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Clinical Trial Results:
A Study to Examine the Effect of Levodopa-Carbidopa Intestinal Gel (LCIG) Therapy Relative to That of Optimized Medical Treatment (OMT) on Non-motor Symptoms (NMS) Associated With Advanced Parkinson's Disease (PD)

Summary
EudraCT number	2014-004865-26
Trial protocol	DE SE IT ES GR
Global end of trial date	18 Nov 2022

Results information
Results version number	v1(current)
This version publication date	22 Nov 2023
First version publication date	22 Nov 2023
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

M12-927

ISRCTN number

US NCT number

NCT02549092

WHO universal trial number (UTN)

Sponsor organisation name

AbbVie Deutschland GmbH & Co. KG

Sponsor organisation address

AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6 4UB

Public contact

Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com

Scientific contact

Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

18 Nov 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

18 Nov 2022

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study was to examine the effect of LCIG relative to that of OMT on NMS associated with advanced PD as assessed by the Non-Motor Symptom Scale (NMSS) Total Score and the Modified Parkinson's Disease Sleep Scale (PDSS)-2 Total Score.

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

26 Oct 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 4

Country: Number of subjects enrolled

Germany: 1

Country: Number of subjects enrolled

Greece: 1

Country: Number of subjects enrolled

Italy: 21

Country: Number of subjects enrolled

Korea, Republic of: 16

Country: Number of subjects enrolled

Australia: 8

Country: Number of subjects enrolled

Spain: 26

Country: Number of subjects enrolled

Sweden: 3

Country: Number of subjects enrolled

United States: 9

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This study was conducted at 32 sites in 9 countries. After a 30- to 67-day Screening Period for required procedures, training, and medication stabilization, eligible participants were randomized to Optimized Medical Treatment (OMT) or Levodopa-Carbidopa Intestinal Gel (LCIG) for a 26-week Treatment Period.

Screening details

Before Treatment Period Day 1, LCIG participants had a percutaneous endoscopic gastrostomy with a jejunal extension (PEG-J; with an initial, optional, temporary nasojejunal [NJ] tube placement to titrate the dose of LCIG prior to the PEG-J).

Period 1 title

Treatment Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Optimized Medical Treatment

Arm description

Participants randomized to continue OMT remained on their current optimized regimen (oral, sublingual or transdermal anti-PD medications and medications to treat NMS per Investigator discretion and/or in accordance with approved product label of the prescribed medications) during the 26-week treatment phase. Changes to anti-PD and NMS medications are to remain stable and can only be made if medically indicated. Participants in the United States or South Korea may have elected to enter an Extension/Transition follow-up period to receive an individually optimized LCIG dose (after NJ and/or PEG-J placement), in order to transition to commercially available LCIG.

Arm type

Optimized Medical Treatment

Investigational medicinal product name

No investigational medicinal product assigned in this arm

LCIG

Arm description

Participants randomized to LCIG at an individually optimized dose, in accordance with the LCIG approved product label for countries participating in the study during the 26-week treatment phase. Changes to anti-PD and NMS medications were to remain stable and were only made if medically indicated. The total daily dose of LCIG was composed of 3 components: (i) the morning dose, (ii) continuous maintenance infusion dose and (iii) extra doses. The continuous infusion was expected to run over a period of 16 consecutive hours each day. Participants in the United States or South Korea may have elected to enter an Extension/Transition follow-up period to receive an individually optimized LCIG dose, in order to transition to commercially available LCIG.

Arm type

Experimental

Investigational medicinal product name

Duodopa

Investigational medicinal product code

Other name

Pharmaceutical forms

Intestinal gel

Routes of administration

Gastroenteral use

Dosage and administration details

The total daily dose of LCIG was composed of 3 components: (i) the morning dose, (ii) continuous maintenance infusion dose and (iii) extra doses. The continuous infusion was expected to run over a period of 16 consecutive hours each day.

Number of subjects in period 1	Optimized Medical Treatment	LCIG
Started	44	45
Completed	41	38
Not completed	3	7
Consent withdrawn by subject	1	3
Adverse event	2	2
Lack of efficacy	-	2

Period 2 title

Extension/Transition Period

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Optimized Medical Treatment

Arm description

Arm type

Optimized Medical Treatment

Investigational medicinal product name

No investigational medicinal product assigned in this arm

LCIG

Arm description

Arm type

Experimental

Investigational medicinal product name

Duodopa

Investigational medicinal product code

Other name

Pharmaceutical forms

Intestinal gel

Routes of administration

Gastroenteral use

Dosage and administration details

Number of subjects in period 2 ^[1]	Optimized Medical Treatment	LCIG
Started	10	14
Transitioned to commercial LCIG	5	7 ^[2]
Completed	5	10
Not completed	5	4
Consent withdrawn by subject	-	1
Other, not specified	4	2
Adverse event	1	1

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Participants in the United States or South Korea may have elected to enter an Extension/Transition follow-up period.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: This row applies to those subjects who transitioned to LCIG after entering the extension/transition period.

Baseline characteristics

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Reporting group title

Optimized Medical Treatment

Reporting group description

Reporting group title

LCIG

Reporting group description

Reporting group values	Optimized Medical Treatment	LCIG	Total
Number of subjects	44	45	89
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	68.6 ± 6.20	66.8 ± 7.34	-
Gender categorical
Units: Subjects
Female	20	16	36
Male	24	29	53
Race
Units: Subjects
White	35	36	71
Black	0	1	1
Asian	9	8	17
Ethnicity
Units: Subjects
Hispanic or Latino	9	8	17
Not Hispanic or Latino	35	37	72
Non-Motor Symptoms Scale (NMSS) Total Score
The NMSS consists of 30 questions in 9 domains (cardiovascular/falls, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, gastrointestinal (GI) tract, urinary, sexual function, miscellaneous). Score of each question is calculated by multiplying severity*frequency. Severity and frequency are rated using a scale ranging from 0 (none) to 3 (severe) for severity and from 1 (rarely) to 4 (very frequent) for frequency. Total score is the sum of 9 domains, and ranges from 0 to 360, with a lower value indicating a more desirable outcome.
Units: score on a scale
arithmetic mean (standard deviation)	±	±	-
Modified Parkinson's Disease Sleep Scale (PDSS-2) Total Score
The PDSS-2 addresses PD-specific sleep disturbances such as restless leg syndrome (RLS), morning akinesia, pain, and sleep apnea. The frequency is assessed for the 15 sleep problems based on a 5-point Likert-type scale (ranging from 0 [never] to 4 [very often]). Scores are calculated for each of the 3 domains (motor symptoms at night, PD symptoms at night, and disturbed sleep) as well as a total score. The PDSS-2 domain scores range from 0 to 20 and the total score is a sum of the 3 domains and ranges from 0 to 60.
Units: score on a scale
arithmetic mean (standard deviation)	±	±	-

Subject analysis set title

Intent-to-Treat Data Set: Optimized Medical Treatment

Subject analysis set type

Intention-to-treat

Subject analysis set description

All participants randomized to the OMT arm who received at least one dose of study drug. Participants with a baseline measurement are reported in this table.

