Clinical Trial Results:
A Multicenter, Multinational, Double-Blind, Placebo-Controlled, 3-Arm, Phase 4 Study To Evaluate The Efficacy Of Rotigotine On Parkinson's Disease-Associated Apathy, Motor Symptoms, And Mood
Summary
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EudraCT number |
2012-002840-26 |
Trial protocol |
AT ES HU IT BG SI RO SK |
Global end of trial date |
04 Mar 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Jun 2016
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First version publication date |
25 Jun 2015
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
PD0005
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01782222 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
UCB BIOSCIENCES GmbH
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Sponsor organisation address |
Alfred-Nobel-Str.10, Monheim, Germany, 40789
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Public contact |
Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, 0049 2173 48 15 15, clinicaltrials@ucb.com
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Scientific contact |
Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, 0049 2173 48 15 15, clinicaltrials@ucb.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
08 Sep 2014
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
04 Mar 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this study is to assess the effects of rotigotine over placebo on improvement of apathy and motor symptoms in subjects with early-stage and advanced-stage idiopathic Parkinson’s disease.
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Protection of trial subjects |
Close monitoring of subjects safety status, including checks of mental health e.g. by CSSR-S questionnaire.
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Background therapy |
Not applicable | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
05 Feb 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Austria: 3
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Country: Number of subjects enrolled |
Hungary: 2
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Country: Number of subjects enrolled |
Poland: 21
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Country: Number of subjects enrolled |
Slovakia: 30
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Country: Number of subjects enrolled |
United States: 66
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Worldwide total number of subjects |
122
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EEA total number of subjects |
56
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
43
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From 65 to 84 years |
72
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85 years and over |
7
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Recruitment
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Recruitment details |
This study was planned to be conducted globally with 480 subjects (160 subjects per treatment group for the Full Analysis Set). Approx. 600 subjects were planned for enrollment in order to obtain 504 subjects for randomization. Subjects were randomized in a 1:1:1 ratio to either Rotigotine low dose, Rotigotine high dose or Placebo. | ||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
The Participant Flow refers to the Randomized Set (RS). The RS included all subjects who were randomized. The outcome of the Interim Analysis was to stop the study, i.e. no more subjects were enrolled into the study and all included subjects completed the study as planned. | ||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | ||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation) | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
Placebo
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Other name |
Placebo
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Pharmaceutical forms |
Transdermal patch
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Routes of administration |
Transdermal use
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Dosage and administration details |
Matching Placebo to Rotigotine.
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Arm title
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Rotigotine, low dose | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson’s Disease and 6 mg / 24 hours for those with early Parkinson’s DiseaseRotigotine: Rotigotine, transdermal patches:10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours);40 cm^2 (8 mg / 24 hours) Optimal dosage:The maximum Rotigotine dose allowed was 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation) | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Rotigotine
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Investigational medicinal product code |
Neupro
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Other name |
Neupro
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Pharmaceutical forms |
Transdermal patch
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Routes of administration |
Transdermal use
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Dosage and administration details |
Rotigotine, transdermal patches:
10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours)
The maximum Rotigotine dose allowed is 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)
Other Name: (6S)-6-propyl-[2 (2 thienyl)ethyl]amino-5,6,7,8-tetrahydro-1-naphthalenol
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Arm title
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Rotigotine, high dose | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's DiseaseRotigotine: Rotigotine, transdermal patches:10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours);40 cm^2 (8 mg / 24 hours) Optimal dosage:The maximum Rotigotine dose allowed was 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation) | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Rotigotine
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Investigational medicinal product code |
Neupro
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Other name |
Neupro
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Pharmaceutical forms |
Transdermal patch
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Routes of administration |
Transdermal use
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Dosage and administration details |
Rotigotine, transdermal patches:
10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours)
The maximum Rotigotine dose allowed is 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)
Other Name: (6S)-6-propyl-[2 (2 thienyl)ethyl]amino-5,6,7,8-tetrahydro-1-naphthalenol
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Rotigotine, low dose
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Reporting group description |
Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson’s Disease and 6 mg / 24 hours for those with early Parkinson’s DiseaseRotigotine: Rotigotine, transdermal patches:10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours);40 cm^2 (8 mg / 24 hours) Optimal dosage:The maximum Rotigotine dose allowed was 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Rotigotine, high dose
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Reporting group description |
Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's DiseaseRotigotine: Rotigotine, transdermal patches:10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours);40 cm^2 (8 mg / 24 hours) Optimal dosage:The maximum Rotigotine dose allowed was 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation) | ||
Reporting group title |
Rotigotine, low dose
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Reporting group description |
Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson’s Disease and 6 mg / 24 hours for those with early Parkinson’s DiseaseRotigotine: Rotigotine, transdermal patches:10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours);40 cm^2 (8 mg / 24 hours) Optimal dosage:The maximum Rotigotine dose allowed was 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation) | ||
Reporting group title |
Rotigotine, high dose
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Reporting group description |
Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's DiseaseRotigotine: Rotigotine, transdermal patches:10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours);40 cm^2 (8 mg / 24 hours) Optimal dosage:The maximum Rotigotine dose allowed was 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation) |
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End point title |
Change from Baseline to the End of the Maintenance Period in the score of the Apathy Evaluation Scale (AS) rated by the patient | ||||||||||||||||||||
End point description |
The Apathy Scale (AS) is an abbreviated version of the Apathy Evaluation Scale. The AS (Starkstein et al, 1992) consists of 14 items phrased as questions by the examiner that are to be answered on a 4-point Likert scale. It was developed specifically for subjects with Parkinson’s disease because the Apathy Evaluation Scale was considered too demanding.
The questions comprising the AS were answered by the subject. The total scores for Apathy Evaluation Scale ranges from 0 (best possible outcome) to 42 (worst possible outcome).
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End point type |
Primary
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End point timeframe |
Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||
Statistical analysis description |
ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
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Comparison groups |
Rotigotine, low dose v Placebo
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Number of subjects included in analysis |
76
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.977 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Least Square Mean | ||||||||||||||||||||
Point estimate |
0.04
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
-2.42 | ||||||||||||||||||||
upper limit |
2.5 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
1.24
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Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||
Statistical analysis description |
ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
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Comparison groups |
Placebo v Rotigotine, high dose
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.859 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Least Square Mean | ||||||||||||||||||||
Point estimate |
-0.22
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
-2.61 | ||||||||||||||||||||
upper limit |
2.18 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
1.21
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End point title |
Change from Baseline to the End of the Maintenance Period in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II (activities of daily living) + III (motor symptoms) | ||||||||||||||||||||
End point description |
Part II of the Unified Parkinson's Disease Rating Scale (UPDRS) assesses the subject’s activities of daily living. Part III assesses motor function. The UPDRS is completed by questioning the subject about his/her general state in conjunction with any observations made by the investigator (or designee) since the previous visit. Part II is subject-rated and Part III is physician-rated. The UPDRS Part II (Activities of Daily Living) consists of 13 items scored between 0 and 4. The sum score was calculated as the sum of these 13 individual scores. The UPDRS Part III (motor subscale) consists of 27 items and sub items scored between 0 and 4. The sum score was calculated as sum of these 27 individual scores. The sum score of UPDRS Parts II and III is the sum of the corresponding single sum scores. A negative value indicates an improvement.
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End point type |
Primary
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End point timeframe |
Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||
Statistical analysis description |
ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
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Comparison groups |
Placebo v Rotigotine, low dose
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Number of subjects included in analysis |
76
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.005 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Least Square Mean | ||||||||||||||||||||
Point estimate |
-7.29
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
-12.3 | ||||||||||||||||||||
upper limit |
-2.28 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
2.53
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Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||
Statistical analysis description |
ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
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Comparison groups |
Placebo v Rotigotine, high dose
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.015 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Least Square Mean | ||||||||||||||||||||
Point estimate |
-6.06
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
-10.9 | ||||||||||||||||||||
upper limit |
-1.21 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
2.45
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End point title |
Change from Baseline to the End of the Maintenance Period in the score of the Apathy Evaluation Scale (AS) rated by the caregiver (where available) | ||||||||||||||||||||
End point description |
The Apathy Scale (AS) is an abbreviated version of the Apathy Evaluation Scale. The AS (Starkstein et al, 1992) consists of 14 items phrased as questions by the examiner that are to be answered on a 4-point Likert scale. It was developed specifically for subjects with Parkinson’s disease because the Apathy Evaluation Scale was considered too demanding.
