12
    Statistical analysis description
    If the primary efficacy variable was statistically significant, each of the secondary variables were to be tested using a fixed sequence as a gatekeeping procedure and at α level of 0.050. Testing was to cease at the point that a secondary variable failed to demonstrate statistical significance.
    Comparison groups
    Optimized Medical Treatment (OMT) v Levodopa-Carbidopa Intestinal Gel (LCIG)
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    superiority [26]
    P-value
    = 0.0002 [27]
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference (LCIG-OMT) at Week 12
    Point estimate
    -2.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.51
         upper limit
    -1.19
    Notes
    [26] - The likelihood-based mixed-effects model repeated measures (MMRM) analysis of the change from baseline to Week 12 used all observed data. The model included fixed, categorical effects for treatment, country, visit, and treatment-by-visit interaction, with continuous fixed covariates for baseline score and the baseline score-by-visit interaction.
    [27] - Two-sided p-value

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    TEAEs /TESAEs: OMT after randomization until 30 d after last visit, ≤ 18 wks; LCIG study tubes removed after last Tx, from tube placement up to 30 d after tube removal, ≤ 16 wks; other LCIG: from tube placement up to 30 d after last study visit, ≤ 16 wks
    Adverse event reporting additional description
    TEAEs and SAEs are defined as any adverse event (AE) with onset date after the day of randomization (OMT group) or from time of tube placement (LCIG group) until 30 d after the last visit (OMT group), or up to 30 d following tube removal (LCIG group) or the last study visit (LCIG group) and were collected whether elicited or spontaneously reported.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Levodopa-Carbidopa Intestinal Gel (LCIG)
    Reporting group description
    The total daily dose of infusion LCIG was composed of three components: (i) the morning dose, (ii) continuous maintenance infusion dose and (iii) extra doses. A temporary nasojejunal (NJ) tube may have been used initially with the infusion pump to determine a participant’s response to this method of treatment and to optimize the dose of LCIG before treatment with a permanent percutaneous endoscopic gastrostomy - with jejunal extension (PEG-J) tube was started. Following optional NJ and/or PEG-J placement and, at the investigator's discretion, the participant may have begun initiation and titration of LCIG infusion on Day 1 once tube placement was confirmed. The dose of LCIG was adjusted to obtain the optimal clinical response. The rate of LCIG infusion is typically within the range of 1 to 10 mL/hour (20 to 200 mg of levodopa/hour) in most instances and runs over a period of 16 consecutive hours each day.

    Reporting group title
    Optimized Medical Treatment (OMT)
    Reporting group description
    Participants randomized to OMT continued their current anti Parkinson’s disease (anti-PD) medication regimen for the duration of the study. All anti-PD medications and medications to treat dyskinesia must have remained stable for the duration of the study unless adjustments were medically indicated. The Investigator provided the prescription for continued OMT.

    Serious adverse events
    Levodopa-Carbidopa Intestinal Gel (LCIG) Optimized Medical Treatment (OMT)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 33 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    SYNCOPE
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    PNEUMOPERITONEUM
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    CYSTITIS
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Levodopa-Carbidopa Intestinal Gel (LCIG) Optimized Medical Treatment (OMT)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 28 (53.57%)
    4 / 33 (12.12%)
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    6 / 28 (21.43%)
    2 / 33 (6.06%)
         occurrences all number
    6
    3
    PROCEDURAL PAIN
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Nervous system disorders
    PARKINSON'S DISEASE
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    General disorders and administration site conditions
    DRUG WITHDRAWAL SYNDROME
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    ANXIETY
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    DIARRHOEA
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    MUSCLE SPASMS
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    URINARY TRACT INFECTION
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 May 2016
    ● Changed the study duration from 26 weeks to 12 weeks ● Removed the exclusion criterion for excluding patients previously treated with continuous subcutaneous apomorphine infusion ● Added language for additional analysis to provide evidence on the construct validity of the UDysRS

    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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