Subject analysis set title

Intent-to-Treat Data Set: LCIG

Subject analysis set type

Intention-to-treat

Subject analysis set description

All participants randomized to LCIG arm who received at least one dose of study drug. Participants with a baseline measurement are reported in this table.

Subject analysis sets values	Intent-to-Treat Data Set: Optimized Medical Treatment	Intent-to-Treat Data Set: LCIG
Number of subjects	43	42
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	±	±
Gender categorical
Units: Subjects
Female
Male
Race
Units: Subjects
White
Black
Asian
Ethnicity
Units: Subjects
Hispanic or Latino
Not Hispanic or Latino
Non-Motor Symptoms Scale (NMSS) Total Score
The NMSS consists of 30 questions in 9 domains (cardiovascular/falls, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, gastrointestinal (GI) tract, urinary, sexual function, miscellaneous). Score of each question is calculated by multiplying severity*frequency. Severity and frequency are rated using a scale ranging from 0 (none) to 3 (severe) for severity and from 1 (rarely) to 4 (very frequent) for frequency. Total score is the sum of 9 domains, and ranges from 0 to 360, with a lower value indicating a more desirable outcome.
Units: score on a scale
arithmetic mean (standard deviation)	112.4 ± 51.37	99.7 ± 46.49
Modified Parkinson's Disease Sleep Scale (PDSS-2) Total Score
The PDSS-2 addresses PD-specific sleep disturbances such as restless leg syndrome (RLS), morning akinesia, pain, and sleep apnea. The frequency is assessed for the 15 sleep problems based on a 5-point Likert-type scale (ranging from 0 [never] to 4 [very often]). Scores are calculated for each of the 3 domains (motor symptoms at night, PD symptoms at night, and disturbed sleep) as well as a total score. The PDSS-2 domain scores range from 0 to 20 and the total score is a sum of the 3 domains and ranges from 0 to 60.
Units: score on a scale
arithmetic mean (standard deviation)	30.3 ± 8.55	29.9 ± 7.36

End points

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Reporting group title

Optimized Medical Treatment

Reporting group description

Reporting group title

LCIG

Reporting group description

Reporting group title

Optimized Medical Treatment

Reporting group description

Reporting group title

LCIG

Reporting group description

Subject analysis set title

Intent-to-Treat Data Set: Optimized Medical Treatment

Subject analysis set type

Intention-to-treat

Subject analysis set description

All participants randomized to the OMT arm who received at least one dose of study drug. Participants with a baseline measurement are reported in this table.

Subject analysis set title

Intent-to-Treat Data Set: LCIG

Subject analysis set type

Intention-to-treat

Subject analysis set description

All participants randomized to LCIG arm who received at least one dose of study drug. Participants with a baseline measurement are reported in this table.

Primary: Change From Baseline to Week 26 in the NMSS Total Score

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End point title

Change From Baseline to Week 26 in the NMSS Total Score

End point description

The NMSS consists of 30 questions in 9 domains (cardiovascular/falls, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, GI tract, urinary, sexual function, miscellaneous). Score of each question is calculated by multiplying severity*frequency. Severity and frequency are rated using a scale ranging from 0 (none) to 3 (severe) for severity and from 1 (rarely) to 4 (very frequent) for frequency. Total score is the sum of 9 domains, and ranges from 0 to 360, with a lower value indicating a more desirable outcome. Repeated-measure analysis. Intent-to-Treat Data Set: all participants who were randomized to the OMT arm, and all participants who were randomized to LCIG arm and received at least one dose of study drug. Participants with baseline and a post-baseline measurement are reported in this table.

End point type

Primary

End point timeframe

Baseline, Week 26

End point values	Optimized Medical Treatment	LCIG
Number of subjects analysed	43	42
Units: score on a scale
least squares mean (standard error)	-23.83 ± 8.30	-32.04 ± 8.53

Statistical Analysis 1

Statistical analysis description

Difference of LCIG - OMT

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.41 ^[2]

Method

mixed model repeated measures

Parameter type

Least Squares (LS) Mean of Difference

Point estimate

-8.21

Confidence interval

level

95%

sides

2-sided

lower limit

-27.98

upper limit

11.55

Variability estimate

Standard error of the mean

Dispersion value

9.91

Notes
[1] - Adjusted for multiplicity using the Hochberg procedure to control the family-wise error rate at a pre-specified significance level (alpha = 0.05).
[2] - P value is from the mixed model repeated measures (MMRM) with the model: change from Baseline=treatment, country, visit, Baseline, treatment-by-visit, and Baseline-by-visit. Unstructured variance-covariance structure was used in the MMRM analysis.

Primary: Change From Baseline to Week 26 in the Modified PDSS-2 Total Score

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End point title

Change From Baseline to Week 26 in the Modified PDSS-2 Total Score

End point description

The PDSS-2 addresses PD-specific sleep disturbances such as restless leg syndrome (RLS), morning akinesia, pain, and sleep apnea. The frequency is assessed for the 15 sleep problems based on a 5-point Likert-type scale (ranging from 0 [never] to 4 [very often]). Scores are calculated for each of the 3 domains (motor symptoms at night, PD symptoms at night, and disturbed sleep) as well as a total score. The PDSS-2 domain scores range from 0 to 20 and the total score is a sum of the 3 domains and ranges from 0 to 60. Repeated measure analysis. Intent-to-Treat Data Set: all participants who were randomized to the OMT arm, and all participants who were randomized to LCIG arm and received at least one dose of study drug. Participants with baseline and a post-baseline measurement are reported in this table.