The questions comprising the AS were answered by the caregiver. The questions were asked in a structured interview format. The caregiver was interviewed by appropriate medical staff and asked questions about the subject in the third person.The total scores for Apathy Evaluation Scale ranges from 0 (best possible outcome) to 42 (worst possible outcome).
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End point type |
Secondary
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End point timeframe |
Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||
Statistical analysis description |
ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
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Comparison groups |
Placebo v Rotigotine, low dose
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Number of subjects included in analysis |
32
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.2 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Least Square Mean | ||||||||||||||||||||
Point estimate |
-3.2
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
-8.17 | ||||||||||||||||||||
upper limit |
1.76 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
2.46
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Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||
Statistical analysis description |
ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
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Comparison groups |
Placebo v Rotigotine, high dose
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Number of subjects included in analysis |
29
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.239 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Least Square Mean | ||||||||||||||||||||
Point estimate |
-3.04
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-8.19 | ||||||||||||||||||||
upper limit |
2.1 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
2.55
|
|
|||||||||||||||||||||
End point title |
Change from Baseline to the End of the Maintenance Period in the sum score of the 8-item Parkinson's Disease Questionnaire (PDQ-8) | ||||||||||||||||||||
End point description |
The 8-Item Parkinson's Disease Questionnaire (PDQ-8) (Peto et al, 1998) is a self-administered questionnaire that provides a reliable measure of overall health status. The PDQ-8 collects 8 items with 5 categories each (0=never, 1=occasionally, 2=sometimes, 3=often, 4=always or cannot do at all). The total score was calculated by summing the scores of all applicable questions and convert the resulting sum to a summary index score between 0 and 100 by multiplying with 100/32. A negative value indicates an improvement.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)
|
||||||||||||||||||||
|
|||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||
Statistical analysis description |
ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
|
||||||||||||||||||||
Comparison groups |
Placebo v Rotigotine, low dose
|
||||||||||||||||||||
Number of subjects included in analysis |
76
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.519 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Least Square Mean | ||||||||||||||||||||
Point estimate |
-2.09
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-8.48 | ||||||||||||||||||||
upper limit |
4.31 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
3.23
|
||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||
Statistical analysis description |
ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
|
||||||||||||||||||||
Comparison groups |
Placebo v Rotigotine, high dose
|
||||||||||||||||||||
Number of subjects included in analysis |
80
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.111 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Least Square Mean | ||||||||||||||||||||
Point estimate |
-5.06
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-11.29 | ||||||||||||||||||||
upper limit |
1.17 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
3.15
|
|
|||||||||||||||||||||
End point title |
Change from Baseline to the End of the Maintenance Period in the sum score of the mood / cognition domain of the Nonmotor Symptom Assessment Scale (NMSS) | ||||||||||||||||||||
End point description |
Nonmotor performance was assessed via the Nonmotor Symptom Assessment Scale (NMSS), an accepted scale that has been validated in an international study (Naidu et al, 2006; Chaudhuri et al, 2007), at the Baseline Visit as well as at the end of the Maintenance Period. The severity and frequency of the subject’s nonmotor symptoms were assessed by the investigator (or designee) in the following 9 domain categories: cardiovascular, including falls; sleep/fatigue; mood/cognition; perceptual problems/hallucinations; attention/memory; gastrointestinal tract; urinary; sexual function; and miscellaneous.
Items are scored for severity (from 0 (none) to 3 (severe)) and frequency (from 1 (rarely) to 4 (very frequent )). The score was calculated as severity x frequency. The theoretical minimum is 0 (best possible outcome) and maximum total score is 360 points (worst possible outcome).