End point type

Primary

End point timeframe

Baseline, Week 26

End point values	Optimized Medical Treatment	LCIG
Number of subjects analysed	43	42
Units: score on a scale
least squares mean (standard error)	-8.98 ± 2.00	-7.41 ± 2.01

Statistical Analysis 1

Statistical analysis description

Difference of LCIG - OMT

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.509 ^[4]

Method

mixed model repeated measures

Parameter type

LS Mean of Difference

Point estimate

1.57

Confidence interval

level

95%

sides

2-sided

lower limit

-3.16

upper limit

6.3

Variability estimate

Standard error of the mean

Dispersion value

2.37

Notes
[3] - Adjusted for multiplicity using the Hochberg procedure to control the family-wise error rate at a pre-specified significance level (alpha = 0.05).
[4] - The P value is from the MMRM with the model: change from Baseline = treatment, country, visit, Baseline, treatment-by-visit, and Baseline-by-visit. The unstructured variance covariance structure was used in the MMRM analysis.

Secondary: Change From Baseline to Week 26 in Parkinson's Disease Questionnaire (PDQ-8) Summary Index Score

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End point title

Change From Baseline to Week 26 in Parkinson's Disease Questionnaire (PDQ-8) Summary Index Score

End point description

The PDQ-8 is a disease-specific instrument designed to measure aspects of health relevant to PD. Eight questions including the mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort are assessed on a 5-point scale: 0 = Never, 1 = Occasionally, 2 = Sometimes, 3 = Often, 4 = Always (or cannot do at all, if applicable). Summary index score is the sum of each question divided by 32 and multiplied by 100. Scores range from 0 to 100 with lower values desirable. Intent-to-Treat Data Set: all participants who were randomized to the OMT arm, and all participants who were randomized to LCIG arm and received at least one dose of study drug.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Optimized Medical Treatment	LCIG
Number of subjects analysed	44	43
Units: score on a scale
least squares mean (standard error)	-1.75 ± 2.96	-5.56 ± 2.97

Statistical Analysis 1

Statistical analysis description

Statistical significance for the 3 key secondary efficacy endpoints (PDQ-8 index score, CGI-C score, and UPDRS Part II) could only be evaluated using the Hochberg procedure for multiplicity control if both primary endpoints had been statistically significant after multiplicity adjustment.

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.291 ^[6]

Method

Repeated measures model

Parameter type

LS mean difference

Point estimate

-3.81

Confidence interval

level

95%

sides

2-sided

lower limit

-10.96

upper limit

3.34

Variability estimate

Standard error of the mean

Dispersion value

3.59

Notes
[5] - Difference of LCIG - OMT
[6] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Secondary: Clinical Global Impression of Change (CGI-C) Final Score

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End point title

Clinical Global Impression of Change (CGI-C) Final Score

End point description

CGI-C score is a clinician's impression of a subject's change in status on a 7-point scale (1 = very much improved, 2 = much improved, 3 = minimally Improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse). Scores range from 1 to 7, with lower score desirable. Intent-to-Treat Data Set: all participants who were randomized to the OMT arm, and all participants who were randomized to LCIG arm and received at least one dose of study drug. Participants with an assessment are reported in this table.

End point type

Secondary

End point timeframe

End of Treatment Period (up to Week 26)

End point values	Optimized Medical Treatment	LCIG
Number of subjects analysed	43	40
Units: score on a scale
least squares mean (standard error)	4.9 ± 0.25	2.5 ± 0.24

Statistical Analysis 1

Statistical analysis description

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

< 0.001 ^[8]

Method

ANCOVA

Parameter type

LS Mean of Difference

Point estimate

-2.3

Confidence interval

level

95%

sides

2-sided

lower limit

-2.84

upper limit

-1.82

Variability estimate

Standard error of the mean

Dispersion value

0.26

Notes
[7] - Difference of LCIG - OMT
[8] - Analysis of covariance (ANCOVA) model: FINAL = treatment, country.

Secondary: Change From Baseline at Week 26 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II Score

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End point title

Change From Baseline at Week 26 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II Score

End point description

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Optimized Medical Treatment	LCIG
Number of subjects analysed	44	43
Units: score on a scale
least squares mean (standard error)	0.53 ± 0.89	-2.26 ± 0.87

Statistical Analysis 1

Statistical analysis description

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

= 0.006 ^[10]

Method

Repeated measures model

Parameter type

LS mean difference

Point estimate

-2.79

Confidence interval

level

95%

sides

2-sided

lower limit

-4.77

upper limit

-0.81

Variability estimate

Standard error of the mean

Dispersion value

0.99

Notes
[9] - Difference of LCIG - OMT
[10] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Secondary: Change From Baseline to Week 26 in the NMSS Domain Scores

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End point title

Change From Baseline to Week 26 in the NMSS Domain Scores

End point description

The NMSS consists of 30 questions in 9 domains. Score is calculated by multiplying severity*frequency. Severity and frequency are rated using a scale of 0 (none) to 3 (severe) for severity and 1 (rarely) to 4 (very frequent) for frequency, with lower values desirable for each score. Cardiovascular/falls scores range from 0-24. Sleep/fatigue scores range from 0-48. Mood/cognition scores range from 0-72. Perceptual problems/hallucinations scores range from 0-36. Attention/memory scores range from 0-36. Gastrointestinal tract scores range from 0-36. Urinary scores range from 0-36. Sexual function scores range from 0-24. Miscellaneous scores range from 0-48. Repeated measure analysis. Intent-to-Treat Data Set: all participants who were randomized to the OMT arm, and all participants who were randomized to LCIG arm and received at least one dose of study drug. Participants with baseline and a post-baseline measurement are reported in this table.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Optimized Medical Treatment	LCIG
Number of subjects analysed	43	42
Units: score on a scale
least squares mean (standard error)
Cardiovascular including falls	-1.84 ± 0.82	-1.76 ± 0.86
Sleep/fatigue	-7.11 ± 2.02	-6.06 ± 2.06
Mood/cognition	-5.99 ± 3.06	-7.84 ± 3.11
Perceptual problems/hallucinations	-1.53 ± 0.70	-1.14 ± 0.72
Attention/memory	-1.20 ± 1.60	-2.15 ± 1.66
Gastrointestinal tract	-0.85 ± 1.09	-3.43 ± 1.14
Urinary	-3.65 ± 1.90	-4.83 ± 1.96
Sexual function	0.88 ± 0.86	0.10 ± 0.90
Miscellaneous	-3.87 ± 1.53	-5.16 ± 1.60

Statistical Analysis 1

Statistical analysis description

Cardiovascular including falls

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

= 0.933 ^[12]

Method

Repeated measures model

Parameter type

LS mean difference

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-1.89

upper limit

2.06

Variability estimate

Standard error of the mean

Dispersion value

0.99

Notes
[11] - Difference of LCIG - OMT
[12] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Statistical Analysis 2

Statistical analysis description

Sleep/fatigue

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

= 0.655 ^[14]

Method

Repeated measures model

Parameter type

LS mean difference

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

-3.63

upper limit

5.74

Variability estimate

Standard error of the mean

Dispersion value

2.35

Notes
[13] - Difference of LCIG - OMT
[14] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Statistical Analysis 3

Statistical analysis description

Mood/cognition

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

= 0.616 ^[16]

Method

Repeated measures model

Parameter type

LS mean difference

Point estimate

-1.85

Confidence interval

level

95%

sides

2-sided

lower limit

-9.18

upper limit

5.48

Variability estimate

Standard error of the mean

Dispersion value

3.67

Notes
[15] - Difference of LCIG - OMT
[16] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Statistical Analysis 4

Statistical analysis description

Perceptual problems/hallucinations

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.645 ^[18]

Method

Repeated measures model

Parameter type

LS mean difference

Point estimate

0.39

Confidence interval

level

95%

sides

2-sided

lower limit

-1.3

upper limit

2.08

Variability estimate

Standard error of the mean

Dispersion value

0.84

Notes
[17] - Difference of LCIG - OMT
[18] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Statistical Analysis 5

Statistical analysis description

Attention/memory

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

= 0.645 ^[20]

Method

Repeated measures model

Parameter type

LS mean difference

Point estimate

-0.94

Confidence interval

level

95%

sides

2-sided

lower limit

-5.03

upper limit

3.14

Variability estimate

Standard error of the mean

Dispersion value

2.04

Notes
[19] - Difference of LCIG - OMT
[20] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Statistical Analysis 6

Statistical analysis description

Gastrointestinal tract

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

= 0.058 ^[22]

Method

Repeated measures model

Parameter type

LS mean difference

Point estimate

-2.58

Confidence interval

level

95%

sides

2-sided

lower limit

-5.25

upper limit

0.09

Variability estimate

Standard error of the mean

Dispersion value

1.34

Notes
[21] - Difference of LCIG - OMT
[22] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Statistical Analysis 7

Statistical analysis description

Urinary

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

P-value

= 0.588 ^[24]

Method

Repeated measures model

Parameter type

LS mean difference

Point estimate

-1.18

Confidence interval

level

95%

sides

2-sided

lower limit

-5.52

upper limit

3.15

Variability estimate

Standard error of the mean

Dispersion value

2.17

Notes
[23] - Difference of LCIG - OMT
[24] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Statistical Analysis 8

Statistical analysis description

Sexual function

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[25]

P-value

= 0.464 ^[26]

Method

Repeated measures model

Parameter type

LS mean difference

Point estimate

-0.78

Confidence interval

level

95%

sides

2-sided

lower limit

-2.88

upper limit

1.33

Variability estimate

Standard error of the mean

Dispersion value

1.05

Notes
[25] - Difference of LCIG - OMT
[26] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Statistical Analysis 9

Statistical analysis description

Miscellaneous

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[27]

P-value

= 0.468 ^[28]

Method

Repeated measures model

Parameter type

LS mean difference

Point estimate

-1.29

Confidence interval

level

95%

sides

2-sided

lower limit

-4.8

upper limit

2.23

Variability estimate

Standard error of the mean

Dispersion value

1.76

Notes
[27] - Difference of LCIG - OMT
[28] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Secondary: Change From Baseline to Week 26 in the Modified PDSS-2 Domain Scores

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End point title

Change From Baseline to Week 26 in the Modified PDSS-2 Domain Scores

End point description

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Optimized Medical Treatment	LCIG
Number of subjects analysed	43	42
Units: score on a scale
least squares mean (standard error)
Motor symptoms at night	-2.21 ± 1.04	-2.79 ± 1.05
PD symptoms at night	-1.77 ± 0.66	-1.53 ± 0.69
Disturbed sleep	-4.88 ± 0.74	-2.89 ± 0.75

Statistical Analysis 1

Statistical analysis description

Motor symptoms at night

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[29]

P-value

= 0.643 ^[30]

Method

repeated measures model

Parameter type

LS Method of Mean of Difference

Point estimate

-0.58

Confidence interval

level

95%

sides

2-sided

lower limit

-3.09

upper limit

1.92

Variability estimate

Standard error of the mean

Dispersion value

1.26

Notes
[29] - Difference of LCIG - OMT
[30] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Statistical Analysis 2

Statistical analysis description

PD symptoms at night

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[31]

P-value

= 0.769 ^[32]

Method

repeated measures model

Parameter type

LS Method of Mean of Difference

Point estimate

0.24

Confidence interval

level

95%

sides

2-sided

lower limit

-1.39

upper limit

1.87

Variability estimate

Standard error of the mean

Dispersion value

0.82

Notes
[31] - Difference of LCIG - OMT
[32] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Statistical Analysis 3

Statistical analysis description

Disturbed sleep

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[33]

P-value

= 0.02 ^[34]

Method

repeated measures model

Parameter type

LS Method of Mean of Difference

Point estimate

1.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.32

upper limit

3.66

Variability estimate

Standard error of the mean

Dispersion value

0.84

Notes
[33] - Difference of LCIG - OMT
[34] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Secondary: Change From Baseline at Week 26 in UPDRS Parts I, III, and IV Score