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)
|
||||||||||||||||||||
|
|||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||
Statistical analysis description |
ANCOVA model for the change from Baseline to End of Treatment containing treatment and disease stage as factors, and Baseline value as covariate.
|
||||||||||||||||||||
Comparison groups |
Placebo v Rotigotine, low dose
|
||||||||||||||||||||
Number of subjects included in analysis |
71
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.06 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Least Square Mean | ||||||||||||||||||||
Point estimate |
-3.62
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-7.39 | ||||||||||||||||||||
upper limit |
0.15 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
1.9
|
||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||
Statistical analysis description |
ANCOVA model for the change from Baseline to End of Treatment containing treatment and disease stage as factors, and Baseline value as covariate.
|
||||||||||||||||||||
Comparison groups |
Placebo v Rotigotine, high dose
|
||||||||||||||||||||
Number of subjects included in analysis |
78
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.034 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Least Square Mean | ||||||||||||||||||||
Point estimate |
-3.88
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-7.46 | ||||||||||||||||||||
upper limit |
-0.3 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
1.8
|
|
|||||||||||||||||||||
End point title |
Change from Baseline to the End of the Maintenance Period in the sum score of the Snaith Hamilton Pleasure Scale (SHAPS) | ||||||||||||||||||||
End point description |
The Snaith Hamilton Pleasure Scale (SHAPS) (Snaith et al, 1995) is a self-report instrument developed for the assessment of hedonic capacity. The sum of the 14 items scores range from 0 to 14. A higher score represents more anhedonic symptoms.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)
|
||||||||||||||||||||
|
|||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||
Statistical analysis description |
ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
|
||||||||||||||||||||
Comparison groups |
Placebo v Rotigotine, low dose
|
||||||||||||||||||||
Number of subjects included in analysis |
76
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.334 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Least Square Mean | ||||||||||||||||||||
Point estimate |
-0.38
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-1.16 | ||||||||||||||||||||
upper limit |
0.4 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
0.39
|
||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||
Statistical analysis description |
ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
|
||||||||||||||||||||
Comparison groups |
Placebo v Rotigotine, high dose
|
||||||||||||||||||||
Number of subjects included in analysis |
80
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.968 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Least Square Mean | ||||||||||||||||||||
Point estimate |
0.02
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-0.74 | ||||||||||||||||||||
upper limit |
0.77 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
0.38
|
|
|||||||||||||||||||||
End point title |
Change from Baseline to the End of the Maintenance Period in the sum score of the Beck Depression Inventory Second Edition (BDI-II) | ||||||||||||||||||||
End point description |
The Beck Depression Inventory (BDI) is a self-report instrument to measure depression symptoms and severity (Beck et al, 1961). The BDI-II is a revised version of the scale in order to be more consistent with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for depression (Beck et al, 1996). There are 21 items in the BDI-II, classified as cognitive-affective (Items 1-13) and somatic-performance (Items 14-21) subscales. The degree of severity is indicated on a 4-point scale; items are rated from 0 (not at all) to 3 (extreme form of each symptom). Scores of 0-13 indicate minimal depression, 14-19 indicate mild depression, 20-28 indicate moderate depression, and 29-63 indicate severe depression.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)
|
||||||||||||||||||||
|
|||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||
Statistical analysis description |
ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
|
||||||||||||||||||||
Comparison groups |
Placebo v Rotigotine, low dose
|
||||||||||||||||||||
Number of subjects included in analysis |
70
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.899 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Least Square Mean | ||||||||||||||||||||
Point estimate |
0.16
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-2.34 | ||||||||||||||||||||
upper limit |
2.66 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
1.26
|
||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||
Statistical analysis description |
ANCOVA model for the change from Baseline to End of Treatment containing treatment and disease stage as factors, and Baseline value as covariate.
|
||||||||||||||||||||
Comparison groups |
Placebo v Rotigotine, high dose
|
||||||||||||||||||||
Number of subjects included in analysis |
78
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.785 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Least Square Mean | ||||||||||||||||||||
Point estimate |
-0.33
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-2.68 | ||||||||||||||||||||
upper limit |
2.03 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
1.19
|
|
|||||||||||||||||||||
End point title |
Change from Baseline to the End of the Maintenance Period in the sum score of the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor subscale) in 'on' state | ||||||||||||||||||||
End point description |
Part III of the Unified Parkinson's Disease Rating Scale (UPDRS) assesses motor function. The UPDRS is completed by questioning the subject about his/her general state in conjunction with any observations made by the investigator (or designee) since the previous visit.