Top of page

End point title

Change From Baseline at Week 26 in UPDRS Parts I, III, and IV Score

End point description

UPDRS is an investigator-used rating tool to follow the longitudinal course of Parkinson's disease of 42 total questions. Part I (Questions 1 – 4), Part II (Questions 5 – 17), Part III (Questions 18 – 31), and Part IV (Questions 32 – 42). Questions 35 – 38 and 40 – 42 are 2-point (0 and 1), all other questions are 5-point (0 – 4). Part I is the sum of Questions 1 – 4; scores range from 0 to 16 with lower value desirable. Part III is the sum of Questions 18 – 31 (Questions 20 – 26 apply to multiple body parts, resulting in 27 answers total); scores range from 0 to 108 with lower value desirable. Part IV is the sum of Questions 32 – 42; scores range from 0 to 23 with lower value desirable. Intent-to-Treat Data Set: all participants who were randomized to the OMT arm, and all participants who were randomized to LCIG arm and received at least one dose of study drug. Participants with baseline and a post-baseline measurement are reported in this table.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Optimized Medical Treatment	LCIG
Number of subjects analysed	44 ^[35]	43 ^[36]
Units: score on a scale
least squares mean (standard error)
Part I; n=44, 43	0.20 ± 0.39	0.39 ± 0.39
Part III; n=43, 43	1.32 ± 1.84	-0.89 ± 1.80
Part IV; n=44, 43	-0.61 ± 0.53	-2.31 ± 0.52

Attachments

Untitled (Filename: Statistical Analyses_Change From Baseline at Week 26 in UPDRS Parts I, III, and IV Score.docx)

Notes
[35] - n=participants with an assessment
[36] - n=participants with an assessment

No statistical analyses for this end point

Secondary: Change From Baseline at Week 26 in Parkinson's Anxiety Scale (PAS) Total Score

Top of page

End point title

Change From Baseline at Week 26 in Parkinson's Anxiety Scale (PAS) Total Score

End point description

PAS is a 12-item scale developed specifically to measure severity in anxiety in Parkinson's disease for the following items: Feeling anxious or nervous; Feeling tense or stressed; Being unable to relax; Excessive worrying about everyday matters; Fear of something bad, or even the worst, happening; Panic or intense fear; Shortness of breath; Heart palpitations or heart beating fast; Fear of losing control; Social situations; Public settings; Specific objects or situations. Severity for each item is rated as: 0, Never; 1 Rarely; 2, Sometimes; 3, Often; 4, Nearly always. Total score is the sum of the12 item scores, with a range of 0 to 48; a lower value is desirable. Intent-to-Treat Data Set: all participants who were randomized to the OMT arm, and all participants who were randomized to LCIG arm and received at least one dose of study drug. Participants with baseline and a post-baseline measurement are reported in this table.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Optimized Medical Treatment	LCIG
Number of subjects analysed	44	41
Units: score on a scale
least squares mean (standard error)	-0.75 ± 1.28	-2.29 ± 1.27

Statistical Analysis 1

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[37]

P-value

= 0.307 ^[38]

Method

repeated measures model

Parameter type

LS Mean of Difference

Point estimate

-1.54

Confidence interval

level

95%

sides

2-sided

lower limit

-4.52

upper limit

1.44

Variability estimate

Standard error of the mean

Dispersion value

1.5

Notes
[37] - Difference of LCIG - OMT
[38] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Secondary: Change From Baseline at Week 26 in Geriatric Depression Scale (GDS-15) Score

Top of page

End point title

Change From Baseline at Week 26 in Geriatric Depression Scale (GDS-15) Score

End point description

The GDS-15 is a screening instrument for depression in the elderly of 15 yes/no questions: 1) Satisfied with life 2) Dropped many activities and interests 3) Life is empty 4) Often get bored 5) In good spirits most of the time 6) Afraid that something bad is going to happen 7) Feel happy most of the time 8) Often feel helpless 9) Prefer to stay at home, rather than going out and doing things 10) Feel that have more problems with memory than most 11) Think it is wonderful to be alive now 12) Feel worthless 13) Feel full of energy 14) Situation is hopeless 15) Most subjects are better off. Answers of 'yes' to questions 2, 3, 4, 6, 8, 9, 10, 12, 14, 15 are scored 1 point. Answers of 'no' to questions 1, 5, 7, 11, 13 are scored 1 point. The 15 items are summed and scores range from 0-15 with lower value desirable. Intent-to-Treat Data Set: all participants randomized to the OMT arm, and all participants randomized to LCIG arm and received at least one dose of study drug.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Optimized Medical Treatment	LCIG
Number of subjects analysed	44	43
Units: score on a scale
least squares mean (standard error)	0.25 ± 0.40	0.17 ± 0.39

Statistical Analysis 1

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[39]

P-value

= 0.868 ^[40]

Method

repeated measures model

Parameter type

LS Mean of Difference

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.99

upper limit

0.84

Variability estimate

Standard error of the mean

Dispersion value

0.46

Notes
[39] - Difference of LCIG - OMT
[40] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Secondary: Change From Baseline at Week 26 in King's PD Pain Scale (KPPS) Score

Top of page

End point title

Change From Baseline at Week 26 in King's PD Pain Scale (KPPS) Score

End point description

The KPPS score is a clinical PD-specific pain scale of 14 items addressing the following 7 domains: musculoskeletal pain, chronic pain, fluctuation-related pain, nocturnal pain, orofacial pain, neuropathic pain, radicular pain. Each domain item is scored by severity (0, none to 3, very severe) multiplied by frequency (0, never to 4, all the time) resulting in a subscore of 0 – 12 (with lower value desirable), the sum of the 14 items gives the total score with a range from 0 to 168 with lower value desirable. Intent-to-Treat Data Set: all participants who were randomized to the OMT arm, and all participants who were randomized to LCIG arm and received at least one dose of study drug.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Optimized Medical Treatment	LCIG
Number of subjects analysed	44	43
Units: score on a scale
least squares mean (standard error)
Total score	-11.32 ± 2.83	-12.46 ± 2.77
Musculoskeletal Pain Score	-1.72 ± 0.63	-1.79 ± 0.62
Chronic pain score	-0.84 ± 0.54	-0.77 ± 0.55
Fluctuation related pain score	-3.77 ± 1.30	-3.14 ± 1.28
Nocturnal pain score	-2.41 ± 1.04	-2.78 ± 1.01
Orofacial pain score	-0.74 ± 0.41	-0.87 ± 0.41
Discoloration and edema score	-0.47 ± 0.65	-2.27 ± 0.65
Radicular pain score	-1.43 ± 0.39	-1.47 ± 0.39

Statistical Analysis 1

Statistical analysis description

Total score

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[41]

P-value

= 0.728 ^[42]

Method

repeated measures model

Parameter type

LS Mean of Difference

Point estimate

-1.14

Confidence interval

level

95%

sides

2-sided

lower limit

-7.68

upper limit

5.39

Variability estimate

Standard error of the mean

Dispersion value

3.28

Notes
[41] - Difference of LCIG - OMT
[42] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Statistical Analysis 2

Statistical analysis description

Musculoskeletal pain score

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[43]

P-value

= 0.916 ^[44]

Method

repeated measures model

Parameter type

LS Mean of Difference

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

1.35

Variability estimate

Standard error of the mean

Dispersion value

0.71

Notes
[43] - Difference of LCIG - OMT
[44] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Statistical Analysis 3

Statistical analysis description

Chronic pain score

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[45]

P-value

= 0.919 ^[46]

Method

repeated measures model

Parameter type

LS Mean of Difference

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-1.28

upper limit

1.42

Variability estimate

Standard error of the mean

Dispersion value

0.68

Notes
[45] - Difference of LCIG - OMT
[46] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Statistical Analysis 4

Statistical analysis description

Fluctuation related pain score

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[47]

P-value

= 0.68 ^[48]

Method

repeated measures model

Parameter type

LS Mean of Difference

Point estimate

0.63

Confidence interval

level

95%

sides

2-sided

lower limit

-2.42

upper limit

3.68

Variability estimate

Standard error of the mean

Dispersion value

1.53

Notes
[47] - Difference of LCIG - OMT
[48] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Statistical Analysis 5

Statistical analysis description

Nocturnal pain score

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[49]

P-value

= 0.767 ^[50]

Method

repeated measures model

Parameter type

LS Mean of Difference

Point estimate

-0.37

Confidence interval

level

95%

sides

2-sided

lower limit

-2.83

upper limit

2.09

Variability estimate

Standard error of the mean

Dispersion value

1.24

Notes
[49] - Difference of LCIG - OMT
[50] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Statistical Analysis 6

Statistical analysis description

Orofacial pain score

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[51]

P-value

= 0.804 ^[52]

Method

repeated measures model

Parameter type

LS Mean of Difference

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-1.15

upper limit

0.9

Variability estimate

Standard error of the mean

Dispersion value

0.51

Notes
[51] - Difference of LCIG - OMT
[52] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Statistical Analysis 7

Statistical analysis description

Discoloration and edema score

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[53]

P-value

= 0.025 ^[54]

Method

repeated measures model

Parameter type

LS Mean of Difference

Point estimate

-1.81

Confidence interval

level

95%

sides

2-sided

lower limit

-3.38

upper limit

-0.23

Variability estimate

Standard error of the mean

Dispersion value

0.79

Notes
[53] - Difference of LCIG - OMT
[54] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Statistical Analysis 8

Statistical analysis description

Radicular pain score

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[55]

P-value

= 0.93 ^[56]

Method

repeated measures model

Parameter type

LS Mean of Difference

Point estimate

-0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.99

upper limit

0.9

Variability estimate

Standard error of the mean

Dispersion value

0.47

Notes
[55] - Difference of LCIG - OMT
[56] - The repeated measures model: change = treatment, country, visit, baseline, treatment * visit, baseline * visit. The unstructured variance-covariance structure is used.

Secondary: Patient Global Impression of Change (PGIC) Final Score

Top of page

End point title

Patient Global Impression of Change (PGIC) Final Score

End point description

The PGIC is a 7-point response scale. The participant was asked by the Investigator or qualified designee to rate their change in status using the following 7-point scale: 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, 7 = Very much worse. PGIC score ranges from 1 to 7 with lower score desirable. Intent-to-Treat Data Set: all participants who were randomized to the OMT arm, and all participants who were randomized to LCIG arm and received at least one dose of study drug. Participants with an assessment are reported in this table.

End point type

Secondary

End point timeframe

End of Treatment Period (up to Week 26)

End point values	Optimized Medical Treatment	LCIG
Number of subjects analysed	43	40
Units: score on a scale
least squares mean (standard error)	4.9 ± 0.25	2.5 ± 0.24

Statistical Analysis 1

Comparison groups

Optimized Medical Treatment v LCIG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[57]

P-value

< 0.001 ^[58]

Method

ANCOVA

Parameter type

LS Mean of Difference

Point estimate

-2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-2.89

upper limit

-1.87

Variability estimate

Standard error of the mean

Dispersion value

0.26

Notes
[57] - Difference of LCIG - OMT
[58] - ANCOVA model: FINAL = treatment, country.

Adverse events

Top of page

Timeframe for reporting adverse events

All adverse events are reported from the time of randomization until 30 days following last OMT dose, last study visit, discontinuation of study drug administration, removal of the PEG-J tube or Last LCIG Commercial Transition Visit have elapsed.

Adverse event reporting additional description

Median duration of follow-up was 191 days for OMT and 565 days for LCIG in the Treatment Period, and was 1366 days for OMT -> LCIG and 1003.5 days for LCIG -> LCIG in the Extension/Transition period.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Optimized Medical Treatment (OMT)

Reporting group description

Participants randomized to continue OMT remained on their current optimized regimen during the 26-week treatment phase. Changes to anti-PD and NMS medications are to remain stable and can only be made if medically indicated.

Reporting group title

Extension/Transition LCIG ->LCIG

Reporting group description

Participants randomized to LCIG in the United States or South Korea who elected to enter an Extension/ Transition follow-up period to receive an individually optimized LCIG dose, in order to transition to commercially available LCIG.

Reporting group title

Extension/Transition OMT->LCIG

Reporting group description

Participants randomized to continue OMT in the United States or South Korea who elected to enter an Extension/Transition follow-up period to receive an individually optimized LCIG dose (after NJ and/or PEG-J placement), in order to transition to commercially available LCIG.

Reporting group title

LCIG

Reporting group description

Serious adverse events	Optimized Medical Treatment (OMT)	Extension/Transition LCIG ->LCIG	Extension/Transition OMT->LCIG	LCIG
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 44 (9.09%)	1 / 14 (7.14%)	2 / 10 (20.00%)	9 / 43 (20.93%)
number of deaths (all causes)	0	0	1	0
number of deaths resulting from adverse events	0	0	1	0
Injury, poisoning and procedural complications
FALL
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
PATELLA FRACTURE
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
LOWER LIMB FRACTURE
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
HUMERUS FRACTURE
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
FEMUR FRACTURE
subjects affected / exposed	1 / 44 (2.27%)	0 / 14 (0.00%)	0 / 10 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
SUBDURAL HAEMATOMA
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
AORTIC VALVE STENOSIS
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (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
Nervous system disorders
NEURALGIA
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
SYNCOPE
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (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
PARKINSON'S DISEASE
subjects affected / exposed	1 / 44 (2.27%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 43 (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
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (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
DEATH
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (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 / 1	0 / 0
Gastrointestinal disorders
PNEUMOPERITONEUM
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	2 / 43 (4.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
INGUINAL HERNIA
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
ILEUS PARALYTIC
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (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
Respiratory, thoracic and mediastinal disorders
PNEUMONIA ASPIRATION
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
DYSPNOEA
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (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
Psychiatric disorders
DEPRESSION
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
ROTATOR CUFF SYNDROME
subjects affected / exposed	0 / 44 (0.00%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
BACTERAEMIA
subjects affected / exposed	1 / 44 (2.27%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 43 (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
PERITONITIS
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (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
URINARY TRACT INFECTION
subjects affected / exposed	1 / 44 (2.27%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 43 (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
STOMA SITE INFECTION
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	2 / 43 (4.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
PYELONEPHRITIS ACUTE
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Metabolism and nutrition disorders
KETOACIDOSIS
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
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	Optimized Medical Treatment (OMT)	Extension/Transition LCIG ->LCIG	Extension/Transition OMT->LCIG	LCIG
Total subjects affected by non serious adverse events
subjects affected / exposed	13 / 44 (29.55%)	4 / 14 (28.57%)	6 / 10 (60.00%)	33 / 43 (76.74%)
Investigations
WEIGHT DECREASED
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	4 / 43 (9.30%)
occurrences all number	0	0	0	4
VITAMIN B6 DECREASED
subjects affected / exposed	1 / 44 (2.27%)	1 / 14 (7.14%)	0 / 10 (0.00%)	2 / 43 (4.65%)
occurrences all number	1	1	0	2
Injury, poisoning and procedural complications
STOMA SITE DERMATITIS
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (0.00%)
occurrences all number	0	0	1	0
PROCEDURAL PAIN
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	4 / 43 (9.30%)
occurrences all number	0	0	0	4
FALL
subjects affected / exposed	7 / 44 (15.91%)	0 / 14 (0.00%)	0 / 10 (0.00%)	4 / 43 (9.30%)
occurrences all number	8	0	0	6
STOMA SITE DISCHARGE
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	4 / 43 (9.30%)
occurrences all number	0	0	1	4
STOMA SITE PAIN
subjects affected / exposed	0 / 44 (0.00%)	1 / 14 (7.14%)	3 / 10 (30.00%)	6 / 43 (13.95%)
occurrences all number	0	1	6	7
STOMA SITE HYPERGRANULATION
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	3 / 43 (6.98%)
occurrences all number	0	0	2	3
Nervous system disorders
PERIPHERAL SENSORY NEUROPATHY
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (0.00%)
occurrences all number	0	0	1	0
PARKINSON'S DISEASE
subjects affected / exposed	3 / 44 (6.82%)	1 / 14 (7.14%)	0 / 10 (0.00%)	2 / 43 (4.65%)
occurrences all number	3	1	0	3
FREEZING PHENOMENON
subjects affected / exposed	3 / 44 (6.82%)	0 / 14 (0.00%)	0 / 10 (0.00%)	1 / 43 (2.33%)
occurrences all number	4	0	0	2
DYSKINESIA
subjects affected / exposed	1 / 44 (2.27%)	0 / 14 (0.00%)	2 / 10 (20.00%)	4 / 43 (9.30%)
occurrences all number	1	0	2	4
General disorders and administration site conditions
PYREXIA
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	4 / 43 (9.30%)
occurrences all number	0	0	0	4
CHEST PAIN
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (0.00%)
occurrences all number	0	0	1	0
Eye disorders
CATARACT NUCLEAR
subjects affected / exposed	0 / 44 (0.00%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	1	0	0
NORMAL TENSION GLAUCOMA
subjects affected / exposed	0 / 44 (0.00%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	1	0	0
Social circumstances
SOCIAL PROBLEM
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (0.00%)
occurrences all number	0	0	1	0
Gastrointestinal disorders
ABDOMINAL DISTENSION
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	2 / 43 (4.65%)
occurrences all number	0	0	1	2
ABDOMINAL DISCOMFORT
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (0.00%)
occurrences all number	0	0	1	0
DIARRHOEA
subjects affected / exposed	1 / 44 (2.27%)	0 / 14 (0.00%)	0 / 10 (0.00%)	3 / 43 (6.98%)
occurrences all number	1	0	0	3
DUODENAL ULCER
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	1 / 43 (2.33%)
occurrences all number	0	0	1	1
DYSPEPSIA
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (0.00%)
occurrences all number	0	0	1	0
DYSPHAGIA
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (0.00%)
occurrences all number	0	0	1	0
GASTRIC MUCOSAL LESION
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (0.00%)
occurrences all number	0	0	1	0
GASTRIC ULCER
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	1 / 43 (2.33%)
occurrences all number	0	0	1	1
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	1 / 43 (2.33%)
occurrences all number	0	0	1	1
CONSTIPATION
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	3 / 43 (6.98%)
occurrences all number	0	0	0	3
ABDOMINAL PAIN
subjects affected / exposed	0 / 44 (0.00%)	1 / 14 (7.14%)	1 / 10 (10.00%)	5 / 43 (11.63%)
occurrences all number	0	1	1	6
Respiratory, thoracic and mediastinal disorders
PRODUCTIVE COUGH
subjects affected / exposed	1 / 44 (2.27%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (0.00%)
occurrences all number	1	0	1	0
COUGH
subjects affected / exposed	1 / 44 (2.27%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (0.00%)
occurrences all number	1	0	1	0
HYPOXIA
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	1 / 43 (2.33%)
occurrences all number	0	0	1	1
Psychiatric disorders
AGITATION
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	3 / 43 (6.98%)
occurrences all number	0	0	0	3
ANXIETY
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	2 / 43 (4.65%)
occurrences all number	0	0	1	2
DEPRESSED MOOD
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	1 / 43 (2.33%)
occurrences all number	0	0	1	1
DEPRESSION
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	4 / 43 (9.30%)
occurrences all number	0	0	0	4
HALLUCINATION
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	4 / 43 (9.30%)
occurrences all number	0	0	0	4
SLEEP ATTACKS
subjects affected / exposed	0 / 44 (0.00%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	1	0	0
PSYCHOTIC DISORDER
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (0.00%)
occurrences all number	0	0	1	0
INSOMNIA
subjects affected / exposed	0 / 44 (0.00%)	1 / 14 (7.14%)	1 / 10 (10.00%)	4 / 43 (9.30%)
occurrences all number	0	1	2	4
IMPULSIVE BEHAVIOUR
subjects affected / exposed	0 / 44 (0.00%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	1	0	0
IMPULSE-CONTROL DISORDER
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (0.00%)
occurrences all number	0	0	1	0
Infections and infestations
STOMA SITE INFECTION
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	5 / 43 (11.63%)
occurrences all number	0	0	2	5
STOMA SITE CELLULITIS
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (0.00%)
occurrences all number	0	0	1	0
ASYMPTOMATIC COVID-19
subjects affected / exposed	0 / 44 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 43 (0.00%)
occurrences all number	0	0	1	0

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Were there any global substantial amendments to the protocol? Yes

07 May 2015

● Clarify that the study will be performed in compliance with ICH-GCP E6(R1). ● Add screening for alcohol abuse. ● Clarify that a movement disorder specialist should perform the interview at screening. ● Clarify that all subjects, selected for the study will be judged to have decision-making capacity, or will have a caregiver, who has the legal right to act on behalf of the subject following national laws. ● To remove the double-barrier method as an acceptable birth control option. ● To allow the Investigator to adjust the anti-PD medications without consulting the Medical Monitor. ● To remove the Bazett's correction method (QTcB) from the ECG analysis. ● To include the text regarding experience for blinded raters. ● To state that protocol deviations affecting subject safety or data robustness should be reported in EU Member States where this is required.

28 Mar 2016

● Incorporate Administrative Change 1. ● Update PC (Product Complaints) Section. ● Clarify the first treatment day for the OMT group. ● Birth Control Inclusion/Exclusion section of the protocol. ● To clarify that all tests at V1 will be used to determine inclusion/exclusion criteria. ● To update Table 3, Study Activities. ● To clarify how data are collected by the blinded raters.

15 Nov 2016

● Increase the number of sites participating in the study. ● Relax the inclusion criteria by lowering the score of the PDSS-2 assessment administrated at baseline from 20 to 18. ● Remove Exclusion Criterion 3: Subject has undergone apomorphine continuous infusion for the treatment of Parkinson's disease. ● Remove Drug/Alcohol Screening from Visit 3. ● Update the Contraception Recommendations and Pregnancy Testing guidelines, including monthly pregnancy testing for women of child bearing potential (WOCBP). ● Update definitions of Relationship to Study Drug.

31 May 2017

● Change the study Reference Safety Information (RSI) from the Duodopa Summary of Product Characteristics (SmPC) to the Levodopa-Carbidopa Intestinal Gel (LCIG), (also known as Duopa or Duodopa) Investigator Brochure (IB).

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Study to Examine the Effect of Levodopa-Carbidopa Intestinal Gel (LCIG) Therapy Relative to That of Optimized Medical Treatment (OMT) on Non-motor Symptoms (NMS) Associated With Advanced Parkinson's Disease (PD)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline to Week 26 in the NMSS Total Score

Primary: Change From Baseline to Week 26 in the NMSS Total Score

Primary: Change From Baseline to Week 26 in the Modified PDSS-2 Total Score

Primary: Change From Baseline to Week 26 in the Modified PDSS-2 Total Score

Secondary: Change From Baseline to Week 26 in Parkinson's Disease Questionnaire (PDQ-8) Summary Index Score

Secondary: Change From Baseline to Week 26 in Parkinson's Disease Questionnaire (PDQ-8) Summary Index Score

Secondary: Clinical Global Impression of Change (CGI-C) Final Score

Secondary: Clinical Global Impression of Change (CGI-C) Final Score

Secondary: Change From Baseline at Week 26 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II Score

Secondary: Change From Baseline at Week 26 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II Score

Secondary: Change From Baseline to Week 26 in the NMSS Domain Scores

Secondary: Change From Baseline to Week 26 in the NMSS Domain Scores

Secondary: Change From Baseline to Week 26 in the Modified PDSS-2 Domain Scores

Secondary: Change From Baseline to Week 26 in the Modified PDSS-2 Domain Scores

Secondary: Change From Baseline at Week 26 in UPDRS Parts I, III, and IV Score

Secondary: Change From Baseline at Week 26 in UPDRS Parts I, III, and IV Score

Secondary: Change From Baseline at Week 26 in Parkinson's Anxiety Scale (PAS) Total Score

Secondary: Change From Baseline at Week 26 in Parkinson's Anxiety Scale (PAS) Total Score

Secondary: Change From Baseline at Week 26 in Geriatric Depression Scale (GDS-15) Score

Secondary: Change From Baseline at Week 26 in Geriatric Depression Scale (GDS-15) Score

Secondary: Change From Baseline at Week 26 in King's PD Pain Scale (KPPS) Score

Secondary: Change From Baseline at Week 26 in King's PD Pain Scale (KPPS) Score

Secondary: Patient Global Impression of Change (PGIC) Final Score

Secondary: Patient Global Impression of Change (PGIC) Final Score

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Study to Examine the Effect of Levodopa-Carbidopa Intestinal Gel (LCIG) Therapy Relative to That of Optimized Medical Treatment (OMT) on Non-motor Symptoms (NMS) Associated With Advanced Parkinson's Disease (PD)