The UPDRS Part III (motor subscale) had to be measured in the “on” state and consisted of 27 items and sub items scored between 0 and 4. The sum score ranged between 0 and 108 and was calculated as sum of the 27 individual scores. If 1 or more items were missing and could not be substituted with a previous post-Baseline value, the sum score was also missing.
A negative value indicates an improvement.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)
|
||||||||||||||||||||
|
|||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||
Statistical analysis description |
ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
|
||||||||||||||||||||
Comparison groups |
Placebo v Rotigotine, low dose
|
||||||||||||||||||||
Number of subjects included in analysis |
76
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.014 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Least Square Mean | ||||||||||||||||||||
Point estimate |
-4.96
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-8.91 | ||||||||||||||||||||
upper limit |
-1.01 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
1.99
|
||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||
Statistical analysis description |
ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
|
||||||||||||||||||||
Comparison groups |
Rotigotine, high dose v Placebo
|
||||||||||||||||||||
Number of subjects included in analysis |
80
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.013 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Least Square Mean | ||||||||||||||||||||
Point estimate |
-4.83
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-8.63 | ||||||||||||||||||||
upper limit |
-1.03 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
1.92
|
|
|||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change from Baseline to the End of the Maintenance Period in the score of the Clinical Global Impression Scale (CGI) Item I (Severity of Illness) | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The Clinical Global Impression (CGI) scales (Guy and Bonato, 1970) were initially developed for a risk-benefit estimation within the treatment of mentally ill patients. The 4 global scales (severity of illness, change in severity from Baseline, therapeutic efficacy, and tolerability of treatment) are used as different measures of treatment outcome in different kinds of pharmacological studies.
The CGI Item 1 (severity of illness) collected 1 answer out of 8 categories (0-‘Not assessed’, 1-‘Normal, not at all ill’, 2-‘Borderline ill’, 3-‘Mildly ill’, 4-‘Moderately ill’, 5-‘Markedly ill’, 6-‘Severely ill’, and 7-‘Among the most extremely ill patients’) at each assessment. The category 0-‘Not assessed’ was considered as missing and therefore used neither for calculation nor for display purposes.
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline (Visit 2) until End of the Maintenance Period/Early Withdrawal (up to 19 weeks after Baseline)
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Treatment Emergent Adverse Events (TEAEs) were reported from Baseline up to the Safety Follow-up Visit (approximately during 19 weeks).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
The Baseline Analysis Population refers to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Placebo: Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Rotigotine, low dose
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson’s Disease and 6 mg / 24 hours for those with early Parkinson’s Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) Optimal dosage: The maximum Rotigotine dose allowed was 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Rotigotine, high dose
|
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Reporting group description |
Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) Optimal dosage: The maximum Rotigotine dose allowed was 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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05 Aug 2013 |
- A description and rationale of the interim analysis to be performed was added.
- The approximate number of participating investigational sites was increased to 120.
- Inclusion Criterion 7 was modified to add “200 mg/day” as the minimum allowed stable dose of levodopa for consistency with the concomitant levodopa section.
- Tables with the study medication administration schedule and De-Escalation Period for subjects with advanced-stage Parkinson’s disease were corrected.
- Wording regarding packaging was updated to remove references to cartons for the de-escalation kits.
- Wording regarding the NMSS was updated to indicate that it could also be assessed by an investigator’s designee.
- The analysis sets to be used for the analyses of efficacy variables were revised.
- The estimated screening failure rate was corrected.
- The references list was updated.
- The Snaith-Hamilton Pleasure Scale (SHAPS) was updated to reflect the version provided to the subjects.
- Additionally, administrative, typographical, and editorial changes were made. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |